Note: Descriptions are shown in the official language in which they were submitted.
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CYCLIC INHIBITORS OF 11BETA-HYDROXYSTEROID
DEHYDROGENASEI
RELATED APPLICATIONS
This application claims priority to International Application No.
PCT/US2009/002653, which designated the United States and was filed on
April 30, 2009. This application also claims priority to International
Application No. PCT/US2009/004261, which designated the United States
and was filed on July 23, 2009. The entire teachings of the above
applications are incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to inhibitors of 11 R-hydroxysteroid
dehydrogenase type 1 (11 R-HSD1), pharmaceutical compositions thereof
and methods of using the same. More particularly, this application is directed
to hydrates of the disclosed inhibitors of 11 R-hydroxysteroid dehydrogenase
type 1.
BACKGROUND OF THE INVENTION
Glucocorticoids, such as cortisol (hydrocortisone), are steroid
hormones that regulate fat metabolism, function and distribution, and play a
role in carbohydrate, protein and fat metabolism. Glucocorticoids are also
known to have physiological effects on development, neurobiology,
inflammation, blood pressure, metabolism, and programmed cell death.
Cortisol and other corticosteroids bind both the glucocorticoid receptor (GR)
and the mineralocorticoid receptor (MR), which are members of the nuclear
hormone receptor superfamily and have been shown to mediate cortisol
function in vivo. These receptors directly modulate transcription via DNA-
binding zinc finger domains and transcriptional activation domains.
Until recently, the major determinants of glucocorticoid action were
attributed to three primary factors: (1) circulating levels of glucocorticoid
(driven primarily by the hypothalamic-pituitary-adrenal (HPA) axis); (2)
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protein binding of glucocorticoids in circulation; and (3) intracellular
receptor
density inside target tissues. Recently, a fourth determinant of
glucocorticoid function has been identified: tissue-specific pre-receptor
metabolism by glucocorticoid-activating and -inactivating enzymes. These
11 J3-hydroxysteroid dehydrogenase (11 3-HSD) pre-receptor control enzymes
modulate activation of GR and MR by regulation of glucocorticoid hormones.
To date, two distinct isozymes of 11 -beta-HSD have been cloned and
characterized: 11 P-HSD1 (also known as 11 -beta-HSD type 1, 11 betaHSD1,
HSD11131, HDL, and HSD11 L) and 11 3-HSD2. 11 P-HSD1 is a bi-directional
oxidoreductase that regenerates active cortisol from inactive 11-keto forms,
whereas 11 3-HSD2 is a unidirectional dehydrogenase that inactivates
biologically active cortisol by converting it into cortisone.
The two isoforms are expressed in a distinct tissue-specific fashion,
consistent with the differences in their physiological roles. 11 P-HSD1 is
widely distributed in rat and human tissues; expression of the enzyme and
corresponding mRNA have been detected in human liver, adipose tissue,
lung, testis, bone and ciliary epithelium. In adipose tissue, increased
cortisol
concentrations stimulate adipocyte differentiation and may play a role in
promoting visceral obesity. In the eye, 11 P-HSD1 may regulate intraocular
pressure and may contribute to glaucoma; some data suggest that inhibition
of 11 P-HSD1 may cause a drop in intraocular pressure in patients with
intraocular hypertension (Kotelevstev et al. (1997), Proc. NatI. Acad. Sci.
USA 94(26):14924-9). Although 11 P-HSD1 catalyzes both 11-beta-
dehydrogenation and the reverse 11 -oxoreduction reaction, 11 P-HSD1 acts
predominantly as a NADPH-dependent oxoreductase in intact cells and
tissues, catalyzing the formation of active cortisol from inert cortisone (Low
et al. (1994) J. Mol. Endocrin. 13: 167-174). In contradistinction, 11 R-HSD2
expression is found mainly in mineralocorticoid target tissues such as kidney
(cortex and medulla), placenta, sigmoid and rectal colon, salivary gland and
colonic epithelial cell lines. 11 3-HSD2 acts as an NAD-dependent
dehydrogenase catalyzing the inactivation of cortisol to cortisone (Albiston
et
al. (1994) Mol. Cell. Endocrin. 105: R11-R17), and has been shown to
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protect the MR from glucocorticoid excess (e.g., high levels of receptor-
active cortisol) (Blum, et al. (2003) Prog. Nucl. Acid Res. Mol. Biol. 75:173-
216).
Mutations in either the 11 R-HSD1 or the 11 R-HSD2 genes result in
human pathology. For example, individuals with mutations in 11 3-HSD2 are
deficient in this cortisol-inactivation activity and, as a result, present
with a
syndrome of apparent mineralocorticoid excess (also referred to as 'SAME')
characterized by hypertension, hypokalemia, and sodium retention (Edwards
et al. (1988) Lancet 2: 986-989; Wilson et al. (1998) Proc. Natl. Acad. Sci.
95: 10200-10205). Similarly, mutations in 11 R-HSD1 and in the gene
encoding a co-localized NADPH-generating enzyme, hexose 6-phosphate
dehydrogenase (H6PD), can result in cortisone reductase deficiency (CRD);
these individuals present with ACTH-mediated androgen excess (hirsutism,
menstrual irregularity, hyperandrogenism), a phenotype resembling
polycystic ovary syndrome (PCOS) (Draper et al. (2003) Nat. Genet. 34:
434-439).
Notably, disruption of homeostasis in the HPA axis by either deficient
or excess secretion or action results in Cushing's syndrome or Addison's
disease, respectively (Miller and Chrousos (2001) Endocrinology and
Metabolism, eds. Felig and Frohman (McGraw-Hill, New York), 4th Ed.: 387-
524). Patients with Cushing's syndrome or receiving glucocorticoid therapy
develop reversible visceral fat obesity. The phenotype of Cushing's
syndrome patients closely resembles that of Reaven's metabolic syndrome
(also known as Syndrome X or insulin resistance syndrome), the symptoms
of which include visceral obesity, glucose intolerance, insulin resistance,
hypertension, type 2 diabetes and hyperlipidemia (Reaven (1993) Ann. Rev.
Med. 44: 121-131). Although the role of glucocorticoids in human obesity is
not fully characterized, there is mounting evidence that 11 R-HSD1 activity
plays an important role in obesity and metabolic syndrome (Bujalska et al.
(1997) Lancet 349: 1210-1213); (Livingstone et al. (2000) Endocrinology
131: 560-563; Rask et al. (2001) J. Clin. Endocrinol. Metab. 86: 1418-1421;
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Lindsay et al. (2003) J. Clin. Endocrinol. Metab. 88: 2738-2744; Wake et al.
(2003) J. Clin. Endocrinol. Metab. 88: 3983-3988).
Data from studies in mouse transgenic models supports the
hypothesis that adipocyte 11 P-HSD1 activity plays a central role in visceral
obesity and metabolic syndrome (Alberts et al. (2002) Diabetologia. 45(11):
1526-32). Over-expression in adipose tissue of 11 P-HSD1 under the control
of the aP2 promoter in transgenic mice produced a phenotype remarkably
similar to human metabolic syndrome (Masuzaki et al. (2001) Science 294:
2166-2170; Masuzaki et al. (2003) J. Clinical Invest. 112: 83-90). Moreover,
the increased activity of 11 P-HSD1 in these mice is very similar to that
observed in human obesity (Rask et al. (2001) J. Clin. Endocrinol. Metab.
86: 1418-1421). In addition, data from studies with 11 R-HSD1-deficient mice
produced by homologous recombination demonstrate that the loss of 11 J3-
HSD1 leads to an increase in insulin sensitivity and glucose tolerance due to
a tissue-specific deficiency in active glucocorticoid levels (Kotelevstev et
al.
(1997) Proc. NatI. Acad. Sci. 94: 14924-14929; Morton et al. (2001) J. Biol.
Chem. 276: 41293-41300; Morton et al. (2004) Diabetes 53: 931-938).
The published data supports the hypothesis that increased
expression of 11 P-HSD1 contributes to increased local conversion of
cortisone to cortisol in adipose tissue and hence that 11 P-HSD1 plays a role
in the pathogenesis of central obesity and the appearance of the metabolic
syndrome in humans (Engeli, et al., (2004) Obes. Res. 12: 9-17). Therefore,
11 P-HSD1 is a promising pharmaceutical target for the treatment of the
metabolic syndrome (Masuzaki, et al., (2003) Curr. Drug Targets Immune
Endocr. Metabol. Disord. 3: 255-62). Furthermore, inhibition of 11 P-HSD1
activity may prove beneficial in treating numerous glucocorticoid-related
disorders. For example, 11 P-HSD1 inhibitors could be effective in combating
obesity and/or aspects of the metabolic syndrome cluster, including glucose
intolerance, insulin resistance, hyperglycemia, hypertension, and/or
hyperlipidemia (Kotelevstev et al. (1997) Proc. NatI. Acad. Sci. 94: 14924-
14929; Morton et al. (2001) J. Biol. Chem. 276: 41293-41300; Morton et al.
(2004) Diabetes 53: 931-938). In addition, inhibition of 11 P-HSD1 activity
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may have beneficial effects on the pancreas, including the enhancement of
glucose-stimulated insulin release (Billaudel and Sutter (1979) Horm. Metab.
Res. 11: 555-560; Ogawa et al. (1992) J. Clin. Invest. 90: 497-504; Davani et
al. (2000) J. Biol. Chem. 275: 34841-34844).
Furthermore, given that inter-individual differences in general
cognitive function have been linked to variability in the long-term exposure
to
glucocorticoids (Lupien et al. (1998) Nat. Neurosci. 1: 69-73) and
dysregulation of the HPA axis resulting in chronic exposure to glucocorticoid
excess in certain brain subregions has been theorized to contribute to the
decline of cognitive function (McEwen and Sapolsky (1995) Curr. Opin.
Neurobiol. 5: 205-216), one might predict that inhibition of 11 P-HSD1 could
reduce exposure to glucocorticoids in the brain and thereby protect against
deleterious glucocorticoid effects on neuronal function, including cognitive
impairment, dementia, and/or depression. Notably, it is known that stress
and glucocorticoids influence cognitive function (de Quervain et al. (1998)
Nature 394: 787-790); and it has been shown that 11 R-HSD1, through its
control of glucocorticoid action in the brain, may have effects on
neurotoxicity (Rajan et al. (1996) Neuroscience 16: 65-70; Seckl (2000)
Neuroendocrinol. 18:49-99).
There is also evidence that glucocorticoids and 11 P-HSD1 play a role
in regulation of in intra-ocular pressure (IOP) (Stokes et al. (2000) Invest.
Ophthalmol. Vis. Sci. 41: 1629-1683; Rauz et al. (2001) Invest. Ophthalmol.
Vis. Sci. 42: 2037-2042); if left untreated, elevated IOP can lead to partial
visual field loss and eventually blindness. Thus, inhibition of 11 P-HSD1 in
the eye could reduce local glucocorticoid concentrations and IOP, and 11 R-
HSD1 hence could potentially be used to treat glaucoma and other visual
disorders.
Transgenic aP2-1 1 3HSD1 mice exhibit high arterial blood pressure
and have increased sensitivity to dietary salt. Moreover, plasma
angiotensinogen levels are elevated in the transgenic mice, as are
angiotensin II and aldosterone; and treatment of the mice with an
angiotensin II antagonist alleviates the hypertension (Masuzaki et al. (2003)
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J. Clinical Invest. 112: 83-90). This suggests that hypertension may be
caused or exacerbated by 11 P-HSD1 activity. Thus, 11 P-HSD1 inhibitors
may be useful for treatment of hypertension and hypertension-related
cardiovascular disorders. Inhibition of 11 P-HSD1 in mature adipocytes is
also expected to attenuate secretion of plasminogen activator inhibitor 1
(PAI-1), which is an independent cardiovascular risk factor (Halleux et al.
(1999) J. Clin. Endocrinol. Metabl. 84: 4097-4105).
Glucocorticoids can have adverse effects on skeletal tissues; and
prolonged exposure to even moderate glucocorticoid doses can result in
osteoporosis (Cannalis (1996) J. Clin. Endocrinol. Metab. 81: 3441-3447).
In addition, 11 P-HSD1 has been shown to be present in cultures of human
primary osteoblasts as well as cells from adult bone (Cooper et al. (2000)
Bone 27: 375-381), and the 11 P-HSD1 inhibitor carbenoxolone has been
shown to attenuate the negative effects of glucocorticoids on bone nodule
formation (Bellows et al. (1998) Bone 23: 119-125). Thus, inhibition of 11 R-
HSD1 is predicted to decrease the local glucocorticoid concentration within
osteoblasts and osteoclasts, thereby producing beneficial effects in various
forms of bone disease, including osteoporosis.
11 P-HSD1 inhibitors may also be useful for immunomodulation.
Although glucocorticoids are perceived to suppress the immune system, in
actuality, there is a complex, dynamic interaction between the HPA axis and
the immune system (Rook (1999) Baillier's Clin. Endocrinol. Metabl. 13:
576-581). Glucocorticoids play a role in modulating the balance between
cell-mediated and humoral immune response, with high glucocorticoid
activity normally associated with a humoral response. Inhibition of 11 3-
HSD1 therefore can be used a means of shifting the immune response
towards a cell-mediated response. Certain disease states, such as
tuberculosis, leprosy (Hansen's disease) and psoriasis, trigger immune
responses that are biased towards a humoral response whereas the more
effective immune response may be a cell-mediated response. Hence, 11 R-
HSD1 inhibitors may be useful for treating such diseases.
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It has been reported that glucocorticoids inhibit wound healing,
especially in diabetic patients with ulcers (Bitar et al. (1999) J. Surg. Res.
82:
234-243; Bitar et al. (1999) Surgery 125: 594-601; Bitar (2000) Surgery 127:
687-695; Bitar (1998) Am. J. Pathol. 152: 547-554). Patients that exhibit
impaired glucose tolerance and/or type 2 diabetes often also have impaired
wound healing. Glucocorticoids have been shown to increase the risk of
infection and delay wound healing (Anstead (1998) Adv. Wound Care
11:277-285). Moreover, there is a correlation between elevated levels of
cortisol in wound fluid and non-healing wounds (EP Patent App. No. 0 902
288). Recent published patent applications have suggested that certain
11 3-HSD1 inhibitors may be useful for promoting wound healing
(PCT/US2006/043,951).
As evidenced herein, there is a continuing need for new and improved
drugs that inhibit 11 R-HSD1. The novel compounds of the instant invention
are effective inhibitors of 11 R-HSD1.
SUMMARY OF THE INVENTION
It has now been found that compounds of Formula Im' or pharmaceutically
acceptable salts thereof, are effective inhibitors of 11 R-HSD1.
The invention is a compound represented by Formula (Im')
O R1
0 N Cyl
R3 N O
H
E
R2 (Im');
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
In a first embodiment of the invention, Formula Im' and its constituent
members are defined herein as follows:
R1 is (a) absent or (b) is selected from (Ci-C6)alkyl, (C2-C6)alkenyl,
(C2-C6)alkynyl, (Cl-C3)alkoxy(C1-C3)alkoxy, or (CT-C3)alkoxy(CT-C3)alkyl and
is optionally substituted with up to four groups independently selected from
fluorine, cyano, oxo, R4, R40-, (R4)2N-, R402C-, R4S, R4S(=O)-, R4S(=0)2-,
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R4C(=O)NR4-, (R4)2NC(=O)-, (R4)2NC(=O)O-, (R4)2NC(=O)NR4-,
R40C(=O)NR4-, (R4)2NC(=NCN)NR4-, (R40)2P(=O)O-, (R40)2P(=O)NR4-,
R4OS(=O)2NR4-, (R4)2NS(=O)20-, (R4)2NS(=O)2NR4-, R4S(=O)2NR4-,
R4S(=O)2NHC(=O)-, R4S(=O)2NHC(=O)O-, R4S(=O)2NHC(=O)NR4-,
R4OS(=O)2NHC(=O)-, R4OS(=O)2NHC(=O)O-, R4OS(=O)2NHC(=O)NR4-,
(R4)2NS(=O)2NHC(=O)-, (R4)2NS(=O)2NHC(=O)O-,
(R4)2NS(=O)2N HC(=O)N R4-, R4C(=O)N HS(=O)2-, R4C(=O)N HS(=O)20-,
R4C(=O)NHS(=O)2NR4-, R40C(=O)NHS(=O)2-, R40C(=O)NHS(=O)20-,
R40C(=O)N HS(=O)2N R4-, (R4)2NC(=O)N HS(=O)2-,
(R4)2NC(=O)NHS(=O)20-, (R4)2NC(=O)NHS(=O)2NR4-, heterocyclyl,
heteroaryl, arylamino and heteroarylamino;
A' is (a) a bond, or (b) (Ci-C3)alkylene, CH2CH2O, wherein the
oxygen is attached to Cy', or CH2C(=O), wherein the carbonyl carbon is
attached to Cy';
Cy' is aryl, heteroaryl, monocyclic cycloalkyl or monocyclic
heterocyclyl and is optionally substituted with 1 to 4 groups independently
selected from fluorine, chlorine, bromine, iodine, cyano, nitro, amino,
hydroxy, carboxy, (Ci-C6)alkyl, hydroxy(C1-C6)alkyl, (C3-C6)cycloalkyl,
hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-
C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2-
C4)alkynyl, halo(C1-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-
C7)cycloalkylalkyl, (CT-C6)alkoxy, (C3-C6)cycloalkoxy, (C4-
C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3-C6)cycloalkoxy,
halo(C4-C7)cycloalkylalkoxy, (Ci-C6)alkylthio, (C3-C6)cycloalkythio,
(C4-C7)cycloalkylalkylthio, halo(C1-C6)alkylthio, halo(C3-C6)cycloalkythio,
halo(C4-C7)cycloalkylalkylthio, (CT-C6)alkanesulfinyl, (C3-
C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl, halo(Ci-
C6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfinyl, halo(C4-
C7)cycloalkylalkanesulfinyl, (Cl-C6)alkanesulfonyl, (C3-
C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl, halo(C1-
C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl,
halo(C4-C7)cyclo-alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino,
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(C1-C6)alkoxy(C1-C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkoxy, (Ci-
C6)alkoxycarbonyl, H2NCO, H2NSO2, (CT-C6)alkylaminocarbonyl, di(Ci-
C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci-C3)alkylaminocarbonyl,
heterocyclylcarbonyl, (C1-C6)alkylaminosulfonyl, di(C1-C6)alkylaminosulfonyl,
heterocyclylsulfonyl, (Cl-C6)alkylcarbonylamino, (Cl-C6)alkyl-
carbonylamino(C1-C6)alkyl, (Cl-C6)alkylsulfonylamino, (Cl-C6)alkyl-
sulfonylamino(C1-C6)alkyl, (Cl-C6)alkoxycarbonyl(C1-C6)alkoxy,
(C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl,
hydroxy(CT-C6)alkoxy, heteroaryl oxo, amino(CT-C6)alkyl,
(C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl
amino(C2-C6)alkoxy, (C1-C6)alkylamino(C2-C6)alkoxy,
di(C1-C6)alkylamino(C2-C6)alkoxy, (Cl-C6)alkylcarbonyl,
(C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl,
{(C3-C6)cycloalkyl}{(C1-C6)alkyl}aminocarbonyl,
di(C3-C6)cycloalkylaminocarbonyl, (C3-C6)cycloalkylaminosulfonyl,
{(C3-C6)cycloalkyl}{(Ci-C6)alkyl}aminosulfonyl,
di(C3-C6)cycloalkylaminosulfonyl, cyano(CT-C6)alkyl,
aminocarbonyl(C1-C6)alkyl, (Cl-C6)alkylaminocarbonyl(C1-C6)alkyl,
di(C1-C6)alkylaminocarbonyl(C1-C6)al kyl,
(C3-C6)cycloalkylaminocarbonyl(C1-C6)alkyl,
{(C3-C6)cycloalkyl}{(C1-C6)alkyl}aminocarbonyl(Ci-C6)alkyl and
di(C3-C6)cycloalkylaminocarbonyl(CT-C6)alkyl;
The oxodihydropyridyl ring in Formula Im' is optionally substituted
with 1 to 4 groups independently selected from fluorine, chlorine, bromine,
iodine, cyano, nitro, amino, hydroxy, carboxy, (Cl-C6)alkyl,
hydroxy(CT-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl,
(C4-C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl,
hydroxy(C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2-C4)alkynyl,
halo(CT-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl,
(CT-C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy,
halo(Ci-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy,
(Ci-C6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio,
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halo(C1-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-
C7)cycloalkylalkylthio,
(CT-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl,
(C4-C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkanesulfinyl,
halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl,
(CT-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkyl-
alkanesulfonyl, halo(C1-C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl,
halo(C4-C7)cyclo-alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino,
(C1-C6)alkoxy(C1-C6)alkoxy, halo(Ci-C6)alkoxy(C1-C6)alkoxy,
(CT-C6)alkoxycarbonyl, H2NCO, H2NSO2, (CT-C6)alkylaminocarbonyl,
1o di(CT-C6)alkylaminocarbonyl, (Cl-C3)alkoxy(C1-C3)alkylaminocarbonyl,
heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl,
heterocyclylsulfonyl, (Ci-C6)alkylcarbonylamino, (Ci-C6)alkylcarbonyl-
amino(Cy-C6)alkyl, (CT-C6)alkylsulfonylamino,
(Cl-C6)alkylsulfonylamino(C1-C6)alkyl, (Cl-C6)alkoxycarbonyl(CT-C6)alkoxy,
(C1-C6)alkoxy(C1-C6)alkyl, halo(Ci-C6)alkoxy(Ci-C6)alkyl,
hydroxy(Ci-C6)alkoxy, heteroaryl, oxo, amino(Ci-C6)alkyl,
(C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl
amino(C2-C6)alkoxy, (C1-C6)alkylamino(C2-C6)alkoxy,
di(Ci-C6)alkylamino(C2-C6)alkoxy, (Ci-C6)alkylcarbonyl,
(C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl,
{(C3-C6)cycloalkyl}{(Ci-C6)alkyl}aminocarbonyl,
di(C3-C6)cycloalkylaminocarbonyl, (C3-C6)cycloalkylaminosulfonyl,
{(C3-C6)cycloalkyl}{(Ci-C6)alkyl}aminosulfonyl,
di(C3-C6)cycloalkylaminosulfonyl, cyano(Ci-C6)alkyl,
aminocarbonyl(CT-C6)alkyl, (Cl-C6)alkylaminocarbonyl(C1-C6)alkyl,
di(C1-C6)alkylaminocarbonyl(C1-C6)al kyl,
(C3-C6)cycloal kylaminocarbonyl(Ci-C6)al kyl,
{(C3-C6)cycloalkyl}{(Ci-C6)alkyl}aminocarbonyl(Ci-C6)alkyl and
di(C3-C6)cycloalkylaminocarbonyl(Cl-C6)alkyl;
E is (a) a bond or (b) (Cl-C3)alkylene or (Cl-C2)alkylenyloxy, wherein
the 0 is attached to R2, each of which is optionally substituted with 1 to 4
groups independently selected from methyl, ethyl, trifluoromethyl or oxo;
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R2 is (Cl-C6)alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl and is
optionally substituted with up to 4 groups independently selected from
fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy,
(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (C3-C6)cycloalkyl,
hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkenyl,
halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2-C6)alkynyl,
(C3-C6)cycloalkyl(C2-C4)alkynyl, halo(Ci-C6)alkyl, halo(C3-C6)cycloalkyl,
halo(C4-C7)cycloalkylalkyl, (Ci-C6)alkoxy, (C3-C6)cycloalkoxy,
(C4-C7)cycloalkylalkoxy, halo(Cl-C6)alkoxy, halo(C3-C6)cycloalkoxy,
halo(C4-C7)cycloalkylalkoxy, (Cl-C6)alkylthio, (C3-C6)cycloalkythio,
(C4-C7)cycloalkylalkylthio, halo(Ci-C6)alkylthio, halo(C3-C6)cycloalkythio,
halo(C4-C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl,
(C3-C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl,
halo(Cl-C6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfinyl,
halo(C4-C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl,
(C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl,
halo(Ci-C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl,
halo(C4-C7)cyclo-alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino,
(C1-C6)alkoxy(C1-C6)alkoxy, halo(Ci-C6)alkoxy(C1-C6)alkoxy,
(Ci-C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl,
di(CT-C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci-C3)alkylaminocarbonyl,
heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl,
heterocyclylsulfonyl, (Ci-C6)alkylcarbonylamino, (Ci-C6)alkylcarbonyl-
amino(Cy-C6)alkyl, (Ci-C6)alkylsulfonylamino,
(Ci-C6)alkylsulfonylamino(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl(CT-C6)alkoxy,
(CT-C6)alkoxy(CT-C6)alkyl, halo(Ci-C6)alkoxy(Ci-C6)alkyl,
hydroxy(Ci-C6)alkoxy, heteroaryl, oxo, amino(Ci-C6)alkyl,
(C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(Ci-C6)alkyl
amino(C2-C6)alkoxy, (CT-C6)alkylamino(C2-C6)alkoxy,
3o di(CT-C6)alkylamino(C2-C6)alkoxy, (CT-C6)alkylcarbonyl,
(C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl,
{(C3-C6)cycloalkyl}{(Ci-C6)alkyl}aminocarbonyl,
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di(C3-C6)cycloalkylaminocarbonyl, (C3-C6)cycloalkylaminosulfonyl,
{(C3-C6)cycloalkyl}{(Ci-C6)alkyl}aminosulfonyl,
di(C3-C6)cycloalkylaminosulfonyl, cyano(Ci-C6)alkyl,
aminocarbonyl(Ci-C6)alkyl, (Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl,
di(Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl,
(C3-C6)cycloal kylaminocarbonyl(Ci-C6)al kyl,
{(C3-C6)cycloalkyl}{(Ci-C6)alkyl}aminocarbonyl(Ci-C6)alkyl and
di(C3-C6)cycloalkylaminocarbonyl(Ci-C6)alkyl;
R3 is selected from (CT-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl,
(C3-C5)cycloalkyl(CT-C4)alkyl, (C1-C3)alkoxy(Ci-C3)alkoxy, or
(C1-C3)alkoxy(C1-C3)alkyl and is optionally substituted with up to four groups
independently selected from fluorine, cyano, oxo, R4, R40-, (R4)2N-, R402C-,
R4C(=O)O-, R4S, R4S(=O)-, R4S(=O)2-, R4C(=O)NR4-, (R4)2NC(=O)-,
(R4)2NC(=O)O-, (R4)2NC(=O)NR4-, R4OC(=O)NR4-, (R4) 2NC(=NCN)NR4-,
(R40)2P(=O)O-, (R40)2P(=O)NR4-, R4OS(=O)2NR4-, (R4)2NS(=O)20-,
(R4)2NS(=O)2NR4-, R4S(=O)2NR4-, R4S(=O)2NHC(=O)-,
R4S(=O)2NHC(=O)O-, R4S(=O)2NHC(=O)NR4-, R4OS(=O)2NHC(=O)-,
R4OS(=O)2NHC(=O)O-, R4OS(=O)2NHC(=O)NR4-, (R4)2NS(=O)2NHC(=O)-,
(R4)2NS(=O)2NHC(=O)O-, (R4)2NS(=O)2NHC(=O)NR4-, R4C(=O)NHS(=O)2-,
R4C(=O)NHS(=O)20-, R4C(=O)NHS(=O)2NR4-, R4OC(=O)NHS(=O)2-,
R4OC(=O)NHS(=O)20-, R4OC(=O)NHS(=O)2NR4-, (R4)2NC(=O)NHS(=O)2-,
(R4)2NC(=O)N HS(=O)20-, (R4)2NC(=O)N HS(=O)2N R4-, spirocycloalkyl;
heterocyclyl (which in turn may be optionally substituted with alkyl,
haloalkyl,
halogen or oxo), heteroaryl (which in turn may be optionally substituted with
alkyl, haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl,
dialkylamino, nitro, cyano, CO2H, CONH2, N-monoalkyl-substituted amido,
N,N-dialkyl-substituted amido, or oxo), arylamino (which in turn may be
optionally substituted with alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen,
trifluoromethyl, dialkylamino, nitro, cyano, CO2H, CONH2,
N-monoalkyl-substituted amido and N,N-dialkyl-substituted amido) and
heteroarylamino (which in turn may be optionally substituted with alkyl,
haloalkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl,
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dialkylamino, nitro, cyano, CO2H, CONH2, N-monoalkyl-substituted amido,
N,N-dialkyl-substituted amido, or oxo); and
R4 is independently selected from H, (C1-C6)alkyl, halo(C1-C6)alkyl,
amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl,
di(CT-C6)alkylamino(C1-C6)alkyl, hydroxy(C1-C6)alkyl and
(C1-C6)al koxy(C1-C6)al kyl.
Alternatively, the first embodiment above excludes the compounds of
structural formulas PR-221 and PR-313, or a pharmaceutically acceptable
salt, enantiomer or diastereomer thereof.
Another embodiment of the invention is a pharmaceutical composition
comprising i) a pharmaceutically acceptable carrier or diluent, and ii) a
compound of Formulas Ik, IM', Im2, Im5, In', In2, In5, 1o', 1o2, Io5, Ip' or
Ip3, or
a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
Another embodiment of the invention is a method of inhibiting
11 R-HSD1 activity comprising the step of administering to a mammal in need
of such treatment an effective amount of a compound of Formulas Ik, Im',
Im2, Im5, In', In2, In5, lo', 1o2, Io5, Ip' or Ip3, or a pharmaceutically
acceptable
salt, enantiomer or diastereomer thereof.
Another embodiment of the invention is a method of treating a subject
with a disease associated with the activity or expression of 11 R-HSD1,
comprising the step of administering to the subject an effective amount of a
compound of Formulas Ik, Im1, Im2, Im5, In', In2, In5, 10', 102, Io5, Ip' or
Ip3, or
a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
Another embodiment of the invention is the use of a compound of
Formulas Ik, Im1, Im2, Im5, In', In2, In5, 101, 102, Io5, Ip' or Ip3, or a
pharmaceutically acceptable salt, enantiomer or diastereomer thereof for the
manufacture of a medicament for inhibiting 11 R-HSD1 activity in a mammal
in need of such treatment.
Another embodiment of the invention is the use of a compound of
Formulas Ik, Im1, Im2, Im5, In', In2, In5, 101, 102, Io5, Ip' or Ip3, or a
pharmaceutically acceptable salt, enantiomer or diastereomer thereof for the
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manufacture of a medicament for treating a subject with a disease
associated with the activity or expression of 11 R-HSD1.
Another embodiment of the invention is a compound of Formulas Ik,
IM', Im2, Im5, In, In2, In5, 1o1, 1o2, Io5, Ip' or Ip3
, or a pharmaceutically
acceptable salt, enantiomer or diastereomer thereof for use in inhibiting
11 R-HSD1 activity in a mammal in need of such treatment.
Another embodiment of the invention is a compound of Ik, Im1, Im2,
Im5, In', In2, In5, 101, 1o2, Io5, Ip' or Ip3, or a pharmaceutically
acceptable salt,
enantiomer or diastereomer thereof for use in for treating a subject with a
disease associated with the activity or expression of 11 R-HSD1.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 is the x-ray powder diffraction pattern of the monohydrate of
Example 48.
Figure 2 is the x-ray powder diffraction pattern of the monohydrate of
Example 75.
DETAILED DESCRIPTION OF THE INVENTION
Another embodiment of the invention is a compound of Formula Ik:
0 R1a 1~ O N
R3 _
Cy2
R2
Ik
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof;
R'a is absent or is methyl or ethyl;
Cy2 is 2-oxo-1,2-dihydropyridyl optionally substituted by 1 to 4 groups
independently selected from halo, hydroxy, methoxy, hydroxymethyl,
methoxycarbonyl, amino, carbamoyl, methylcarbamoyl, dimethylcarbamoyl,
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(2-methoxyethyl)aminocarbonyl, acetylaminomethyl, methylsulfonyl,
methylsulfonylamino, methylaminosulfonyl, isopropylaminosulfonyl,
dimethylaminosulfonyl, pyrrolidine-1-sulfonyl, methylsulfonylaminomethyl,
tetrazolyl, methyl, trifluoromethyl, acetyl, 2-hydroxyethyl and 1-aminoethyl;
R2 is phenyl, thienyl, pyridyl or isopropyl each optionally substituted
with halo, methyl, methylthio or (4-morpholino)methyl; and
R3 is methyl, ethyl, propyl, butyl, vinyl, allyl or ethoxyethyl each
optionally substituted with up to two groups independently selected from
Methyl, HO-, MeO-, H2N-, MeC(=O)NH-, MeS(=O)2NH-, H2NC(=O)-,
McNHC(=O)-, HO2C-, (HO)2P(=O)O-, H2NS(=O)20-, H2NS(=0)2NH-,
MeNHC(=O)NH-, MeNHC(=O)O-, oxo, cyano, HO2C-, HOCH2CH2NH-,
4-morpholino, HOCH2C(=O)NH-, H2NCH2C(=O)NH-, EtNHC(=O)NH,
MeOC(=O)NH-, MeNHC(=NC=N)NH-, Me-, MeS-, McSO2- McS02N(Me)-,
MeS(=O)2NHC(=O)-, imidazolylamino-, imidazolyl, tetrazolyl, H2NCONH-,
H2NCO2-, HOCH2CH2O-, MeNH-, Me2N- and MeCONMe.
Another embodiment of the invention is a compound of any one of
Formulas Im', Im2 and Im5 or a pharmaceutically acceptable salt, enantiomer
or diastereomer thereof:
O R1
O N Cyl
R3
H
_k j N O
E
R2
O R1
I,
O N Cyr
R3
E N O
~R2 H
Im' Im2
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0 R1
I
O N Cyr
R3
NH
E
R2 O Im5.
In Formulas Im', Im2 and Im5, the oxodihydropyridyl ring is optionally
substituted (substitution at ring carbons bonded to hydrogen and ring
nitrogen atoms bonded to hydrogen atoms are encompassed, i.e., a
"substitutable ring nitrogen atom") with up to four substituents as described
above. Suitable substituents for the oxodihydropyridyl ring and suitable
values for R', R2, R3, A', Cy' and E are as defined above in the first
embodiment. Alternatively, suitable substituents for Cy' and the
oxodihydropyridyl ring in Formulas Im', Im2 and Im5 are independently
fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy, carboxy,
(Ci-C6)alkyl, hydroxy(Ci-C6)alkyl, (C3-C6)cycloalkyl,
hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkenyl,
halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2-C6)alkynyl,
(C3-C6)cycloalkyl(C2-C4)alkynyl, halo(CT-C6)alkyl, halo(C3-C6)cycloalkyl,
halo(C4-C7)cycloalkylalkyl, (Ci-C6)alkoxy, (C3-C6)cycloalkoxy,
(C4-C7)cycloalkylalkoxy, halo(Ci-C6)alkoxy, halo(C3-C6)cycloalkoxy,
halo(C4-C7)cycloalkylalkoxy, (Cl-C6)alkylthio, (C3-C6)cycloalkythio,
(C4-C7)cycloalkylalkylthio, halo(Cl-C6)alkylthio, halo(C3-C6)cycloalkythio,
halo(C4-C7)cycloalkylalkylthio, (Ci-C6)alkanesulfinyl,
(C3-C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl,
halo(Cl-C6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfinyl,
halo(C4-C7)cycloalkylalkanesulfinyl, (Ci-C6)alkanesulfonyl,
(C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl,
halo(Ci-C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl,
halo(C4-C7)cyclo-alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino,
(CT-C6)alkoxy(CT-C6)alkoxy, halo(Ci-C6)alkoxy(CT-C6)alkoxy,
(Ci-C6)alkoxycarbonyl, H2NCO, H2NS02, (Ci-C6)alkylaminocarbonyl,
di(Ci-C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci-C3)alkylaminocarbonyl,
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heterocyclylcarbonyl, (Cl-C6)alkylaminosulfonyl, di(C1-C6)alkylaminosulfonyl,
heterocyclylsulfonyl, (Cl-C6)alkylcarbonylamino,
(C1-C6)alkylcarbonylamino(C1-C6)alkyl, (C1-C6)alkylsulfonylamino,
(Cl-C6)alkylsulfonylamino(C1-C6)alkyl, (Cl-C6)alkoxycarbonyl(C1-C6)alkoxy,
(C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl,
hydroxy(CT-C6)alkoxy, heteroaryl, amino(CT-C6)alkyl,
(C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl
amino(C2-C6)alkoxy, (C1-C6)alkylamino(C2-C6)alkoxy,
di(CT-C6)alkylamino(C2-C6)alkoxy, (CT-C6)alkylcarbonyl,
(C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl,
{(C3-C6)cycloalkyl}{(Ci-C6)alkyl}aminocarbonyl,
di(C3-C6)cycloalkylaminocarbonyl, (C3-C6)cycloalkylaminosulfonyl,
{(C3-C6)cycloalkyl}{(Ci-C6)alkyl}aminosulfonyl,
di(C3-C6)cycloalkylaminosulfonyl, cyano(CT-C6)alkyl,
aminocarbonyl(C1-C6)alkyl, (Cl-C6)alkylaminocarbonyl(C1-C6)alkyl,
di(C1-C6)alkylaminocarbonyl(Ci-C6)al kyl,
(C3-C6)cycloal kylaminocarbonyl(C1-C6)al kyl,
{(C3-C6)cycloalkyl}{(Ci-C6)alkyl}aminocarbonyl(Ci-C6)alkyl and
di(C3-C6)cycloalkylaminocarbonyl(C1-C6)alkyl; and values for R1, R2, R3, A',
Cy' and E are as defined above in the first embodiment. Alternatively,
suitable substituents for Cy' include (Cl-C4 )alkyl, (Cl-C4 )alkoxy, (Cl-C4
)haloalkyl, (Cl-C4 )haloalkoxy, halogen, cyano and nitro; suitable
substituents
for a substitutable ring nitrogen atom in the oxodihydropyridyl ring in
Formulas Im', Im2 and Im5 include (Ci-C4)alkyl, (C3-C4)cycloalkyl,
(C3-C4)cycloalkyl(C1-C2)alkyl, and (Cl-C4)haloalkyl; suitable substituents for
a ring carbon atom in the oxodihydropyridyl ring in Formulas Im', Im2 and
Im5 include fluorine, chlorine, cyano, hydroxy, amino, (Ci-C4)alkyl,
(C3-C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C2)alkyl, halo(Ci-C4)alkyl,
(CT-C4)alkoxy, (Cl-C4)haloalkoxy, CONH2, (CT-C4)alkylaminocarbonyl,
3o di(C1-C4)alkylaminocarbonyl and (Cl-C4)alkylcarbonylamino; and suitable
values for R1, R2, R3, A', Cy' and E are as defined above in the first
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embodiment. In another alternative, the embodiments in this paragraph
exclude the following compounds:
(R)-6-(3-hydroxypropyl)-3-((S)-1 -(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)eth
yl)-6-phenyl-1,3-oxazinan-2-one
O
QOAN
N O
H
OH (PR-221); and
(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-
yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
O
OA N
/ N O
OH I (PR-313);
or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.
For each of the embodiments described in the previous paragraph, R1
is preferably methyl or ethyl.
For each of the embodiments described in the paragraph immediately
following Formulas Im', Im2 and Im5, R1 is preferably methyl or ethyl; and R3
is McSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2,
3-hydroxypropyl, 3-h yd roxy-3-m ethyl butyl, 2-hydroxyethyl,
2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately
following Formulas Im', Im2 and Im5 , R1 is preferably methyl or ethyl; and R3
is H2NC(=O)CMe2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl
or 2-cyano-2-methylpropyl.
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For each of the embodiments described in the paragraph immediately
following Formulas Im', Im2 and Im5, R1 is preferably methyl or ethyl; R2 is
phenyl optionally substituted with 1, 2 or 3 substituents selected from halo,
cyano, CONH2, (Ci-C4)alkyl, (Ci-C4)haloalkyl, and SO2Me; and R3 is
McSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2,
3-hydroxypropyl, 3-h yd roxy-3-m ethyl butyl, 2-hydroxyethyl,
2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately
following Formulas Im', Im2 and Im5, R1 is preferably methyl or ethyl; R2 is
phenyl optionally substituted with 1, 2 or 3 substituents selected from halo,
cyano, CONH2, (Ci-C4)alkyl, (Ci-C4)haloalkyl, and SO2Me; and R3 is
H2NC(=O)CMe2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or
2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately
following Formulas Im', Im2 and Im5, R1 is preferably methyl or ethyl; and R3
is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately
following Formulas Im', Im2 and Im5, R1 is preferably methyl or ethyl; R2 is
phenyl or fluorophenyl; and R3 is 2-hydroxy-2-methylpropyl or
2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately
following Formulas Im', Im2 and Im5, R1 is preferably methyl or ethyl; R2 is
phenyl or fluorophenyl; R3 is 2-hydroxy-2-methylpropyl or
2-cyano-2-methylpropyl; the substituent on the substitutable ring nitrogen
atom in the oxodihydropyridyl ring in Formulas Im', Im2 and Im5 is (Cl-C4
)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C2)alkyl, or (Cl-C2
)haloalkyl;
and one or two ring carbon atoms in the oxodihydropyridyl ring in Formulas
Im1, Im2 and Im5 are optionally substituted with methyl or ethyl.
Another embodiment of the invention is a compound of any one of
Formulas In', In2 and In5, or a pharmaceutically acceptable salt, enantiomer
or diastereomer thereof:
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O R1
O N )"', Cyr
R3
H
-k j N O
R2
O R1
O N )"', Cyr
R3
R2 H O
In' In2
ill
R3
-kj NH
R2
In5.
In Formulas In', In2 and In5, the oxodihydropyridyl ring is optionally
substituted (substitution at ring carbons bonded to hydrogen and at nitrogen
atoms bonded to hydrogen atoms are encompassed, i.e., a "substitutable
ring nitrogen atom") with up to four substituents as described above for Cy2.
Suitable substituents for the oxodihydropyridyl ring and suitable values for
R', R2, R3 and Cy' are as defined above in the first embodiment.
Alternatively, suitable substituents for Cy' and the oxodihydropyridyl ring in
Formulas In', In2 and In5 are independently fluorine, chlorine, bromine,
iodine, cyano, nitro, amino, hydroxy, carboxy, (Ci-C6)alkyl,
hydroxy(CT-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl,
(C4-C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl,
hydroxy(C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2-C4)alkynyl,
halo(Ci-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl,
(Ci-C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy,
halo(CT-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy,
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(CT-C6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio,
halo(C1-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-
C7)cycloalkylalkylthio,
(Ci-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl,
(C4-C7)cycloalkylalkanesulfinyl, halo(Ci-C6)alkanesulfinyl,
halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl,
(CT-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkyl-
alkanesulfonyl, halo(Ci-C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl,
halo(C4-C7)cyclo-alkylalkanesulfonyl, (Ci-C6)alkylamino, di(Ci-C6)alkylamino,
(C1-C6)alkoxy(C1-C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkoxy,
(CT-C6)alkoxycarbonyl, H2NCO, H2NSO2, (CT-C6)alkylaminocarbonyl,
di(Ci-C6)alkylaminocarbonyl, (Ci-C3)alkoxy(Ci-C3)alkylaminocarbonyl,
heterocyclylcarbonyl, (Ci-C6)alkylaminosulfonyl, di(Ci-C6)alkylaminosulfonyl,
heterocyclylsulfonyl, (Cl-C6)alkylcarbonylamino,
(Cl-C6)alkylcarbonylamino(CT-C6)alkyl, (Cl-C6)alkylsulfonylamino,
(Ci-C6)alkylsulfonylamino(Ci-C6)alkyl, (Ci-C6)alkoxycarbonyl(Ci-C6)alkoxy,
(C1-C6)alkoxy(C1-C6)alkyl, halo(Ci-C6)alkoxy(Ci-C6)alkyl,
hydroxy(CT-C6)alkoxy, heteroaryl, amino(CT-C6)alkyl,
(C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl
amino(C2-C6)alkoxy, (C1-C6)alkylamino(C2-C6)alkoxy,
di(Ci-C6)alkylamino(C2-C6)alkoxy, (Ci-C6)alkylcarbonyl,
(C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl,
{(C3-C6)cycloalkyl}{(Ci-C6)alkyl}aminocarbonyl,
di(C3-C6)cycloalkylaminocarbonyl, (C3-C6)cycloalkylaminosulfonyl,
{(C3-C6)cycloalkyl}{(Ci-C6)alkyl}aminosulfonyl,
di(C3-C6)cycloalkylaminosulfonyl, cyano(CT-C6)alkyl,
aminocarbonyl(CT-C6)alkyl, (Cl-C6)alkylaminocarbonyl(C1-C6)alkyl,
di(Ci-C6)alkylaminocarbonyl(Ci-C6)al kyl,
(C3-C6)cycloal kylaminocarbonyl(Ci-C6)al kyl,
{(C3-C6)cycloalkyl}{(Ci-C6)alkyl}aminocarbonyl(Ci-C6)alkyl and
di(C3-C6)cycloalkylaminocarbonyl(C1-C6)alkyl; and values for R1, R2, R3 and
Cy' are as defined above in the first embodiment. Alternatively, suitable
substituents for Cy' include (Cl-C4 )alkyl, (Cl-C4 )alkoxy, (Cl-C4 )haloalkyl,
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(Cl-C4 )haloalkoxy, halogen, cyano and nitro; suitable substituents for a
substitutable ring nitrogen atom in the oxodihydropyridyl ring in Formulas
In',
In2 and In5 include (C1-C4 )alkyl, (C3-C4)cycloalkyl,
(C3-C4)cycloalkyl(C1-C2)alkyl and (C1-C4)haloalkyl; suitable substituents for
a
ring carbon atom in the oxodihydropyridyl ring in Formulas In', In2 and In5
include fluorine, chlorine, cyano, hydroxy, amino, (Cl-C4)alkyl,
(C3-C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C2)alkyl, halo(Cl-C4)alkyl,
(Cl-C4)alkoxy, (Ci-C4)haloalkoxy, CONH2, (Cl-C4)alkylaminocarbonyl,
di(C1-C4)alkylaminocarbonyl and (Cl-C4)alkylcarbonylamino; and suitable
values for R1, R2, R3, and Cy' are as defined above in the first embodiment.
In another alternative, the embodiments described in this paragraph exclude
the compounds PR-221 and PR-313; or a pharmaceutically acceptable salt,
enantiomer or diastereomer thereof.
For each of the embodiments described in the previous paragraph, R1
is preferably methyl or ethyl.
For each of the embodiments described in the paragraph immediately
following Formulas In', In2 and In5, R1 is preferably methyl or ethyl; and R3
is
McSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2,
3-hydroxypropyl, 3-hydroxy-3-methyl butyl, 2-hydroxyethyl,
2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately
following Formulas In', In2 and In5, R1 is preferably methyl or ethyl; and R3
is
H2NC(=O)CMe2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or
2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately
following Formulas In', In2 and In5, R1 is preferably methyl or ethyl; R2 is
phenyl optionally substituted with 1, 2 or 3 substituents selected from halo,
cyano, CONH2, (Cl-C4)alkyl, (Cl-C4)haloalkyl and SO2Me; and R3 is
McSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2,
3-hydroxypropyl, 3-hydroxy-3-methyl butyl, 2-hydroxyethyl,
2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
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For each of the embodiments described in the paragraph immediately
following Formulas In', In2 and In5, R1 is preferably methyl or ethyl; R2 is
phenyl optionally substituted with 1, 2 or 3 substituents selected from halo,
cyano, CONH2, (Ci-C4)alkyl, (Ci-C4)haloalkyl and SO2Me; and R3 is
H2NC(=O)CMe2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or
2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately
following Formulas In', In2 and In5, R1 is preferably methyl or ethyl; and R3
is
2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately
following Formulas In', In2 and In5, R1 is preferably methyl or ethyl; R2 is
phenyl or fluorophenyl; and R3 is 2-hydroxy-2-methylpropyl or
2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately
following Formulas In', In2 and In5, R1 is preferably methyl or ethyl; R2 is
phenyl or fluorophenyl; R3 is 2-hydroxy-2-methylpropyl or
2-cyano-2-methylpropyl; the substituent on the substitutable ring nitrogen
atom in the oxodihydropyridyl rings in Formulas In', In2 and In5 is
(Ci-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, or
(Ci-C2)haloalkyl; and one or two ring carbon atoms in the oxodihydropyridyl
rings in Formulas In', In2 and In5 are optionally substituted with methyl or
ethyl.
Another embodiment of the invention is a compound of any one of
Formulas lo', lot and Io5, or a pharmaceutically acceptable salt thereof:
O R1 (G~~n 0 R1 G
1)n
O N O 'A, N
R3 R3
-L"J R2 I Rz
N
O N O
H H
101 102
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O R1 (G)n
O N
R3
R2
NH
O
105.
In Formulas lo', 1o2 and Io5, the oxodihydropyridyl ring in Formulas lo', 1o2
and Io5 is optionally substituted (substitution at ring carbons bonded to
hydrogen and at nitrogen atoms bonded to hydrogen atoms are
encompassed, i.e., a "substitutable ring nitrogen atom") with up to four
substituents as described above in the first embodiment; suitable values for
G1 are fluorine, chlorine, bromine, iodine, cyano, nitro, amino, hydroxy,
carboxy, (Ci-C6)alkyl, hydroxy(CT-C6)alkyl, (C3-C6)cycloalkyl,
hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2-C6)alkenyl,
halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2-C6)alkynyl,
(C3-C6)cycloalkyl(C2-C4)alkynyl, halo(C1-C6)alkyl, halo(C3-C6)cycloalkyl,
halo(C4-C7)cycloalkylalkyl, (Ci-C6)alkoxy, (C3-C6)cycloalkoxy,
(C4-C7)cycloalkylalkoxy, halo(C1-C6)alkoxy, halo(C3-C6)cycloalkoxy,
halo(C4-C7)cycloalkylalkoxy, (C1-C6)alkylthio, (C3-C6)cycloalkythio,
(C4-C7)cycloalkylalkylthio, halo(C1-C6)alkylthio, halo(C3-C6)cycloalkythio,
halo(C4-C7)cycloalkylalkylthio, (Cl-C6)alkanesulfinyl,
(C3-C6)cycloalkanesulfinyl, (C4-C7)cycloalkylalkanesulfinyl,
halo(C1-C6)alkanesulfinyl, halo(C3-C6)cycloalkanesulfinyl,
halo(C4-C7)cycloalkylalkanesulfinyl, (Cl-C6)alkanesulfonyl,
(C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkylalkanesulfonyl,
halo(C1-C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl,
halo(C4-C7)cyclo-alkylalkanesulfonyl, (C1-C6)alkylamino, di(C1-C6)alkylamino,
(C1-C6)alkoxy(C1-C6)alkoxy, halo(C1-C6)alkoxy(C1-C6)alkoxy,
(CT-C6)alkoxycarbonyl, H2NCO, H2NSO2, (CT-C6)alkylaminocarbonyl,
di(C1-C6)alkylaminocarbonyl, (Cl-C3)alkoxy(C1-C3)alkylaminocarbonyl,
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heterocyclylcarbonyl, (Cl-C6)alkylaminosulfonyl, di(C1-C6)alkylaminosulfonyl,
heterocyclylsulfonyl, (Cl-C6)alkylcarbonylamino,
(C1-C6)alkylcarbonylamino(C1-C6)alkyl, (C1-C6)alkylsulfonylamino,
(Cl-C6)alkylsulfonylamino(C1-C6)alkyl, (Cl-C6)alkoxycarbonyl(C1-C6)alkoxy,
(C1-C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl,
hydroxy(CT-C6)alkoxy, heteroaryl, amino(CT-C6)alkyl,
(C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl
amino(C2-C6)alkoxy, (C1-C6)alkylamino(C2-C6)alkoxy,
di(CT-C6)alkylamino(C2-C6)alkoxy, (CT-C6)alkylcarbonyl,
(C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl,
{(C3-C6)cycloalkyl}{(Ci-C6)alkyl}aminocarbonyl,
di(C3-C6)cycloalkylaminocarbonyl, (C3-C6)cycloalkylaminosulfonyl,
{(C3-C6)cycloalkyl}{(Ci-C6)alkyl}aminosulfonyl,
di(C3-C6)cycloalkylaminosulfonyl, cyano(CT-C6)alkyl,
aminocarbonyl(C1-C6)alkyl, (Cl-C6)alkylaminocarbonyl(C1-C6)alkyl,
di(C1-C6)alkylaminocarbonyl(Ci-C6)al kyl,
(C3-C6)cycloal kylaminocarbonyl(C1-C6)al kyl,
{(C3-C6)cycloalkyl}{(Ci-C6)alkyl}aminocarbonyl(Ci-C6)alkyl and
di(C3-C6)cycloalkylaminocarbonyl(Ci-C6)alkyl; n is 0, 1, 2 or 3; and suitable
substituents for the oxodihydropyridyl ring and suitable values for R1, R2 and
R3 are as defined above in the first embodiment. Alternatively, n is 0, 1, 2
or
3; suitable values for G1 and substituents for the oxodihydropyridyl ring in
Formulas lo', 102 and io5 are independently fluorine, chlorine, bromine,
iodine, cyano, nitro, amino, hydroxy, carboxy, (Cl-C6)alkyl,
hydroxy(CT-C6)alkyl, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl,
(C4-C7)cycloalkylalkyl, (C2-C6)alkenyl, halo(C2-C6)alkenyl,
hydroxy(C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl(C2-C4)alkynyl,
halo(C1-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl,
(CT-C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy,
halo(CT-C6)alkoxy, halo(C3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy,
(C1-C6)alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio,
halo(C1-C6)alkylthio, halo(C3-C6)cycloalkythio, halo(C4-
C7)cycloalkylalkylthio,
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(CT-C6)alkanesulfinyl, (C3-C6)cycloalkanesulfinyl,
(C4-C7)cycloalkylalkanesulfinyl, halo(C1-C6)alkanesulfinyl,
halo(C3-C6)cycloalkanesulfinyl, halo(C4-C7)cycloalkylalkanesulfinyl,
(Ci-C6)alkanesulfonyl, (C3-C6)cycloalkanesulfonyl, (C4-C7)cycloalkyl-
alkanesulfonyl, halo(C1-C6)alkanesulfonyl, halo(C3-C6)cycloalkanesulfonyl,
halo(C4-C7)cyclo-alkylalkanesulfonyl, (Cl-C6)alkylamino, di(C1-C6)alkylamino,
(C1-C6)alkoxy(C1-C6)alkoxy, halo(Ci-C6)alkoxy(C1-C6)alkoxy,
(Ci-C6)alkoxycarbonyl, H2NCO, H2NSO2, (Ci-C6)alkylaminocarbonyl,
di(CT-C6)alkylaminocarbonyl, (Cl-C3)alkoxy(C1-C3)alkylaminocarbonyl,
heterocyclylcarbonyl, (Cl-C6)alkylaminosulfonyl, di(C1-C6)alkylaminosulfonyl,
heterocyclylsulfonyl, (Ci-C6)alkylcarbonylamino,
(Ci-C6)alkylcarbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino,
(Cl-C6)alkylsulfonylamino(C1-C6)alkyl, (Cl-C6)alkoxycarbonyl(C1-C6)alkoxy,
(C1-C6)alkoxy(C1-C6)aIkyl, halo(C1-C6)alkoxy(C1-C6)alkyl,
hydroxy(Ci-C6)alkoxy, heteroaryl, amino(Ci-C6)alkyl,
(C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(Ci-C6)alkyl
amino(C2-C6)alkoxy, (C1-C6)alkylamino(C2-C6)alkoxy,
di(CT-C6)alkylamino(C2-C6)alkoxy and (Cl-C6)alkylcarbonyl; and values for
R', R2 and R3 are as defined above in the first embodiment. Alternatively, n
is 0, 1, 2 or 3; suitable values for G1 include (Cl-C4 )alkyl, (Cl-C4 )alkoxy,
(Cl-C4 )haloalkyl, (Cl-C4 )haloalkoxy, halogen, cyano and nitro; suitable
substituents for a substitutable ring nitrogen atom in the oxodihydropyridyl
ring in Formulas lo', lot and Io5 include C1-C4 alkyl, (C3-C4)cycloalkyl,
(C3-C4)cycloalkyl(C1-C2)alkyl and C1-C4 haloalkyl; suitable substituents for a
ring carbon atom in the oxodihydropyridyl ring in Formulas lo', lot and Io5
include fluorine, chlorine, cyano, hydroxy, amino, (Cl-C4)alkyl,
(C3-C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C2)alkyl, halo(Ci-C4)alkyl,
(Cl-C4)alkoxy, (Ci-C4)haloalkoxy, CONH2, (Cl-C4)alkylaminocarbonyl,
di(C1-C4)alkylaminocarbonyl and (Cl-C4)alkylcarbonylamino; and suitable
values for R1, R2 and R3 are as defined above in the first embodiment. In
another alternative, the embodiments described in this paragraph exclude
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the compounds PR-221 and PR-313; or a pharmaceutically acceptable salt,
enantiomer or diastereomer thereof.
For each of the embodiments described in the previous paragraph, R1
is preferably methyl or ethyl.
For each of the embodiments described in the paragraph immediately
following Formulas lo', lot and lo5, R1 is preferably methyl or ethyl; and R3
is
McSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2,
3-hydroxypropyl, 3-hydroxy-3-methyl butyl, 2-hydroxyethyl,
2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately
following Formulas lo', lot and lo5, R1 is preferably methyl or ethyl; and R3
is
H2NC(=O)CMe2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or
2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately
following Formulas lo', lot and lo5, R1 is preferably methyl or ethyl; R2 is
phenyl optionally substituted with 1, 2 or 3 substituents selected from halo,
cyano, CONH2, (CT-C4)alkyl, (CT-C4)haloalkyl and SO2Me; and R3 is
McSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2,
3-hydroxypropyl, 3-hydroxy-3-methyl butyl, 2-hydroxyethyl,
2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately
following Formulas lo', lot and lo5, R1 is preferably methyl or ethyl; R2 is
phenyl optionally substituted with 1, 2 or 3 substituents selected from halo,
cyano, CONH2, (Ci-C4)alkyl, (Ci-C4)haloalkyl and SO2Me; and R3 is
H2NC(=O)CMe2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or
2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately
following Formulas lo', lot and lo5, R1 is preferably methyl or ethyl; and R3
is
2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately
following Formulas lo', lot and lo5, R1 is preferably methyl or ethyl; R2 is
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phenyl or fluorophenyl; and R3 is 2-hydroxy-2-methylpropyl or
2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately
following Formulas lo', lot and lo5, R1 is preferably methyl or ethyl; R2 is
phenyl or fluorophenyl; R3 is 2-hydroxy-2-methylpropyl or
2-cyano-2-methylpropyl; the substituent on the substitutable ring nitrogen
atom in the oxodihydropyridyl ring in Formulas lo', lot and lo5 is (Cl-C4
)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl, or (C1-C2
)haloalkyl;
and one or two ring carbon atoms in the oxodihydropyridyl rings in Formulas
lo', lot and lo5 are optionally substituted with methyl or ethyl.
Another embodiment of the invention (referred to herein as the "First
Alternate Embodiment") is a compound represented by Structural Formulas
101, lot and lo5, wherein: n is 0 or 1, preferably 0; each G1 is independently
(Cl-C4 )alkyl, (CT-C4)alkoxy, (Cl-C4 )haloalkyl, (Cl-C4 )haloalkoxy, halogen,
cyano or nitro; the oxodihydropyridyl is substituted at its ring nitrogen atom
with hydroxy(Ci-C6)alkyl, (Ci-C6)alkylcarbonylamino(Cl-C6)alkyl,
(Cl-C6)alkylsulfonylamino(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl,
amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl,
di(Cl-C6)alkylamino(Ci-C6)alkyl, cyano(Cl-C6)alkyl,
aminocarbonyl(Cl-C6)alkyl, (Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl,
di(Cl-C6)alkylaminocarbonyl(Ci-C6)al kyl,
(C3-C6)cycloal kylaminocarbonyl(C1-C6)al kyl,
{(C3-C6)cycloalkyl}{(Ci-C6)alkyl}aminocarbonyl(Ci-C6)alkyl or
di(C3-C6)cycloalkylaminocarbonyl(Ci-C6)alkyl; the oxodihydropyridyl is
optionally substituted at one or more substitutable ring carbon atoms with a
group independently selected from fluorine, chlorine, cyano, hydroxy, amino,
(Ci-C4)alkyl, (C3-C4)cycloalkyl, (C3-C4)cycloalkyl(Ci-C2)alkyl,
halo(Ci-C4)alkyl, (Ci-C4)alkoxy, (Ci-C4)haloalkoxy, CONH2,
(Ci-C4)alkylaminocarbonyl, di(Ci-C4)alkylaminocarbonyl and
(Ci-C4)alkylcarbonylamino; R1 is methyl or ethyl; R2 is phenyl, thienyl,
pyridyl
or isopropyl each optionally substituted with up to three groups
independently selected from halo, methyl, methylthio, (4-morpholino)methyl
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or cyclopropyl; and R3 is methyl, ethyl, propyl, butyl, vinyl, allyl or
ethoxyethyl
each optionally substituted with up to two groups independently selected
from methyl, HO-, MeO-, H2N-, MeC(=O)NH-, MeS(=O)2NH-, H2NC(=O)-,
MeNHC(=O)-, HO2C-, (HO)2P(=O)O-, H2NS(=O)20-, H2NS(=0)2NH-,
MeNHC(=O)NH-, MeNHC(=O)O-, oxo, cyano, HO2C-, HOCH2CH2NH-,
4-morpholino, HOCH2C(=O)NH-, H2NCH2C(=O)NH-, EtNHC(=O)NH,
MeOC(=O)NH-, MeNHC(=NC=N)NH-, Me-, MeS-, McSO2- McS02N(Me)-,
MeS(=O)2NHC(=O)-, imidazolylamino-, imidazolyl, tetrazolyl, H2NCONH-,
H2NCO2-, HOCH2CH2O-, MeNH-, Me2N- and MeCONMe.
Alternatively for Structural Formulas lo', lot and lo5, R2 is phenyl
optionally substituted with 1, 2 or 3 substituents independently selected from
halo, cyano, CONH2, (Ci-C4)alkyl, (Ci-C4)haloalkyl and SO2Me; and R3 is is
McS02NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2,
3-hydroxypropyl, 3-hydroxy-3-methyl butyl, 2-hydroxyethyl,
2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the remainder of
the variables are as described above for the First Alternate Embodiment.
Alternatively for Structural Formulas lo', lot and lo5, R3 is
H2NC(=O)CMe2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or
2-cyano-2-methylpropyl; and the remainder of the variables are as described
above for the First Alternate Embodiment.
Alternatively for Structural Formulas lo', lot and lo5, R2 is phenyl
optionally substituted with 1, 2 or 3 substituents independently selected from
halo, cyano, CONH2, (CT-C4)alkyl, (Cl-C4)haloalkyl and SO2Me; and R3 is
H2NC(=O)CMe2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or
2-cyano-2-methylpropyl; and the remainder of the variables are as described
in the First Alternate Embodiment.
Alternatively for Structural Formulas lo', lot and lo5, R3 is
2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the remainder of
the variables are as described in the First Alternate Embodiment.
Alternatively for Structural Formulas lo', lot and lo5, R2 is phenyl or
fluorophenyl; and R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl;
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and the remainder of the variables are as described in the First Alternate
Embodiment.
Alternatively for Structural Formulas lo', lot and Io5, R2 is phenyl or
fluorophenyl; R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; one
or two ring carbon atoms in the oxodihydropyridyl rings are optionally
substituted with fluorine, methyl or ethyl; and the remainder of the variables
are as described in the First Alternate Embodiment.
For the embodiment described in the previous seven paragraphs, n is
0 and all of the substitutable ring carbons in the oxodihydropyridyl are
preferably unsubstituted.
Another embodiment of the invention is a compound represented by
any one of Formulas Ip' and Ip3, or a pharmaceutically acceptable salt
thereof:
O R1
(G')n
O
Rs Gzb
R2
N O
G2a
Ip'
O R1
(Gl)n
O
R3 G2b
R2
N 'G2a
O
I3
p.
In Formulas Ip' and Ip3, G1 is (CT-C4)alkyl, (Cl-C4)alkoxy, (Cl-C4)haloalkyl,
(Cl-C4)haloalkoxy, halogen, cyano or nitro; n is 0, 1 or 2; G2a is P-C4
)alkyl,
(C3-C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C2)alkyl or (Ci-C4)haloalkyl; G2b is
hydrogen, fluorine, chlorine, cyano, hydroxy, amino, (Ci-C4)alkyl,
(C3-C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C2)alkyl, halo(CT-C4)alkyl,
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(CT-C4)alkoxy, (Cl-C4)haloalkoxy, CONH2, (CT-C4)alkylaminocarbonyl,
di(C1-C4)alkylaminocarbonyl or (Cl-C4)alkylcarbonylamino; and suitable
values for R1, R2 and R3 are as defined above in the first embodiment. In
another alternative, the embodiments described in this paragraph exclude
the compounds PR-221 and PR-313; or a pharmaceutically acceptable salt,
enantiomer or diastereomer thereof.
For each of the embodiments described in the previous paragraph, R1
is preferably methyl or ethyl.
For each of the embodiments described in the paragraph immediately
following Formulas Ip' and Ip3, R1 is preferably methyl or ethyl; and R3 is
McSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2,
3-hydroxypropyl, 3-hydroxy-3-methyl butyl, 2-hydroxyethyl,
2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately
following Formulas Ip' and Ip3, R1 is preferably methyl or ethyl; and R3 is
H2NC(=O)CMe2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or
2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately
following Formulas Ip' and Ip3, R1 is preferably methyl or ethyl; R2 is phenyl
optionally substituted with 1, 2 or 3 substituents selected from halo, cyano,
CONH2, (Cl-C4)alkyl, (CT-C4)haloalkyl and SO2Me; and R3 is
McSO2NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2,
3-hydroxypropyl, 3-hydroxy-3-methyl butyl, 2-hydroxyethyl,
2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately
following Formulas Ip' and Ip3, R1 is preferably methyl or ethyl; R2 is phenyl
optionally substituted with 1, 2 or 3 substituents selected from halo, cyano,
CONH2, (Ci-C4)alkyl, (Ci-C4)haloalkyl and SO2Me; and R3 is
H2NC(=O)CMe2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or
2-cyano-2-methylpropyl.
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For each of the embodiments described in the paragraph immediately
following Formulas Ip1 and Ip3, R1 is preferably methyl or ethyl; and R3 is
2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl.
For each of the embodiments described in the paragraph immediately
following Formulas Ip1 and Ip3, R1 is preferably methyl or ethyl; R2 is phenyl
or fluorophenyl; and R3 is 2-hydroxy-2-methylpropyl or
2-cyano-2-methylpropyl.
For each of the embodiment described in the paragraph immediately
following Formulas Ip1 and Ip3, R1 is preferably methyl or ethyl; R2 is phenyl
or fluorophenyl; R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl;
the substituent G2a is selected from (Cl-C4 )alkyl, (C3-C4)cycloalkyl,
(C3-C4)cycloalkyl(C1-C2)alkyl, and (Ci-C2)haloalkyl; and G2b is optionally
selected from hydrogen, methyl or ethyl.
For each of the embodiment described in the paragraph immediately
following Formulas Ip1 and Ip3, R1 is preferably methyl or ethyl; R2 is phenyl
or fluorophenyl; R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl;
the substituent G2a is selected from haloalkyl, (Cl-C4 )alkyl,
(C3-C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C2)alkyl, and (CT-C2)haloalkyl; and
G2b is optionally selected from hydrogen, methyl or ethyl.
For each of the embodiment described in the paragraph immediately
following Formulas Ip1 and Ip3, R1 is preferably methyl or ethyl; R2 is phenyl
or fluorophenyl; R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl;
the substituent G2a is selected from difluoromethyl, ethyl substituted with
one
to three fluorine (preferably, 2-fluoroethyl or 2,2,2-fluoroethyl), (C1-C4
)alkyl,
(C3-C4)cycloalkyl, (C3-C4)cycloalkyl(C1-C2)alkyl, and (CT-C2)haloalkyl; and
G2b is optionally selected from hydrogen, methyl or ethyl.
Another embodiment of the invention (referred to herein as the "Second
Alternate Embodiment") is a compound represented by Structural Formulas
Ip1 and Ip3, wherein: n is 0 or 1, preferably 0; each G1 is independently
(Cl-C4 )alkyl, (CT-C4)alkoxy, (Cl-C4 )haloalkyl, (Cl-C4 )haloalkoxy, halogen,
cyano or nitro; G2a is hydroxy(Ci-C6)alkyl, (Ci-C6)alkyl-
carbonylamino(Ci-C6)alkyl, (Ci-C6)alkylsulfonylamino(Ci-C6)alkyl,
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(C1-C6)alkoxy(C1-C6)alkyl, amino(Cl-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl,
di(Cl-C6)alkylamino(Cl-C6)alkyl, cyano(Cl-C6)alkyl,
aminocarbonyl(Ci-C6)alkyl, (Ci-C6)alkylaminocarbonyl(Ci-C6)alkyl,
di(Ci-C6)alkylaminocarbonyl(Ci-C6)al kyl,
(C3-C6)cycloalkylaminocarbonyl(Cl-C6)alkyl,
{(C3-C6)cycloalkyl}{(Cl-C6)alkyl}aminocarbonyl(Ci-C6)alkyl or
di(C3-C6)cycloalkylaminocarbonyl(Ci-C6)alkyl; G2b is hydrogen, fluorine,
chlorine, cyano, hydroxy, amino, (Ci-C4)alkyl, (C3-C4)cycloalkyl,
(C3-C4)cycloalkyl(C1-C2)alkyl, halo(Cl-C4)alkyl, (CT-C4)alkoxy,
(Cl-C4)haloalkoxy, CONH2, (Cl-C4)alkylaminocarbonyl,
di(Ci-C4)alkylaminocarbonyl or (Ci-C4)alkylcarbonylamino; R' is methyl or
ethyl; R2 is phenyl, thienyl, pyridyl or isopropyl each optionally substituted
with up to three groups independently selected from halo, methyl, methylthio
or (4-morpholino)methyl; and R3 is methyl, ethyl, propyl, butyl, vinyl, allyl
or
ethoxyethyl each optionally substituted with up to two groups independently
selected from methyl, HO-, MeO-, H2N-, MeC(=O)NH-, MeS(=O)2NH-,
H2NC(=O)-, MeNHC(=O)-, HO2C-, (HO)2P(=O)O-, H2NS(=O)20-,
H2NS(=O)2NH-, MeNHC(=O)NH-, MeNHC(=O)O-, oxo, cyano, HO2C-,
HOCH2CH2NH-, 4-morpholino, HOCH2C(=O)NH-, H2NCH2C(=O)NH-,
EtNHC(=O)NH, MeOC(=O)NH-, MeNHC(=NC=N)NH-, Me-, MeS-, McSO2-
McSO2N(Me)-, MeS(=O)2NHC(=O)-, imidazolylamino-, imidazolyl, tetrazolyl,
H2NCONH-, H2NCO2-, HOCH2CH2O-, MeNH-, Me2N- and MeCONMe.
Alternatively for Structural Formulas Ip' and Ip3, R2 is phenyl
optionally substituted with 1, 2 or 3 substituents independently selected from
halo, cyano, CONH2, (Ci-C4)alkyl, (Ci-C4)haloalkyl and SO2Me; and R3 is
McS02NHCH2CH2CH2, H2NC(=O)CH2CH2, H2NC(=O)CMe2CH2,
3-hydroxypropyl, 3-h yd roxy-3-m ethyl butyl, 2-hydroxyethyl,
2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the remainder of
the variables are as described above for the Second Alternate Embodiment.
Alternatively for Structural Formulas Ip' and Ip3, R3 is
H2NC(=O)CMe2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or
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2-cyano-2-methylpropyl; and the remainder of the variables are as described
above for the Second Alternate Embodiment.
Alternatively for Structural Formulas Ip' and Ip3, R2 is phenyl
optionally substituted with 1, 2 or 3 substituents independently selected from
halo, cyano, CONH2, (CT-C4)alkyl, (Cl-C4)haloalkyl and SO2Me; and R3 is
H2NC(=O)CMe2CH2, 3-hydroxy-3-methylbutyl, 2-hydroxy-2-methylpropyl or
2-cyano-2-methylpropyl; and the remainder of the variables are as described
in the Second Alternate Embodiment.
Alternatively for Structural Formulas Ip' and Ip3, R3 is
2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; and the remainder of
the variables are as described in the Second Alternate Embodiment.
Alternatively for Structural Formulas Ip' and Ip3, R2 is phenyl or
fluorophenyl; and R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl;
and the remainder of the variables are as described in the Second Alternate
Embodiment.
Alternatively for Structural Formulas Ip' and Ip3, R2 is phenyl or
fluorophenyl; R3 is 2-hydroxy-2-methylpropyl or 2-cyano-2-methylpropyl; one
or two substitutable ring carbon atoms in the oxodihydropyridyl rings are
optionally substituted with fluorine, methyl or ethyl; and the remainder of
the
variables are as described in the Second Alternate Embodiment.
For the embodiment described in the previous seven paragraphs, n is
0 and G2b is preferably -H.
Another embodiment of the invention is a hydrate or monohydrate of
(S)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(1-methyl -6-oxo-1,6-dihydropyri
din-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one,
(S)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(1-methyl -2-oxo-1,2-
dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one, 3-{(S)-1-[4-
(1-Cyclopropyl-2-oxo-1,2-dihydro-pyridin-4-yl)-phenyl]-ethyl}-(S)-6-(2-
hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one and
pharmaceutically acceptable salts thereof. Both, neutral and salt forms of
the hydrate and monohydrate are also included. Preferably, the salt form is
pharmaceutically acceptable.
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Compounds of the invention are also disclosed in INHIBITORS OF
11 3-HYDROXYSTEROID DEHYDOGENASE I, U.S. Provisional Application
No. 61/ 61/135,933, filed July 25, 2008 (Attorney Docket No. 4370.1000-
000); Cyclic Inhibitors Of 11 R-Hydroxysteroid Dehydrogenase 1, U.S.
Provisional Application No. 61/135,933, filed May 1, 2008; Cyclic Inhibitors
Of 11 R-Hydroxysteroid Dehydrogenase 1, U.S. Provisional Application No.
61/137,148, filed July 25, 2008; and Cyclic Inhibitors Of 11 R-Hydroxysteroid
Dehydrogenase 1, International Application No. PCT/US2008/009017, filed
July 25, 2008; the entire teachings of these applications are incorporated
herein by reference in their entirety.
DEFINITIONS
The term "alkyl" means a straight or branched hydrocarbon radical
having 1-10 carbon atoms and includes, for example, methyl, ethyl, n-propyl,
isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-
heptyl, n-
octyl, n-nonyl, n-decyl and the like.
The term "cycloalkyl" means a monocyclic, bicyclic or tricyclic,
saturated hydrocarbon ring having 3-10 carbon atoms and includes, for
example, cyclopropyl (c-Pr), cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1 ]heptyl, spiro [4.4]nonane,
adamantyl and the like.
The term "aryl" means an aromatic radical which is a phenyl group, a
naphthyl group, an indanyl group or a tetrahydronaphthalene group. An aryl
group is optionally substituted with 1-4 substituents. Exemplary substituents
include alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl,
dialkylamino, nitro, cyano, CO2H, CONH2, N-monoalkyl-substituted amido
and N,N-dialkyl-substituted amido.
The term "heteroaryl" means a 5- and 6-membered heteroaromatic
radical which may optionally be fused to a saturated or unsaturated ring
containing 0-4 heteroatoms selected from N, 0, and S and includes, for
example, a heteroaromatic radical which is 2- or 3-thienyl, 2- or 3-furanyl, 2-
or 3- pyrrolyl, 2-,3-, or 4-pyridyl, 2-pyrazinyl, 2-, 4-, or 5-pyrimidinyl, 3-
or 4-
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pyridazinyl, 1 H-indol-6-yl, 1 H-indol-5-yl, 1 H-benzimidazol-6-yl, 1 H-
benzimidazol-5-yl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 2-, 3-, 5-, 6-, 7- or
8-
quinoxalinyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-
or 8-
isoquinolinyl, 2-, 4-, or 5-thiazolyl, 2-, 3-, 4-, or 5-pyrazolyl, 2-, 3-, 4-,
or 5-
imidazolyl. A heteroaryl is optionally substituted. Exemplary substituents
include alkyl, alkoxy, alkylthio, alkylsulfonyl, halogen, trifluoromethyl,
dialkylamino, nitro, cyano, CO2H, CONH2, N-monoalkyl-substituted amido
and N,N-dialkyl-substituted amido, or by oxo to form an N-oxide.
The term "heterocyclyl" means a 4-, 5-, 6- and 7-membered saturated
or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms
independently selected from N, 0, and S. Exemplary heterocyclyls include
pyrrolidine, pyrrolidin-2-one, 1-methylpyrrolidin-2-one, piperidine, piperidin-
2-
one, dihydropyridine, tetrahydropyridine, piperazine, 1-(2,2,2-
trifluoroethyl)piperazine, 1,2-dihydro-2-oxopyridine, 1,4-dihydro-4-
oxopyridine, piperazin-2-one, 3,4,5,6-tetrahydro-4-oxopyrimidine, 3,4-
dihydro-4-oxopyrimidine, tetrahydrofuran, tetrahydropyran,
tetrahydrothiophene, tetrahydrothiopyran, isoxazolidine, 1,3-dioxolane, 1,3-
dithiolane, 1,3-dioxane, 1,4-dioxane, 1,3-dithiane, 1,4-dithiane, oxazolidin-2-
one, imidazolidin-2-one, imidazolidine-2,4-dione,
tetrahydropyrimidin-2(1 H)-one, morpholine, N-methylmorpholine, morpholin-
3-one, 1,3-oxazinan-2-one, thiomorpholine, thiomorpholine 1,1-dioxide,
tetra hydro-1,2,5-thiaoxazole 1,1-dioxide, tetrahydro-2H-1,2-thiazine 1,1-
dioxide, hexahydro-1,2,6-thiadiazine 1,1-dioxide, tetra hydro-1,2,5-
thiadiazole
1,1-dioxide isothiazolidine 1,1-dioxide, 6-oxo-1,6-dihydropyridazin-3-yl, 6-
oxo-1,6-dihydropyridazin-4-yl, 5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl and 5-
oxo-4,5-dihydro-1 H-imidazol-2-yl. A heterocyclyl can be optionally
substituted with 1-4 substituents. Exemplary substituents include alkyl,
haloalkyl, halogen and oxo.
The term "spirocycloalkyl" means a cycloalkyl group which shares one
ring carbon with another alkyl or cycloalkyl group.
As used herein the terms "subject" and "patient" may be used
interchangeably, and means a mammal in need of treatment, e.g.,
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companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows,
pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats,
mice, guinea pigs and the like). Typically, the subject is a human in need of
treatment.
When a disclosed compound or its pharmaceutically acceptable salt
is named or depicted by structure, it is to be understood that solvates or
hydrates of the compound or its pharmaceutically acceptable salts are also
included. "Solvates" refer to crystalline forms wherein solvent molecules are
incorporated into the crystal lattice during crystallization. Solvate may
include water or nonaqueous solvents such as ethanol, isopropanol, DMSO,
acetic acid, ethanolamine, and EtOAc. Solvates, wherein water is the
solvent molecule incorporated into the crystal lattice, are typically referred
to
as "hydrates." Hydrates include stoichiometric hydrates as well as
compositions containing variable amounts of water. Some of the
compounds disclosed in the exemplification may be in the anhydrous form..
The term "compound" also includes labeling at one or more positions
with deuterium. "Labeled with deuterium at a position" means that the
amount deuterium at the position is greater than the amount that is present
at natural abundance. In certain instances, the deuterium at each position in
a "compound" is at natural abundance.
Certain of the disclosed compounds may exist in various
stereoisomeric forms. Stereoisomers are compounds that differ only in their
spatial arrangement. Enantiomers are pairs of stereoisomers whose mirror
images are not superimposable, most commonly because they contain an
asymmetrically substituted carbon atom that acts as a chiral center.
"Enantiomer" means one of a pair of molecules that are mirror images of
each other and are not superimposable. Diastereomers are stereoisomers
that are not related as mirror images, most commonly because they contain
two or more asymmetrically substituted carbon atoms. The symbol "*" in a
structural formula represents the presence of a chiral carbon center. "R" and
"S" represent the configuration of substituents around one or more chiral
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carbon atoms. Thus, "R*" and "S*" denote the relative configurations of
substituents around one or more chiral carbon atoms.
"Racemate" or "racemic mixture" means a compound of equimolar
quantities of two enantiomers, wherein such mixtures exhibit no optical
activity; i.e., they do not rotate the plane of polarized light.
"Geometric isomer" means isomers that differ in the orientation of
substituent atoms in relationship to a carbon-carbon double bond, to a
cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on
each side of a carbon-carbon double bond may be in an E (substituents are
on opposite sides of the carbon-carbon double bond) or Z (substituents are
oriented on the same side) configuration.
"R," "S," "St," "R*," "E," "Z," "cis," and "trans," indicate configurations
relative to the core molecule.
The compounds of the invention may be prepared as individual
isomers by either isomer-specific synthesis or resolved from an isomeric
mixture. Conventional resolution techniques include forming the salt of a
free base of each isomer of an isomeric pair using an optically active acid
(followed by fractional crystallization and regeneration of the free base),
forming the salt of the acid form of each isomer of an isomeric pair using an
optically active amine (followed by fractional crystallization and
regeneration
of the free acid), forming an ester or amide of each of the isomers of an
isomeric pair using an optically pure acid, amine or alcohol (followed by
chromatographic separation and removal of the chiral auxiliary), or resolving
an isomeric mixture of either a starting material or a final product using
various well known chromatographic methods.
When the stereochemistry of a disclosed compound is named or
depicted by structure, the named or depicted stereoisomer is at least 60%,
70%, 80%, 90%, 99% or 99.9% by weight pure relative to the other
stereoisomers. When a single enantiomer is named or depicted by
structure, the depicted or named enantiomer is at least 60%, 70%, 80%,
90%, 99% or 99.9% by weight optically pure. Percent optical purity by
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weight is the ratio of the weight of the enantiomer over the weight of the
enantiomer plus the weight of its optical isomer.
When a disclosed compound is named or depicted by structure
without indicating the stereochemistry, and the compound has at least one
chiral center, it is to be understood that the name or structure encompasses
one enantiomer of compound free from the corresponding optical isomer, a
racemic mixture of the compound and mixtures enriched in one enantiomer
relative to its corresponding optical isomer.
When a disclosed compound is named or depicted by structure
without indicating the stereochemistry and has at least two chiral centers, it
is to be understood that the name or structure encompasses a diastereomer
free of other diastereomers, a pair of diastereomers free from other
diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric
pairs, mixtures of diastereomers in which one diastereomer is enriched
relative to the other diastereomer(s) and mixtures of diastereomeric pairs in
which one diastereomeric pair is enriched relative to the other
diastereomeric pair(s).
The compounds of the invention may be present in the form of
pharmaceutically acceptable salts. For use in medicines, the salts of the
compounds of the invention refer to non-toxic "pharmaceutically acceptable
salts." Pharmaceutically acceptable salt forms include pharmaceutically
acceptable acidic/anionic or basic/cationic salts.
Pharmaceutically acceptable basic/cationic salts include, the sodium,
potassium, calcium, magnesium, diethanolamine, n-methyl-D-glucamine, L-
lysine, L-arginine, ammonium, ethanolamine, piperazine and
triethanolamine salts.
Pharmaceutically acceptable acidic/anionic salts include, the acetate,
benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium
edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate,
edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate,
glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride,
hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate,
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maleate, malonate, mandelate, mesylate, methylsulfate, mucate, napsylate,
nitrate, pamoate, pantothenate, phosphate/diphospate, polygalacturonate,
salicylate, stearate, subacetate, succinate, sulfate, hydrogensulfate,
tannate, tartrate, teoclate, tosylate, and triethiodide salts.
The following abbreviations have the indicated meanings:
Abbreviation Meaning
A% Area percentage
Boc tert-butoxy carbonyl or t-butoxy carbonyl
(Boc)20 di-tert-butyl dicarbonate
Cbz Benzyloxycarbonyl
CbzCl Benzyl chloroformate
c-Pr cyclopropyl
DAST diethylaminosulfur trifluoride
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DCC N,N'-dicyclohexylcarbodiimide
DCU N,N'-dicyclohexylurea
DIAD diisopropyl azodicarboxylate
DIBAL-H diisobutylaluminum hydride
DIEA N,N-diisopropylethylamine
DMAP 4-(dimethylamino)pyridine
DMF N,N-dimethylformamide
DMPU 1,3-dimethyl -3,4,5,6-tetrahydro-2(1 H)-pyrimidinone
2,4-DNP 2,4-dinitrophenylhydrazine
dppf 1,1'-Bis(diphenylphosphino)ferrocene
DPTBS Diphenyl-t-butylsilyl
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dr diastereomer ratio
EDC.HCI, EDCI 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride
Equiv equivalents
EtOAc Ethyl acetate
Fmoc 1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]-
Fmoc-OSu 1-[[(9H-fluoren-9-ylmethoxy)carbonyl]oxy]-2,5-
pyrrolidinedione
h, hr hour(s)
HOBt 1 -hydroxybenzotriazole
HATU 2-(7-Aza-1 H-benzotriazole-1 -yl)-1,1,3,3-
tetramethyluronium hexafluorophosphate
HBTU 2-(1 H-Benzotriazol-1 -yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate
KHMDS potassium hexamethyldisilazane
LAH or LiAIH4 lithium aluminum hydride
LC-MS liquid chromatography-mass spectroscopy
LHMDS lithium hexamethyldisilazane
m-CPBA meta-chloroperoxybenzoic acid
Me methyl
MsCI methanesulfonyl chloride
Min minute
MS mass spectrum
MTBE, TBME Methyl t-butyl ether
NaH sodium hydride
NaHCO3 sodium bicarbonate
NaN3 sodium azide
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NaOH sodium hydroxide
Na2SO4 sodium sulfate
NMM N-methylmorpholine
NMP N-methylpyrrolidinone
Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)
PE petroleum ether
Quant quantitative yield
rt room temperature
Satd saturated
SOCI2 thionyl chloride
SFC supercritical fluid chromatography
SPA scintillation proximity assay
SPE solid phase extraction
TBAF tetrabutylammonium fluoride
TBS t-butyldimethylsilyl
TBDPS t-butyldiphenylsilyl
TBSCI t-butyldimethylsilyl chloride
TBDPSCI t-butyldiphenylsilyl chloride
TEA triethylamine or Et3N
TEMPO 2,2,6,6-tetramethyl -1-piperidinyloxyfree radical
Teoc 1-[2-(trimethyl silyl)ethoxycarbonyloxy]-
Teoc-OSu 1 -[2-(tri m ethyl s i lyl)ethoxyca rbonyloxy] pyrrol id in -2,5-
dione
Text External temperature
Tint Internal temperature
TFA trifluoroacetic acid
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Tic, TLC thin layer chromatography
TMS trimethyisiiyl
TMSCI chiorotrimethyisiiane or trimethyisiiyl chloride
tR retention time
TsOH p-toiuenesuifonic acid
GENERAL DESCRIPTION OF SYNTHETIC METHODS
Compounds of Formula I* can be prepared by several processes. In
the discussion below, A', Cy', E, R', R2, R3, Y and n have the meanings
indicated above unless otherwise noted. Cy2 is an optionally substituted 2-
oxo-1,2-dihydropyridyl group. In cases where the synthetic intermediates
and final products of Formula I* described below contain potentially reactive
functional groups, for example amino, hydroxyl, thiol and carboxylic acid
groups, that may interfere with the desired reaction, it may be advantageous
to employ protected forms of the intermediate. Methods for the selection,
introduction and subsequent removal of protecting groups are well known to
those skilled in the art. (T.W. Greene and P. G. M. Wuts "Protective Groups
in Organic Synthesis" John Wiley & Sons, Inc., New York 1999). Such
protecting group manipulations are assumed in the discussion below and not
described explicitly. Generally, reagents in the reaction schemes are used
in equimoiar amounts; however, in certain cases it may be desirable to use
an excess of one reagent to drive a reaction to completion. This is
especially the case when the excess reagent can be readily removed by
evaporation or extraction. Bases employed to neutralize HCI in reaction
mixtures are generally used in slight to substantial excess (1.05 - 5
equivalents).
In a first process a compound of Formula I*, can be prepared by
reaction of an aminoaicohol intermediate of Formula II with a reagent of
Formula III, wherein Z' and Z2 are leaving groups such as chloride, 1-
imidazoiyl or aryioxide in an inert solvent such as THF, CH2CI2, toluene or
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MeCN, usually in the presence of an organic or inorganic base such as
triethylamine or NaHCO3 respectively, at -10 C to 120 C:
R1 O I1
A
2
OH HNCy1-CyZ IyOI~ 0 N~ ~Cy-Cy
R3 -k"Aj + Z1' \Z2 R3 \J
n \ Yn
R2 I I III R2 1*
Certain instances of reagent III are especially convenient because they are
commercially available. For example when Z' and Z2 are both chloride, III is
phosgene. When Z' and Z2 are both 1-imidazolyl, III is carbonyl diimidazole.
When Z' is chloride and Z2 is p-nitrophenoxide, III is p-nitrophenyl
chloroformate. When Z' and Z2 are both OCC13, III is triphosgene and as
little as one third of molar equivalent can be used.
Aminoalcohol intermediates of Formula II can be prepared by
reduction of amides of Formula IV using a hydride reagent such as BH3.THF
solution, BH3.Me2S or LiAIH4 in an inert solvent ethereal such as THE or
DME at 20 C to 100 C for between 1 h and 48 h:
R1
R1
1
A
~A\ OH HNC N" Cy1-Cy2
OH HN Cy1-Cy2
O E Yn
R3 R3
\
E\ Yn \R2
R2 IV II
Intermediates of Formula IV can be prepared by coupling of a R-
hydroxyacid of Formula V with an amine of Formula VI using standard
peptide coupling reagents such as EDC in the presence of HOBt and N,N-
diisopropylethylamine in an inert solvent such as CH2CI2 at 0 - 30 C for
between 1 h and 24 h:
R1
OH OH I
R1 Al
R3 \ I OH HNC Cy1-Cy2
E\ Yõ O + H2NCy1-CY2 R3
R2 \ O
E Yõ
V VI R2 IV
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Amine intermediates of Formula VI, wherein A' = CH2 and R1 is
absent, can be prepared by reduction of amides of Formula VII using a
hydride reagent such as BH3.THF solution, BH3.Me2S or LiAIH4 in an inert
solvent ethereal such as THE or DME at 20 C to 100 C for between 1 h
and 48 h:
O R1
II
I_I
H2N /\ Cy1 Cy2 H2N~ Cy1 Cy2
VII VI
Amine intermediates of Formula VI, wherein A' is a bond, R1 is
absent and Cy' is not an aromatic or heteroaromatic ring, can be prepared
from ketones of formula VIII via oximes of Formula IX or by reductive
amination of a ketone of Formula VIII with ammonia:
R1
O HON
Cy1-Cy2 Cy1-Cy2 Al
H2N Cy1-Cy2
VIII IX VI
Methods for the conversion of ketones to oximes are described in Smith, M.
B. and March, J. "March's Advanced Organic Chemistry" pp 1194-1195, 5th
Edition, Wiley, New York, NY, 2001. Methods for the reduction of oximes to
primary amines are described in Smith, M. B. and March, J. "March's
Advanced Organic Chemistry" p 1555, 5th Edition, Wiley, New York, NY,
2001. Methods for the reductive amination of ketones are described in
Baxter, E. W. and Reitz, A. B. "Organic Reactions" Volume 59, Ed.
Overman, L. E., Wiley Interscience, 2002.
Similarly amine intermediates of Formula VI, wherein A' is CH and R1
is methyl or ethyl, can be prepared by reduction t-butylsulfinylimines of
Formula Vllib which can be prepared from ketones of Formula Villa and t-
butylsulfinamide or by addition of organometallic reagents of Formula R1M,
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wherein R1 is Me or Et and M is Li, MgCI, MgBr or MgI, to t-
butylsulfinylimines of Formula Vllld which can be prepared from aldehydes
of Formula Vlllc.
R1 R1
/ S
O Cy'-Cy2 O \N Cy'-Cy2
Villa Vlllb R1
Al
H2N \Cy1-Cy2
VI
H
R1M
O Cy1-Cy2 %S\ Cy1-Cy2
Vilic Vllld
High stereoselectivity is often achieved in such reactions using chiral
t-butylsulfinylimines.
Intermediates of Formula II, wherein n = 0, can be prepared by
reaction of oxetanes of Formula X with amines of Formula VI as described in
Smith, M. B. and March, J. "March's Advanced Organic Chemistry" p 505, 5th
Edition, Wiley, New York, NY, 2001:
R1
R1
O I
1
A
R3 ~A\ 1_ 2 OH HNCy1-C
1 + H2N Cy Cy y2
R3 \J
E
R2 E Yn
X VI R2 II
Intermediates of Formula II can also be prepared by reductive
amination of 3-hydroxyaldehydes of Formula Xa with amines of Formula VI.
Methods for the reductive amination of aldehydes are described in Baxter, E.
W. and Reitz, A. B. "Organic Reactions" Volume 59, Ed. Overman, L. E.,
Wiley Interscience, 2002.
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R1
1
OH CHO R
I 1 I
A1
R3 A\ 1 2 OH HNCy1C
+ H2N Cy Cy y2
R3 \
E
\R2 E Yn
Xa VI R2 II
Aldehydes of Formula Xa can be prepared from homoallylic alcohols of
Formula XXI by treatment with Os04 and Na104.
Intermediates of Formula II, wherein A' = CH2 and R1 is absent, can
be prepared by reduction of amide intermediates of formula XI using a
hydride reagent such as BH3.THF solution, BH3.Me2S or LiAIH4 in an inert
solvent ethereal such as THE or DME at 20 C to 100 C for between 1 h
and 48 h:
R1
O 1
Al
OH HN Cy1 Cy2 OH HN Cy1y
R3 R3 \
\ n E Yn
R2 XI R2 II
Amide intermediates of Formula XI can be prepared by reaction of an
amino-alcohol intermediate of Formula XII with activated carboxylic acid of
Formula XIII wherein Z3 = chloride or an activated ester, such as an N-
hydroxysuccinimide ester:
O
OH NH2 0 OH HNCY 1-CY2
R3 \J + R3
Z3 Cy1-Cy2 Y
E Yn E n
\R2 \R2
XII XIII XI
Amino-alcohol intermediates of Formula XII, wherein n = 0, can be
prepared by reaction of an epoxide of Formula XIV with cyanide ion followed
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by reduction of the resulting hydroxynitrile of Formula XV with hydrogen gas
in the presence of a catalyst or with a hydride source such as LiAIH4:
O OH OH NH2
R3 R3 CN R3
R2iE R211E R2,E Mn
XIV XV X11
Epoxide compounds of formula XIV can, in turn, be prepared in a number of
ways including, as described in Aube, J. "Epoxidation and Related
Processes" Chapter 3.2 in Volume 1 of "Comprehensive Organic Synthesis"
Edited by B. M. Trost, I. Fleming and Stuart L. Schreiber, Pergamon Press,
New York, 1992.
Hydroxynitrile intermediates of Formula XV can be prepared by
treatment of ketones of Formula XVI with acetonitrile anion, formed by
treatment of acetonitrile with n-BuLi or LDA, in an inert, anhydrous solvent
such as THE at low temperature:
OH
R3 R3 -k-1- CN
R211E R2.~ E
XVI XV
Amino-alcohol intermediates of Formula XII, wherein n is 0, can be
prepared by treatment of sulfonate intermediates of Formula XVII, wherein
RA is for example methyl, trifluoromethyl or p-methylphenyl, with ammonia:
OH OH NH2
R3 OS02RA R3
R2~E R2~E Mn
XVII XII
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Amino-alcohol intermediates of Formula XII can be prepared by
treatment of sulfonate intermediates of Formula XVII with sodium azide to
give an azide intermediate of Formula XVIII, followed by catalytic
hydrogenation or by Staudinger reduction with PPh3 in wet THF:
OH OH OH NH2
R3 OS02RA R3 N3---" R34\
2 "E 2iE E (Y)n
XVII XVI I I X11
Sulfonate intermediates of Formula XVII can be prepared from diol
intermediates of Formula XIX with a sulfonyl chloride RASO2CI:
OH OH
R3 _k"_~ RASO2CI Rs
OH OS02RA
R2,E R2'~E
XIX XVII
Diol intermediates of Formula XIX can be prepared by hydroboration
of allyl alcohols of Formula XX:
OH OH
Rs Rs
OH
R2 E R2 E
XX XIX
Diol intermediates of Formula XIX can be prepared by ozonolysis and
reduction of homoallyl alcohols of Formula XXI:
OH OH
R3 R3
OH
R21~ E R 2 ~ E
XXI XIX
Aminoalcohol intermediates of Formula II, wherein A' is a bond, R1 is
absent, and Cy' is a heteroaryl group or an aryl group bearing at least one
strongly electron withdrawing group such as CF3, can be prepared by
reaction of an aminoalcohol intermediate of Formula XII with a compound of
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Formula XXII, wherein Cy' is a heteroaryl group or an aryl group bearing at
least one strongly electron withdrawing group such as CF3 and RB is a
leaving group such a fluoro, chloro, bromo or iodo:
R1
OH NH2 RB A1
r
, C z OH HN Cy-Cyz
R3 1 J + CY Y
2.~E (Y)n R3
R ~.
E n II
XII XXI I \R2
Aminoalcohol intermediates of Formula II, wherein A' is (Ci)alkylene
can be prepared by reaction of an aminoalcohol of Formula XII with an
aldehyde or methyl ketone of Formula XII in the presence of a reducing
agent such as NaCNBH3 or Na(OAc)3BH:
R1
OH NH2 R1 Al
OH HNC ~Cyl-Cyz
R3 I \~ +
~E (Y)n O Cyr-Cy2
-- R3 \J
Rz
E Yn
XII XXI I \R2 I I
Methods for the reductive amination of aldehydes and ketones are described
in Baxter, E. W. and Reitz, A. B. "Organic Reactions" Volume 59, Ed.
Overman, L. E., Wiley Interscience, 2002.
In a second process a compound of Formula I* can be prepared by
reaction of a ketocarbamate of Formula XXIV, wherein RD is alkyl or arylalkyl
group such as methyl, t-butyl or benzyl, with an organometallic reagent of
Formula XXV wherein M includes, but is not limited to, MgCI, MgBr, MgI or
Li:
ORD R1 0 R1
O-- N/ Oy1-Cyz R3 O '1~ N -ICyI-CyZ
O + M R3 \J
Y n E\ Yn
R2/E XXIV Rz 1*
xxv
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In specific examples, organometallic reagent XXV is allylmagnesium
bromide, allylzinc(II) bromide, (2-methylallyl)magnesium chloride or (2-
methoxy-2-oxoethyl)zinc(II) bromide. In certain cases when M is MgCI,
MgBr or MgI, it is advantageous to add CeCl3 to the reaction mixture.
Ketocarbamates of Formula XXIV can be prepared by reaction of
aminoketones of Formula XXVI with intermediates of Formula XXVII wherein
RE is a leaving group such as chloride, succinyloxy, imidazolyl or t -
b u toxyca rboxyca rbo n yl :
R1
ORD R1
HN CY1-CY2 ORD /A \
O N Cy1-Cy2
O +
RE O
Yr,
R2/E XXVI XXVII R21~,E
XXIV
Aminoketones of Formula XXVI, wherein n = 0, can be prepared by
reaction of a,(3-unsaturated ketones of Formula XXVIII with amines of
Formula VI:
R1
1 Al
0 i HN/ Cy1-Cy2
A1
+ H2N/ Cy1-Cy2 O
/E Yõ
R2
XXVII VI R2 E XXVI
Aminoketones of Formula XXVI, wherein n = 0, can be prepared by
reaction of J3-dialkylaminoketones of Formula XXVIII, wherein RF is lower
alkyl especially methyl, with amines of Formula VI:
R1
0 R 1 Al
HN \Cy1-Cy2
N/R Al 0
R2/E RF + H2N/ Cy1-Cy2
Yõ
XXVIII VI R2/E XXVI
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J3-Dialkylaminoketones of Formula XXVIII are in turn derived from a, J3-
unsaturated ketones of Formula XXVII with dialkylamines of Formula
RFNHRF.
In a third process a compound of Formula I* can be prepared by
reaction of a compound of Formula XVII with an isocyanate of Formula XXIX
in the presence of a base:
0 R'
OH OSO2RA
R O)~ N A 1~1 C 1-C 2
J + \ I Y Y 0 R 3 E Mn \C\NA\CY1-Cy2 R3
Y
R2 E\ n
XVII XXIX Rz 1*
Isocyanates of Formula XXIX can be prepared from amines of Formula VI by
treatment with phosgene, diphosgene or triphosgene. This third process is
described in greater detail in U.S. Provisional Application Serial No.
61/137,013, filed July 25, 2008 entitled SYNTHESIS OF INHIBITORS OF
11 3-HYDROXYSTEROID DEHYDROGENASE TYPE 1 (Attorney Docket
No. 4370.1001 -000), the entire teachings of which are incorporated herein
by reference.
In a fourth process a compound of Formula I* can be prepared by
reaction of a halo compound of Formula, wherein Hal is chlorine or bromine,
with an isocyanate of Formula XXIX in the presence of a base:
O R1
/A
O H Hal Ri 0 N \Cy1-Cy2
3
R
\
2111' Mn + \C N 1-1 1-1 A CY'-CYz 3 J
R
R
XXX XXIX E\ R2 Yn
1*
Halo compounds of Formula XXX can be prepared by reaction of
J3-haloketones of Formula XXXI with organometallic reagents of Formula
XXV wherein M is a metal containing radical including MgCI, MgBr, MgI or
Li. The reaction is optionally carried out in the presence of anhydrous
cerium trichloride:
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0 Hal OH Hal
`-J\
y + M R3 R3
4~\j
R2E )n E (y)n
R
XXXI XXV XXX
In a fifth process a compound of Formula I*, wherein A' is CH2 or
CH2CH2 and R1 is absent, can be prepared by reaction of a compound of
Formula XXXII, with a compound of Formula XXXIII, wherein A' is CH2 or
CH2CH2 and RG is a leaving group such as Br, I, OSO2Me, OSO2CF3 or
OSO2Ph, in the presence of a base such as NaH or K2CO3:
0
0 NH O N~ Cy1-Cy2
R3 + RCS A, -" Cy,-Cy2 R3
E (Y)n J
R2 E \
Yn
XXXI I XXXI I I R2 1*
Compounds of Formula XXXII can be prepared by treatment of
compounds of Formula XII with various reagents of Formula III, wherein Z'
and Z2 are leaving groups such as chloride, 1-imidazolyl or aryloxide in an
inert solvent such as THF, CH2CI2, toluene or McON, usually in the presence
of an organic or inorganic base such as triethylamine or NaHCO3
respectively, at -10 C to 120 C:
0
OH NH2 O
O INH
R3~ J \ + Z1 Z2 R3 lj~
E (y)n
R,E (y)n
XII III R2
XXXII
In a sixth process a compound of Formula I*, wherein A' is a bond
and R1 is absent, can be prepared by reaction of a compound of Formula
XXXII, with a compound of Formula XXII, wherein RB is a leaving group such
as chloro, bromo, iodo or OS02CF3, in the presence of a base such as
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K2CO3 and a copper or palladium catalyst in an inert solvent such as
dioxane, DMF or NMP at elevated temperature:
o I \ R1
W
/ A
O NH RB O N/ Cy1-Cyz
R3 + Cy1-Cyz R3 \J
R2.1 E ~Y)n E Y,
1*
XXXII XXI I R
In a seventh process a compound of Formula I* can be prepared by
Suzuki coupling of a compound of Formula XXXIV, wherein Cy' is aryl or
heteroaryl and Rx is bromo, iodo, or trifluoromethanesulfonyloxy, with a
boronic acid (RY is hydrogen) or a boronate ester of Formula XXXV (RY is
(Ci-C6)alkyl and the two groups RY taken together form a (Ci-C12)alkylene
group).
O R1 IOI R1
/A\ y.~ '41
R3 O N II CyrRX + (RYO)zg O N/ Cy1-C
Cy2 R3
E Yn E Yn
Rz Rz
XXXIV XXXV 1*
In an eighth process a compound of Formula XXXIV, wherein Cy' is
aryl or heteroaryl and Rx is bromo, iodo, or trifluoromethanesulfonyloxy, can
be reacted with bis(pinacolato)diboron in the presence of a palladium
catalyst to give a boronate ester of Formula XXXVI which can be further
reacted with a heterocyclic compound of Formula XXXVII, wherein Rx is
bromo, iodo, or trifluoromethanesulfonyloxy, again in the presence of a
palladium catalyst, to give a compound of Formula I*.
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111 111
O N O
Rx
B~
R3 \ R3
O
E Yn E Yn
R2 \R2
XXXIV XXXVI
0 R'
li
Rx Cy2 0 N Cyi-Cy2
XXXVII R3
E Y0
R2
In a ninth process a compound of Formula I* can be prepared from
another compound of Formula I*. For example:
(1) a compound of Formula I*, wherein R1 or R3 is w-hydroxy(C2-
C6)alkyl, can be oxidized to a compound of Formula I*, wherein R1 or R3 is
w-carboxy(Ci-C5)alkyl, using Jones reagent.
(2) a compound of Formula I*, wherein R1 or R3 is w-carboxy(Ci-
C6)alkyl, can be coupled with ammonia or a (Cl-C6)alkylamine using a
standard peptide coupling reagent such as EDC to afford a compound of
Formula I*, wherein R1 or R3 is w-H2NC(=O)(C1-C6)alkyl or w-{(Ci-
C6)aI kyI N HC(=O)}(C1 -C6)al kyI .
(3) a compound of Formula I*, wherein R1 or R3 is w-hydroxy(Ci-
C6)alkyl, can be converted to its methanesulfonate or
trifluoromethanesulfonate, treated with sodium azide and reduced to give a
compound of Formula I*, wherein R1 or R3 is w-amino(Ci-C6)alkyl.
(4) a compound of Formula I*, wherein R1 or R3 is amino(Ci-C6)alkyl,
can be reacted with acetic anhydride or acetyl chloride to give a compound
of Formula I*, wherein R1 or R3 is {acetylamino}(C1-C6)alkyl.
(5) a compound of Formula I*, wherein R1 or R3 is amino(Ci-C6)alkyl,
can be reacted with methanesulfonyl chloride to give a compound of
Formula I*, wherein R1 or R3 is {methanesulfonylamino}(C1-C6)alkyl.
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(6) a compound of Formula 1*, wherein R1 is (C2-C6)alkenyl, is
hydroborated to afford a compound of Formula 1*, wherein R1 is hydroxy(C2-
C6)al kyl .
(7) a compound of Formula 1*, wherein R3 is (C2-C6)alkenyl, is
hydroborated to afford a compound of Formula 1*, wherein R3 is hydroxy(C2-
C6)al kyl .
(8) a compound of Formula 1*, wherein R1 is (C2-C6)alkenyl, can be
reacted with osmium tetroxide and N-methylmorpholine-N-oxide to afford a
compound of Formula 1*, wherein R1 is vicinal dihydroxy(C2-C6)alkyl,.
(9) a compound of Formula 1*, wherein R3 is (C2-C6)alkenyl, can be
reacted with osmium tetroxide and N-methylmorpholine-N-oxide to afford a
vicinal diol compound of Formula 1*, wherein R3 is vicinal dihydroxy(C2-
C6)alkyl,.
(10) a compound of Formula 1*, wherein R1 is (C2-C6)alkenyl, can be
reacted with ozone followed by NaBH4 to give a compound of Formula 1*,
wherein R1 is w-hydroxy(Ci-C5)alkyl.
(11) a compound of Formula 1*, wherein R3 is (C2-C6)alkenyl, can be
reacted with ozone followed by NaBH4 to give a compound of Formula 1*,
wherein R3 is w-hydroxy(Ci-C5)alkyl.
(12) a compound of Formula 1*, wherein R1 or R3 is amino(C1-C6)alkyl,
can be reacted with an (Cl-C6)alkyl isocyanate to give a compound of
Formula 1*, wherein R1 or R3 is (Ci-C6)alkylaminocarbonylamino(Ci-C6)alkyl.
(13) a compound of Formula 1*, wherein R1 or R3 is amino(Ci-C6)alkyl,
can be reacted with an (Cl-C6)alkyl chloroformate to give a compound of
Formula 1*, wherein R1 or R3 is (Cl-C6)alkoxycarbonylamino(C1-C6)alkyl.
(14) a compound of Formula 1*, wherein R1 or R3 is amino(Ci-C6)alkyl,
can be reacted with chlorosulfonyl isocyanate or sulfamide to give a
compound of Formula 1*, wherein R1 or R3 is aminosulfonylamino(C1-
C6)al kyl .
(15) a compound of Formula 1*, wherein R1 or R3 is amino(Ci-C6)alkyl,
can be reacted with a (Ci-C6)alkylsulfamoyl chloride to give a compound of
Formula 1*, wherein R1 or R3 is (Cl-C6)alkylaminosulfonylamino(C1-C6)alkyl.
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(16) a compound of Formula 1*, wherein R1 or R3 is hydroxy(C1-
C6)alkyl, can be reacted with chlorosulfonyl isocyanate to give a compound
of Formula 1*, wherein R1 or R3 is aminosulfonyloxy(Ci-C6)alkyl.
(17) a compound of Formula 1*, wherein R1 or R3 is hydroxy(Ci-
C6)alkyl, can be reacted with p-nitrophenyl chloroformate, pentafluorophenyl
chloroformate or carbonyl diimidazole, followed by ammonia, a (Ci-
C6)alkylamine or a di(Ci-C6)alkylamine to give a compound of Formula 1*,
wherein R1 or R3 is aminocarboxy(Ci-C6)alkyl, (Ci-C6)alkyl
aminocarboxy(CT-C6)alkyl or di(C1-C6)alkyl aminocarboxy(C1-C6)alkyl.
(18) a compound of Formula 1*, wherein R1 or R3 is hydroxy(C1-
C6)alkyl, can be reacted with POC13 to give a compound of Formula 1*,
wherein R1 or R3 is (HO)2P(=O)O(C1-C6)alkyl.
(19) a compound of Formula 1*, wherein R3 is ally) or homoallyl, can
be reacted with oxygen in the presence of PdC12 and CuCI to afford a
compound of Formula 1*, wherein R3 is 2-oxopropyl or 3-oxobutyl
respectively.
(20) a compound of Formula 1*, wherein R3 is 2-oxopropyl or 3-
oxobutyl, can be reacted with MeMgX, wherein X is Cl, Br or I, to give a
compound of Formula 1*, wherein R3 is 2-hydroxy-2-methylpropyl or 3-
hydroxy-3-methyl propyl respectively.
(21) a compound of Formula 1*, wherein R3 is -CH2CO2Me can be
treated with MeMgX, wherein X is Cl, Br or I, to give a compound of Formula
1*, wherein R3 is 2-hydroxy-2-methylpropyl.
(22) a compound of Formula 1*, wherein R3 is ally) or -
CH2C(Me)=CH2, can be hydrocyanated with TsCN in the presence of
triphenylsilane and various cobalt catalysts to afford compounds of Formula
1*, wherein R3 is -CH2CH(CN)Me or -CH2CMe2CN respectively.
(23) a compound of Formula 1*, wherein R3 is CH2C(Me)2CN, can be
treated with acetamide in the presence of PdC12 to give a compound of
Formula 1*, wherein R3 is CH2CMe2CONH2.
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(24) a compound of Formula I*, wherein R3 is -CH2C(Me)=CH2 can
be treated with m-CPBA followed by lithium triethylborohydride to afford a
compound of Formula I*, wherein R3 is 2-hydroxy-2-methylpropyl.
In a tenth process, certain compounds of the invention of Formula I**
are prepared as follows:
Hal OH Hal
O
Yn +
E n
IE ==(-M
R2~ xxxi LII LIII R2
R1 O R1
~NAIN, Cyl-Cy2 O NCyl_Cy2
xxxix Yn ~
E
\R2 LIV
0 R1 O R1
O O NACy1-Cy2 HO A
O N Cy1-Cy2
\Yn \
E Yn
\R2 LV E\R2 I**
Halo compounds of Formula LIII can be formed by the treatment of
R-haloketones of Formula XXXI with organometallic reagents of Formula LII,
wherein M denotes MgCI, MgBr, MgI, ZnBr or ZnI and the reaction is
optionally performed in the presence of anhydrous cerium trichloride in an
inert anhydrous solvent, such as tetrahydrofuran, at about -25 to 0 C for
about 0.5 h.
Cyclic carbamates of Formula LIV can be prepared from the reaction
between R-haloalcohols of Formula LIII where Hal is a chloride and
isocyanates of Formula XXXIX in the presence of a base, such as but not
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limited to DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), in a refluxing inert
solvent, such as but not limited to tetrahydrofuran.
Tertiary alcohols of Formula LVII can be derived from trisubstituted
alkenes of Formula LIV by first epoxidizing the alkene with an epoxidation
reagent, such as m-CPBA (3-chloroperbenzoic acid), in an inert solvent,
such as dichloromethane to produce the corresponding epoxides of Formula
LV. The resulting epoxide is then reductively ring opened to provide the
corresponding tertiary alcohol I* via treatment with a strong hydride reagent,
such as lithium triethylborohydride, in an anhydrous inert solvent, such as
tetrahydrofuran.
In a variation of the tenth process, a compound of the invention of
Formula I*** is prepared by using a "Suzuki" coupling reaction of a boronate
ester of Formula LIX with a haloheterocycle of Formula LX.
R1
OH Hal I1
E Yn
Br
R2
Lill LVI
O R1 O R1
Al HO I1 /
O \N O N
E JJYn / Br E JYn Br
"R2 LVII R2 LVIII
O R1
O i I
HO A1
HO NHal Cy2
O N ~acY2
LX ~J Yn
y~ ~O E2
R2
LIX
The boronate ester of Formula LIX is prepared by reaction of a bromide of
Formula LVIII with bis(pinacolato)diboron. LVIII is prepared by epoxidation
of alkene LVII, followed by reductive epoxide opening as described above,
for 2-methyl-2-hydroxypropyl group is introduced via epoxidation and hydride
ring opening as described above for conversion of LIV to I**.
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This tenth process is described in greater detail in U.S. Provisional
Application Serial No. 61/137,013, filed July 25, 2008 entitled SYNTHESIS
OF INHIBITORS OF 11[3-HYDROXYSTEROID DEHYDROGENASE TYPE 1
(Attorney Docket No. 4370.1001 -000), the entire teachings of which are
incorporated herein by reference.
LC-MS METHODS
Method 1 [LC-MS (3 min)]
Column: Chromolith SpeedRod, RP-1 8e, 50 x 4.6 mm; Mobil phase: A:
0.01 %TFA/water, B: 0.01 %TFA/CH3CN; Flow rate: 1 mL/min; Gradient:
Time (min) A% B%
0.0 90 10
2.0 10 90
2.4 10 90
2.5 90 10
3.0 90 10
Method 2 (10-80)
Column YMC-PACK ODS-AQ, 50x2.Omm 5pm
Mobile A: water (4 L) + TFA (1.5 mL))
Phase B: acetonitrile (4 L) + TFA (0.75 mL))
TIME(min) A% B%
0 90 10
2.2 20 80
2.5 20 80
Flow Rate 1 mL/min
Wavelength UV 220 nm
Oven Temp 50 C
MS ESI
ionization
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Method 3 (30-90)
Column YMC-PACK ODS-AQ, 50x2.Omm 5pm
Mobile A: water (4 L) + TFA (1.5 mL))
Phase B: acetonitrile (4 L) + TFA (0.75 mL))
TIME(min) A% B%
0 70 30
2.2 10 90
2.5 10 90
Flow Rate 1 mL/min
Wavelength UV220
Oven Temp 50 C
MS ESI
ionization
Method 4:
Column Waters Xbridge C18 30x4.6mm 2.5pm
Mobile A: water + 0.1% F30002H
Phase B: acetonitrile
TIME (min) A% B%
0 90 10
0.15 90 10
3.15 10 90
4.50 10 90
4.75 20 10
5.00 20 10
Flow Rate 1.2 mL/min
Wavelength UV 220, 230, or 254 nm
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Method 5:
Column Merck Cromolith Speed ROD, RP18e, 50x4.6 mm
Mobile A: water + 0.1% HCO2H
Phase B: acetonitrile + 0.1% HCO2H
TIME (min) A% B%
0.00 90 10
4.50 10 90
5.00 10 90
5.50 90 10
Flow Rate 1.5 mL/min
Wavelength UV 220, 230, or 254 nm
PREPARATION 1
(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methyl propyl)-6-phenyl-
1,3-oxazinan-2-one
Method 1
0
NH2 NCO 0 N
triphosgene
(S) (S) \ '-O 'Br
NaHCOs DBU,THF
Br Br reflux / II
O 0
~MgBr HO
/ CI CI O11 N \ CuCI, PdC12
- -Br
/
O 0
OAN \ O~N
/ Br I \ / Br
O H NaCIO2/NaHPO4 O OH
O + O
N N
iN \ \ \ O MeMgBr \ / Br
0
O O O
Br
OH
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Step 1: (S)-1-bromo-4-(1-isocyanatoethyl)benzene
To a solution of (S)-1-(4-bromophenyl)ethanamine (240 g, 1.2 mol) in
methylene chloride (3 L) and satd aq NaHCO3 (3 L) solution was added
triphosgene (118 g, 0.396 mol) at 0 C. The mixture was stirred for 15 min.
The organic phase was separated, dried over Na2SO4 and concentrated to
give 1-bromo-4-(1-isocyanato-ethyl) -benzene (170 g, 63%).
Step 2: 1-chloro-3-phenylhex-5-en-3-ol
To a solution of 3-chloro-1 -phenylpropan-1 -one (170 g, 1.01 mol) in
anhydrous THE (1200 mL) was added allylmagnesium bromide (1.2 L,
1 mol/L) at -78 C under nitrogen. The formed mixture was stirred for 30 min
at -78 C. The reaction was quenched with aqueous NaHCO3 solution. The
organic phase was separated, dried over Na2SO4 and concentrated to give
the crude product, which was purified by column chromatography (petroleum
ether/EtOAc=100:1) to afford 1-chloro-3-phenylhex-5-en-3-ol (180 g, 86%).
1H NMR (CDC13): 2.27 (m, 2H), 2.51 (m, 1 H), 2.74 (m, 1 H), 3.22 (m, 1 H),
3.58 (m, 1 H), 5.16 (m, 2H), 5.53 (m, 1 H), 7.23 (m, 1 H), 7.39 (m, 4H).
Step 3: (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-
one
A mixture of 1-chloro-3-phenyl-hex-5-en-3-ol (105 g, 0.050 mmol),
(S)-(-)-1-(- bromophenyl)ethyl isocyanate (170 g, 0.752 mol), and DBU (228
g, 1.5 mot) in THE (1700 mL) was heated to reflux overnight. The mixture
was diluted with EtOAc and washed with 1 N aq HCI. The aqueous phase
was extracted with EtOAc (3 x). The combined organic phase was dried
over Na2SO4. After the solvents were evaporated, the crude product was
purified by column chromatography (petroleum ether/EtOAc =20:1 to 5:1) to
give (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
(100 g, 34 %). 1H NMR (CDC13): 1.39 (d, 3H), 2.14 (m, 1 H), 2.24 (m, 2H),
2.48-2.61 (m, 3H), 2.82 (m, 2H), 5.01 (m, 2H), 5.52 (q, 1 H), 5.73 (m, 1 H),
6.62 (d, 2H), 7.12 (m, 2H), 7.28 (m, 2H).
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Step 4: (S)-3-((S)-1 -(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-
oxazinan-2-one and 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-
1,3-oxazinan-6-yl)propanal
To a solution of (R)-6-allyl-3-((S)-1 -(4-bromophenyl)ethyl)-6-phenyl-
1,3- oxazinan-2-one (31 g, 78 mmol) and CuCI (19.3 g, 195 mmol) in dry
DMF (150 mL) was added H2O (50 mL) and PdCl2 (4.10 g, 23 mmol) at rt.
After addition, the mixture was stirred overnight under oxygen. After TLC
showed the starting material had disappeared, the solid was filtered off.
Water (200 mL) and EtOAc (200 mL) was added, the organic layers were
separated and the aqueous layer was extracted with EtOAc (3 x 40 mL).
The combined organic layer was washed with brine, dried over Na2SO4,
filtered and concentrated to give a residue which was purified by column
chromatography (petroleum ether/EtOAc =5:1 to 1:1) to give a mixture of
(S)-3-((S)-1 -(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-oxazinan-2-
one and 3-((R)- 3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-
oxazinan-6-yl)propanal, (26 g, 81 %).
Step 5: (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-
oxazinan-2-one
To a mixture of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-
phenyl-1,3- oxazinan-2-one and 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-
oxo-6-phenyl-1,3-oxazinan-6- yl)propanal (20 g, 48.2 mmol) in t-BuOH (250
mL) and 2-methyl-2-butene (50 mL) was added a solution of NaCIO2 (19.3 g,
0.213 mol) and NaH2PO4 (28 g, 0.179 mol) in H2O (300 mL) at 0 C. The
formed mixture was stirred for 1 h at 0 C. The mixture was treated with
water (100 mL) and extracted with CH2CI2. The combined organic layer was
dried over Na2SO4, filtered and concentrated to leave a residue, which was
purified by column chromatography (petroleum ether/EtOAc =5:1 to 2.5:1) to
afford (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-phenyl-1,3-
oxazinan-2-one (10.0 g, 83%). 1H NMR (CDCI3): 1.49 (d, 3H), 2.12 (s, 3H),
2.33 (m, 2H), 2.63 (m, 1 H), 2.86-3.08 (m, 3H), 5.57 (q, 1 H), 6.66 (d, 2H),
7.19 (m, 2H), 7.33 (m, 5H).
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Step 6: (S)-3-((S)-1- (4-bromophenyl) ethyl)-6- (2- hydroxy-2-m ethylpropyl)-
6- phenyl-1,3- oxazinan-2- one
To a solution of (S)-3-((S)-1 -(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-
phenyl-1,3-oxazinan-2-one (20 g, 46.4 mmol) in anhydrous THE (200 mL)
was added dropwise methylmagnesium bromide (31 mL, 144 mmol) at -78
C under nitrogen. Then the mixture was stirred at rt for 1 h. The reaction
mixture was quenched with aq NaHCO3 (50 mL) under ice water bath. The
organic layers were separated. The aqueous layer was extracted with
EtOAc (150 mL). The combined organic layers were washed with brine,
dried over Na2SO4 and concentrated in vacuo to give the crude product,
which was purified column chromatography (petroleum ether/EtOAc =5:1 to
2:1) to afford (S)-3-((S)-1 -(4-bromophenyl)ethyl)-6-(2-hydroxy-2-
methylpropyl)-6-phenyl-1,3-oxazinan-2- one (13 g, 65%). After re-
crystallization from EtOH, 4 g of the pure compound was obtained. 1H NMR
(CDC13): 1.06 (s, 3H), 1.12 (s, 3H), 1.44 (d, 3H), 2.14 (m, 3H), 2.21 (m, 1
H),
2.33 (m, 1 H), 2.76 (m, 1 H), 5.54 (q, 1 H), 6.74 (d, 2H), 7.16 (d, 2H), 7.28
(m,
5H).
Alternative Procedure for Method 1 Step 2
0
101 Br OH
"ZZt CI CI
Zn NH4CI(aq)
A solution of 3-chloro-1 -phenylpropan-1 -one (100 g, 0.595 mot) in
THE (280 ml) was added dropwise to a well-stirred mixture of zinc powder
(need not be activated) (40 g, 1.231 mot, satd aq NH4CI solution (1500 ml)
and THE (400 ml). Allyl bromide (143 g, 1.19 mot) was dissolved in THE
(200 ml) was slowly added to the reaction mixture. The reaction was mildly
exothermic, and the mixture began to reflux spontaneously. After refluxing
had ceased, the mixture was stirred for 1 h. The mixture was extracted with
EtOAc, dried over anhydrous Na2SO4, and concentrated to give 1 -chloro-3-
phenylhex-5-en-3-ol (122 g, 97%). 1H NMR: (400MHz, CDC13): 6=2.24(s,
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1 H), 2.34 (m, 2H), 2.53 (m, 1 H), 2.75 (m, 1 H), 3.20 (m, 1 H), 3.58 (m, 1
H),
5.18 (t, 1 H), 5.51 (m, 1 H), 7.26 (m, 1 H), 7.26-7.39 (m, 3H).
(R)-6-allyl-3-((S)-1-(4-bromophenyl)propyl)-6-phenyl-1,3-oxazinan-2-
one was prepared from (S)-1 -(4-bromophenyl)propan-1 -amine following
procedures analogous to those described in Preparation 1 Method 1 Steps 1
to 3 above.
(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-
methylpropyl)-1,3-oxazinan-2-one was prepared from (R)-6-allyl-3-((S)-1-(4-
bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one following
procedures analogous to those described in Preparation 1 Method 1 Steps 4
and 6.
Method 2
0 Me
0 CIMg (1.2 equiv)
Me OH O N I \
CI CeCI3 (1.4 equiv) (e0 \ ((Me Br
THF, -25 C ~ ~ 1I IT
DBU
THF, reflux O Me
H2N Me Me OAN 'a Br
CH2CI2 OCN
sat. aq. NaHCO3 I OMe / Br
Br Br
m-CPBA,
CH2CI2
O Me 0 Me
O~N I \ OAN I \
Super-Hydride C"uie
Br OH O
Me
Step 1. 1-Chloro-5-methyl-3-phenyl-hex-5-en-3-ol
To a stirred suspension of magnesium turnings (46.7 g, 1.94 mol) in
1500 mL of THF (H20 <100 ppm based on Karl Fischer titration) was
charged 53.0 mL of 1 M DIBAL-H in hexane under nitrogen at rt. Then 3-
chloro-2-methyl prop- 1-ene (160 g, 1.77 mol) was introduced while
maintaining the internal temperature below 30 C. The resulting solution was
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agitated for 2 h at rt. The solution was titrated in the presence of 1.1'-
bipyridine to indicate 0.8 M of the corresponding Grignard reagent. To a dry
flask containing 307.0 g of anhydrous CeC13 (1.25 mol) at rt under nitrogen
was added 1556.8 mL of the Grignard reagent (0.8 M, 1.25 mol). The
resulting slurry was cooled to -10 C and agitated for 0.5 h. To the slurry
was added 200 g of 3-chloro-1-phenylpropan-1-one (1.19 mol) in 200 mL of
THE while maintaining the internal temperature below 0 C. After the
mixture was stirred for 0.5 h, 1200 mL of 1 M aq HCI was added to obtain a
clear solution while maintaining the internal temperature below 30 C. After
the phase cut, the aqueous layer was extracted with EtOAc (500 mL). The
combined organic layers were washed with brine and dried over sodium
sulfate. Removal of the solvent under vacuum produced crude
1-chloro-5-methyl-3-phenyl-hex-5-en-3-ol, which was chased with THE to
achieve H2O <500 ppm based on Karl Fischer titration. The crude product
(306 g, 83wt%, 95% yield) was used directly in Step 3. 1H-NMR
spectroscopy (500 MHz, CDC13) 6 7.38-7.37 (d. J= 7.8 Hz, 2H), 7.33 (t, J=
7.9 Hz, 2H), 7.24 (t, J= 7.4 Hz, 1 H), 4.91 (s, 1 H), 4.76 (s, 1 H), 3.57
(ddd, J=
5.6, 10.7, and 10.7, 1H), 3.13 (ddd, J= 4.7, 10.7 and 10.7 Hz, 1H), 2.66 (d,
J= 13.3 Hz, 1 H), 2.54 (d, J= 11.3 Hz, 1 H), 2.53 (s, 1 H), 2.36 (ddd, J= 5.4,
10.6 and 13.9 Hz. 1 H), 2.29 (ddd, J=5.6, 11.3 and 13.3 Hz, 1 H), 1.29 (s,
3H).
13C-NMR spectroscopy (125 MHz, CDC13) 6 144.3, 141.4, 128.0, 126.6,
124.8, 116.1, 74.2, 51.2, 46.0, 39.9, 23.9.
Step 2. 1 -Bromo-4-((S)-1 -isocyanato-ethyl)-benzene
To a 10 L jacketed reactor was charged 241 g of sodium bicarbonate
(2.87 mot, 2.30 equiv) and 5 L of deionized water. The resulting solution
was agitated for 10-20 min, until the solids dissolved (homogeneous). To
the clear solution was charged 250 g (1.25 mot, 1.00 equiv) of (S)-(-)-1-(4-
bromophenyl)ethylamine as a solution in 1.00 L of dichloromethane. An
additional 4 L of dichloromethane was charged to the reactor. The biphasic
solution was agitated and cooled to T;nt=2-3 C. Triphosgene (126 g, 424
mmol, 0.340 equiv) was charged to the reactor in approximately two equal
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portions - 6 min apart. It should be noted that a slight exotherm was noted
upon the addition of triphosgene. The resulting murky solution was agitated
at T;nt=2-5 C for 30 min, at which point HPLC analysis indicates >99 A%
conversion (220 nm). The dichloromethane layer was cut and dried with
anhydrous sulfate. The resulting solution was passed through a celite plug
and concentrated to -1.5 L which fine particles of a white solid developed.
The solution was filtered and concentrated to a thick oil via reduced pressure
to produce 239 g of 1-bromo-4-((S)-1-isocyanato-ethyl)-benzene (93.7 wt%,
79.4 % yield). 1H-NMR spectroscopy (400 MHz, CD2CI2) 6 7.53 (d, J= 11.4
Hz, 2 H), 7.26 (d, J= 8.2 Hz, 2 H), 4.80 (q, J= 6.7 Hz, 1H), 1.59 (d, J= 6.7
Hz,
3 H). The material was used in Step 3 without further purification.
Step 3. (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methyl aIlyl)-6-phenyl-1,3-
oxazinan-2-one
To a dried 10 L jacketed reactor under a nitrogen atmosphere was
charged 1-chloro-5-methyl-3-phenyl-hex-5-en-3-ol (167 g, 81.7 wt%, 610
mmol, 1.00 equiv), 1-bromo-4-((S)-1-isocyanato-ethyl)-benzene (219 g, 93.7
wt%, 911 mmol, 1.50 equiv), anhydrous tetrahydrofuran (3.00 L), and then
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 409 mL, 2.73 mol, 4.50 equiv).
The resulting solution was agitated and refluxed (Tint= 67-69 C, Text= 75 C)
for 19 h, at which point HPLC analysis indicated - 1A% (220 nm) of the 1-
chloro-5-methyl-3-phenyl-hex-5-en-3-ol remained. The dark solution was
cooled to Tint= 20-25 C. Two liters of tetrahydrofuran were removed by
distillation under reduced pressure. The remaining dark solution was diluted
with 4.0 L of ethyl acetate and 1.0 L of hexanes. The resulting solution was
washed with 4.0 L of a 1.0 M aqueous solution of hydrogen chloride (note:
the wash is slightly exothermic). The aqueous solution was cut and the
remaining organic solution was dried with anhydrous sodium sulfate, filtered
and then concentrated to an oil via reduced pressure. The resulting material
was subjected to flash silica chromatography (5-30 % ethyl acetate/hexanes,
1.74 kg of silica) to produce 137.8 g of material (59 wt%, 3.1:1
diastereomeric ratio favoring the desired diastereomer (R)-3-((S)-1-(4-
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bromophenyl)ethyl)-6-(2-methyl allyl)-6-phenyl-1,3-oxazinan-2-one, 32.3 %
yield). The material was used in Step 4 without further purification.
Analytical data for (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-
methylallyl)-6-phenyl-1,3-oxazinan-2-one: 1H-NMR spectroscopy (500 MHz,
CD2CI2) 6 7.42-7.35 (m, 3 H), 7.33-7.31 (m, 2H), 7.25-7.23 (m, 2H), 6.80-
6.74 (m, 2), 5.55 (q, J= 7.1 Hz, 1 H), 5.37-5.36 (m, 1 H), 4.89 (s, 1 H), 4.69
(s,
1 H), 2.96-2.93 (m, 1 H), 2.61 (dd, J= 13.8 and 26.4 Hz, 2 H), 2.37-2.25 (m,
3H), 1.68 (s, 3H), 1.50 (d, J= 7.1 Hz, 3 H). 13C-NMR spectroscopy (125 MHz,
CD2CI2) 6 152.5, 141.5, 140.1, 138.3, 130.6, 128.1, 128.0, 126.9, 124.4,
120.2, 115.3, 82.4, 52.1, 50.1, 35.6, 29.8, 23.4, 14.5.
Analytical data for (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-
methylallyl)-6-phenyl-1,3-oxazinan-2-one: 1H-NMR spectroscopy (400 MHz,
CD2CI2) 6 7.50-7.48 (m, 2H), 7.43-7.39 (m, 2H), 7.35-7.32 (m, 3H), 7.20-7.18
(m, 2H), 5.60 (q, J= 7.1 Hz, 1 H), 4.85 (s, 1 H), 4.66 (s, 1 H), 2.73-2.67 (m,
2H), 2.60 (dd, J= 13.9 and 19.4 Hz, 2H), 2.28 (dt, J= 3.3 and 13.7 Hz, 1 H),
2.14-2.05 (m, 1 H), 1.66 (s, 3H), 1.24 (d, J= 7.2 Hz, 3 H). 13C-NMR
spectroscopy (100 MHz, CD2CI2) 6 153.4, 142.5, 141.0, 140.1, 131.8, 129.3,
128.9, 127.8, 125.3, 121.5, 116.3, 83.9, 53.2, 51.0, 36.6, 31.3, 24.3, 15.4.
Step 4. (6S)-3-((S)-1-(4-bromophenyl)ethyl)-6-((2-methyloxiran-2-yl)methyl)-
6-phenyl-1,3-oxazinan-2-one
To a 1.0 L 2-neck RBF was charged (R)-3-((S)-1-(4-
bromophenyl)ethyl)-6-(2-methyl allyl)-6-phenyl-1,3-oxazinan-2-one (135.8 g,
59 wt%, 3.1:1 dr, 193 mmol, 1.00 equiv), dichloromethane (700 mL), and
then 3-chloroperbenzoic acid (m-CPBA, 70%, 95.3 g, 386 mmol, 2.0 equiv).
The resulting solution was agitated at rt (Tint=20-25 C) for 1 h, which HPLC
analysis indicates >99 A% (220 nm) conversion. The resulting solution was
diluted with 700 mL of methyl tert-butyl ether (MTBE) and washed with
1x500 mL of 30 wt% solution of sodium thiosulfate and 1x500 mL of
saturated aqueous solution of sodium bicarbonate. The wash sequence was
repeated until the peak on an HPLC trace of the organic solution that
corresponds to a HPLC sample peak of m-CPBA is <2.5 A% (220 nm),
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which in this example the wash sequence was repeated 3 times. The
resulting organic layer was dried with anhydrous sodium sulfate, filtered and
then concentrated to an oil via reduced pressure. The resulting material was
diluted with 200 mL of anhydrous tetrahydrofuran and then concentrated to a
thick oil via reduced pressure to provide (6S)-3-((S)-1-(4-bromophenyl)ethyl)-
6-((2-methyl oxiran-2-yl)methyl)-6-phenyl-1,3-oxazinan-2-one which was
used directly in Step 5.
Step 5. (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methyl propyl)-6-
phenyl-1,3-oxazinan-2-one
To a 2.0 L 3-neck oven-dried RBF was charged the crude (6S)-3-((S)-
1-(4-bromophenyl)ethyl)-6-((2-methyloxiran-2-yl)methyl)-6-phenyl-1,3-
oxazinan-2-one and 750 mL of anhydrous THF. The resulting solution was
agitated and cooled to Tint= 2-3 C. To the agitated clear solution was
charged 1.0 M lithium triethylborohydride in tetrahydrofuran (Super Hydride,
348 mL, 348 mmol, 1.8 equiv). The addition is exothermic and addition was
controlled to maintain Tint= < 8 C. The resulting solution was agitated at
Tint= 2-3 C for 1.5 h and then allowed to warm to Tint= 10-13 C over a 2.5
h,
which HPLC analysis indicates -94 A% (220 nm) conversion. To the
agitated solution was charged a solution of hydrogen peroxide (95.7 mL of a
35 wt% aqueous solution diluted with 400 mL of water, 1.08 mol, 5.60
equiv). The addition is highly exothermic and addition was controlled to
maintain Tint= < 25 C. The resulting solution was diluted with 1.00 L of
methyl tert-butyl ether (MTBE) and washed with 1.00 L of water followed by
500 mL of a -30 wt% solution of sodium thiosulfate. The organic solution
was dried with anhydrous sodium sulfate, filtered, and then concentrated via
reduced pressure. The resulting material was subjected to flash silica
chromatography (10-60% ethyl acetate, 600 g of silica) to produce 68 g of
material consisting of both diastereomers (1.98:1 dr) and 41 g of the desired
diastereomer, (>99:1 dr). The material consisting of the mixed fractions was
recrystallized from 250 mL of isopropyl acetate (IPAC) and 200 mL of
heptane (anti-solvent) to produce upon filtration 31.3 g of product (95.7 A%
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at 220 nm, 74:1 dr). The two samples were combined to produce 72.3 g of
(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methyl propyl)-6-phenyl-
1,3-oxazinan-2-one (83.6 % yield for the two step operation). 1H-NMR
spectroscopy (400 MHz, CDC13) 6 7.37-7.29 (m, 5H), 7.25-7.21 (m, 2H),
6.82-6.79 (m, 2H), 5.61 (q, J= 6.9 Hz, 1 H), 2.83 (ddd, J= 2.5, 5.4 and 11.6
Hz, 1 H), 2.39 (ddd, J= 5.7, 12.0 and 14.1 Hz, 1 H), 2.27 (ddd, J= 2.6, 4.8
and
14.0 Hz, 1 H), 2.21-2.14 (m, 3H), 2.08 (s, 1 H), 1.49 (d, J= 7.0 Hz, 3H), 1.18
(s, 3H), 1.13 (s, 3H). 13C-NMR spectroscopy (100 MHz, CDC13) 6 153.2,
142.6, 138.5, 131.6, 129.13, 129.10, 128.0, 125.3, 121.6, 84.2, 71.4, 54.1,
53.3, 36.4, 33.6, 32.1, 30.8, 15.6.
PREPARATION 2
(S)-6-(2-hydroxy-2-methylpropyl)- 6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -
1,3,2-dioxaborol-an-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one
0 ~:Q\ 0
ON B-B
O O O N
Br \ / OO
KOAc, PdC12(dppf) B
O \
OH DMSO OH
To a solution of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-
methylpropyl)-6-phenyl-1,3-oxazinan-2-one (6.6 g, 15.2 mmol) and
4,4,4',4',5,5,5',5'- octamethyl- 2,2'-bi(1,3,2- dioxaborolane) (6.1g, 24.3
mmol)
in dry DMSO (20 mL) was added KOAc (4.8 g, 48.6 mmol) and Pd(dppf)c12
(372 mg, 0.46 mmol). After addition, the mixture was allowed to warm to
100 C for 20 h. After TLC showed the starting material had disappeared,
the solid was filtered off. Water (60 mL) and EtOAc (20mL) were added.
The layers were separated and the aqueous layer was extracted with EtOAc
(3 x 15 mL). The combined organic layer was washed with brine, dried over
Na2SO4, filtered and concentrated to give a residue, which was purified by
column chromatography to give (S)-6-(2-hydroxy-2-methylpropyl)- 6-phenyl-
3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborol-an-2-yl)phenyl)ethyl)-1,3-
oxazinan-2-one (4.4 g, 60%).
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(S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-
one was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-
m ethyl propyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one following an analogous
procedure.
(S)-6-(2-hydroxy-2-methyl propyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-
tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-one was
prepared from (S)-3-((S)-1-(4-bromophenyl)propyl)-6-(2-hydroxy-2-
methylpropyl)-6-phenyl-1,3-oxazinan-2-one following an analogous
procedure.
(R)-6-Methoxymethyl -6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl -
[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-[1,3]oxazinan-2-one was prepared
from 3-[1-(4-bromo-phenyl)-ethyl]-6-methoxymethyl -6-phenyl-[1,3]oxazinan-
2-one following an analogous procedure.
PREPARATION 3
3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-
d imethylpropanenitrile
-H-
N N-
O O
ON I \ ON I \ --' a--- Br TsCN, PhSiH, EtOH I \ Br
CN
Preparation of Cobalt(II) Complex
A 50 mL flask was charged with N,N'-bis(3,5-di-tert-butylsalicylidene)-
1,1,2,2-tetramethylethenediamine (0.430 g, 0.78 mmol, 1.0 equiv), EtOH (17
mL), and Co(OAc)2 (0.139 g, 0.78 mmol, 1.0 equiv). The mixture was
degassed and then heated to reflux under nitrogen for 3 h, cooled to room
temperature. The precipitate was filtered and the purple solid was washed
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with EtOH (10 ml-) and dried under high vacuum to give 0.353 g (75%) of
the cobalt(II) complex.
A mixture of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methyl aIlyl)-6-
phenyl-1,3-oxazinan-2-one (490 mg, 1.18 mmol), the cobalt(II) complex
whose preparation is described immediately above (8 mg, 0.01 equiv), TsCN
(257 mg, 1.2 equiv), and PhSiH3 (137 mg, 157 pL, 1.07 equiv) in ethanol (10
ml-) was stirred 4 h at rt. After removing the solvent under reduced
pressure, the residue was purified by chromatography on a 40g silica gel
column, eluted with a 25-80% EtOAc in hexanes gradient to afford 3-((R)-3-
((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-
dimethylpropanenitrile (267 mg, 51 % yield). LC-MS (3min. method) tR =
1.89min., m/z 441, 443 (M+1)
PREPARATION 4
2,2-dim ethyl -3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-
dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrile
O o
IO B_B; I0I 'J"ja O I N 0 O OAN
Br Pd(dppf)C12, B'0
CN KOAc, DMSO CN 0
90 C
3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-
yl)-2,2-dimethylpropanenitrile (467 mg, 1.06 mmol), 4,4,4',4',5,5,5',5'-
octamethyl-2,2'-bi(1,3,2-dioxaborolane) (538mg, 2equiv), KOAc (333mg, 3.2
equiv), PdC12(dppf)CH2CI2 (27 mg, 0.033 equiv) were mixed with dry DMSO
(6 mL). The mixture was degassed and refilled with N2 gas 3 times. The
mixture was then heated overnight at 90 C under protection of N2 gas. After
being cooled to rt, the mixture was diluted with EtOAc (30 mL), washed with
water (20 mL). The aqueous layer was extracted with EtOAc (2 x 15 mL).
The combined organic layers were washed by water (15 mL), brine (2 x 10
ml-) and dried over Na2SO4. After filtration and concentration, the residue
was purified chromatography on a 40g silica gel column, eluted with a 20-
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50% EtOAc in Hexanes gradient, to afford 2,2-dim ethyl -3-((R)-2-oxo-6-
phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-
1,3-oxazinan-6-yl)propanenitrile (393 mg, 76% yield).
PREPARATION 5
3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-
6-yl)-2-methyl propanenitrile
Method 1
O
O'J~ N
\ / Br
O ~MgBr HO F
CI CeCl3, THF Cl DBU, THE, reflux
F
F
0/`N
Br
F /
N N cat.
TsCN
Co PhSiH3
O O EtOH
rt
89%
O fO~
O \Br LiHMDS 0' `N \
Mel .
/ / Br
CN CN
Step 1. 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol
A 250-mL flask was charged with anhydrous CeCl3 (5.58 g, 22.6
mmol) and THF (40 mL). The mixture was vigorously stirred for 3.5 h at rt.
The suspension was then cooled to -78 C and a solution of allylmagnesium
bromide (1.0 M in THF, 21 mL, 21.0 mmol) was added. After stirring for 2 h
at -78 C, a solution of 3-chloro-1 -(4-fluorophenyl)propan-1 -one (2.522 g,
13.5 mmol) in THF (30 mL) was added via cannula. The reaction mixture
was allowed to slowly warm to 8 C while stirring overnight (18 h). The
reaction was then quenched with satd aq NaHCO3, extracted with EtOAc,
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and dried over Na2SO4. After the solvents were evaporated, the residue was
purified by chromatography on silica gel eluted with hexanes/EtOAc to afford
of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-ol (3.0049 g, 97%) as an oil. LC-MS
Method 1 tR = 1.79 min, m/z 213, 211 (M-OH)+; 1H NMR (400 MHz, CDC13) 6
7.37-7.32 (m, 2H), 7.07-7.02 (m, 2H), 5.57-5.47 (m, 1 H), 5.20-5.19 (m, 1 H),
5.16 (m, 1 H), 3.59-3.52 (m, 1 H), 3.24-3.18 (m, 1 H), 2.70 (dd, J = 13.8, 5.9
Hz, 1 H), 2.50 (dd, J = 13.8, 8.5 Hz, 1 H), 2.29 (t, J = 7.9 Hz, 2H), 2.22 (s,
1 H); 19F NMR (376 MHz, CDC13) 6 -116.52 (m).
Step 2. (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-
oxazinan-2-one and (S)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-
fluorophenyl)-1,3-oxazinan-2-one.
A mixture of 1-chloro-3-(4-fluorophenyl)hex-5-en-3-o1 (0.4129 g, 1.8
mmol, 1.0 equiv), (S)-(-)-1-(4-bromophenyl)ethyl isocyanate (0.5005 g, 2.2
mmol, 1.2 equiv), and DBU (0.7375 g, 4.8 mmol, 2.7 equiv) in THE (10 ml-)
was heated to reflux for 25 h. The mixture was diluted with EtOAc and
washed with 1 N aq HCI. The aqueous phase was extracted with EtOAc (2
x). The combined organic phase was dried over Na2SO4. After the solvents
were evaporated, the crude product was directly used in the next step
without further purification.
An analytical sample was purified by chromatography on silica gel
eluted with hexanes/EtOAc to afford the two diastereomers of 6-allyl-3-((S)-
1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one.
Isomer 1: (S)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-
fluorophenyl)-1,3-oxazinan-2-one. LC-MS Method 1 tR = 2.03 min, m/z 420,
418 (MH+); 1H NMR (400 MHz, CDC13) 6 7.46 (d, J = 8.2 Hz, 2H), 7.31-7.28
(m, 2H), 7.17 (d, J = 8.2 Hz, 2H), 7.07 (t, J = 8.5 Hz, 2H), 5.76-5.66 (m,
2H),
5.10-4.99 (m, 2H), 2.75-2.52 (m, 4H), 2.23-2.19 (m, 1 H), 2.08-2.00 (m, 1 H),
1.24 (d, J = 7.0 Hz, 3H); 19F NMR (376 MHz, CDC13) 6 -115.07 (m).
Isomer 2: (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-
fluorophenyl)-1,3-oxazinan-2-one. LC-MS Method 1 tR = 1.98 min, m/z 420,
418 (MH+); 1H NMR (400 MHz, CDC13) 6 7.25-7.20 (m, 4H), 7.05-7.01 (m,
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2H), 6.71 (d, J = 8.5 Hz, 2H), 5.74-5.64 (m, 1 H), 5.58 (q, J = 7.0 Hz, 1 H),
5.09-4.99 (m, 2H), 2.92-2.87 (m, 1 H), 2.63-2.50 (m, 2H), 2.33-2.16 (m, 3H),
1.47 (d, J = 7.0 Hz, 3H); 19F NMR (376 MHz, CDC13) 6 -114.91 (m).
Step 3
A mixture of (R)-6-allyl-3-((S)-1 -(4-bromophenyl)ethyl)-6-(4-
fluorophenyl)-1,3-oxazinan-2-one (1.067 g, 2.55 mmol, 1.0 equiv), the
cobalt(II) catalyst described in Preparation 3 (0.016 g, 0.0264 mmol, 0.010
equiv), TsCN (0.555 g, 3.06 mmol, 1.2 equiv), and PhSiH3 (0.294 g, 2.72
mmol, 1.07 equiv) in EtOH (5 mL) was stirred at room temperature for 4 h.
After the solvent was removed under reduced pressure, the residue was
purified by chromatography on silica gel eluted with hexanes/ethyl acetate to
afford 1.0130 g (89%) of 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-
fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2-methyl propanenitrile as a solid. LC-
MS tR = 1.83, 1.86 min in 3 min chromatography, m/z 445, 447 (MH+); 1H
NMR (400 MHz, CDC13) 6 7.32-7.22 (m, 4H), 7.13-7.05 (m, 2H), 6.80-6.73
(m, 2H), 5.60-5.56 (m, 1 H), 3.00-1.94 (m, 7H), 1.51-1.49 (m, 3H), 1.35-1.32
(m, 1.5H), 1.27-1.24 (m, 1.5H); 19F NMR (376 MHz, CDC13) 6 -113.08 (m), -
113.69(m).
Step 4
To a solution of 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-
fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2-methyl propanenitrile (0.332 g,
0.746 mmol) and Mel (1.40 g, 13 equiv) in THE (12 mL) at -78 0 was added
2.4 mL (2.4 mmol, 3.2 equiv) of a 1.0 M LiHMDS solution in THE The
resulting mixture was stirred overnight, with the temperature slowly rising to
ambient. The reaction mixture was quenched with brine (1 mL), diluted with
CH2CI2, and dried over Na2SO4. After the solvents were evaporated, the
residue was purified by reversed-phase HPLC (SunFireTM Prep C18 OBDTM
5 m 19 x 50 mm column, 10% -90% CH3CN/H2O, 0.1 % CF3000H over 8
min and then 90% CH3CN/H2O, 0.1 % CF3000H over 2 min, flow rate 20
mL/min) to afford 0.255 g (74%) of 3-((R)-3-((S)-1 -(4-bromophenyl)ethyl)-6-
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(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2,2-dimethyl propanenitrile. LC-MS
Method 1 tR = 1.89 min, m/z 459, 461 (MH+); 1H NMR (400 MHz, CD3OD) 6
7.31-7.27 (m, 2H), 7.22-7.18 (m, 2H), 7.04-6.99 (m, 2H), 6.83 (d, J = 8.2 Hz,
2H), 5.41 (q, J = 7.0 Hz, 1 H), 3.02-2.97 (m, 1 H), 2.42-2.36 (m, 1 H), 2.29-
2.08 (m, 4H), 1.42 (d, J = 7.0 Hz, 3H), 1.30 (s, 3H), 1.22 (s, 3H); 19F NMR
(376 MHz, CD3OD) 6 -116.50 (m).
Method 2
0
OH
~ CI
CI OCN C6H4Br p O N
F DBU, THF, reflux \ Br
F F ~
l~f
-N N-
00 O
0 II N \
TsCN, PhSiH3 / Br
EtOH F O
CN
1o Step 1
A solution of 3-chloro-1 -(4-fluorophenyl)-propan-1 -one (18.6 g, 0.1
mol) in THE (50 mL) was added to a well-stirred suspension of zinc power
(13 g, 0.2 mol) in a mixture of aqueous saturated NH4CI solution (260 mL)
and THE (65 mL). A solution of 3-iodo-2-methyl prop- 1-ene (36.4 g, 0.2 mol)
in THE (50 mL) was added dropwise. The reaction mixture was mildly
exothermic, and began to reflux spontaneously. After the refluxing had
ceased, the mixture was stirred for 1 h. TLC showed the 3-chloro-1 -(4-
fluorophenyl)propan-1 -one not reacted completely. A solution of 3-iodo-2-
methylprop-1-ene (18.2 g, 0.1 mol) in THE (30 mL) was added, and the
mixture was stirred at rt overnight. The mixture was extracted with EtOAc (2
x 500 mL). The combined organic layer was dried and concentrated. The
residue was purified by column chromatography on silica gel eluted with
petroleum ether/ EtOAc 50:1-*30:1-*5:1, to give 1 -chloro-3-(4-fluorophenyl)-
5-m ethylhex-5-en-3-ol (17 g, yield 76 %) as an oil.
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Step 2
A mixture of 1 -ch loro-3-(4-fl uoroph enyl)-5-m ethyl h ex-5-en -3-ol (3.15
g, 13 mmol), (S)-(-)- 1-(- bromophenyl)ethyl isocyanate (3.5 g, 16 mmol), and
DBU (8 g, 33 mmol) in THE (80 ml-) was heated to reflux for 25 h. The
mixture was diluted with EtOAc and washed with 1 N aq HCI. The aqueous
phase was extracted with EtOAc (3 x). The combined organic phase was
dried over Na2SO4. After the solvents were evaporated, the crude product
was purified by column to give (R)-3-((S)-1-(4-bromophenyl)-ethyl)-6-(4-
fluorophenyl)-6-(2-methyl aIlyl)-1,3-oxazinan-2-one (2.13 g, yield: 38 %).
1o Step 3
A mixture of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-
(2-methylallyl)-1,3-oxazinan-2-one (2.13 g, 4.9 mmol), the cobalt(II) catalyst
described in Preparation 3 (0.032 g, 0.053 mmol), TsCN (1.11 g, 6.12
mmol), and PhSiH3 (0.6 g, 5.54 mmol) in EtOH (10 ml-) was stirred at room
temperature for 8 h. After the solvent was removed under reduced pressure,
the residue was purified by column chromatography to give 3-((R)-3-((S)-1-
(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2,2-
dimethylpropanenitrile (1.84 g, 81.1%).
PREPARATION 6
3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-
dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)-2,2-d imethyl propanen
itrile
0 0, B- Bo 0
O lu' N p p O lu,
N I\
\ / B,
Br Pd d CI , KOAc
O
F F /
CN CN
To a solution of 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-
fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2,2-dimethyl propanenitrile (730 mg,
1.59 mmol) in DMSO (8 ml-) was added bis(pinacolato)diboron (480 mg,
1.89 mmol), KOAc (480 mg, 4.89 mmol) and Pd(dppf)C12 (45 mg, 0.042
mmol) under nitrogen atmosphere. The formed mixture was stirred at 90 C
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for 20 h. The reaction was quenched with water and extracted with EtOAc.
The combined organic phase was dried over anhydrous Na2SO4 and
concentrated to give the crude product, which was purified by column
chromatography to give 3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1 -(4-(4,4,5,5-
tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)-2,2-
dimethylpropanenitrile (191 mg, 23.7%).
PREPARATION 7
(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one
O \ O. B-B/ O
O N O O O N
Br r \ B-O
KOAc, PdC12(dppf) / O
F DMSO F
A mixture of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-
fluorophenyl)-1,3-oxazinan-2-one (0.4910 g, 1.17 mmol, 1.0 equiv),
bis(pinacolato)diboron (0.3925 g, 1.55 mmol, 1.3 equiv), KOAc (0.3696 g,
3.76 mmol, 3.2 equiv), and PdC12(dppf).CH2CI2 (0.0316 g, 0.0386 mmol,
0.033 equiv) in DMSO (6 ml-) was heated at 90 C under N2 for 20 h. After
cooling, the reaction mixture was partitioned between EtOAc and water. The
organic phase was washed with brine, and dried over Na2SO4. After the
solvents were evaporated, the residue was purified by chromatography on
silica gel eluted with hexanes/ethyl acetate to give 0.4776 g (87%) of (R)-6-
allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-
2-
yl)phenyl)ethyl)-1,3-oxazinan-2-one as a white solid.
PREPARATION 8
(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-pheny 1-1,3-
oxazinan-2-one
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O O
ON p~N I \
Br I /
OH
To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-
1,3-oxazinan- 2-one (5 g, 12.5 mmol) in tetrahydrofuran (60 ml-) was added
BH3 THE (25 mL, I mol/L, 25 mmol) at 0 C under nitrogen atmosphere. The
formed mixture was stirred for 2 h. The reaction was quenched with water.
Then NaOH (3 mol/L, 10 mL) and H202 (15 mL) were added to the above
mixture. When the reaction was over, the mixture was extracted with EtOAc.
The combined organic phase was concentrated to give the crude product,
which was purified by column chromatography to give (R)-3-((S)-1-(4-
bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-pheny I-1,3- oxazinan-2-one (2.5
g, 40%). 1H NMR: (400MHz, CDC13): 6=1.48 (t, 3H), 1.53 (m, 1 H), 1.73 (m,
1 H), 1.93-1.98(m, 2H), 2.17-2.28 (m,3H), 3.57 (t, 2H), 5.59 (m, 1 H), 6.72
(m,
2H), 7.20(m, 2H), 7.25-7.37 (m, 5H).
(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-
hydroxypropyl)-1,3-oxazinan-2-one was prepared from (R)-6-allyl-3-((S)-1-
(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one following an
analogous procedure.
(R)-3-((S)-1-(4-bromophenyl)propyl)-6-(3-hydroxypropyl)-6-phenyl-
1,3-oxazinan-2-one was prepared from (R)-6-allyl-3-((S)-1-(4-
bromophenyl)propyl)-6-phenyl-1,3-oxazinan-2-one following an analogous
procedure.
PREPARATION 9
(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one
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O p
O10 N p10 N
Br \ I BOO
0A
OH OH
To a solution of ((R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-
hydroxypropyl)-6- phenyl-1,3-oxazinan-2-one (2 g, 4.8 mmol) in DMSO (30
ml-) were added bis(pinacolato)diboron (1.58 g, 6.3 mmol), KOAc (1.51 g,
15.4 mmol) and PdC12 (130 mg, 0.16 mmol) under nitrogen atmosphere.
The formed mixture was stirred at 90 C for 20 h. The reaction was
quenched with water and extracted with EtOAc. The combined organic
phase was concentrated to give the crude product, which was purified by
column chromatography to give(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-
one (1.7 g, 77%). 1H NMR: (400MHz, CDC13): b=1.18 (t, 1 H), 1.33 (S, 11 H),
1.43 (m, 2H), 1.48 (m, 3H), 1.71(m, 1 H), 1.88 (m,2H), 2.1-2.3 (t, 3H), 2.7(m,
1 H) , 3.5 (m, 2H), 5.5 (m, 1 H),6.72 (m, 2H), 7.25-7.37 (m, 5H),7.48(m, 2H).
(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1 -(4-(4,4,5,5-
tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one was
prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-
hydroxypropyl)-1,3-oxazinan-2-one following an analogous procedure.
(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1 -(4-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-one was prepared
from (R)-3-((S)-1-(4-bromophenyl)propyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-
oxazinan-2-one following an analogous procedure.
(R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1 -(4-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)phenyl)propyl)-1,3-oxazinan-2-one was prepared
from (R)-3-((S)-1-(4-bromophenyl)propyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-
oxazinan-2-one following an analogous procedure.
PREPARATION 10
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(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(methoxymethyl)-6-phenyl-1,3-
oxazinan-2-one
O OH OH OH OH O
\ O O IO OH I/ O
O 0
OHHN c'rV 0 N I\ 0 N I\
0 Br -\ 0 / Br I-\ ` / Br
O 0
Step 1. 1-Methoxy-2-phenyl-pent-4-en-2-ol
2-Methoxy-1-phenyl-ethanone (5.00 g) dissolved in tetrahydrofuran
(50 mL) was added to 2 M allylmagnesium chloride in tetrahydrofuran (21
mL) at room temperature. The solution was stirred at room temperature for
3 h and then 10 % aqueous NH4CI solution (50 mL) was added. The
resulting mixture was extracted with tert-butyl methyl ether (3x 50 mL) and
the combined extracts were washed with water (50 mL) and brine (50 mL).
The solvent was evaporated to afford the title compound as a colorless oil.
Yield: 6.40 g (quantitative). Mass spectrum (ESI+): m/z = 175 [M+H-H2O]+
Step 2. 5-Methoxy-4-phenyl-pentane-1,2,4-trio)
OS04 (4% in water, 2 mL; alternatively, K20sO4 may be used)
followed by N-methyl-morpholine-N-oxide (5.20 g) was added to a solution of
1-methoxy-2-phenyl-pent-4-en-2-ol (1.10 g) in tetrahydrofuran (10 mL)
chilled in an ice bath. The cooling bath was removed and the solution was
stirred at room temperature overnight. Then, 10% aqueous Na2S205
solution (10 mL) was added and the resulting mixture was stirred at room
temperature for another 1.5 h. After removal of the organic solvent under
reduced pressure, the remaining mixture was extracted with ethyl acetate.
The combined extracts were washed with brine and dried (MgS04). The
solvent was evaporated to afford the title compound in good purity (ca.
95%). Yield: 1.20 g (96% of theory). Mass spectrum (ESI-): m/z = 225 [M-
H]-
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Step 3. 3-Hydroxy-4-methoxy-3-phenyl-butyraldehyde
Na104 (5.20 g) was added to a mixture of 5-methoxy-4-phenyl-
pentane-1,2,4-triol (1.10 g), dichloromethane (10 mL), and water (5 mL)
chilled in an ice bath. The mixture was stirred vigorously while warming to
ambient temperature in the cooling bath and further stirred at this
temperature overnight. Then, water (20 mL) and dichloromethane (50 mL)
were added, the organic layer was separated, and the aqueous layer was
extracted with dichloromethane (2x 25 mL). The combined organic phases
were washed with water and dried (MgS04). After removal of the solvent,
the title compound was yielded which was directly submitted to the next
reaction step (glycol cleavage).
Yield: 0.94 g (quantitative)
Step 4. 4-[(S)-1-(4-Bromo-phenyl)-ethylamino]-1-methoxy-2-phenyl-butan-2-
OI
(S)-1-(4-Bromo-phenyl)-ethylamine (0.93 g), NaB(OAc)3 (0.98 g), and
acetic acid (0.27 mL) were added in the given order to a solution of 3-
hydroxy-4-methoxy-3-phenyl-butyraldehyde (0.90 g) in tetrahydrofuran (20
mL) at ca. 10-15 C. The cooling bath was removed and the mixture was
stirred at room temperature for 2 h. Then, water (50 mL) and 1 M aqueous
NaOH solution (20 mL) were added and the resulting mixture was stirred for
another 30 min. The mixture was extracted with ethyl acetate and the
combined extracts were washed with water and brine. After drying (MgS04),
the solvent was removed to give the title compound which was submitted to
the subsequent reaction step without further purification. Yield: 1.80 g
(quantitative). Mass spectrum (ESI+): m/z = 378/380 (Br) [M+H]+
Step 5. 3-[(S)-1-(4-Bromo-phenyl)-ethyl]-(R)-6-methoxymethyl -6-phenyl-
[1,3]oxazinan-2-one and 3-[(S)-1-(4-Bromo-phenyl)-ethyl]-(S)-6-
methoxymethyl-6-phenyl-[1,3]oxazinan-2-one
Triphosgene (157 mg) was added to an ice-cold solution of 4-[(S)-1-
(4-bromo-phenyl)-ethylamino]-1-methoxy-2-phenyl-butan-2-ol (1:1
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diastereomeric mixture, 200 mg) and EtNiPr2 (91 pL) in dichloromethane (5
mL). The resulting solution was stirred with cooling for 2 h and at room
temperature overnight. Then, the solution was concentrated under reduced
pressure and the residue was purified by HPLC on reversed phase
(MeCN/H20/NH3) to afford the title compounds in separate fractions.
Isomer 1: 3-[(S)-1-(4-Bromo-phenyl)-ethyl]-(R)-6-methoxymethyl -6-
phenyl-[1,3]oxazinan-2-one. Yield: 45 mg (21 % of theory). Mass spectrum
(ESI+): m/z = 404 [M+H]+ 1H NMR (400 MHz, DMSO-d6) 6 1.41 (d, J = 7.1
Hz, 3H), 2.19 (td, J = 11.2, 5.2 Hz, 1 H), 2.24-2.34 (m, 1 H), 2.34-2.41 (m,
1 H), 3.02-3.09 (m, 1 H), 3.27 (s, 3H), 3.49 (d, B part of an AB signal, J =
10.6
Hz, 1 H), 3.53 (d, A part of an AB signal, J = 10.6 Hz, 1 H), 5.34 (q, J = 7.0
Hz, 1 H), 6.80 (dm, J = 8.4 Hz, 2H), 7.27 (dm, J = 8.4 Hz, 2H), 7.32-7.42 (m,
5H).
Isomer 2: 3-[(S)-1-(4-Bromo-phenyl)-ethyl]-(S)-6-methoxymethyl -6-
phenyl-[1,3]oxazinan-2-one. Yield: 45 mg (21 % of theory). Mass spectrum
(ESI+): m/z = 404 [M+H]+ 1H NMR (400 MHz, DMSO-d6) 6 1.20 (d, J = 7.2
Hz, 3H), 2.13-2.23 (m, 1 H), 2.32-2.40 (m, 1 H), 2.63-2.72 (m, 1 H), 2.73-2.81
(m, 1 H), 3.26 (s, 3H), 3.48 (d, B part of an AB signal, J = 10.6 Hz, 1 H),
3.55
(d, A part of an AB signal, J = 10.6 Hz, 1 H), 5.35 (q, J = 7.2 Hz, 1 H), 7.19
(dm, J = 8.4 Hz, 2H), 7.32-7.45 (m, 5H), 7.53 (dm, J = 8.4 Hz, 2H).
PREPARATION 11
N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-
yl)propyl)-N-methylacetamide
0
0-1-N O N\ MsCI O N\ HN- Br
B, Br NaH
N
OH OMs
0
Step 1
To a solution of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-
hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one (200 mg, 0.48 mmol) in CH2CI2
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(5 mL) was added Et3N (240 mg, 2.4 mmol) and methanesulfonyl chloride
(164 mg, 1.4 mmol) at 0 C. The reaction solution was stirred at rt for 1 h.
The reaction was quenched with H2O and the mixture was extracted with
CH2CI2. The organic phase was concentrated to give 3-((R)-3-((S)-1-(4-
bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl
methanesulfonate (234 mg, 98%), which was used for the next step without
further purification.
Step 2
To a solution of 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-
1,3-oxazinan-6-yl)propyl methanesulfonate (234 mg, 0.24 mmol) in CH2CI2
(3 mL) was added NaH (82 mg, 3.4 mmol) at 0 C. The mixture was stirred
at rt for 30 min. Then N-methylacetamide (204 mg, 2.8 mmol) was added
the above mixture. The formed mixture was stirred at 80 C for 5 h. After
the reaction was over, the reaction was quenched with water and the mixture
was extracted with EtOAc. The combined organic phase was concentrated
to give the crude product, which was purified by preparative TLC to give N-
(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-
yl)propyl)-N-methyl acetamide (150 mg, 68%). LC-MS Method 2 tR = 1.50
min, m/z = 497, 495, 475, 473. 'H NMR (400MHz, CDC13): 6=1.41 (m, 1 H),
1.48 (t, 3H), 1.73 (m, 1 H), 1.83-1.95 (m, 2H), 2.01 (m, 3H), 2.1-2.3 (m, 3H),
2.71 (m, 1 H), 2.81 (s, 3H), 3.1 (m, 1 H), 3.2 (m, 1 H), 5.5 (m, 1 H), 6.72
(m,
2H), 7.10 (m, 2H), 7.20 (m, 2H), 7.37 (m, 3H).
(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-(2-oxopyrrolidin-1-yl)propyl)-
6-phenyl-1,3-oxazinan-2-one was prepared from (R)-3-((S)-1-(4-
bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one
following an analogous procedure using pyrrolidin-2-one in Step 2.
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PREPARATION 12
(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(1,-dioxo-isothiazolidin-2-yl)ethyl)-6-
phenyl-1,3-oxazinan-2-one
0 0
O~N 1. 03 O N
2. NaBH4 01
OH
To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-
1,3-oxazinan-2- one (3 g, 7.5 mmol) in CH2CI2 (50 ml-) was treated with 03
at -78 C till the mixture turned blue. Then NaBH4 (285 mg, 75 mmol) was
added to the solution at 0 C, and the reaction solution was stirred at room
temperature for 3 hours. The reaction was quenched by H2O, and the
mixture was extracted with EtOAc. The combined organic phase was
concentrated to give the crude product, which was purified by preparative
TLC to give (S)-3-((S)-1-(4-bromo- phenyl)ethyl)-6-(2-hydroxyethyl)-6-
phenyl-1,3-oxazinan-2-one (2.5 g, 84%). 1H NMR (CDC13): 1.48 (t, 3H),
2.05-2.41 (m, 4H), 2.71-2.92 (m, 2H), 3.51 (m, 1 H), 3.71 (m, 1 H), 5.58 (m,
1 H), 6.73 (d, 2H), 7.12 (m, 2H), 7.23-7.45 (m, 6H).
(S)-3-((S)-1-(4-bromophenyl)propyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-
oxazinan-2-one was prepared from (R)-6-allyl-3-((S)-1-(4-
bromophenyl)propyl)-6-phenyl-1,3-oxazinan-2-one following a procedure
analogous to that described immediately above.
PREPARATION 13
(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(1,1-dioxo-isothiazolidin-2-yl)ethyl)-
6-phenyl-1,3-oxazinan-2-one
0
o
o N
o N I 1. McSO2CI
Br 2. N 0
OH 0 N,S O
Step 1
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To a solution of (S)-3-((S)-1 -(4-bromophenyl)ethyl)-6-(2-
hydroxyethyl)-6-phenyl-1,3- oxazinan-2-one (300 mg, 0.75 mmol) in
dichloromethane (20 mL) were added Et3N (390 mg, 3.75 mmol) and
methanesulfonyl chloride (256 mg, 2.25 mmol) at 0 C. The reaction
solution was stirred at rt for 1 h. The reaction was quenched with H2O and
the mixture was extracted with dichloromethane. The organic phase was
concentrated to give 2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-
1,3-oxazinan-6-yl)ethyl-methane sulfonate (352.8 mg, 98%), which was used
for the next step without further purification.
Step 2
To a solution of 2-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-
1,3-oxazinan- 6-yl)ethyl-methanesulfonate (360 mg, 0.75 mmol) and K2CO3
(207 mg, 1.5 mmol) in acetonitrile (10 mL) was added isothiazolidine 1,1-
dioxide (121 mg, 4.6 mmol), and the mixture was refluxed overnight. The
mixture was filtered and the filtrate was concentrated to give the crude
product, which was purified by preparative HPLC to afford compound (S)-3-
((S)-1-(4-bromophenyl)ethyl)-6-(2-(1,1-dioxo-isothiazolidin-2-yl)ethyl)-6-
phenyl-1,3-oxazinan-2-one (2.43 mg, 1 %). LC-MS Method 2 tR = 1.37 min,
m/z = 509, 507. 1H NMR (CDC13): 1.48 (t, 3H), 2.05-2.41 (m, 7H), 2.71-2.92
(m, 2H), 3.11 (m, 3H), 3.21 (m, 2H), 5.58 (m, 1 H), 6.73 (d, 2H), 7.18 (m, 1
H),
7.23 (m, 3H);7.35 (m, 3H).
(R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-(1,1-dioxo-isothiazolidin-2-
yl)propyl)-6-phenyl-1,3-oxazinan-2-one was prepared from from from (R)-3-
((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-
one following an analogous procedure.
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PREPARATION 14
(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-((1-
hydroxycyclopropyl)methyl)-1,3-oxazinan-2-one
0 0 0
0-1-N KMnOa Q& SOCI2 0&
F I / Br NalOa / ` \ OH Br McOH OOMe Br
F F
0
O"k N
EtMgBr
Ti(i-Pr0)4 Br
OH
Step 1
To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-
fluorophenyl)-1,3 -oxazinan-2-one (450 mg, 1.01 mmol) in acetone (10 ml-)
was added a solution of KMnO4 (190 mg, 1.2 mmol) and Na104 (1.5 g, 7.2
mmol) in water (10 mL). The mixture was stirred for 2 h at 0 C. The
mixture was filtered and the filtrate was adjusted to pH 5-6 with aqueous 1 N
aq HCI solution. The mixture was extracted with EtOAc. The organic phase
washed with brine, dried over anhydrous Na2SO4 and concentrated to give
2-((S)-3-((S)-1-(4-bromophen-yl)ethyl)-6- (4-fluorophenyl)-2-oxo-1,3-
oxazinan-6-yl)acetic acid (540 mg, crude), which was used for the next step
without purification.
Step 2
To a solution of 2-((S)-3-((S)-1-(4-bromophen-yl)ethyl)-6- (4-
fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)acetic acid (540 mg, 1.24 mol) in
MeOH (20 ml-) was added SOC12 (5 ml-) at 0 C, and the reaction mixture
was stirred at rt for 2 h. The reaction mixture was concentrated and the
residue was purified by preparative TLC to give methyl 2-((S)-6-(4-
fluorophenyl)-3-((S)-1-(4-(1-methyl -6-oxo-1,6-dihydropyridin-3-yl)phenyl)-
ethyl)-2-oxo-1,3-oxazinan-6-yl)acetate (150 mg, 27%). 'H NMR (CDC13):
6=1.49 (d, 3H), 2.19 (m, 1 H), 2.44 (m, 1 H), 2.60 (m, 1 H), 2.77-3.08 (m,
3H),
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3.51 (s, 3H), 5.52 (m, 2H), 6.62 (d, 2H), 6.98 (t, 2H), 7.23 (t, 2H), 7.28 (m,
2H).
Step 3
To a solution of methyl 2-((S)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-
6-oxo-1,6-d ihydropyrid in-3-yl)phenyl)-ethyl)-2-oxo-1,3-oxazinan-6-yl)acetate
(150 mg, 0.33 mmol), and tetraisopropoxytitanium (189 mg, 0.66 mmol) in
THE (20 ml-) was added 3.0 M ethylmagnesium bromide (4 mL, 12 mmol) at
rt under nitrogen. Then the mixture was stirred for 2 h. The reaction was
quenched with aqueous NH4CI solution, and the mixture was filtered. The
filtrate was extracted with EtOAc. The combined organic phase was washed
with brine, dried over anhydrous Na2SO4, and concentrated to give the crude
product, which was purified by preparative HPLC to give (S)-3-((S)-1-(4-
bromophenyl)ethyl)-6-(4-fluorophenyl)-6-((1-hydroxycyclopropyl)methyl)-1,3-
oxazinan-2-one (2.51 mg, 2%). 1H NMR (CDCI3): 0.03 (m, 1 H), 0.18 (m,
1 H), 0.49 (m, 1 H), 0.60 (m, 1 H), 1.43 (m, 3H), 2.08 (s, 2H), 2.26 (m, 1 H),
2.37 (m, 2H), 2.88 (m, 1 H), 5.53 (m, 1 H), 6.66 (d, 2H), 6.97 (t, 2H), 7.16
(m,
2H), 7.26 (m, 2H).
PREPARATION 15
N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-
yl)propyl)-N-methylmethanesulfonamide
O 0
O1~1 N Mel O N
Br Br
NaH
NH N
i
OOS" OOS~
To a solution of 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-
1,3- oxazinan-6-yl) propyl methanesulfonate (180 mg, 0.36 mmol) in DMF (5
ml-) was added NaH (14.6 mg, 0.36 mmol) at 0 C. The mixture was stirred
at rt for 30 min. Then iodomethane (153 mg, 1.1 mmol) was added to the
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above mixture. The formed mixture was stirred at 40 C for 3 h. After the
reaction was over, the reaction was quenched with NH4CI solution and the
mixture was extracted with EtOAc. The combined organic phase was
concentrated to give the crude product, which was purified by preparative
TLC to give N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-
oxazinan-6- yl)propyl)-N-methylmethanesulfonamide (100 mg, 55%).
LC-MS Method 2 tR = 1.41 min, m/z = 511, 509. 1H NMR (400MHz, CDC13):
6=1.45 (m, 1 H), 1.48 (t, 3H), 1.83-1.97 (m, 3H), 2.1-2.2 (m, 3H), 2.61 (s,
3H),
2.71 (s, 3H), 2.91 (m, 1 H), 3.0 (m, 2H), 5.5 (m, 1 H), 6.72 (m, 2H), 7.10 (m,
2H), 7.20 (m, 2H), 7.37 (m, 3H).
EXAMPLE 1
(S)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-
yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
o O
O~N I Olj~ N
Br NH
OH OH O
To a solution of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-
methylpropyl)-6-phenyl-1,3-oxazinan-2-one (112 mg, 0.259 mmol) in 1,4-
dioxane (3 mL) was added 6-oxo-1,6-dihydropyridin-3-ylboron ic acid (55 mg,
0.40 mmol), followed by Pd(dppf)C12 (11 mg, 0.015 mmol), and an aq
solution of Cs2CO3 (0.48 mL, 2M in H20). A reflux condenser was attached
and the apparatus was degassed and flushed with N2 three times. The
reaction was heated to 90 C for 24 h. After cooling to rt the mixture was
diluted with water and extracted three times with EtOAc. The organic layers
were washed with brine, dried over Na2SO4, filtered and concentrated. The
residue was purified by prep HPLC to afford the title compounds (21.6 mg)
as an oil. LC-MS Method 1 tR = 1.25 min, m/z = 447, 389; 1H NMR (CD3OD)
0.96 (s, 3H), 1.28 (s, 3H), 1.57 (d, 3H), 2.16 (s, 2H), 2.21 (m, 1 H), 2.46
(m,
2H), 3.03 (m, 1 H), 5.57 (q, 1 H), 6.66 (d, 1 H), 7.02 (d, 2H), 7.25-7.40
(7H),
7.66 (s, 1 H), 7.90 (d, 1 H).
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EXAMPLE 2
(S)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(2-oxo-1,2-dihydropyridin-4-
yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
O
OA N
/ I NH
OH O
The title compound was prepared from (S)-6-(2-hydroxy-2-
methylpropyl)- 6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborol-an-
2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-iodopyridin-2(1 H)-one following
a procedure analogous to that described in Example 1. LC-MS Method 1 tR =
1.23 min, m/z = 389, 447 (M+1); 1H NMR (CD3OD) 7.40 (d, J = 6.7 Hz, 1 H),
7.31 (d, J = 8.2 Hz, 2H), 7.29-7.20 (m, 5H), 6.96 (d, J = 8.2 Hz, 2H), 6.57-
6.52 (m, 2H), 5.49 (q, J = 7.0 Hz, 1 H), 2.98-2.93 (m, 1 H), 2.47-2.34 (m,
2H),
2.16-2.09 (m, 1 H), 2.07 (s, 2H), 1.45 (d, J = 7.0 Hz, 3H), 1.19 (s, 3H), 0.87
(s, 3H).
EXAMPLE 3
(S)-3-((S)-1-(4-(1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-
(2-hydroxy-2-methyl propyl)-6-phenyl-1,3-oxazinan-2-one
Br >-B(OH)2, Cu(OAc)2, BiPy Br
Na2CO3, air, dichloroethane, 70 C
N O
H O 58%
O
PdCl2(dppf) O
O11N Cs2CO3, Dioxane ''
74% O N
\ ` / I \ E / BOO
N O O
OH OH
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Step 1. 5-bromo-1-cyclopropylpyridin-2(1 H)-one
A mixture of 5-bromo-2-hydroxypyridine (0.8300 g, 4.77 mmol, 1.0
equiv), Cu(OAc)2 (0.902 g, 4.96 mmol, 1.04 equiv), bipyridine (0.785 g, 5.03
mmol, 1.05 equiv), cyclopropylboronic acid (0.846 g, 9.85 mmol, 2.06 equiv)
and Na2CO3 (1.110 g, 10.47 mmol, 2.20 equiv) in dichloroethane (30 mL)
was stirred at 70 C for 22 h under air. The reaction mixture was quenched
with satd aq NH4CI, diluted with CH2CI2, dried over Na2SO4. After the
solvent was removed under reduced pressure, the residue was purified by
chromatography on silica gel eluted with hexanes/EtOAc to afford 0.585 g
(58%) of 5-bromo-1-cyclopropylpyridin-2(1 H)-one. LC-MS Method 1 tR =
1.05 min, m/z 214, 216 (MH+); 1H NMR (400 MHz, CDC13) 6 7.41 (d, J = 2.7
Hz, 1 H), 7.31 (dd, J = 9.7, 2.9 Hz, 1 H), 6.47 (d, J = 9.9 Hz, 1 H), 3.33-
3.27
(m, 1 H), 1.17-1.12 (m, 2H), 0.89-0.84 (m, 2H); 13C NMR (100 MHz, CDC13) 6
162.58, 142.29, 137.00, 121.77, 97.92, 32.83, 6.93.
Step 2. (S)-3-((S)-1-(4-(1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-
yl)phenyl)ethyl)-6-(2-hydroxy-2-methyl propyl)-6-phenyl-1,3-oxazinan-2-one
To a solution of (S)-6-(2-hydroxy-2-methyl propyl)-6-phenyl-3-((S)-1-
(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-
one (0.729 g, 1.52 mmol) in 1,4-dioxane (16 mL) were added 5-bromo-1-
cyclopropylpyridin-2(1 H)-one (0.323 g, 1.51 mmol), 2 M aq Cs2CO3 (4 mL),
and PdC12(dppf).CH2CI2 (0.079 g, 0.0964 mmol). The mixture was degassed
and heated, under a nitrogen atmosphere, at 120 C for 16 h. The mixture
was diluted with CH2CI2, dried over Na2SO4. After the solvents were
evaporated, the residue was purified by chromatography on silica gel eluted
with MeOH/CH2CI2 to afford 0.543 g (74%) of (S)-3-((S)-1-(4-(1-cyclopropyl-
6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methyl propyl)-6-
phenyl-1,3-oxazinan-2-one. LC-MS Method 1 tR = 1.41 min, m/z 487 (MH+);
1H NMR (400 MHz, CD3OD) 6 7.66-7.64 (m, 2H), 7.30-7.19 (m, 7H), 6.94 (d,
J = 8.2 Hz, 2H), 6.52 (d, J = 10 Hz, 1 H), 5.48 (q, J = 7.0 Hz, 1 H), 3.32-
3.26
(m, 1 H), 2.97-2.92 (m, 1 H), 2.46-2.32 (m, 2H), 2.16-2.09 (m, 1 H), 2.08 (s,
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2H), 1.45 (d, J= 7.0 Hz, 3H), 1.19 (s, 3H), 1.10-1.05 (m, 2H), 0.90-0.86 (m,
5H); 13C NMR (100 MHz, CD3OD) 6 165.59, 155.82, 144.08, 141.05, 139.60,
136.60, 136.30, 129.77, 128.86, 128.64, 126.83, 126.15, 121.93, 120.53,
85.33, 71.67, 55.18, 54.78, 37.46, 34.10, 33.04, 31.79, 30.00, 15.60, 7.49,
7.47.
EXAMPLE 4
(S)-3-((S)-1-(4-(1-(difluoromethyl)-6-oxo-1,6-dihydropyridin-3-
yl)phenyl)ethyl)-6-(2-hydroxy-2-methyl propyl)-6-phenyl-1,3-oxazinan-2-one
o
Br PdC12(dppf) ON
\
O~N Cs2CO3
B H2o
O F~F dioxane Ohi N O
OH
F /1 F
A microwave vial equipped with a flea stirbar was charged with (S)-6-
(2-hydroxy-2-methyl propyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-
dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (20 mg, 0.047 mmol), 5-
bromo-1-(difluoromethyl)pyridin-2(1H)-one (25 mg, 0.113 mmol), Cs2CO3 (27
mg, 0.083 mmol), H2O (0.1 mL) and dry dioxane (1 mL). The mixture was
sparged with N2 for 10 min and heated at 110 C in the microwave for 0.5 h.
The mixture was diluted with glacial HOAc (0.1 mL) and MeOH (0.5 mL) and
filtered. The filtrate was directly purified by prep HPLC to afford (S)-3-((S)-
1-
(4-(1-(difluoromethyl)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(2-
hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (11.8 mg, 57%) as an
oil. LC-MS Method 1 tR = 1.55 min, m/z = 497, 248; 1H NMR (CDCI3) 1.13
(s, 3H), 1.19 (s, 3H), 1.56 (d, 3H), 2.15-2.35 (s, 4H), 2.42 (m, 2H), 2.88 (m,
1 H), 5.71 (q, 1 H), 6.64 (d, 1 H), 7.04 (d, 2H), 7.18 (d, 2H), 7.30-7.40
(5H),
7.52 (1 H), 7.60 (m, 1 H), 7.75 (t, 1 H).
5-bromo-1-(difluoromethyl)pyridin-2(1 H)-one was prepared as
described in Ando, M.; Wada, T.; Sato, N. Org. Lett. 2006, 8, 3805-3808.
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EXAMPLE 5
(S)-3-((S)-1-(4-(1-(difluoromethyl)-2-oxo-1,2-dihydropyridin-4-
yl)phenyl)ethyl)-6-(2-hydroxy-2-methyl propyl)-6-phenyl-1,3-oxazinan-2-one
HO2CCF2SO2F I
y N N~F
CI MeCN 0 F
\
NyF
O 0 N \ O F O N I\
/
\ "-( , I / g~0 PdCl2(dppfl \ \10
O Cs2CO3 O N F
OH H2O, dioxane OH O F
Step 1
A stirred mixture of 2-chloro-4-iodopyridine (1.33 g, 5.6 mmol) and
powdered NaHCO3 (935 mg, 11.2 mmol) in MeCN (2 mL) was warmed to 40
C in an oil bath and a solution of 2,2-difluoro-2-(fluorosulfonyl)acetic acid
(0.57 mL, 5.6 mmol) in MeCN (10 mL) was added dropwise over 10 min.
The mixture was stirred at 40 C for 2 h. LC-MS showed partial conversion
to desired product. Powdered NaHCO3 (935 mg, 11.2 mmol) was added
followed by a solution of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (0.57 mL,
5.6 mmol) in MeCN (10 mL) dropwise over 10 min. The mixture was stirred
at 40 C for 2 h. The mixture was diluted with satd aq NaHCO3 (25 mL) and
concentrated under reduced pressure. The aqueous residue was extracted
with EtOAc (90 mL). The organic extract was washed with brine (20 mL),
dried over Na2SO4 and concentrated to afforded an amber oil (1.14 g).
Chromatography on a 40-g silica gel cartridge, eluted with a 0-40% EtOAc in
hexanes gradient, afforded 1 -(difluoromethyl)-4-iodopyridin-2(1 H)-one (255
mg, yield 16%, estimated purity 45%) as yellow oil. LC-MS Method 1 tR =
1.23 min, m/z = 272. The material was used without further purification.
Step 2
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A microwave vial equipped with a flea stir bar was charged with (S)-6-
(2-hydroxy-2-methyl propyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-
dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (52 mg, 0.11 mmol), 1-
(difluoromethyl)-4-iodopyridin-2(1 H)-one (29 mg, 0.11 mmol), Cs2CO3 (71
mg, 0.22 mmol), H2O (0.1 mL) and dry dioxane (1 mL). The mixture was
sparged with N2 for 5 min and PdC12(dppf) (5 mg, 0.007 mmol) was added.
The mixture was sparged with N2 for 5 min and heated at 110 C in the
microwave for 1 h. The mixture was diluted with 5% aq HCI (0.2 mL) and
MeOH (2 mL) and filtered. The filtrate was directly purified by prep HPLC to
afford a brown oil (16.2 mg) which was applied to a 2-g silica SPE cartridge
which was eluted sequentially with 25 and 50% EtOAc in hexanes (15 mL of
each) and EtOAc (3 x 15 mL) to afford five fractions. Fractions 3 and 4 were
pooled and concentrated to afford (S)-3-((S)-1-(4-(1-(difluoromethyl)-2-oxo-
1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methyl propyl)-6-phenyl-
1,3-oxazinan-2-one (13.4 mg, 25%) as a colorless oil. LC-MS Method 1 tR =
1.57 min, m/z = 497, 439; 1H NMR (CD3OD) 0.96 (s, 3H), 1.27 (s, 3H), 1.56
(d, 3H), 2.15 (s, 2H), 2.21 (m, 1 H), 2.40-2.60 (2H), 3.08 (m, 1 H), 5.59 (q,
1 H),6.66 (s, 1 H), 6.74 (d, 1 H), 7.07 (d, 2H), 7.30-7.40 (5H), 7.45 (d, 2H),
7.77 (1 H), 7.79 (t, 1 H).
EXAMPLE 6
2,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl -6-oxo-1,6-dihydropyridin-3-
yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide
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O Brn O
O N I I O N
Pd PPh CI
O ~ 3~2 2,
CN Dioxane, 2M Cs2CO3 CN N O
85 C
O
MeCONH2 ON
PdCl2
CONH2 N O
Step 1
A mixture of 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-
tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-
yl)propanenitrile (392 mg, 0.775 mmol), 5-bromo-1-methylpyridin-2(1H)-one
(220 mg, 1.5 equiv), 2M aq Cs2CO3 solution (900 pL), Pd(PPh3)2CI2 (40 mg,
7 mol%) and anhydrous 1,4-dioxane (8.5 mL) was degassed and refilled with
N2 gas 3 times. The mixture was then heated overnight at 85 C under
protection of N2 gas. After being cooled to rt, the mixture was diluted with
EtOAc (20 mL), washed by water (20 mL). The aqueous layer was extracted
with EtOAc (2 x 10 mL). The combined organic layers were washed by
water (10 mL), brine (2 x 10 mL) and dried over Na2SO4. After filtration and
concentration, the residue was purified by Gilson to afford 34mg product (9%
yield). LC-MS (3min. method) tR = 1.44min., m/z 470 (M+1). 1H NMR
(CDC13) 6 7.68(dd, 1 H), 7.52(d, 1 H), 7.31(q, 2H), 7.16(d, 2H), 7.07(t, 2H),
6.97(d, 2H), 6.91(d, 1 H), 5.66(q, 1 H), 3.71(s, 3H), 2.99(dt, 1 H), 2.47(dd,
2H),
2.27(m, 1 H), 2.13(s, 2H), 1.55(d, 3H), 1.44(s, 3H), 1.24(s, 3H).
Step 2
A THF:H20 (2mL, 3:1) solution of 2,2-dim ethyl -3-((R)-3-((S)-1-(4-(1-
methyl -6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-
oxazinan-6-yl)propanenitrile (55 mg, 0.12 mmol), acetamide (177 mg, 3
mmol) and PdC12 (21 mg, 0.12 mmol) was stirred overnight. The solvent
was removed and the crude material redissolved in CH3CN. The crude
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product was purified via prep HPLC to afford 2,2-dimethyl -3-((R)-3-((S)-1-(4-
(1-methyl -6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-
oxazinan-6-yl)propanamide (28 mg). LC-MS Method 1 tR = 1.25 min, m/z =
488 (M+1); 1H NMR (CDC13) 7.55 (dd, 1 H, J = 9Hz, 3Hz), 7.42 (d, 1 H, J =
3Hz), 7.32 (d, 1 H, J = 4 Hz), 7.29 (m, 4H), 7.14 (d, 2H, 8Hz), 7.00 (d, 2H, J
=
8Hz), 6.79 (d, 1 H, J = 9 Hz), 5.66 (q, 1 H, J = 8Hz), 3.62 (s, 3H), 2.95-2.89
(m, 1 H), 2.5 (d, 1 H, J = 15 Hz), 2.26-2.1 (m, 3H), 2.2 (d, 1 H, J = 15 Hz),
2.5
(d,1H,J=15Hz),2.26-2.10(m,3H),2.2(d,1H,J=15Hz),1.53(d,3H,J=
7Hz), 1.22 (s, 3H), 1.20 (s, 3H)
EXAMPLE 7
(S)-6-(2-amino-2-methyl propyl)-3-((S)-1-(4-(1-methyl -6-oxo-1,6-
dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
0
OAN
O
NH2 1 O
A foil covered flask charged with 2,2-dimethyl -3-((R)-3-((S)-1-(4-(1-
methyl -6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-
oxazinan-6-yl)propanamide (20 mg, 0.04 mmol) in 1:1 CH3CN/H2O (1 mL)
was treated with Phl(O2CCF3)2 (31 mg, 0.07 mmol). The reaction was
complete after 24 h. The solvent was removed and the crude material
purified by prep HPLC to afford (S)-6-(2-amino-2-methyl propyl)-3-((S)-1-(4-
(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-
2-one (16 mg). LC/MS ES+ = 460 (M+1). LC-MS Method 1 tR = 1.06 min,
m/z = 460 (M+1); 1H NMR (CDC13) 7.60 (dd, 1 H, J = 9Hz, 2Hz), 7.46 (d, 1 H,
J = 3Hz), 7.39-7.27 (m, 5H), 7.20 (d, 2H, J = 7 Hz), 7.1 (d, 2H, J =8 Hz),
6.78
(d, 1 H, J = 9Hz, 5.61 (q, 1 H, J = 7Hz), 3.65 (s, 3H), 2.87 (m, 1 H), 2.80
(d,
1 H, J = 16Hz), 2.23 (d, 1 H, J = 16 Hz), 2.19-2.08 (m, 3H), 1.54 (d, 3H, J =
7Hz), 1.41 (s, 3H), 0.96 (s, 3H).
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EXAMPLE 8
N-(2-methyl-1-((S)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-
yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propan-2-yl)acetamide
0
OAN I \
O
HN TO ~ O
A CH2CI2 (1 mL) solution of (S)-6-(2-amino-2-methyl propyl)-3-((S)-1-
(4-(1-methyl -6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-
oxazinan-2-one (5 mg, 0.009 mmol) was treated with DMAP (5mg, 0.04
mmol), i-Pr2NEt (10 drops), and acetic anhydride (20 drops). The reaction
was stirred overnight. The reaction solution was washed with water. The
organic layer was evaporated and the crude material purified by prep HPLC
affording N-(2-methyl-1-((S)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-
3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propan-2-yl)acetamide
(0.88 mg). LC-MS Method 1 tR = 1.3 min, m/z = 502 (M+1).
EXAMPLE 9
Methyl 2-methyl-1-((S)-3-((S)-1-(4-(1-methyl-6-oxo-l,6-dihydropyridin-3-
yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propan-2-ylcarbamate
0
OA N I \
O
HN'~f O N O
O\
A CH2CI2 (1 mL) solution of (S)-6-(2-amino-2-methyl propyl)-3-((S)-1-
(4-(1-methyl -6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-
oxazinan-2-one (5 mg, 0.009 mmol) was treated with DMAP (5mg, 0.04
mmol), i-Pr2NEt (10 drops), and methyl chloroformate (20 drops). The
reaction was stirred overnight. The reaction solution was by prep HPLC
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affording methyl 2-methyl-1-((S)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-
dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propan-2-
ylcarbamate (2.58 mg). LC-MS Method 1 tR = 1.45 min, m/z = 518 (M+1); 1H
NMR (CDC13) 7.66 (dd, 1 H, J = 9Hz, 2Hz), 7.48 (d, 1 H, J = 3Hz), 7.35-7.27
(m, 5H), 7.15 (d, 2H, J =8 Hz), 7.01 (d, 2H, J = 8 Hz), 6.87 (d, 1 H, J =
9Hz),
5.67 (q, 1 H, J = 7 Hz), 3.69 (s, 3H), 2.2 (s, 3H), 1.54 (d, 3H, J = 7 Hz),
1.46-
1.36 (m, 2H), 1.30 (s, 3H), 1.20 (s, 3H).
EXAMPLE 10
N-(2-methyl-1-((S)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-
yl)phenyl)ethyl)-6-phenyl-l ,3-oxazinan-6-yl)propan-2-yl)methanesulfonamide
0
0A N
O
HN,S~ H O
X10
The title compound was prepared from N-(1-((S)-3-((S)-1-(4-
bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2-methyl propan-2-
yl)methanesulfonamide and 2-oxo-l,2-dihydropyridin-5-ylboron ic acid
following a procedure analogous to that described in Example 4. LC-MS
Method 1 tR = 1.3 min, m/z = 524 (M+1); 1H NMR (CDC13) 7.81 (d, 1 H, J =
9Hz), 7.63 (br s, 1 H), 7.39-7.31 (m, 5H), 7.18 (d, 2H, J = 8Hz), 7.03 (d, 2H,
J
=7 Hz), 6.79 (d, 1 H, J =9 Hz), 5.67 (q, 1 H, J = 6Hz), 2.93 (s, 3H), 2.90 (m,
1 H), 2.49 (d, 1 H, J =15 Hz), 2.32 (d, 1 H, J =15 Hz), 2.28-2.18 (m, 3H),
1.54
(d, 3H, J = 7Hz), 1.36 (s, 3H), 1.25 (s, 3H).
N-(1-((S)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-
oxazinan-6-yl)-2-methyl propan-2-yl)methanesulfonamide was prepared from
3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-
dimethylpropanenitrile by sequential application of procedures analogous to
those described in Examples 6 Step 2, Example 7 and Example 11.
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EXAMPLE 11
N-(2-methyl-1-((S)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-
yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propan-2-
yl)methanesulfonamide
O
OA N I \
O
HNO O
-S~
/"O
A CH2CI2 (1 mL) solution of (S)-6-(2-amino-2-methyl propyl)-3-((S)-1-
(4-(1-methyl -6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-
oxazinan-2-one (5 mg, 0.009 mmol) was treated with DMAP (5mg, 0.04
mmol), i-Pr2NEt (10 drops), and MsCI (20 drops). The reaction was stirred
overnight. The reaction solution was washed with water. The organic layer
was evaporated and the crude material purified by prep HPLC affording N-
(2-methyl-1 -((S)-3-((S)-l-(4-(1-methyl-6-oxo-l ,6-dihydropyridin-3-
yl)phenyl)ethyl)-2-oxo-6-phenyl-l ,3-oxazinan-6-yl)propan-2-
yl)methanesulfonamide (3.30 mg). LC-MS Method 1 tR = 1.39 min, m/z =
538 (M+1); 1H NMR (CDC13) 7.61 (dd, 1 H, J = 9Hz, 3Hz), 7.46 (d, 1 H, J =
2Hz), 7.40-7.27 (m, 5H), 7.17 (d, 2H, J = 8Hz), 7.04 (d, 2H, J = 8Hz), 6.79
(d, 1 H, J = 9Hz), 5.67 (q, 1 H, J = 7 Hz), 3.66 (s, 3H), 2.93 (s, 3H), 2.31-
2.22
(m, 2H), 1.55 (d, 3H, J = 7Hz), 1.48-1.36 (m, 2H), 1.33 (s, 3H), 1.24 (s, 3H).
EXAMPLE 12
N-methyl-N-(2-methyl-1 -((S)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-
3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propan-2-
yl)methanesulfonamide
O
OA N
0
c".0
/N`S 1O
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To a rt solution of N-(2-methyl-1-((S)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-
dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-6-yl)propan-2-
yl)methanesulfonamide (7 mg, 0.013 mmol) in THF, NaH (10 mg, 0.20
mmol) was added followed by methyl iodide (30 uL, 0.080 mmol). The
reaction was heated to 60 C for 5 h. The flask was cooled to rt then to 0 C
before quenching with satd aq NH4CI. The mixture was extracted with
EtOAc (3x) and the combined organic layers were dried over Na2SO4,
filtered, evaporated and purified by prep HPLC to afford N-methyl-N-(2-
methyl-1 -((S)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-
yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propan-2-
yl)methanesulfonamide (4.63 mg). LC-MS Method 1 tR = 1.45 min, m/z =
552 (M+1); 1H NMR (CDC13) 7.55 (dd, 1 H, J = 9Hz, 3Hz), 7.41 (d, 1 H, J = 3
Hz), 7.35 -7.27 (m, 5H), 7.13 (d, 2H, J = 8Hz), 6.98 (d, 2H, J = 8Hz), 6.79
(d, 1 H, J =9 Hz), 6.55 (q, 1 H, J = 7Hz), 3.62 (s, 3H), 2.91-2.86 (m, 1 H),
2.86
(s, 3H), 2.73 (d, 1 H, J = 15 Hz), 2.74 (s, 3H), 2.46 (d, 1 H, J = 15Hz), 2.39
-
2.36 (m, 2H), 2.25-21.6 (m, 1 H), 1.53 (d, 3H, J = 7 Hz), 1.53 (s, 3H), 1.22
(s,
3H).
EXAMPLE 13
N-(2-methyl-1 -((S)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-
yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propan-2-
yl)methanesulfonamide
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0
I
0
O~N \ p N \
ON Acetamide, PdCl2 / Phl(OC2CCF Br
/
3)2 a(-
CN Br Br
McCN, H2O O NHZ NH2
O
O O O
McSO2Cl 0B B QOAN ""P õ .. / B
Et 0
3N Pd(dppf)C12, KOAc H
N O
HN.S02Me \S02Me
O
/ 0N
H
N\ N~
S02Me
Pd(Phh3)CI, Cs2CO3 0
Step 1
To a solution of 3-(R-3-S-1 -(4-bromophenyl)-ethyl)-2-oxo-6-phenyl-
1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile (1 g, 2.27 mmol) in a mixture of
THF/H20 (3:1, 10 mL) was added acetamide (3.35 g, 56.75 mmol) and
PdCI2 (0.402 g, 2.27 mmol). The reaction was stirred overnight. The solvent
was removed, and the residue was purified by TLC to afford 3-(R-3-S-1-(4-
bromophenyl)-ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-
dimethylpropanamide (0.745 g, 71.6%).
Step 2
To a solution of 3-(R-3-S-1 -(4-bromophenyl)-ethyl)-2-oxo-6-phenyl-
1,3-oxazinan-6-yl)-2,2-dimethylpropanamide (0.74 g, 1.612 mmol) in a
mixture of CH3CN/H20 (20 mL, 1:1) was added Phl(OC2CCF3)2 (1.178 g,
2.74 mmol). The mixture reaction was stirred overnight. The mixture was
extracted with EtOAc (30 mL). The organic layer was washed with brine,
and concentrated to afford S-6-(2-amino-2-methyl propyl)-3-S-1-(4-
bromophenyl)-ethyl)-6-phenyl-1,3-oxazinan-2-one (0.6 g, 87%).
Step 3
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To a solution of S-6-(2-amino-2-methyl propyl)-3-S-1-(4-bromophenyl)-
ethyl)-6-phenyl-1,3-oxazinan-2-one (0.6 g, 1.39 mmol) in CH2CI2 (10 mL)
was added Et3N (0.84 g, 8.34 mmol). The mixture was cooled at 0 C, MsCI
(0.48 g, 4.17 mmol) was added. The reaction was stirred at rt for 1 h. The
mixture was evaporated to afford the crude product. The residue was
purified by column to afford N-1 -S-3-S-1 -(4-bromophenyl)-ethyl)-2-oxo-6-
phenyl-1,3-oxazinan-6-yl)-2-methylpropan-2-yl)-methyl-sulfonamide (0.5 g,
70.4%).
1o Step 4
To a solution of N-1-S-3-S-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-
1,3-oxazinan-6-yl)-2-m ethylpropan-2-yl)-methyl-sulfonamide (0.5 g, 0.98
mmol) and 4,4,4',4',5,5,5',5'- octamethyl- 2,2'-bi-(1,3,2- dioxaborolane)
(0.399 g, 1.57 mmol) in dry DMSO (15 mL) was added KOAc (0.31 g, 3.14
mmol) and Pd(dppf)C12 (0.025 g, 0.03 mmol) under N2 atmosphere. After
addition, the mixture was stirred at 90 C overnight. After TLC showed the
starting material had disappeared, the solid was filtered off. Water (30 mL)
and EtOAc (50 mL) was added, the mixture was extracted with EtOAc (3 x
30 mL). The combined organic layer was washed with brine (50 mL), dried
over Na2SO4, filtered, and concentrated to dryness. The residue was
purified by column chromatography to afford N-(2-methyl-1 -S-2-oxo-6-
phenyl-3-S-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-
1,3-oxazinan-6-yl)propan-2-yl)-methyl-sulfonamide (0.2 g, yield: 37%).
Step 5
To a solution of N-(2-methyl-l-S-2-oxo-6-phenyl-3-S-1-4-4,4,5,5-
tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propan-
2-yl)-methyl sulfonamide (150 mg, 0.27 mmol) and 4-iodo-1 -methylpyridin-
2(1 H)-one in dry 1,4-dioxane (5 mL) was added Cs2CO3 (0.3 mL, 6 mmol)
3o and Pd(PPh3)C12 (20 mg). After addition, the mixture was warmed at 110 C
for 2 min. After TLC showed the starting material had disappeared, the solid
was filtered off. Water (20 mL) and EtOAc (30 mL) were added. The
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organic layer was separated, and the aqueous layer was extracted with
EtOAc (3 x 30 mL). The combined organic layer was washed with brine,
dried over Na2SO4, filtered, and concentrated to give the crude product,
which was purified by preparative HPLC to provide N-2-methyl-1-S-3-S-1-4-
(1-methyl -2-oxo-1,2-dihydropyridin-4-yl)-phenyl)-ethyl)-2-oxo-6-phenyl-1,3-
oxazinan-6-yl) propan-2- yl) methyl sulfonamide (20 mg, 14%). LC-MS
Method 2 tR = 1.154 min, m/z = 538.1; 1H NMR (CDCI3): 51.25 (s, 3H), 1.32
(s, 3H), 1.55 (d, 3H), 2.50 (d, 2H), 2.91 (s, 3H), 3.63 (s, 3H), 4.54 (b, 1
H),
5.67 (m, 1 H), 6.53 (d, 1 H), 6.92 (s, 1 H), 7.06 (d, 2H), 7.30-7.50 (m, 8H).
EXAMPLE 14
2,2-d imethyl -3-((R)-2-oxo-3-((S)-1-(4-(2-oxo-1,2-dihydropyridin-4-
yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-6-yl)propanenitrile
O
OAN
NH
N
O
The title compound was prepared from 2,2-dimethyl-3-((R)-2-oxo-6-
phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-
1,3-oxazinan-6-yl)propanenitrile and 4-iodopyridin-2(1 H)-one following a
procedure analogous to that described in Example 4. LC-MS Method 1 tR =
1.36 min, m/z = 456(M+1); 1H NMR (CDC13) 7.77(d, 1 H), 7.43-7.32(m, 7H),
7.01(t, 4H), 5.67(q, 1 H), 2.99(dd, 1 H), 2.57-2.43(m, 2H), 2.32(m, 1 H),
2.17(s,
2H), 1.57(d, 3H), 1.40(s, 3H), 1.33(s, 3H).
EXAMPLE 15
3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1 -(4-(6-oxo-1,6-dihydropyridin-3-
yl)phenyl)ethyl)-1,3-oxazinan-6-yl)-2,2-dimethyl propanenitrile
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O
OA N
F N H O
The title compound was prepared from 3-((R)-3-((S)-1-(4-
bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)-2,2-
dimethylpropanenitrile and 2-oxo-1,2-dihydropyridin-5-ylboron ic acid
following a procedure analogous to that described in Example 4. LC-MS
Method 1 tR = 1.37 min, m/z = 474(M+1); 1H NMR (CDC13) 7.97, (dd, 1 H),
7.73(s, 1 H), 7.33(m, 2H), 7.20(d, 2H), 7.17(t, 2H), 6.98(m, 3H), 5.67(q, 1
H),
3.00(dt, 1 H), 2.49(m, 2H), 2.30(m, 1 H), 2.13(s, 2H), 1.55(d, 3H), 1.45(s,
3H),
1.34(s, 3H).
EXAMPLE 16
3-((R)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-
yl)phenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile
O O
O)~ N \ N~ O~N
B _0 \ _~F
/ 0 F / N
F CN
CN 0
A mixture of 3-((R)-6-(4-fluorophenyl)-2-oxo-3-((S)-1-(4-(4,4,5,5-
tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)-2,2-
dimethylpropanenitrile (100mg, 0.21 mmol) and 4-iodo-1-methyl-1 H-pyridin-
2-one (40 mg, 0.17 mmol), Pd(PPh3)2C12 (20 mg), and aq. Cs2CO3 solution
(2.0 mL, 2M) in 1,4-dioxane (5 mL) was stirred at reflux for 2 h. The organic
phase was separated and concentrated to give the crude product, which was
purified by preparative TLC to give 3-((R)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-
methyl -2-oxo-l ,2-d ihydropyrid in-4-yl)phenyl)ethyl)-2-oxo-l ,3-oxazinan-6-
yl)-
2,2-dimethylpropanenitrile (55 mg, 66%). LC-MS Method 2 tR = 1.096 min,
m/z = 488.3; 1H NMR (CDC13): 5 1.27 (s, 3H), 1.40 (s, 3H), 1.48 (d, 3H),
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2.06 (s, 2H), 2.23 (m, 1 H), 2.41 (m, 2H), 2.90 (m, 1 H), 3.51 (s, 3H), 5.60
(m,
1 H), 6.27 (m, 1 H), 6.65 (d, 1 H), 6.89 (d, 2H), 6.99 (t, 2H), 7.26 (m, 5H).
EXAMPLE 17
6-(2-hydroxy-2-methylpropyl)-6-isopropyl-3-((S)-1-(4-(1-methyl-2-oxo-1,2-
dihydropyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one
OH
O 0 C r-\ 0 MsCI, Et3N
OH p-TsOH O O LiAIHZ 0 0 0 0
OMe Toluene, reflux OMe THE OH CHZCIZ IY v OMs
H2N r-\ O
I-OBr O O HCI Cl Mg
K2CO3, reflux CH3OH THE
Br Br
0 O
OH
triphosgene ON O1~1 N \
Br = Br
CH2CI2
Br
Y
0
ON \ m-CPBA O~N \ super-hydride ON
Br
Br CHZCIZ / Br
O OH
BrO \ O
pN
~O B-B O 0 0 N O N,,
0 ~_
B' 0 - i~
Pd(dppf)CI2 , -:?5 Pd(PPh3)2CI2, Cs2CO3 ~\ N
KOAc OH 0 OH 0
Step 1
To a solution of methyl 4-methyl-3-oxopentanoate (72 g, 0.5 mol), and
ethylene glycol (56 g, 1 mol) in toluene (500 mL) was added 4-
m ethylbenzenesulfonic acid (1.9 g, 0.01 mol). The mixture was stirred at
reflux with a Dean-Stark trap to remove water. The reaction mixture was
washed with a small amount of water and brine, dried over anhydrous
Na2SO4, and concentrated in vacuum to give the crude methyl 2-(2-
isopropyl-1,3-dioxolan-2-yl)-acetate (67 g 71 % yield), which was used for the
next step without further purification.
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Step 2
In a flame-dried three neck flask equipped with an addition funnel,
magnetic stirring bar, rubber septum, and a nitrogen inlet, was placed LiAIH4
(3.12 g, 82.1 mmol) and THE (700 mL). After being cooled at 0 C, a
solution of methyl 2-(2-isopropyl-1,3-dioxolan-2-yl) acetate (12 g, 63.8 mmol)
in THE (160 mL) was added dropwise with stirring. The mixture was warmed
to rt, and stirred for 24 hours. The reaction was quenched by adding water
(5 mL), 15% aqueous NaOH (10 mL), and water (5 mL) slowly. The organic
layer was separated, and the residue was extracted with EtOAc (3x100 mL).
The combined organic phase was dried over Na2SO4, and concentrated to
afford the crude product, which was purified by column chromatography to
give 2-(2-isopropyl-1,3-dioxolan-2-yl)-ethanol (6.8 g, 67%). 1H NMR (CDC13):
5 0.90 (d, J = 6.8 Hz, 6H), 1.87-1.96 (m, 3H), 2.81 (br, 1 H), 3.69-3.72 (m,
2H), 3.92-4.01 (m, 4H).
Step 3
To a solution of 2-(2-isopropyl-1,3-dioxolan-2-yl)-ethanol (8.0 g, 50
mmol) and triethylamine (23.5 mL, 170 mmol) in anhydrous CH2C12 (120 mL)
was added methanesulfonyl chloride (11.6 mL, 150 mmol) at 0 C, and the
reaction mixture was stirred at rt till the reaction was finished. The
reaction
mixture was washed with water and brine, dried over Na2SO4, filtered, and
concentrated to give the crude 2-(2-isopropyl-1,3-dioxolan-2-yl)ethyl
methanesulfonate (12 g, crude), which was used for the next step without
further purification.
Step 4
To a solution of 2-(2-isopropyl-1,3-dioxolan-2-yl)ethyl
methanesulfonate (12 g, 50 mmol) and (S)-1-(4-methoxyphenyl)-ethyl amine
(19.9 g, 100 mmol) in CH3CN (250 mL) was added K2CO3 (8 g, 58 mmol),
and the mixture was refluxed for 10 h. The solution was filtered, and the
filtrate was concentrated to afford the crude product, which was purified by
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column chromatography to give (S)-1 -(4-bromophenyl)-N-(2-(2-isopropyl-1,3-
dioxolan-2-yl)ethyl)ethanamine (6.5 g, 38% yield).
Step 5
To a solution of (S)-1-(4-bromophenyl)-N-(2-(2-isopropyl-1,3-dioxolan-
2-yl)ethyl)ethanamine (6.5 g, 19 mmol) in MeOH (60 mL) was added conc
HCI (60 mL). The mixture was stirred at 65 C till the reaction was finished.
The mixture was cooled to 0 C, and the pH of the mixture was adjusted to 7
by adding the satd aq NaHCO3. The mixture was concentrated, and the
residue was extracted with EtOAc (3 x 100 mL). The organic layer was
washed with brine, dried over Na2SO4, and concentrated to give (S)-1-(1-(4-
bromophenyl)ethylamino)-4-methylpentan-3-one (5.5 g, 97% yield), which
was used for the next step without further purification. 1H NMR (CDC13): 5
1.07 (d, J = 6.8 Hz, 6H), 1.29 (d, J = 6.4 Hz, 3H), 1.89 (br, 1 H), 2.54-2.62
(m,
4H), 2.66-2.69 (m, 1 H), 3.68-3.72 (m, 1 H), 7.18-7.20 (m, 2H), 7.41-7.44 (m,
2H).
Step 6
To a suspension of Mg (11 g, 458 mmol) and 12 (0.5g) in anhydrous
THE (50 mL) was added 3-chloro-2-methylprop-1-ene (1 mL) to initiate the
reaction. THE (300 mL) was added, more solution of 3-chloro-2-methylprop-
1-ene (15 mL) in THE (20 mL) was dropped into the reaction at 0 C under
N2 over 30 min. A solution of (S)-1-(1-(4-bromophenyl)-ethyl amino)-4-
methylpentan-3-one (5g) in THE (50mL) was added dropwise at -78 C over
45 min. The reaction was stirred at rt for 2 h, cautiously quenched with satd
aq NH4CI, and filtered. The filtrate was extracted with EtOAc (3 x 100 mL),
washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo
to give 1-(S-1-(4-bromophenylamino)-3-isopropyl -5-methyl hex-5-en-3-ol (6.4
g, 90% yield ), which was used for the next step without further purification.
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Step 7
To a solution of 1 -(S-1 -(4-bromophenylamino)-3-isopropyl-5-
m ethylhex-5-en-3-ol (6.4 g, 16.8 mmol) and triethylamine (5.34 g, 52 mmol)
in CH2CI2 (260 ml-) was added triphosgene (2.52 g, 8.5 mmol) at 0 0 under
N2, and the mixture was stirred at rt overnight. The reaction mixture was
quenched with water, and extracted with CH2CI2 (3 x 50 mL). The combined
organic layer was washed with brine, dried over Na2SO4, filtered, and
concentrated to afford the crude product, which was purified by column
chromatography to give two isomers of 3-((S)-1-(4-bromophenyl)ethyl)-6-
isopropyl-6-(2-methylallyl)-1,3-oxazinan-2-one.
Isomer 1 :(1.85 g, 27% yield) 1H NMR (0D013): 50.83(d, J = 7.2 Hz,
3H), 0.89 (d, J = 7.2 Hz, 3H), 1.45 (d, J = 6.8 Hz, 3H), 1.64-1.70 (m, 2H),
1.79 (s, 3H), 1.88-1.95 (m, 1 H), 2.20 -2.34 (m, 2H), 2.59-2.65 (m, 1 H), 3.01-
3.08 (m, 1 H), 4.70 (s, 1 H), 4.87 (s, 1 H), 5.68-5.77 (m, 1 H), 7.14 (d, J =
8.4
Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H).
Isomer 2: (1.25g, 18% yield) 1H NMR (0D013): (50.87 (d, J = 6.8 Hz,
3H), 0.92(d, J = 6.8 Hz, 3H), 1.50 (d, J = 7.2 Hz, 3H), 1.60-1.66 (m, 1 H),
1.78 (s, 3H), 1.73-1.79 (m, 1 H), 1.78 -2.05 (m, 1 H), 2.08 (d, J = 14.0 Hz,
1 H), 2.30 (d, J = 14.0 Hz, 1 H), 2.62-2.68 (m, 1 H), 2.98-3.05 (m, 1 H), 4.64
(s,
1 H), 4.84 (s, 1 H), 5.70-5.75 (m, 1 H), 7.13 (d, J = 8.4 Hz, 2H), 7.40 (d, J
= 8.4
Hz, 2H).
Step 8
To a solution of 3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-6-(2-
methylallyl)-1,3-oxazinan-2-one. isomer 1(500 mg, 1.32mmol) in dry CH2CI2
(64 ml-) was added m-CPBA (455 g, 2.64 mmol) at rt. The reaction mixture
was stirred until the starting material was consumed (monitored by TLC).
The mixture was diluted with (CH3)3000H3 (70 mL), washed with 30%
Na2S203, and aq NaHCO3 (3 x), dried over Na2SO4, filtered, and
concentrated to give 3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-6-((2-
methyloxiran-2-yl)methyl)-1,3-oxazinan-2-one isomer 1 (520 mg, 99%),
which was used directly for the next step without further purification.
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Step 9
To a solution of 3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-6-((2-
methyloxiran-2-yl)methyl)-1,3-oxazinan-2-one isomer 1 (520 mg, 1.32 mmol)
in THE (32 mL) was added dropwise LiEt3BH (Super-Hydride, 13.6 mL,
13.6mmol) at 0 0 under N2 over 30 min., the resulting solution was stirred at
10-13 0 for 21.5 h. To the mixture was added H202 (40 mL). The resulting
solution was diluted with (CH3)3000H3 (380 mL), and washed with water,
30% aq Na2S203, and brine. The organic phase was dried over Na2SO4,
and filtered. The filtrate was concentrated to give the crude product, which
was purified by column chromatography to afford 3-((S)-1-(4-
bromophenyl)ethyl)-6-(2-hydroxy-2-methyl propyl)-6-isopropyl -1,3-oxazinan-
2-one isomer 1 (320 mg, 61 %). 1H NMR (0D013): (50.82 (d, J = 6.8 Hz, 3H),
0.95 (d, J = 6.8 Hz, 3H), 1.31 (s, 3H), 1.34 (s, 3H), 1.51 (d, J = 10.0 Hz,
3H),
1.61 (d, J = 15.2 Hz, 1 H), 1.78-1.84 (m,1 H), 1.91 (d, J = 15.2 Hz, 1 H),
2.02-
2.15 (m, 2H), 2.36 (br, 1 H), 2.62-2.68 (m, 1 H), 3.03-3.09 (m, 1 H), 5.73 (t,
J =
7.2 Hz, 1 H), 7.17-7.19 (m, 2H), 7.44-7.48 (m, 2H).
Step 10
To a solution of 3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-
m ethyl propyl)-6-isopropyl -1,3-oxazinan-2-one isomer 1 (315 mg, 0.793
mmol) in DMSO (10 mL) was added 4,4,5,5-tetramethyl -1,3,2-dioxaborolan-
2-yl)-1,3,2-dioxaborolane (602 mg, 2.38 mmol), CH3CO2K (770 mg, 79.3
mmol), Pd(dppf)2C12 (50 mg, 0.06 mmol) under N2, the reaction was stirred
at 90 0 for 4 h. The mixture was quenched with NH4CI, and extracted with
EtOAc, washed with water and brine. The organic phase was dried over
Na2SO4 and filtered. The filtrate was concentrated to give the crude product,
which was purified by preparative TLC to give 6-(2-hydroxy-2-methyl propyl)-
6-isopropyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-
yl)phenyl)ethyl)-1,3-oxazinan-2-one isomer 1 (250 mg, 71 %).
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Step 11
To a solution of 6-(2-hydroxy-2-methyl propyl)-6-isopropyl-3-((S)-1-(4-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-
one isomer 1 (250 mg, 0.39mmol), 4-bromo-1-methylpyridin-2(1H)-one (127
mg, 0.68 mmol), Cs2CO3 (2N, 4 mL) in 1,4-dioxane (20 mL) was added
Pd(PPh3)2CI2 (54 mg, 0.056 mmol) under N2. The reaction mixture was
refluxed for 2h, quenched with water, and extracted with EtOAc. The
organic phase was washed with H2O and brine, dried over Na2SO4, and
filtered. The filtrate was concentrated to give the crude product, which was
purified by preparative TLC and preparative HPLC to afford 6-(2-hydroxy-2-
methyl propyl)-6-isopropyl -3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-
yl)phenyl)ethyl)-1,3-oxazinan-2-one isomer 1 (79 mg, 47% yield). LC-MS
Method 2 tR = 1.023 min, m/z = 427.6; 1H NMR (CDC13) 0.85 (d, , 3H), 0.96
(d, 3H), 1.26 (s, 3H), 1.28 (s, 3H), 1.54 (m, 4H), 1.84-1.88 (m, 2H), 2.04
(br,
1 H), 2.01-2.18 (m, 2H), 2.75 (m, 1 H), 3.10 (m, 1 H), 3.52 (s, 3H), 5.80 (t,
1 H),
6.37 (m, 1 H), 6.74 (m, 1 H), 7.28 (m, 1 H), 7.25-7.37(m, 2H), 7.50 (m, 2H).
6-(2-hydroxy-2-methyl propyl)-6-isopropyl-3-((S)-1-(4-(1-methyl-2-oxo-
1,2-dihydropyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one isomer 2 was
prepared from 3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl -6-(2-methyl allyl)-
1,3-oxazinan-2-one isomer 2 following procedures analogous to those
described in Steps 8 - 11 above. LC-MS Method 2 tR = 1.023 min, m/z =
427.6; 1H NMR (CDC13) 0.79 (d, 3H), 0.92 (d, 3H), 1.27 (s, 3H), 1.30 (s, 3H),
1.51 (d, 3H), 1.58 (d, 1 H), 1.73-1.81 (m, 1 H), 1.88 (d, 1 H), 2.0 (br, 1 H),
2.04-
2.08 (m, 2H), 2.65-2.68 (m, 1 H),3.04-3.07 (m, 1 H), 3.52 (s, 3H), 5.75 (t, 1
H),
6.37 (m, 1 H), 6.74 (m, 1 H), 7.21-7.35 (m, 3H), 7.51 (m, 2H).
EXAMPLE 18
6-cyclopropyl-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(1-methyl -2-oxo-1,2-
dihydropyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one
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O O
ON OB-B~ ON
O O B'O -):q V-t / Br
Pd(dPPflC12 O
OH KOAc OH
Br I O
N
O O~ N
Pd(PPh3)2C12, Cs2CO3
OH O
The two diastereomers of 3-((S)-1-(4-bromophenyl)ethyl)-6-
cyclopropyl-6-(2-hydroxy-2-methyl propyl)-1,3-oxazinan-2-one were prepared
from methyl 3-cyclopropyl-3-oxopropanoate following procedures analogous
to those described in Example 17 Steps 1 - 7. The title compound was
prepared as follows.
Step 1
To a solution of 3-((S)-1-(4-bromophenyl)ethyl)-6-cyclopropyl-6-(2-
hydroxy-2-methylpropyl)-1,3-oxazinan-2-one isomer 1 (230 mg, 0.58 mmol)
in DMSO (15 mL) was added 4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)-
1,3,2-dioxaborolane (450 mg, 1.77 mmol), CH3CO2K (800 mg, 8.16 mmol),
Pd(pddf)2CI2 (50 mg, 0.06 mmol) under N2. The reaction was stirred at 900C
for 34 h, quenched with NH4CI, and extracted with EtOAc. The organic
phase was washed with water and brine, dried over Na2SO4, and filtered.
The filtrate was concentrated to give the crude product, which was purified
by preparative TLC to give 6-cyclopropyl-6-(2-hydroxy-2-methyl propyl)-3-
((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-
oxazinan-2-one isomer 1 (140 mg, 54.3%).
Step 2
To a solution of 6-cyclopropyl-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-
(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-
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one isomer 1 (140 mg, 0.316 mmol), 4-bromo-1-methylpyridin-2(1H)-one
(74.3 mg, 0.316 mmol), 2 M aq Cs2CO3 (3 mL) in 1,4-dioxane(20 mL) was
added Pd(dppf)2CI2 (30 mg, 0.043 mmol) under N2. The reaction mixture
was refluxed for 2h, quenched with water, and extracted with EtOAc. The
organic phase was washed with H2O and brine, dried over Na2SO4, and
filtered. The filtrate was concentrated to give the crude product, which was
purified by preparative TLC and preparative HPLC to afford 6-cyclopropyl-6-
(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-
yl)phenyl)ethyl)-1,3-oxazinan-2-one isomer 1 (49.5 mg, 37.7%). LC-MS
1o Method 2 tR = 1.016 min, m/z = 367.2; 1H NMR (CDC13) 0.50 (m, 2H), 0.62
(m, 2H), 0.97 (m,1 H), 1.32 (m, 6H), 1.58 (d, 3H), 1.97(m, 3H), 2.28 (m,1 H),
2.78 (m, 1 H), 3.40 (m, 1 H), 3.58 (s,3H) ,5.85 (m, 1 H), 6.41 (d, 1 H), 6.79
(s,
1 H), 7.33 (d, 1 H), 7.41 (d, 1 H), 7.56 (d, 1 H)
6-cyclopropyl-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(1-methyl-2-
oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one isomer 2 was
prepared from 3-((S)-1-(4-bromophenyl)ethyl)-6-cyclopropyl-6-(2-hydroxy-2-
methylpropyl)-1,3-oxazinan-2-one isomer 2 following procedures analogous
to those described in Steps 1 and 2 immediately above. LC-MS Method 2 tR
= 0.99 min, m/z = 367.1; 1H NMR (CDC13) 0.02 (m, 3H), 0.23 (m, 1 H), 0.51
(m,1 H), 0.96 (s, 6H), 1.17 (d, 3H), 1.40-1.60 (m, 4H), 1.94 (m,1 H), 2.55 (m,
1 H), 2.73 (m, 1 H), 3.20 (s,3H) ,5.41 (m, 1 H), 6.03 (d, 1 H), 6.40 (s, 1 H),
6.98
(m, 1 H) , 7.03 (m, 2H), 7.18 (m, 2H)
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EXAMPLE 19
(R)-6-(2-(5-methyl -1,3,4-oxadiazol-2-yl)ethyl)-3-((S)-1-(4-(1-methyl-2-oxo-
1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
ON 1. BH3 O~N Jones ~~N \
Br 2. H2O2 Br reagent Br
O
OH OH
O
O
'-INHNH2 O~N Burgess Reagent / O~N 40
OB/ O
B`0
Br Br
microwave
O Pd(dppf)C12, KOAc
NH N
~NH N~
O
O O
0 N I\ I I N. O~N
B
Pd(PPh3)2CI2, Cs2CO3, N~
N 0 NN' 0 O
Step 4
To a solution of N'-acetyl-3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-
6-phenyl-1,3-oxazinan-6-yl)propanehydrazide (0.1 g, 0.21 mmol) in THE (2
mL) was added Burgess Reagent (75 mg, 0.315 mmol). The sealed vial was
irradiated in the microwave at 100 C for 15 min. The mixture was extracted
with EtOAc (3 x 30 mL). The combined organic layer was washed with brine
(50 mL), dried over Na2SO4, filtered, and concentrated. The residue was
purified by preparative TLC to afford (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-
(5-methyl -1,3,4-oxadiazol-2-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one (58 mg,
yield: 59%). 1H NMR (CDC13): (51.49-1.51 (m, 3H), 2.23-2.26 (m, 2H), 2.30-
2.33 (m, 2H), 2.42 (s, 3H), 2.43-2.45 (m, 1 H), 2.49-2.54 (m, 1 H), 2.87-2.91
(m, 1 H), 3.06-3.09 (m, 1 H), 5.61-5.63 (m, 1 H), 6.76-6.78 (d, 2H), 7.20-7.22
(m, 2H), 7.26-7.33 (m, 2H), 7.35-7.37 (m, 3H).
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Step 5
To a solution of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(5-methyl -
1,3,4-oxadiazol-2-yl)ethyl)-6-phenyl-1,3-oxazinan-2-one (490 mg, 1.04
mmol), and 4,4,4',4',5,5,5',5'-octamethyl -2,2'-bi(1,3,2-dioxaborolane) (424
mg, 1.67 mmol) in dry DMSO (20 mL) was added KOAc (326 mg, 3.33
mmol) and Pd(dppf)C12 (25.3 mg, 0.031 mmol) under N2 atmosphere. The
mixture was warmed at 100 C for 3 h. After TLC showed the starting
material had disappeared, the solid was filtered off, water (50mL) and EtOAc
(50 mL) were added, and the mixture was extracted with EtOAc (3 x 50 mL).
The combined organic layer was washed with brine (50 mL), dried over
Na2SO4, filtered, and concentrated. The residue was purified by prep TLC to
afford (R)-6-(2-(5-methyl -1,3,4-oxadiazol-2-yl)ethyl)-6-phenyl-3-((S)-1-(4-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-
one (0.395 g, yield:73.6%).
Step 6
To a solution of (R)-6-(2-(5-methyl -1,3,4-oxadiazol-2-yl)ethyl)-6-
phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-
1,3-oxazinan-2-one (60 mg, 0.12 mmol) and 4-iodo-1-methylpyridin-2(1 H)-
one (33 mg, 0.14 mmol) in dry 1,4-dioxane (15 mL) were added Cs2CO3
(2M, 1 mL) and Pd(PPh3)C12 (7.7 mg, 0.01 mmol). The mixture was heated
at reflux for 2 h under N2 atmosphere, the solid was filtered off, and the
mixture was diluted with water (30 mL) and EtOAc (30 mL). The combined
organic layers was washed with brine (50 mL), dried over Na2SO4, filtered,
and concentrated. The residue was purified by prep TLC to afford (R)-6-(2-
(5-methyl -1,3,4-oxadiazol-2-yl)ethyl)-3-((S)-1-(4-(1-methyl -2-oxo-1,2-
dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (25 mg, yield:
41.8%). LC-MS Method 2 tR = 0.984 min, m/z = 499.1; 1H NMR (CDC13):
(51.48-1.50 (m, 3H), 2.16-2.20 (m, 1 H), 2.23-2.26 (m, 1 H),2.27-2.32 (m, 2H),
2.39 (s, 3H), 2.40-2.47 (m, 1 H), 2.49-2.54 (m, 1 H), 2.87-2.90 (m, 1 H), 2.98-
3.01 (m, 1 H), 3.58 (s, 3H), 5.62-5.64 (m, 1 H), 6.45-6.48 (m, 1 H), 6.87 (s,
1 H), 6.92-6.94 (d, 2H), 7.20-7.24 (m, 4H), 7.25-7.35 (m, 4H).
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EXAMPLE 20
(S)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(l-(2-hydroxyethyl)-2-oxo-1,2-
dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
0
~~0 AN 0 ~ N
ICH2CH2OH I HO
0 O O"0
NH N~/\OH
K2C03 N ~
O Pd(PPh3)2C12 HO \OH
OS2OO3 0
Step 1
To the mixture of 4-iodopyridin-2(1 H)-one (50 mg, 0.213 mmol) in
DMF (3mL) was added 2-iodoethanol (73 mg, 0.426mmo1), K2CO3 (88 mg,
0.638 mmol) at rt. The mixture was stirred for 2 h at rt. After the reaction
was finished, the mixture was washed with water and extracted with EtOAc.
The organic phase was washed with brine, dried over Na2SO4, filtered, and
concentrated to give the crude product, which was purified by TLC to provide
1-(2-hydroxyethyl)-4-iodopyridin-2(1 H)-one (60 mg 100 %).
Step 2
A mixture of compounds (S)-6-(2-hydroxy-2-methyl propyl)-6-phenyl-3-
((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-
oxazinan-2-one (72 mg 0.150 mmol), 1-(2-hydroxyethyl)-4-iodopyridin-2(1H)-
one (48 mg 0.181 mmol), Pd(PPh3)2C12 (14 mg, 0.020 mmol), and Cs2CO3 (2
mL) in 1,4-dioxane (8 mL) was stirred at reflux for 2h. After the reaction was
finished, the mixture was washed with water, and extracted with EtOAC.
The organic phase was washed with brine, dried over Na2SO4, filtered, and
concentrated to get the crude product, which was purified by TLC to provide
compound (S)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(1-(2-hydroxyethyl)-
2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
(19.7 mg, 28 %). LC-MS Method 2 tR = 1.065 min, m/z = 491.2; 1HNMR
(CDC13): (51.10 (d, 6H), 1.50 (d, 3H), 2.20 (m, 5H), 2.35 (m, 1 H), 3.50 (m,
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1 H), 3.90 (m, 2H), 4.10 (m, 2H), 5.60 (m, 1 H), 6.40 (m, 1 H), 6.70 (s, 1 H),
6.95 (d, 2H), 7.35 (m,8H).
EXAMPLE 21
(6S)-6-(2,3-dihydroxy-2-methyl propyl)-3-((S)-1-(4-(l-methyl -2-oxo-1,2-
dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
O OH Br / \ 0
I~ NCO 0"~O N I \ Os04
C1 - Zn, THE 0_'~F DBU Br
O
O 40 _Ept ~ N-
O N O O \ O
Br Pd(dppf)CI2, KOAc 0_6 1. Pd(PPh3)2CI2
Cs2CO3
HO HO 2 OH Separation
OH
O O
0 1~1 N / O)~ N
N N
HO" HO
HO HO
Step 1
A solution of 3-chloro-1-phenylpropan-1-one (16.8 g, 0.1 mol) in THE
(50 mL) was added to a well-stirred suspension of zinc powder (13 g, 0.2
mol) in a mixture of satd aq NH4CI solution (260 mL) and THE (65 mL). A
solution of 3- iodo-2-m ethyl prop- 1 -ene (36.4 g, 0.2 mol) in THE (50 mL)
was
added dropwise. The reaction was mildly exothermic, and the mixture
began to reflux spontaneously. After refluxing had ceased, the mixture was
stirred for 1 h. TLC showed the 3-chloro-1-phenylpropan-1-one had not
reacted completely. A solution of 3-iodo-2-methylprop-1-ene (18.2 g, 0.1
mol) in THE (30 mL) was added, and the mixture was stirred at rt overnight.
The mixture was extracted with EtOAc (2 x 500 mL). The combined organic
layer was dried and concentrated. The residue was purified by column
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chromatography on silica gel eluted with petroleum ether/ EtOAc
50:1-*30:1-*5:1, to give 1 -ch loro-5-m ethyl -3-ph enyl h ex-5-en -3-ol (17
g,
yield 76 %) as an oil. 1H NMR (CDC13): (51.28 (s, 3H), 2.31 (m, 2H), 2.54 (m,
2H), 2.68 (d, 1 H), 3.15 (m, 1 H), 3.58 (m, 1 H), 4.78 (m, 1 H), 4.93 (m, 1
H),
7.27 (t, 1 H), 7.38 (m, 4H).
Step 2
A mixture of 1-chloro-5-methyl-3-phenylhex-5-en-3-ol (2.9 g, 13
mmol), (S)-1 -bromo-4-(1 -isocyanatoethyl)benzene (3.5 g, 16 mmol), and
DBU (8 g, 33 mmol) in THE (80 mL) was heated at reflux overnight. The
mixture was diluted with EtOAc, and washed with 1 N aq HCI. The aqueous
phase was extracted with EtOAc (3 x), and the combined organic phase was
dried over Na2SO4. After the solvents were evaporated, the crude product
was purified by column chromatography to give (R)-3-((S)-1-(4-
bromophenyl)-ethyl)-6-(2-methyl aIlyl)-6-phenyl-1,3-oxazinan-2-one (1.62 g,
yield: 30 %).
Step 3
To a solution of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methyl allyl)-
6-phenyl-1,3- oxazinan-2-one (300 mg, 0.726 mmol), 4-methylmorpholine 4-
oxide (195 mg, 1.44 mmol) in a mixture of H2O (6 mL), THE (30 mL) and t-
BuOH (12 mL) was added osmium (VIII) oxide (4%, 0.231 mL) at 0 C. The
mixture was stirred at rt overnight. The mixture was quenched with 3%
NaHSO3 (15 mLx3) and extracted with EtOAc. The organic layer was dried
over Na2SO4 and concentrated to give the crude product (S)-3-((S)-1-(4-
bromophenyl)-ethyl)-6-(2,3-dihydroxy-2-methyl propyl)-6-phenyl-1,3-
oxazinan-2-one (242 mg, 74.5%).
Step 4
To a solution of (S)-3-((S)-1-(4-bromophenyl)-ethyl)-6-(2,3-dihydroxy-
2-methyl propyl)-6-phenyl-1,3-oxazinan-2-one (235 mg, 0.524 mmol) in
DMSO (5 mL) were added KOAc (771.6 mg, 7.86 mmol), Pd(dppf)C12 (40
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mg) under N2. The mixture was stirred at 90 C for 3 h. The reaction
mixture was quenched with water and extracted with EtOAc. The organic
layer was dried over Na2SO4 and concentrated to give the crude product,
which was purified by preparative TLC to afford (S)-6-(2,3-dihydroxy-2-
methyl propyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-
2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (121 mg, 46.6%).
Step 5
A mixture of (S)-6-(2,3-dihydroxy-2-methyl propyl)-6-phenyl-3-((S)-1-
(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-
one (105 mg, 211.9 mmol), 4-iodo-1-methylpyridin-2(1 H)-one (65 mg, 275.5
mmol), Pd(PPh3)2C12 (20 mg) in aq. Cs2CO3 solution (3 ml-) was stirred at
reflux for 2 h. After the reaction was finished, the mixture was washed with
water and extracted with EtOAc. The organic layer was dried over Na2SO4
and concentrated to give the crude product, which was purified by
preparative HPLC to afford two isomers of (65)-6-(2,3-dihydroxy-2-
methyl propyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-
yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
Isomer 1 (6.11 mg, 6%): LC-MS Method 2 tR = 0.84 min, m/z = 477.4;
1H NMR (CDC13): 5 0.97 (s, 3H), 1.55 (d, 3H), 2.27 (m, 3H), 2.38 (m, 3H),
2.91 (m, 1 H), 3.34 (d, 1 H), 3.58 (s, 3H), 5.68 (m, 1 H) ,6.35 (d, 1 H), 6.71
(s,
1 H), 7.02 (d, 2H), 7.36 (m, 8H).
Isomer 2 (6.78 mg, 6.7%): LC-MS Method 2 tR = 0.832 min, m/z =
477; 1H NMR (CDC13): 5 1.14 (s, 3H), 1.48 (d, 3H), 2.09 (m, 1 H), 2.14 (m,
2H), 2.31 (m, 2H), 2.81 (m, 1 H), 3.24 (d, 1 H), 3.27 (d, 1 H), 3.50 (s, 3H),
5.62
(m, 1 H), 6.28 (d, 1 H), 6.63 (s, 1 H), 6.98 (d, 2H), 7.27 (m, 8H).
EXAMPLE 22
(6S)-6-(2-hydroxy-3-methoxy-2-methyl propyl)-3-((S)-1-(4-(1-methyl-2-oxo-
1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
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O
I I N
. / O N
x Name O gg
/ O N O O
õ yam/
\ "' / Br 65 C, 2h Br Pd(dppf)CI2, KOAc 0
HO
HO OMe
OMe
O O
II N /õ0 11 N
O
1. Pd(PPh3)ZCIZ I N
CSZCO3 HOI" HO N,
2. Separation
MeO Me O/
Step 1
Sodium (90 mg) was added to MeOH (5 mL). When sodium had
disappeared, a solution of 6(S)-3-(S-1-(4-bromophenyl)ethyl)-6-((2-
methyloxiran-2-yl)-methyl)-6-phenyl-1,3-oxa zinan-2-one (500 mg,
1.16mmol) was added to the mixture. The mixture was stirred at 65 C for 5
h. The mixture was added H2O and concentrated. The residue was
extracted with EtOAc, the organic layer was dried over Na2SO4 and
concentrated to give the crude product, which was purified by preparative
TLC (2:1 PE/EtOAc) to afford (S)-3-(S-1-(4-bromophenyl)ethyl)-6-(2-
hydroxy-3-methoxy-2-methyl propyl)-6-phenyl-1,3-oxazinan-2-one (227 mg,
42.3%).
Step 2
To a solution of (S)-3-(S-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-3-
methoxy-2-methyl propyl)-6-phenyl-1,3-oxazinan-2-one (205 mg, 0.443
mmol) in DMSO (5 mL) was added KOAc (435.13 mg, 4.43 mmol),
Pd(dppf)C12 (45 mg) under N2. The mixture was stirred at 90 C for 3 hours.
The reaction mixture was quenched by water and extracted with EtOAc.
The organic layer was dried over Na2SO4 and concentrated to give the crude
product, which was purified by preparative TLC (PE:EA=1:2) to afford (S)-6-
(2-hydroxy-3-methoxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-
tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (113
mg, 50%).
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Step 3
A mixture of (S)-6-(2-hydroxy-3-methoxy-2-methyl propyl)-6-phenyl-3-
((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-
oxazinan-2-one (100 mg, 196.29 mmol), 4-iodo-1-methylpyridin-2(1H)-one
(60.49 mg, 255.2mmol), Pd(PPh3)2CI2 (20 mg), and aq Cs2CO3 solution (2
mol/L, 3 ml-) in 1,4-dioxane (4 ml-) was stirred at reflux for 2 hours. After
the
reaction was finished, the mixture was washed with water and extracted with
EtOAc. The organic layer was dried over Na2SO4 and concentrated to give
the crude product, which was purified by preparative HPLC to afford two
isomers of (65)-6-(2-hydroxy-3-methoxy-2-methyl propyl)-3-((S)-1-(4-(1-
methyl -2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-
one.
Isomer 1 (5.25 mg, 5.6%): LC-MS Method 2 tR = 0.921 min, m/z =
403.2; 1H NMR (CDC13): 5 0.94 (s, 3H), 1.47 (d, 3H), 2.28 (m, 4H), 2.35 (m,
1 H), 2.82 (m,1 H), 3.11 (d, 1 H), 3.16 (s, 3H), 3.25 (d, 1 H), 3.50 (s, 3H),
5.62
(m, 1 H), 6.27 (d, 1 H), 6.63 (s, 1 H), 6.92 (d, 2H), 7.25 (m,8H).
Isomer 2 (5.40 mg, 5.8%): LC-MS Method 2 tR = 0.923 min, m/z =
513.1; 1H NMR (CDC13): 5 1.18 (s, 3H), 1.47 (d, 3H), 2.11 (m, 2H), 2.23 (m,
2H), 2.45 (m, 1 H), 2.81 (d, 2H), 2.96 (d, 1 H), 3.15 (s, 3H), 3.50 (s, 3H),
5.62
(m, 1 H), 6.27 (d, 1 H), 6.65 (s, 1 H), 6.90 (d, 2H), 7.26 (m, 8H).
EXAMPLE 23
(S)-6-(2-fluorophenyl)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(1-methyl-6-
oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one
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F F 0 F O H2N F 0
COCI McNHOMe 4"'MgBr \ / Br
/ / O'~ THE \ \Br
1 2
0
F OH
O N m-CPBA
MgCI N Triphosgene
Br
Br THE
0 F
a--- LiEt3BH F 0 N 400B BO 0 N \
I Ot
0~N
Br Pd(dppf)CI2, KOAc B/
O
OH
O ~OH O F O
N, 0 N
Br
Pd(PPh3)2CI2
HO i
Step 1
To a solution of 2-fluorobenzoyl chloride (50 g, 0.31 mol) in CH2CI2
(200 mL) was added N,O-dimethylhydroxylamine (46 g, 0.47 mol), and a
solution of triethylamine (127 g, 1.26 mol) in CH2CI2 (100 mL) at 0 C. The
reaction mixture was warmed slowly to rt, and stirred for 3 h. The mixture
was quenched with iced water and extracted with CH2CI2 (200 mL). The
organic layer was dried over Na2SO4, filtered, and concentrated to afford 2-
fluoro-N-methoxy-N-methylbenzamide (48 g, yield: 84.6 %).
Step 2
A solution of 2-fluoro-N-methoxy-N-methylbenzamide (16 g, 87.4
mmol) in THE (150 mL) was cooled to -78 C. Vinylmagnesium bromide (120
mL,120 mmol) was slowly added, and the mixture stirred at -78 C for 10
min, slowly warmed to rt, and stirred for another 3 h. The reaction mixture
was quenched with 1 N aq HCI (100 mL) at 0 C. The aqueous layer was
extracted with EtOAc (100 mL). The combined organic phase was washed
with brine (50 mL), dried over Na2SO4, and concentrated. The residue was
purified by column chromatography to afford 1-(2-fluorophenyl)-prop-2-en-1-
one (7.6 g, yield: 58.4 %) as a colorless oil.
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Step 3
To a solution of 1-(2-fluorophenyl)-prop-2-en-1 -one (5.6 g, 37.3 mmol)
in CH3CN (50 mL) was added (S)-1 -(4-bromophenyl)-ethylam ine (7.4 g, 37
mmol), and the mixture was stirred for 12 h at 40 C. The solution was
concentrated to afford the crude product, which was purified by column
chromatography to give (S)-3-(1-(4-bromophenyl)-ethylamino)-1-(2-
fluorophenyl)-propan-1-one (4 g, yield: 30.7%) as a yellow liquid.
1o Step 4
To a suspension of Mg (2.5 g, 104 mmol), 12 (0.1 g) in anhydrous THE
(15 mL) was added 3-chloro-2-methylprop-1-ene (0.6 mL, 6 mmol). After a
solution of 3-chloro-2-methylprop-1-ene (9 mL, 90 mmol) in THE (120 mL)
was dropped at 0 C under N2 in 30 min. (S)-3-(1-(4-bromophenyl)-
ethylamino)-1-(2-fluorophenyl)-propan-1-one (3 g , 8.6 mmol) in THE (50
mL) was added dropwise at -78 C over 45 min. The reaction mixture was
stirred at rt for 2 h and cautiously quenched by addition of satd aq NH4CI.
The mixture was extracted with EtOAc, and the organic layer was washed
with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give
1-(S-1-(4-bromophenyl)-ethylamino)-3-(2-fluorophenyl)-5-methyl hex-5-en-3-
ol (3.3 g , yield: 94.5% ), which was used for the next step without further
purification.
Step 5
A mixture of 1-(5-1-(4-bromophenyl)ethylamino)-3-(2-fluorophenyl)-5-
methylhex -5-en-3-ol (2 g, 5 mmol) in a solution of triethylamine (1.5 g, 15
mmol) in 1,2-dichloroethane (100 mL) was added triphosgene (1.46 g, 5
mmol) at 0 C under N2, and the mixture was heated at 100 C for 4 h. The
reaction mixture was quenched with water, and extracted with CH2CI2 (100
mL). The combined organic layer was washed with brine, dried over
Na2SO4, filtered, and concentrated to afford the crude product (2.1 g , yield:
99 % ), which was used for the next step without further purification.
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Step 6
To a solution of (S)-3-(1-(4-bromophenyl)ethyl)-6-(2-fluorophenyl)-6-
(2-methylallyl) -1,3-oxazinan-2-one (3.2 g, 7.4 mmol) in dry CH2CI2 (100 mL)
was added m-CPBA (2.6 g, 14.8 mmol) at rt and the mixture was stirred
overnight. The mixture was diluted with (CH3)3000H3 (100 mL), washed
with 30% aq Na2S203 and aq NaHCO3, dried over Na2SO4, filtered, and
concentrated to give 3-(S-1 -(4-bromophenyl)-ethyl)-6-(2-fluorophenyl)-6-(2-
methyloxiran-2-yl-methyl)-1,3-oxazinan-2-one (2.8 g, yield: 84.3%), which
was used directly for the next step without further purification.
Step 7
To a solution of 3-(S-1 -(4-bromophenyl)-ethyl)-6-(2-fluorophenyl)-6-(2-
methyloxiran -2-yl)-methyl)-1,3-oxazinan-2-one (2.2 g, 4.92 mmol) in THE
(100 mL) was added dropwise LIEt3BH (Super-hydride, 50 mL, 50 mmol) at
0 0 under N2 for 30 min., and the resulting mixture was stirred at 2-3 C for
1.5 h, and stirred for 2.5 h at 10-13 C . H202 (20 mL) was added dropwise
and the reaction mixture was diluted with (CH3)3000H3 (280 mL). The
mixture was washed with water, 30% aq Na2S203 and brine. The organic
phase was dried over Na2SO4 and filtered. The filtrate was concentrated to
give the crude product, which was purified by column chromatography to
afford (S)-3-(S-1-(4-bromophenyl)-ethyl)-6-(2-fluorophenyl)-6-(2-hydroxy-2-
methylpropyl)-1,3-oxazinan-2-one (550 mg, 23.9 %) as a white solid. 1H
NMR (CDCI3): 5 1.03 (s, 3H), 1.14 (s, 3H), 1.43 (d, J = 6.8 Hz, 3H), 2.08-
2.13 (m, 1 H), 2.17 (d, J = 2.8 Hz, 1 H), 2.21-2.22 (m, 1 H), 2.31 (dd, J =
0.8,
15.2 Hz, 1 H), 2.77-2. 81 (m, 1 H), 5.56 (q, J = 2.8 Hz, 2 H), 6.82-6.83 (m,
2H), 6.85-6.94 (m, 1 H), 7.08-7.13 (m, 1 H), 7.18-7.25 (m, 1 H), 7.26-7.40 (m,
2H), 7.42-7.44 (m, 1 H).
Step 8
To a solution of (S)-3-(S-1-(4-bromophenyl)-ethyl)-6-(2-fluorophenyl)-6-
(2-hydroxy-2-methyl propyl)-1,3-oxazinan-2-one (540 mg, 1.2 mmol) in
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DMSO (15 mL) was added 4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)-
1,3,2-dioxaborolane (900 mg, 3.3 mmol), CH3CO2K (1.5 g, 16 mmol),
Pd(dppf)C12 (108 mg, 0.13 mmol) under N2, and the reaction was stirred at
90 C for 2.5 h. The mixture was quenched with water, and extracted with
EtOAc (90 mL). The organic layer was washed with water and brine, dried
over Na2SO4, and filtered. The filtrate was concentrated to give the crude
product, which was purified by preparative TLC to afford (S)-6-(2-
fluorophenyl)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl -
1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (360 mg, 62 %) as
a yellow liquid.
Step 9
To a solution of (S)-6-(2-fluorophenyl)-6-(2-hydroxy-2-methyl propyl)-
3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-
oxazinan-2-one (120 mg, 0.24 mmol), 5-bromo-1-methylpyridin-2-(1H)-one
(54 mg, 0.28mmo), 2N aq Cs2CO3 (2 mL) in dioxane (8 mL) was added
Pd(PPh3)2C12 (17 mg, 0.024 mmol) under N2. The reaction mixture was
refluxed for 2 h and quenched by addition of water. The mixture was
extracted with EtOAc (30 mL), and the organic layer was washed with H2O
and brine, dried over Na2SO4, and filtered. The filtrate was concentrated to
give the crude product, which was purified by preparative TLC and
preparative HPLC to afford (S)-6-(2-fluorophenyl)-6-(2-hydroxy-2-
methyl propyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-
yl)phenyl)ethyl)-1,3-oxazinan-2-one (14 mg, yield:10 %). LC-MS Method 2
tR = 1.2 min, m/z = 473.9; 1H NMR (CDC13): (51.21 (s, 3H), 1.30 (s, 3H), 1.48
(d, J = 7.2 Hz, 3H), 2.15-2.26 (m, 3H), 2.33 (dd, J= 11.2, 26.4 Hz, 1 H), 2.43-
2.46 (m, 1 H), 2.79-2.85 (m, 1 H), 3.63 (s, 3H), 5.62 (q, J = 6.8 Hz, 1 H),
6.58-
6.60 (m, 1 H), 6.89-6.94 (m, 1 H), 7.00-7.02 (m, 2 H), 7.10-7.24 (m, 3H), 7.34-
7.39 (m, 1 H), 7.40-7.45 (m, 1 H), 7.48-7.70 (m, 2H).
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EXAMPLE 24
(S)-6-(3-fluorophenyl)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(1-methyl-6-
oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one
O
OAN
E ~`'~1 ~ I \
~ N O
OH
The title compound was prepared from (S)-3-(1-(4-
bromophenyl)ethylamino)-1-(3-fluorophenyl)propan-1-one following
procedures analogous to those described in Steps 4-9 in Example 23. LC-
MS Method 2 tR = 1.416 min, m/z = 500.9; 1H NMR (CDC13) 1.18 (s, 3H),
1.29 (s, 3H), 1.47 (d, 3H), 2.05-2.28 (m, 4H), 2.31-2.39 (m, 1 H), 2.82-2.87
(m, 1 H), 3.58 (s, 3H), 5.64 (q, 1 H), 6.57-6.59 (m, 1 H), 6.88-7.19 (m, 5H),
7.21-7.25 (m, 2 H), 7.28 (m, 1 H), 7.36 (m, 1 H), 7.40-7.45 (m, 1 H), 7.45-
7.48
(m, 1 H)
(S)-3-(1-(4-bromophenyl)ethylamino)-1-(3-fluorophenyl)propan-1-one
was prepared as shown below.
O 0 O
F Ni MeMgBr F I Me2NH F N
/ O THE / (HCHO)n I /
1-1
H2N Br O
& F
EtOH, H2O, reflux I / H I /
Br
Step 1
A solution of 3-fluoro-N-methoxy-N-methylbenzamide (16 g, 87.4
mmol) in THE (150 mL) was cooled to -78 C. Vinylmagnesium bromide (120
mL,1 20 mmol) was added slowly. The mixture was stirred at -78 C for 10
min, at rt for 3 h, and quenched by addition of 1 N aq HCI (100 mL) at 0 C.
The aqueous layer was extracted with EtOAc (100 mL). The combined
organic phase was washed with brine (50 mL), dried over Na2SO4, and
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concentrated. The residue was purified by column chromatography to afford
1-(3-fluorophenyl)ethanone (9.7 g, yield: 75 %) as a colorless oil.
Step 2
1-(3-F Iuorophenyl)ethanon e (17 g, 0.123 mol), dimethylamine (13.7 g,
0.172 mol), and paraformaldephyde (5.5 g, 0.185 mol) were suspended in
ethanol (50 mL), and conc HCI solution (0.3 mL) was added. The mixture
was heated at reflux overnight. The solvent was removed under vacuum,
and the residue was washed with EtOAc (3 x) to give 3-(dimethylamino)-1-
(3-fluorophenyl)propan-1 -one (20.7 g, 88%), which was used for the next
step without purification.
Step 3
A solution of 3-dimethylamino-1 -(3-fluoro-phenyl)-propan-1 -one (17 g,
0.087 mol) and (S)-1-(4-bromophenyl)-ethanamine (17 g, 0.087 mol) in a
mixture of EtOH (50 mL) and H2O (50 mL) was refluxed at 80 C overnight.
The solvent was removed under vacuum, and the residue was purified by
column chromatography to afford (S)-3-(1-(4-bromophenyl)-ethylamino)-1-(3-
fluorophenyl)-propan-1-one (6.2 g, 20%).
EXAMPLE 25
(S)-3-((S)-1-(4-(1-(2-fluoroethyl)-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-
6-(2-hydroxy-2-methyl propyl)-6-phenyl-1,3-oxazinan-2-one
NH I~y Tf20, Et3N
F'~~OH F,,,,-\OTf 0 N
CH2CI2, -78 C - r. t. K2CO3 F
0
O
OxN
B-
O N
HO
Pd(PPh3)2CI2
N Cs2CO3 HO F
O
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1-(2-fluoroethyl)-4-iodopyridin-2(1 H)-one was prepared from 4-
iodopyridin-2(1 H)-one and 2-fluoroethyl trifluoromethanesulfonate following a
procedure analogous to that described in Example 20 Step 1.
The title compound was prepared from (S)-6-(2-hydroxy-2-
methyl propyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-
2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 1-(2-fluoroethyl)-4-iodopyridin-
2(1 H)-one following a procedure analogous to that described in Example 6
Step 1. LC-MS Method 2 tR = 1.09 min, m/z = 515, 493, 475, 435.
EXAMPLE 26
(S)-6-(2-fluorophenyl)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(1-methyl-2-
oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one
O
F OAN
N
OH O
The title compound was prepared from (S)-6-(2-fluorophenyl)-6-(2-
hydroxy-2-methyl propyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-iodo-1-methylpyridin-2(1 H)-one
following a procedure analogous to that described in Example 23 Step 9.
LC-MS Method 2 tR = 1.58 min, m/z = 501, 479, 421.
EXAMPLE 27
(S)-6-(3-fluorophenyl)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(1-methyl-2-
oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one
O
OAN
N
F OH O
The title compound was prepared from (S)-6-(3-fluorophenyl)-6-(2-
hydroxy-2-methyl propyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
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2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-iodo-1-methylpyridin-2(1 H)-one
following a procedure analogous to that described in Example 23 Step 9.
LC-MS Method 2 tR = 1.57 min, m/z = 501, 479, 421.
EXAMPLE 28
6-(3-hydroxypropyl)-6-isopropyl-3-((S)-1-(4-(1-methyl-2-oxo-1,2-
dihydropyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one
O
IO~NI
OII 4O 0 /~\ / / / O
\OB-BON HO
O N ~~ \ N
Ot O N 0
/ B 0 +
Pd(dppf Pd(PPh3)2CIp, CsZCO3,
dioxane
OH OH OIk N
HO
~-~ \ N0
1o Step 1
To a mixture of 3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-
isopropyl-1,3 -oxazinan-2-one (100 mg, 0.26 mmol), 4,4,4',4',5,5,5',5'-
octamethyl-2,2'-bi(1,3,2-dioxaborolane) (198 mg, 0.783 mmol), potassium
acetate (256 mg, 2.61 mmol) in DMSO (5 mL) was added Pd(dppf)C12 (21
mg, 0.0261 mmol) under N2. The mixture was stirred at 85 C for 3 h,
treated with EtOAc (50 mL) and water (50 mL). The organic layer was
washed with water (2x50 mL) and brine (50 mL), dried, and concentrated to
give the crude product. The crude product was purified by preparative TLC
to give 6-(3-hydroxypropyl)-6-isopropyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -
1,3,2-
dioxaborolan-2-yl) phenyl)ethyl)-1,3-oxazinan-2-one (40 mg, 35%),
Step 2
A mixture of 6-(3-hydroxypropyl)-6-isopropyl-3-((S)-1-(4-(4,4,5,5-
tetramethyl -1,3,2- dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (40
mg, 0.092 mmol), 4-iodo-1-methylpyridin-2(IH)-one (20 mg, 0.085 mmol),
Pd(PPh3)2C12 (6 mg, 0.0085 mmol), and Cs2CO3 (2 N, 0.425 mL, 0.85 mmol)
in 1,4-dioxane (2 mL) was refluxed for 3 h under N2. The reaction mixture
was treated with EtOAc (20 mL) and water (20 mL), and the organic layer
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was dried and concentrated in vacuo. The residue was purified by
preparative HPLC to give two isomers.
Isomer 1: (2.20 mg, 6%). LC-MS Method 2 tR = 1.06 min, m/z = 413;
m/z = 1H NMR (CD3OD): 5 1.00 (m, 6H), 1.62 (m, 7H), 1.82 (m, 1 H), 2.10
(m, 2H), 2.85 (m, 1 H), 3.29 (m, 1 H), 3.54 (t, 2H), 3.63 (s, 3H), 5.71 (q, 1
H),
6.78 (dd, 1 H), 6.83 (d, 1 H), 7.51 (d, 2H), 7.75 (m, 3H),
Isomer 2: (2.10 mg, 6%) LC-MS Method 2 tR = 1.03 min, m/z = 413;
1H NMR (CD3OD): 5 0.86 (m, 6H), 1.53 (m, 5H), 1.71 (m, 4H),1.92 (m, 1 H),
2.82 (m, 1 H), 3.25 (m, 1 H), 3.49 (t, 2H), 3.52 (s, 3H), 5.59 (q, 1 H), 6.67
(dd,
1 H), 6.72 (d, 1 H), 7.39 (d, 2H), 7.63 (m, 3H),
EXAMPLE 29
(R)-6-(3-hydroxypropyl)-3-((S)-1 -(4-(6-oxo-1,6-dihydropyridin-3-
yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
O HZN -B(OH)2 101
O N I\ N. 0--N
I\ _
/ Br Pd(Ph3P)zC1z BH
/ I \ NaOH
/ Cs2CO3 N NH HzOz
z
OI 0
OI~N 0) \N
0.... HZSO4
NaN02 I N O
N NH2 H
OH OH
Step 1
A mixture of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-
oxazinan-2-one (150 mg, 0.375 mmol) and 6-aminopyridin-3-ylboronic acid
(56 mg, 0.45 mmol), Pd(Ph3P)2CI2 (15 mg), and aqueous Cs2CO3 solution
(0.5 mL, 2 M) in 1,4-dioxane (10 ml-) was stirred and heated to reflux for 2
h.
The organic phase was separated, and concentrated to give the crude
product, which was purified by preparative HPLC to give (R)-6-allyl-3-((S)-1-
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(4-(6- aminopyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (90 mg,
60%).
Step 2
To a solution of (R)-6-allyl-3-((S)-1-(4-(6-aminopyridin-3-
yl)phenyl)ethyl)-6-phenyl-1,3- oxazinan-2-one (90 mg, 0.23 mmol) in
tetrahydrofuran (10 mL) was added BH3 THE (3.0 mL, I mol/L, 4 mmol) at 0
C under nitrogen atmosphere. The formed mixture was stirred for 2 h. The
reaction was quenched by water. Then NaOH (2 mL, 3 mol/L) and H202 (1
mL) was added to the above mixture. When the reaction was over, the
mixture was extracted with EtOAc. The combined organic phase was
concentrated to give the crude product, which was purified by preparative
HPLC to give (R)-3-((S)-1-(4-(6-aminopyridin -3-yl)phenyl)ethyl)-6-3-
hydroxypropyl)-6-phenyl-1,3-oxa zinan -2- one (40 mg, 41 %).
Step 3
(R)-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(3-hydroxypropyl)-
6-phenyl-1,3-oxazinan-2-one (40 mg, 0.09 mmoL) was dissolved in 3.5 M
H2SO4 (10 mL), and 2 M NaNO2 (10 mL) was added at 0 C. The reaction
mixture was stirred at rt for 2 h and treated with NaOH solution. The mixture
was extracted with EtOAc. The combined organic layer was washed with
brine, dried over anhydrous Na2SO4, and concentrated to afford the residue,
which was purified by preparative HPLC to give (R)-6-(3-hydroxypropyl)-3-
((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-
2-one (10 mg, 20%). LC-MS Method 2 tR = 1.66, min, m/z = 433, 455; 1H
NMR (CDC13): 1.36 (m, 2H), 1.50 (m, 3H), 1.68 (m, 2H), 1.92 (m, 2H), 2.10-
2.30 (m, 3H), 2.84 (m, 1 H), 3.50 (m, 2H), 5.12 (m, 1 H), 6.62 (m, 1 H), 6.86
(m, 2H), 7.08 (m, 2H), 7.18-7.32 (m, 5H), 7.46 (m, 1 H), 7.62 (m, 1 H).
EXAMPLE 30
(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-
yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
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Br Mel Br Nzzz
N O NaH N O
H
O O
O~N Br OAN
O N 'O
OH OH
Step 1
To a suspension of NaH (4.8 g, 0.2 mol) in THE (10 mL) was added a
solution of 5- bromopyridin-2(1 H)-one (8.6 g, 0.05 mol) in THE (120 mL) at 0
C. The resulting mixture was stirred for 1 h and CH3I (35.5 g, 0.25 mol) was
added. The mixture was stirred for 3 h. The reaction was quenched with
aqueous NH4CI solution. The organic phase was concentrated to give the
crude product, which was purified by column chromatography to give 5-
bromo-1-methylpyridin-2(1 H)-one (8.9 g, 96.78 %). 1H NMR (CDCI3): 6= 3.5
(S, 3H), 6.52 (m, 1 H), 7.32 (m, 1 H),7.45(m, 1 H).
Step 2
A mixture of (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1 -(4-(4,4,5,5-
tetramethyl- 1,3,2- dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (1.7
g, 3.7 mmol) and 5-bromo-1- methylpyridin-2(1 H)-one (816 mg, 4.4 mmol),
Pd(Ph3P)2CI2 (200mg), and aq Cs2CO3 solution (4mL, 2M) in 1,4-dioxane
(30 mL) was stirred and heated to reflux for 2 h. When the reaction was
over, the mixture was washed with water and extracted with EtOAc, and the
organic phase was washed with brine, dried over Na2SO4, filtered and
concentrated to give crude product, which was purified by preparative TLC
to give (R)-6-(3-hydroxypropyl) -3-((S)-1-(4-(1-methyl -6- oxo-1,6-
dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan- 2-one (614 mg ,
37%). LC-MS Method 2 tR = 1.075 min, m/z = 447.1; 1H NMR (CDCI3):
6=1.38 (m, 1 H),1.47 (d, 3H), 1.73 (m, 2H), 1.98 (m, 2H), 2.20 (m, 1 H), 2.31
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(m, 2H), 2.94 (m, 1 H), 3.51 (m, 2H), 3.56 (s, 3H), 5.63 (m, 1 H), 6.67 (m, 1
H),
6.87 (m, 2H), 7.05 (m, 2H), 7.31-7.41 (m, 6H), 7.48 (m, 1 H).
EXAMPLE 31
(S)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-3-((S)-1 -(4-(l -methyl-6-oxo-1,6-
dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one
O O
OAN 1. Na104, Os04 OAN
2. NaBH4
OH
F 1 O F O
To a solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-
oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (0.064 g, 0.144
mmol, 1.0 equiv) in THF-H20 (1:1, 6 mL) were added Na104 (0.145 g, 0.678
mmol, 4.7 equiv) and Os04 (2.5 wt.% solution in t-BuOH, 0.048 g, 0.0047
mmol, 0.033 equiv), and the mixture was stirred at rt for 1 h. The mixture
was diluted with EtOAc, dried over Na2SO4, and concentrated under reduced
pressure. The residue was dissolved in MeOH (3 mL) and NaBH4 (0.100 g)
was added. After the mixture was stirred for 0.5 h at rt, acetone was added.
The solvents were removed in vacuo, the residue was treated with saturated
brine, extracted with CH2CI2, and dried over Na2SO4. After the solvent was
evaporated, the residue was purified by reversed-phase HPLC (SunFireTM
Prep C18 OBDTM 5 m 19 x 50 mm column, 10% -90% CH3CN/H20, 0.1 %
CF3000H over 8 min and then 90% CH3CN/H20, 0.1 % CF3000H over 2
min, flow rate 20 mL/min) to afford (S)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-
3-((S)-1-(4-(1-methyl -6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-
oxazinan-2-one. LC-MS Method 1 tR = 1.21 min, m/z = 451 (M+1); 1H NMR
(400 MHz, CD3OD) 6 7.80 (m, 1 H), 7.69 (d, J = 9.4 Hz, 1 H), 7.22-7.19 (m,
4H), 7.00-6.92 (m, 4H), 6.52 (d, J = 9.4 Hz, 1 H), 5.45 (q, J = 7.0 Hz, 1 H),
3.60-3.52 (m, 1 H), 3.52 (s, 3H), 3.24-3.18 (m, 1 H), 3.02-2.98 (m, 1 H), 2.39-
2.35 (m, 1 H), 2.23-2.12 (m, 2H), 2.01 (t, J = 7.3 Hz, 2H), 1.43 (d, J = 7.0
Hz,
3H); 19F NMR (376 MHz, CD3OD) 6 -117.19 (m).
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EXAMPLE 32
(S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(1-methyl-6-
oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one
Method 1
0
0
\ H2N B(OH)2 O N
/ Br Pd(Ph3P)2CI2 F / Na2NO2
F Cs2CO3 N NH2
I0I 0
ON 0)~N
\ / \ Nal _ I \ / \ KMnO4
F~% Mel F / NalO4
H O i O
0 0
0IkN SOCI2 ON
MeMgBr
F I/ / I\ MeOH F I/ I\
HO VO 0 MeO N 0
0
O--I-N I
F /
N O
HO
Step 1
A mixture of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-
fluorophenyl)-1,3-oxa zinan- 2-one (1.6 g, 3.84 mmol) and 6-aminopyridin-3-
ylboronic acid (1.0 g, 4.61 mmol), Pd(Ph3P)2C12 (150 mg), and aq Cs2CO3
solution (3.84 mL, 2 M) in 1,4-dioxane (150 mL) was stirred and heated to
reflux for 2 h. The mixture was filtered and the filtrate was extracted with
EtOAc. The combined organic phase was washed with brine, dried over
anhydrous Na2SO4, and concentrated to give (R)-6-allyl-3-((S)-1-(4- (6-
aminopyridin -3-yl) phenyl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (1.5
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g, 90%), which was used for the next step without purification. 1H NMR
(CDC13): 6=1.51 (d, 3H), 2.17-2.31 (m, 3H), 2.54-2.60 (m, 2H), 2.90 (m, 1 H),
4.46 (s, 2H), 4.99-5.09 (m, 2H), 5.65-5.71 (m, 2H), 6.54 (m, 2H), 6.88 (d,
2H), 7.03 (t, 2H), 7.21-7.27 (m, 3H), 7.58 (d, 1 H), 8.22 (d, 1 H).
Step 2
To a solution of (R)-6-allyl-3-((S)-1-(4-(6-aminopyridin-3-
yl)phenyl)ethyl)-6-(4- fluorophenyl)-1,3-oxazinan-2-one (1.5 g, 3.47 mmoL)
in 3.5 M H2SO4 (25 mL) was added 2 M NaNO2 (15 mL) at 0 C. The
reaction mixture was stirred at rt overnight. The reaction was treated with
aqueous NaOH solution (8%), and the mixture was extracted with CH2CI2.
The combined organic layer was washed with brine, dried over anhydrous
Na2SO4 and concentrated to give crude product , which was purified by
preparative TLC to give (R)-6-ally)-6-(4 -fluorophenyl)-3-((S)-1-(4-(6-oxo-1,6-
dihydropyridin-3-yl)phenyl) ethyl)-1,3- oxazinan-2-one (891 mg, 59%). 1H
NMR (CDC13): 6=1.52 (d, 3H), 2.15-2.38 (m, 3H), 2.51-2.60 (m, 2H), 2.94 (m,
1 H), 4.99-5.11 (m, 2H), 5.65-5.74 (m, 2H), 6.67 (m, 1 H), 6.89 (d, 2H), 7.00
(t, 2H), 7.13-7.20 (m, 2H), 7.20-7.27 (d, 2H), 7.33 (m, 1 H), 7.46 (m, 1 H),
7.77 (m, 1 H).
Step 3
To a suspension of NaH (330 mg, 8.24 mmol) in THE (20 mL) was
added a solution of (R)-6- allyl-6-(4-fluorophenyl)-3-((S)-1 -(4-(6-oxo-1,6-
dihydropyridin-3-yl)phenyl)ethyl)- 1,3- oxazinan-2-one (891 mg, 0.1 74mmol)
in THE (30 mL) at 0 C, and the resulting mixture was stirred for 1 h. CH3I (2
ml) was added and the mixture was stirred overnight. The reaction was
quenched by aqueous NH4CI solution. The organic phase was separated,
and concentrated to give the crude product, which was purified by
preparative TLC to give (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-
oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (634 mg, 69%).
1H NMR (CDC13): 6=1.52 (d, 3H), 2.16-2.35 (m, 3H), 2.52-2.64 (m, 2H), 2.94
(m, 1 H), 3.61 (s, 3H), 5.00-5.11 (m, 2H), 5.66-5.74 (m, 2H), 6.64 (d, 1 H),
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6.90 (d, 2H), 7.02 (t, 2H), 7.11-7.14 (d, 2H), 7.25-7.28 (m, 2H), 7.41 (m, 1
H),
7.53 (m, 1 H).
Step 4
To a solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-
oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (320 mg,
0.717mmol) in acetone (20 mL) was added aqueous KMnO4 and Na104
solution (15 mL). Then the formed mixture was stirred for 30 min at 0 C.
The mixture was filtered, and the filtrate was adjusted to pH = 5-6 with 1 N
aq HCI solution. The mixture was extracted with EtOAc, and the combined
organic phase was washed with brine, dried over anhydrous Na2SO4 and
concentrated to give 2-((S)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-
1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)acetic acid.
Step 5
To a solution of 2-((S)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-
1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)acetic acid
(290 mg, 0.625 mol) in MeOH (20 mL) was added SOC12 (2 mL) at 0 C, and
the reaction mixture was stirred at rt for 2 h. The reaction mixture was
concentrated to give the residue, which was purified by preparative TLC to
give methyl 2-((S)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl -6-oxo-1,6-
dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)acetate (130 mg,
43.5%). 1H NMR (CDC13): 6=1.52 (d, 3H), 2.36-2.55 (m, 3H), 2.67-2.71 (m,
2H), 2.90-3.04 (m, 3H), 3.68 (s, 3H), 3.71 (s, 3H), 5.66 (m, 2H), 6.66 (d, 1
H),
6.90 (d, 2H), 7.03 (t, 2H), 7.13-7.15 (d, 2H), 7.23-7.29 (m, 2H), 7.42 (m, 1
H),
7.56 (m, 1 H).
Step 6
To a solution of methyl 2-((S)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-
6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)acetate
(130 mg, 0.22 mmol) in dry THE (20 mL) was added MeMgBr (2 mL) at -78
C, and the mixture was stirred under N2 at rt overnight. The reaction was
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quenched with water, and the mixture was extracted with EtOAc. The
combined organic phase was dried over Na2SO4, and concentrated to give
the residue, which was purified by preparative HPLC to give (S)-6-(4-
fluorophenyl) -6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(l-methyl-6-oxo-1,6-
dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (24 mg, 30%). LC-MS
Method 2 tR = 1.116 min, m/z = 479.1; 1H NMR (CDC13): 1.1 (m, 6H), 1.18
(m, 1 H), 1.48 (d, 3H), 1.58 (m, 1 H), 1.80-2.00 (m, 2H), 2.21 (m, 3H), 2.86
(m,
1 H), 5.55 (m, 1 H), 7.72 (m, 2H), 7.00 (m, 2H), 7.18 (m, 4H).
lo Method 2
0
ON ON I \ O11 N \
Br CuCI, PdC12 McMgBr~ / Br
F/ F OH
O
4O O ON Br I O1~' N
B B
O b \ BOO N O \ / 1 \
F I/ OH O F / OH i O
Step 1
To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-
fluorophenyl) -1,3-oxazinan-2-one (5 g, 12 mmol) and CuCI (2.75 g, 27.8
mmol) in dry DMF (50 mL) was added H2O (20 mL) and PdC12 (950 mg, 3.2
mmol) at room temperature. The mixture was vigorously stirred under a
balloon of oxygen for 24 h. After TLC showed the starting material had
disappeared, the solid was filtered off. Water (200 mL) and EtOAc (50 mL)
was added, the layers were separated and the aqueous layer was extracted
with EtOAc (3 x 40 mL). The combined organic layer was washed with
brine, dried over Na2SO4, filtered and concentrated to give (S)-3-((S)-1-(4-
bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-oxopropyl)-1,3-oxazinan -2-one
(5.25 g, 92%), which was purified by column chromatography. 1H NMR
(CDC13): 1.47 (s, 3H), 2.06 (s, 3H), 2.10-2.36 (m, 3H), 2.58 (m, 1 H), 2.90
(m,
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2H), 5.58 (m, 1 H), 6.69 (m, 1 H), 6.79 (m, 1 H), 7.02 (m, 2H), 7.19-7.33 (m,
4H).
Step 2
To a solution of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-
6-(2-oxopropyl)-1,3-oxazinan -2-one (5.25 g, 12.1 mmol) in anhydrous THE
(100 mL) was added dropwise methylmagnesium bromide (20 mL, 60 mmol)
at -78 C under nitrogen. Then the mixture was stirred at rt for 2 h. The
reaction mixture was cooled in an ice bath and quenched with aqueous
NH4CI. The layers were separated. The aqueous layer was extracted with
EtOAc (15 mL) washed with a brine (30 mL), dried over Na2SO4 and
concentrated in vacuo to give the crude product, which was purified by
preparative HPLC and chiral HPLC to afford (S)-3-((S)-1-(4-
bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methyl propyl)-1,3-
oxazinan-2-one (2.5 mg, 46%). 1H NMR (CDC13): 1.08 (s, 3H), 1.12 (s, 3H),
1.48 (m, 3H), 1.99 (m, 1 H), 2.10-2.24 (m, 4H), 2.35 (m, 1 H), 2.85 (m, 1 H),
5.61 (m, 1 H), 6.80 (m, 2H), 6.99 (m, 2H), 7.15-7.28 (m, 5H).
Step 3
A mixture of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-
(2-hydroxy-2- methylpropyl)-1,3-oxazinan-2-one (640 mg, 1.42 mmol),
4,4,4',4',5,5,5',5'-octamethyl-2,2'- bi(1,3,2-dioxaborolane) (470 mg, 1.85
mmol), PdCl2dppf (40 mg, 0.047mmol , KOAc (490 mg, 4.97 mmol) in
DMSO (8 mL) was heated at 90 C for 20 h. The mixture was diluted with
EtOAc, and washed with water. The organic phase was separated, and
concentrated to give the crude product, which was purified by preparative
TLC to afford (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-
(4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-
2-one (700 mg, 99%). 1H NMR (CDC13): 6=1.08 (s, 3H), 1.13 (s, 3H), 1.32
(s, 12H), 1.51 (t, 3H), 1.94 (m, 2H), 2.16 (m, 5H), 2.33 (m, 1 H), 2.83 (m, 1
H),
5.69 (m, 1 H), 6.99 (m, 4H), 7.25 (m, 2H), 7.61 (m, 2H).
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Step 4
A mixture of (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methyl propyl)-3-
((S)-l-(4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-
oxazinan-2-one (700 mg, 1.41 mmol), 5-bromo-1-methylpyridin-2(1 H)-one
(398 mg, 2.12 mmol), PdC12(Ph3P)2 (70 mg), Cs2CO3 (1.5 mL, 3.0 mmol) in
1,4-dioxane (15 mL) was heated under reflux for 2 h. The mixture was
diluted with EtOAc, and washed with water. The organic phase was
separated, and concentrated to give the crude product, which was purified
by preparative TLC to afford (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-
methyl propyl)-3-((S)-1-(4-(1-methyl-6-oxo- 1,6-dihydropyridin-3-
yl)phenyl)ethyl)-1,3-oxazinan-2-one (150 mg, 22%). 1H NMR (CDC13):
6=1.12 (s, 3H), 1.13 (s, 3H), 1.51 (t, 3H), 2.16 (m, 2H), 2.21 (m, 2H), 2.41
(m, 1 H), 2.92 (m, 1 H), 3.63 (s, 3H), 5.69 (q, 1 H), 6.69 (m, 1 H), 6.99 (m,
4H),
7.18 (m, 2H)37.27 (m, 2H) 6 7.42 (m, 1 H), 7.52 (m, 1 H).
EXAMPLE 33
(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-
dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one
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O 0
NH2
pN I \ BHg 0 N \ (HO)2B _/
N
\ a Br NaOH H2O2 / Br
II Pd(Ph3P)2CI2
F F / CS2CO3
OH
O
O
0)~ N I \ \
O N
\ / \ H2SO4 _ \ I / \ TBSCI
/ NaN02
F N NH2 F I/ I N O
OH 0H H
O
O
I O N \
O N N H TBAF
Mel
F / N O
F N 0 OTBS
OTBS
O
O-k N
F I/ N O
OH
Step 1
To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-
fluorophenyl)-1,3- oxazinan -2-one (1.1 9g, 2.8mmol) in THE (30 mL) was
added BH3 THE (8.5 mL, I mol/L, 8.5mmol) at 0 C under nitrogen
atmosphere. The formed mixture was stirred for 2 h. The reaction was
quenched with water. Then NaOH (1 mol/L, 6mL) and H202 (5 mL) were
added to the above mixture. When the reaction was over, the mixture was
extracted with EtOAc. The combined organic phase was concentrated to
give the crude product, which was purified by preparative TLC to give (R)-3-
((S)-1-(4-bromophenyl) ethyl)-6- (4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-
oxazinan-2-one (1.13 g, 92%).
Step 2
A mixture of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-
(3-hydroxypropyl)- 1,3-oxazinan-2-one (520mg, 1.2mmol) and 6-
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aminopyridin-3-ylboronic acid (280mg, 1.44mmol), Pd(Ph3P)2C12 (100mg),
and aq Cs2CO3 solution (3mL, 2M) in 1,4-dioxane (20 mL) was stirred and
heated to reflux for 2 h. The organic phase was separated, and
concentrated to give crude product, which was purified by preparative TLC
to give (R)-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(4-fluoophenyl)-6-
(3-hydroxy propyl)-1,3-oxazinan-2-one .(400mg,74%).
Step 3
(R)-3-((S)-1-(4-(6-aminopyridin-3-yl)phenyl)ethyl)-6-(4-fluorophenyl)-
6-(3-hydroxypropyl)-1,3-oxazinan-2-one (400 mg, 0.88 mmoL) was dissolved
in 3.5 M H2SO4 (10 mL), and 2 M NaNO2 (6 mL) was added at 0 C. The
reaction mixture was stirred at rt for 20 min. The reaction mixture was then
treated with aqueous NaOH solution (8%), and extracted with CH2C12. The
combined organic layer was washed with brine, dried over anhydrous
Na2SO4, and concentrated to give crude product, which was purified by
preparative TLC to give (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-
(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (350 mg,
0.78 mmol). 1H NMR (CDC13): 6=1.10-1.25 (m, 8H), 1.37 (m, 1 H), 1.42-1.55
(m, 2H), 1.78-1.93 (m, 2H), 2.10-2.38 (m, 2H), 2.87 (m, 2H), 3.52-3.58 (m,
1 H), 3.31-3.97 (m, 1 H), 4.12-4.19 (m, 1 H), 5.53-5.63 (m, 1 H), 6.85-7.15
(m,
3H), 7.35-7.55 (m, 1 H), 7.75-7.89 (m, 1 H), 8.10-8.12 (m, 1 H).
Step 4
A mixture of (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1 -(4-(6-
oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (100 mg, 0.78
mmol), imidazole (142.8 mg, 2.1 mmol), and tert-butylchlorodimethylsilane
(350 mg, 2.34 mmol) in CH2C12 (20 mL) was stirred overnight. The mixture
was washed with water and extracted with EtOAc. The combined organic
phase was washed with brine, dried over Na2SO4, filtered and concentrated
to give crude (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-6-(4-fluorophenyl)-
3-
((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one
(120 mg), which was used for the next step without further purification.
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Step 5
To a suspension of NaH (18 mg, 0.72 mmol) in THE (0.5 mL) was
added a solution of (R)-6-(3-(tert-butyldimethyl silyloxy)propyl)-6-(4-
fluorophenyl)-3-((S)-1-(4-(6-oxo-l ,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-
oxazinan-2-one (100mg, 0.18 mmol) in THE (10 mL) at 0 C. The resulting
mixture was stirred for 1 h. Then CH3I (613 mg, 43.2 mmol) was added, and
the mixture was stirred for 3 h. The reaction was quenched with aq NH4CI
solution. The organic phase was separated, and concentrated to give (R)-6-
(3-(tert-butyldimethyl silyloxy)propyl)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-
methyl-
6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (104
mg,100%), which was used for the next step without further purification.
Step 6
A mixture of (R)-6-(3-(tert-butyldimethylsilyloxy)propyl)-6-(4-fluorophenyl)-3-
((S)-1-(4-(1-methyl -6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-
2-one (200 mg, 0.35 mmol) and TBAF (182 mg,0.7 mmol) in CH3CN was
stirred and heated to reflux for 15 min. When the reaction was over, the
mixture was washed with water and extracted with EtOAc. The combined
organic phase was washed with brine, dried over Na2SO4, filtered and
concentrated to give crude product, which was purified by preparative HPLC
to give (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-
oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (5.01 mg, 4%).
LC-MS Method 2 tR = 1.065 min, m/z = 464.21; 1H NMR (CDCI3): 6=1.38 (m,
1 H),1.47 (d, 3H), 1.63 (m, 2H), 1.91 (m, 2H), 2.10-2.30 (m, 3H), 2.87 (m,
1 H), 2.84 (m, 1 H), 3.51 (m, 2H), 3.56 (s, 3H), 5.63 (m, 1 H), 6.67 (m, 1 H),
6.87-6.98 (m, 4H), 7.15 (m, 2H), 7.27 (m, 1 H), 7.29(m, 1 H), 7.32 (m, 1 H),
7.55(m, 1 H).
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EXAMPLE 34
N-(3-((R)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-
3-yl)phenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)propyl)methanesulfonamide
O
O~N
O~N \ 1. McS02Cl
2. McS02NH2, K2CO3
I / O O
F / N O F o N O
OH H.S~
The title compound was prepared from (R)-6-(4-fluorophenyl)-6-(3-
hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-
yl)phenyl)ethyl)-1,3-oxazinan-2-one by treatment with (i) McSO2CI and (ii)
McSO2NH2. LC-MS Method 2 tR = 1.02 min, m/z = 542.3; 1H NMR (CDC13)
1.35 (m, 1 H), 1.53 (d, 3H), 1.69 (m, 1 H), 1.89 (m, 1 H), 2.00 (m, 1 H), 2.17-
2.33 (m, 3H), 2.89 (s, 3H), 2.97 (m, 1 H), 3.06 (m, 2H), 3.66 (s, 3H), 4.38
(s,
1 H), 5.67 (m, 1 H), 6.82 (d, 1 H), 6.99 (m, 4H), 7.15 (m, 2H), 7.22 (m, 2H),
7.47 (s, 1 H), 7.63 (d, 1 H).
EXAMPLE 35
3-((R)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-
phenyl-1,3-oxazinan-6-yl)propanamide
O
(HO)2B
~N \ I % OAN
O
N NH2 \ / \
\ ` Br O
N NH2
H2N O 0 NH2
O O
NaNO2 OAN OAN
H2SO4
I / I I /
N O N OH
0 NH2 H 0 NH2
The title compound was prepared from 3-((R)-3-((S)-1-(4-
bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide following
procedures analogous to those described in Example 33 Steps 2 and 3. LC-
MS Method 2 tR = 0.999 min, m/z = 446.1; 1H NMR (CD3OD) 1.53 (d, 3H),
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1.91-2.01 (m, 1 H), 2.18-2.34 (m, 4H), 2.35-2.51 (m, 2H), 3.03-3.12 (m, 1 H),
5.56 (m, 1 H), 6.62 (d, 2H), 7.03 (d, 2H), 7.24-7.44 (m, 7H), 7.59 (m, 1 H),
7.87 (m, 1 H).
EXAMPLE 36
(S)-6-(2-hydroxyethyl)-3-((S)-1-(4-(l-methyl-6-oxo-1,6-dihydropyridin-3-
yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
0 0
ON \ (HO)ZB N NH2 O)LN
/ \ H2SO4
Br Pd(Ph3P)ZCIZ N NaN Z
OH CS2CO3 OH N NH2
0 0
O)~ N 0 1~1 N \
I I Mel
OH H O OTBS H O
0
O)~ N 0
Et4NF OAN
OTBS 0 C&I N 0
N %4
OH
The title compound was prepared from (S)-3-((S)-1-(4-
bromophenyl)ethyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one using a
procedure analogous to that described in Example 33 Steps 2 to 6. LC-MS
Method 2 tR = 1.038 min, m/z = 433.1; 1H NMR (CDC13) 1.48 (d, 3H), 2.06-
2.19 (m, 2H), 2.11-2.31 (m, 3H), 2.84 (m, 1 H), 3.50 (m ,1 H), 3.54 (s, 3H),
3.72 (m, 1 H), 5.62 (m, 1 H), 6.60 (d, 1 H), 6.86 (d, 2H), 7.06 (d, 2H), 7.26
(m,
3H), 7.32 (m, 3H), 7.47 (d, 1 H).
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EXAMPLE 37
(S)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(1-methyl -6-oxo-1,6-
dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
Method 1
0 0
ON (HO)2B NH2 OAN
\ N H2SO4
/ Br Pd(Ph3P)2CI2 / \ I NaNO2
Cs2CO3 N NH2
0 0
O--l- N 0-1-N
H 02
Mel \
/ I I N O I/ I CuCI, PdCl2
H i 0
0 0
0AN MeMgBr 0AN
O N 0 I/ I N O
1 OH I
The title compound was prepared from (R)-6-allyl-3-((S)-1-(4-
bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one using procedures
analogous to those described in Example 33 Steps 2, 3 and 5, followed by
procedures analogous to those described in Preparation 1 Method 1 Steps 4
and 6. LC-MS Method 2 tR = 1.116 min, m/z = 461.1; 1H NMR (CDCI3) 1.09
(s, 3H), 1.16 (s, 3H), 1.51 (m, 3H), 2.05-2.20 (4H), 2.40 (m, 1 H), 2.84 (m,
1 H), 3.59 (s, 3H), 5.64 (m, 1 H), 6.62 (m, 1 H), 6.96 (m, 2H), 7.14 (m, 2H),
7.28-7.39 (m, 5H), 7.48 (m, 1 H), 7.50 (m, 1 H).
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Method 2
O1~1 N O N
CuCI, PdC12 Br MeMgBr
=' Br
Br 0
OH
0
0 II
O O Br 0 N
B 0 N
0 B 0 0 N O /
i x
0-- OH i 0
OH
Step 1
To a solution of (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-
1,3- oxazinan- 2-one (20 g, 50 mmol) and CuCI (12.4 g, 125 mmol) in dry
DMF (50 mL) was added H2O (12 mL) and PdCl2 (2.66 g, 15 mmol) at 0 - -5
C. After addition, the mixture was allowed to warm to rt gradually for 48 h
under 02. After TLC showing the stating material had disappeared, the solid
was filtered off. Water (200 mL) and EtOAc (50mL) were added. The layers
were separated and the aqueous layer was extracted with EtOAc (3 x 40
mL). The combined organic layer was washed with brine, dried over
Na2SO4, filtered and concentrated to give a residue, which was purified by
column chromatography to give (S)-3-((S)-1-(4-bromo-phenyl)ethyl)-6-(2-
oxopropyl)-6-phenyl-1,3-oxazinan-2-one (12 g, 58%).
Step 2
To a solution of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-oxopropyl)-6-
phenyl-1,3- oxazinan- 2-one (12 g, 28.8 mmol) in anhydrous THE (100 mL)
was added dropwise methylmagnesium bromide (48 mL, 144 mmol) at -78
C under nitrogen. The mixture was stirred at rt for 1 h. The reaction
mixture was quenched with aqueous NH4CI solution (50 mL) in ice water
bath. The layers were separated and the aqueous layer was extracted with
EtOAc (150 mL). The combined organic phases were washed with brine (30
mL), dried over Na2SO4 and concentrated in vacuo to give the crude
product, which was purified by preparative HPLC and chiral HPLC to afford
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(S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-methyl propyl)-6-phenyl-
1,3-oxazinan-2- one (6.6 g, 53%).
Step 3
To a solution of (S)-3-((S)-1 -(4-bromophenyl)ethyl)-6-(2-hydroxy-2-
methylpropyl)-6-phenyl-1,3-oxazinan-2-one (6.6 g, 15.2 mmol) and
4,4,4',4',5,5,5',5'- octamethyl- 2,2'-bi(1,3,2- dioxaborolane) (6.1g, 24.3
mmol)
in dry DMSO (20 mL) was added KOAc (4.8 g, 48.6 mmol) and Pd(dppf)c12
(372 mg, 0.46 mmol). After addition, the mixture was allowed to warm to
100 C for 20 h. After TLC showed the starting material had disappeared,
the solid was filtered off. Water (60 mL) and EtOAc (20mL) were added.
The layers were separated and the aqueous layer was extracted with EtOAc
(3 x 15 mL). The combined organic layer was washed with brine, dried over
Na2SO4, filtered and concentrated to give a residue, which was purified by
column chromatography to give (S)-6-(2-hydroxy-2-methylpropyl)- 6-phenyl-
3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborol-an-2-yl)phenyl)ethyl)-1,3-
oxazinan-2-one (4.4 g, 60%).
Step 4
To a solution of (S)-6-(2-hydroxy-2-methylpropyl)-6- phenyl-3-((S)- 1-
(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)ethyl)-1,3-oxazinan-
2-one (2.2 g, 4.58 mmol) and 5-bromo-1-methylpyridin-2(1 H)-one (1.37 g,
7.33 mmol) in dry 1,4-dioxane (4 mL) was added aqueous CSC03 solution
(10 mL, 10 mmol) and Pd(PPh3)2C12 (967 mg, 1.38 mmol). After addition,
the mixture was heated at 110 C for 30 min in a microwave. After TLC
showed the stating material had disappeared, the solid was filtered off.
Water (20 mL) and EtOAc (1 OmL) were added. The layers were separated
and the aqueous layer was extracted with EtOAc (3 x 10 mL). The
combined organic layer was washed with brine, dried over Na2SO4, filtered
and concentrated to give a residue, which was purified by preparative HPLC
to give (S)-6-(2-hydroxy-2- methyl propyl)-3-((S)-1-(4-(1-methyl-6-oxo- 1,6-
dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (730 mg,
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35%). 'H NMR (CDC13): 1.09 (s, 3H), 1.16 (s, 3H), 1.51 (m, 3H), 2.05-2.20
(4H), 2.40 (m, 1 H), 2.84 (m, 1 H), 3.59 (s, 3H), 5.64 (m, 1 H), 6.62 (m, 1
H),
6.96 (m, 2H), 7.14 (m, 2H), 7.28-7.39 (m, 5H), 7.48 (m, 1 H), 7.50 (m, 1 H).
The compound was recrystallized by two methods.
Recrystallization Method A
A mixture of (S)-6-(2-hydroxy-2- methyl propyl)-3-((S)-1-(4-(1-methyl-
6-oxo- 1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
(ca. 2.94 g) and isopropyl acetate (160 mL) was vigorously stirred at room
temperature or warmed at 50 C until most of the solid was dissolved. The
resulting mixture was filtered through an HPLC filter and then the filtrate
was
slowly stirred at room temperature overnight. The solids were filtered,
washed with isopropyl acetate and dried at rt under high vacuum to afford
1.43 g (49%) of a crystalline solid. M.p. 95-101 C. This form was
determined to be a hydrate which released 3.6% water by weight on heating.
Single crystal X-ray crystallography carried out by prosedures similar to
those described in Example 48 and 75 showed that this form was a
monohydrate.
Recrystallization Method B
A mixture of (S)-6-(2-hydroxy-2- methyl propyl)-3-((S)-1-(4-(1-methyl-
6-oxo- 1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
(ca. 10.03 g) and isopropyl acetate (600 mL) was heated to reflux in a 130
C oil bath until the solid was completely dissolved to form a homogeneous
solution. Heating was stopped and the resulting solution was slowly stirred
while slowly cooling to room temperature in the oil bath overnight. The solids
were filtered, washed with isopropyl acetate and dried at rt under high
vacuum to afford 7.30 g (73%) of crystalline solid. M.p. 180-181 C. This
form was determined to be anhydrous.
X-ray Structure Determination of the Monohydrate of Example 37
The monohydrate of Example 37, C28H32N2O4-H2O, crystallizes in the
monoclinic space group P21 (systematic absences OkO: k=odd) with
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a=13.3180(13)A, b=6.4263(6)A, c=14.6616(14)A, 13=94.671(3)0
,
V=1250.7(2)A3, Z=2 and dcalc=1.271 g/cm3. X-ray intensity data were
collected on a Rigaku Mercury CCD area detector employing graphite-
monochromated Mo-Ku radiation (X=0.71073 A) at a temperature of 143K.
Preliminary indexing was performed from a series of twelve 0.5 rotation
images with exposures of 30 seconds. A total of 458 rotation images were
collected with a crystal to detector distance of 35 mm, a 20swing angle of -
12 , rotation widths of 0.5 and exposures of 45 seconds: scan no. 1 was a
~-scan from 135 to 315 at w = 10 and x = 20 ; scan no. 2 was an w-scan
from -20 to 5 at x = -90 and ~ = 45 ; scan no. 3 was an w-scan from -14
to 10 at x = -90 and ~ = 0 . Rotation images were processed using
CrystalClear (CrystalClear: Rigaku Corporation, 1999.), producing a listing of
unaveraged F2 and 6(F2) values which were then passed to the
CrystalStructure (CrystalStructure: Crystal Structure Analysis Package,
Rigaku Corp. Rigaku/MSC (2002)) program package for further processing
and structure solution on a Dell Pentium III computer. A total of 7348
reflections were measured over the ranges 5.58 <-20<--50.02 , -14
< q< 15, -6<- K<- 7, -17<- 1<-15 yielding 3878 unique reflections (R;nt =
0.0164). The intensity data were corrected for Lorentz and polarization
effects and for absorption using REQAB (minimum and maximum
transmission 0.844, 1.000).
The structure was solved by direct methods (SIR97 (SIR97:
Altomare, A., M. Burla, M. Camalli, G. Cascarano, C. Giacovazzo, A.
Guagliardi, A. Moliterni, G. Polidori & R. Spagna (1999). J. Appl. Cryst., 32,
115-119)). Refinement was by full-matrix least squares based on F2 using
SHELXL-97 (SHELXL-97: Program for the Refinement of Crystal Structures,
Sheldrick, G.M. (1997), University of Gottingen, Germany). All reflections
were used during refinement (F2 's that were experimentally negative were
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replaced by F2 = 0). The weighting scheme used was w=1/[62(F2 O )+
0.0507P2 + 0.0056P] where P = (Fo + 2F2
C )/3 . Non-hydrogen atoms were
refined anisotropically and hydrogen atoms were refined isotropically.
Refinement converged to R1=0.0327 and wR2=0.0741 for 3641 reflections
for which F > 46(F) and R1=0.0356, wR2=0.0770 and GOF = 1.071 for all
3878 unique, non-zero reflections and 453 variables: R1 = I IIFoI - IFcII / I
IFoI
wR2={Iw(F2 -F2
GOF={~w(F0 -FC)2/(np)}'/2
where n = the number of reflections and p = the number of parameters
refined. The maximum 4/6 in the final cycle of least squares was 0.000 and
the two most prominent peaks in the final difference Fourier were +0.126
and -0.156 e/A3.
Table A. lists cell information, data collection parameters, and
refinement data. Final positional and equivalent isotropic thermal
parameters are given in Table B. Anisotropic thermal parameters are in
Table C.
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Table A. Summary of Structure Determination of the Monohydrate of
Example 37
Formula: C28H2N2O4'H2O
Formula weight: 478.57
Crystal class: monoclinic
Space group: P21 (#4)
Z 2
Cell constants:
a 13.3180(13)A
b 6.4263(6)A
c 14.6616(14)A
R 94.671(3)
V 1250.7(2)A3
0.87 cm-'
crystal size, mm 0.34 x 0.12 x 0.07
Dcalc 1.271 g/Cm3
F(000) 512
Radiation: Mo-Ka, (X=0.71073A)
20 range 5.58 - 50.02
hkl collected: -14<-11 <-15; -6<- K<-7;
- 17<-X<-15
No. reflections measured: 7348
No. unique reflections: 3878 (R;nt=0.0164)
No. observed reflections 3641 (F>46)
No. reflections used in refinement 3878
No. parameters 453
R indices (F>46) R1=0.0327
wR2=0.0741
R indices (all data) R1=0.0356
wR2=0.0770
GOF: 1.071
Final Difference Peaks, e/A3 +0.126, -0.156
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Table B. Refined Positional Parameters for the Monohydrate of
Example 37
Atom x z U ,
Cl 0.26084(12) 0.6441(3) 0.04394(11) 0.0257(4)
C2 0.18059(11) 0.7202(3) 0.18228(11) 0.0256(4)
C3 0.24317(13) 0.3609(3) 0.15652(11) 0.0273(4)
C4 0.23141(13) 0.4175(3) 0.05530(12) 0.0279(4)
C5 0.20783(13) 0.4862(3) 0.31228(11) 0.0265(4)
C6 0.31214(12) 0.4069(3) 0.34628(11) 0.0257(4)
C7 0.33149(12) 0.2036(3) 0.37391(11) 0.0275(4)
C8 0.42946(12) 0.1350(3) 0.39698(12) 0.0285(4)
C9 0.51160(12) 0.2672(3) 0.39040(11) 0.0259(4)
010 0.49143(14) 0.4714(3) 0.36273(13) 0.0332(4)
011 0.39419(13) 0.5402(3) 0.34183(13) 0.0337(4)
C12 0.61661(12) 0.1894(3) 0.40629(10) 0.0261(4)
C13 0.69391(12) 0.3119(3) 0.44100(12) 0.0288(4)
C14 0.81872(12) 0.0435(3) 0.42781(11) 0.0322(4)
C15 0.73791(13) -0.0848(3) 0.39052(13) 0.0347(4)
C16 0.64152(13) -0.0148(3) 0.38095(13) 0.0316(4)
C17 0.11974(13) 0.3459(3) 0.33161(13) 0.0308(4)
C18 0.8723(2) 0.3836(4) 0.4866(2) 0.0448(6)
C19 0.36756(12) 0.6953(3) 0.08492(10) 0.0252(4)
C20 0.38835(13) 0.8848(3) 0.12700(12) 0.0322(4)
C21 0.48576(14) 0.9382(4) 0.16024(13) 0.0365(5)
C22 0.56470(14) 0.8013(4) 0.15183(13) 0.0376(5)
C23 0.54480(14) 0.6122(4) 0.11008(13) 0.0394(5)
C24 0.44725(13) 0.5584(3) 0.07634(12) 0.0327(4)
C25 0.25008(13) 0.7270(3) -0.05467(12) 0.0296(4)
C26 0.16219(13) 0.6620(3) -0.12314(12) 0.0330(4)
C27 0.1729(2) 0.7843(4) -0.21160(14) 0.0426(5)
C28 0.0585(2) 0.7030(4) -0.09002(14) 0.0431(5)
N1 0.20819(10) 0.5306(2) 0.21329(9) 0.0249(3)
N2 0.79116(10) 0.2432(3) 0.45199(9) 0.0309(4)
01 0.18963(8) 0.7664(2) 0.09316(7) 0.0269(3)
02 0.14620(9) 0.8564(2) 0.22967(8) 0.0331(3)
03 0.90880(9) -0.0090(3) 0.43797(9) 0.0431(4)
04 0.17736(10) 0.4451(2) -0.13975(9) 0.0378(3)
H3a 0.3181(13) 0.331(3) 0.1766(12) 0.028(5)
H3b 0.2034(14) 0.229(4) 0.1670(12) 0.033(5)
H4 0.129(2) 0.406(5) -0.189(2) 0.084(9)
H4a 0.158(2) 0.400(3) 0.0311(13) 0.040(5)
H4b 0.272(2) 0.314(4) 0.019(2) 0.048(6)
H5 0.1980(13) 0.625(3) 0.3374(12) 0.028(5)
H7 0.2761(13) 0.104(3) 0.3761(12) 0.029(5)
H8 0.4408(12) -0.012(3) 0.4184(12) 0.027(5)
H10 0.551(2) 0.567(4) 0.3546(14) 0.044(6)
H11 0.383(2) 0.688(4) 0.3194(14) 0.041(5)
H13 0.6829(13) 0.453(4) 0.4616(12) 0.033(5)
H15 0.7581(14) -0.231(4) 0.3692(13) 0.038(5)
H16 0.588(2) -0.102(4) 0.350(2) 0.051(6)
H17a 0.125(2) 0.202(4) 0.299(2) 0.050(6)
H17b 0.1208(13) 0.321(3) 0.3978(14) 0.032(5)
H17c 0.054(2) 0.412(4) 0.3103(13) 0.039(5)
H18a 0.921(2) 0.388(5) 0.445(2) 0.079(8)
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Atom x z U ,
H18b 0.840(2) 0.499(6) 0.510(2) 0.092(10)
H18c 0.911(2) 0.315(6) 0.540(2) 0.103(11)
H2O 0.333(2) 0.980(5) 0.131(2) 0.065(7)
H21 0.4975(14) 1.079(4) 0.1869(14) 0.043(6)
H22 0.636(2) 0.834(4) 0.1769(14) 0.049(6)
H23 0.600(2) 0.514(4) 0.1029(13) 0.044(6)
H24 0.4343(14) 0.427(4) 0.0444(14) 0.038(5)
H25a 0.2503(13) 0.882(4) -0.0512(12) 0.030(5)
H25b 0.3131(13) 0.680(3) -0.0832(11) 0.023(4)
H27a 0.124(2) 0.731(4) -0.259(2) 0.042(5)
H27b 0.165(2) 0.943(5) -0.197(2) 0.066(7)
H27c 0.239(2) 0.752(4) -0.2360(14) 0.044(6)
H28a 0.0495(14) 0.617(4) -0.030(2) 0.048(6)
H28b 0.052(2) 0.865(5) -0.076(2) 0.058(7)
H28c 0.004(2) 0.655(4) -0.141(2) 0.048(6)
05 -0.04759(10) 0.7816(3) 0.28103(11) 0.0424(4)
H5a 0.020(2) 0.821(5) 0.272(2) 0.074(8)
H5b -0.055(2) 0.834(5) 0.332(2) 0.083 10
Ueq= 1 13[U11 (aa*) +U22(bb*) +U33(cc*)
+2U12aa*bb*cosy+2U13aa*cc*cosp+2U23bb*c
c*cosal
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Table C. Refined Thermal Parameters (U's) for the Monohydrate of
Example 37
Atom U11 U22 U33 U23 U13 U12
C1 0.0236(8) 0.0275(10) 0.0261(9) -0.0028(8) 0.0023(6) 0.0036(7)
C2 0.0217(8) 0.0252(10) 0.0300(9) 0.0005(8) 0.0018(6) 0.0019(7)
C3 0.0336(9) 0.0215(10) 0.0271(9) -0.0028(8) 0.0045(7) 0.0033(8)
C4 0.0307(9) 0.0258(10) 0.0267(9) -0.0023(8) 0.0000(7) -0.0016(8)
C5 0.0284(9) 0.0259(11) 0.0252(9) -0.0016(8) 0.0019(6) 0.0054(7)
C6 0.0273(8) 0.0277(10) 0.0220(8) -0.0030(8) 0.0013(6) 0.0018(7)
C7 0.0247(9) 0.0283(10) 0.0302(9) 0.0040(8) 0.0049(6) -0.0030(8)
C8 0.0276(9) 0.0263(11) 0.0317(9) 0.0058(8) 0.0027(7) 0.0010(8)
C9 0.0261(8) 0.0281(10) 0.0229(8) -0.0020(8) -0.0011(6) -0.0030(7)
C10 0.0306(9) 0.0254(11) 0.0424(10) 0.0007(9) -0.0050(7) -0.0061(8)
C11 0.0348(10) 0.0211(10) 0.0434(11) -0.0002(9) -0.0071(7) -0.0021(8)
C12 0.0262(8) 0.0289(10) 0.0230(8) 0.0008(8) 0.0013(6) -0.0020(7)
C13 0.0235(9) 0.0348(12) 0.0280(9) -0.0038(8) 0.0018(6) -0.0010(8)
C14 0.0297(9) 0.0448(13) 0.0221(8) 0.0032(9) 0.0021(6) 0.0042(9)
C15 0.0328(10) 0.0318(12) 0.0395(10) 0.0026(9) 0.0029(7) 0.0047(9)
C16 0.0284(9) 0.0283(11) 0.0376(10) 0.0025(9) -0.0001(7) -0.0011(8)
C17 0.0262(9) 0.0374(12) 0.0292(10) 0.0034(9) 0.0038(7) 0.0032(8)
C18 0.0231(9) 0.062(2) 0.0490(12) -0.0180(12) 0.0007(9) -0.0071(10)
C19 0.0268(9) 0.0268(10) 0.0225(8) -0.0011(8) 0.0047(6) 0.0008(7)
C20 0.0313(9) 0.0317(11) 0.0340(10) -0.0011(9) 0.0044(7) 0.0019(9)
C21 0.0379(10) 0.0361(12) 0.0354(10) -0.0036(9) 0.0021(7) -0.0098(9)
C22 0.0295(10) 0.0527(14) 0.0303(10) 0.0015(10) 0.0011(7) -0.0058(9)
C23 0.0269(10) 0.0524(14) 0.0393(11) -0.0022(10) 0.0047(7) 0.0094(10)
C24 0.0335(9) 0.0339(12) 0.0310(10) -0.0047(9) 0.0039(7) 0.0050(8)
C25 0.0313(9) 0.0306(12) 0.0274(9) 0.0036(8) 0.0056(7) 0.0019(8)
C26 0.0342(10) 0.0346(12) 0.0295(9) 0.0017(9) -0.0007(7) 0.0043(8)
C27 0.0501(12) 0.050(2) 0.0281(10) 0.0031(10) 0.0021(9) 0.0070(11)
C28 0.0337(10) 0.060(2) 0.0351(11) 0.0011(11) -0.0005(8) 0.0065(10)
N1 0.0282(7) 0.0225(8) 0.0241(7) -0.0002(6) 0.0031(5) 0.0034(6)
N2 0.0231(7) 0.0421(11) 0.0273(7) -0.0062(7) 0.0004(5) -0.0018(7)
01 0.0266(6) 0.0277(7) 0.0271(6) 0.0028(5) 0.0051(4) 0.0070(5)
02 0.0373(6) 0.0269(7) 0.0364(7) -0.0009(6) 0.0101(5) 0.0095(6)
03 0.0280(7) 0.0620(11) 0.0387(7) 0.0003(7) 0.0001(5) 0.0109(6)
04 0.0378(7) 0.0382(8) 0.0358(7) -0.0046(6) -0.0064(5) 0.0040(6)
05 0.0347(8) 0.0494 10 0.0428(8) -0.0025(8) 0.0019(6) 0.0070(7)
The form of the anisotropic displacement parameter is:
ex -27r2 a*2U11h2+b*2U22k2+c* U3312+ 2b*c*U23k1+2a*c*U13h1+2a*b*Ul2hk .
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EXAMPLE 38
3-((R)-3-((S)-1-(4-(1-methyl -6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-
oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide
O
OAN
N O
O NH2 1
The title compound was prepared from (R)-6-allyl-3-((S)-1-(4-(1-
methyl -6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-
one using a procedure analogous to that described in Example 29 Step 2
followed by treatment with (i) Jones reagent and (ii) NH3, EDC, HOBt. LC-
MS Method 2 tR = 1.028 min, m/z = 460.2; 1H NMR (CDC13) 1.53 (d, 3H),
1.91-2.01 (m, 1 H), 2.11-2.42 (m, 5H), 2.46-2.54 (m, 1 H), 2.88-2.96 (m, 1 H),
3.60 (s, 3H), 5.26 (s, 1 H), 5.42 (s, 1 H), 5.66 (m, 1 H), 6.69 (d, 1 H), 6.95-
7.03
(d, 2H), 7.12-7.20 (m, 2H), 7.24-7.41 (m, 5H), 7.52 (m, 1 H).
EXAMPLE 39
N-(3-((R)-3-((S)-1-(4-(1-methyl -6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-
oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)methanesulfonamide
O
OAN
N O
NH
O'
O
The title compound was prepared from (R)-6-(3-hydroxypropyl)-3-((S)-
1-(4-(1-methyl -6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-
oxazinan-2-one by treatment with (i) McS02C1 and (ii) McS02NH2, K2CO3.
LC-MS Method 2 tR = 1.095 min, m/z = 524.1; 1H NMR (CDC13) 1.30-1.41
(m, 1 H), 1.52 (d, 3H), 1.71 (m, 1 H), 1.87-2.07 (m, 3H), 2.09-2.20 (m, 3H),
2.22-2.32 (m, 2H), 2.88 (s, 3H), 3.06 (m, 2H), 3.60 (s, 3H), 4.32 (s, 1 H),
5.65
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(m, 1 H), 6.67 (d, 1 H), 6.94 (m, 2H), 7.11 (d, 2H), 7.25 (m, 1 H), 7.27-7.40
(m,
4H), 7.53 (dd, 1 H).
EXAMPLE 40
(S)-6-(2-hydroxyethyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-
yl)phenyl)propyl)-6-phenyl-1,3-oxazinan-2-one
O
O'it, N
O
OH N O
The title compound was prepared from (S)-3-((S)-1-(4-
bromophenyl)propyl)-6-(2-hydroxyethyl)-6-phenyl-1,3-oxazinan-2-one
following a procedure analogous to that described in Example 18 using 5-
bromo-1-methylpyridin-2(1 H)-one in Step 2. LC-MS Method 2 tR = 1.627
min, m/z = 447.1; 1H NMR (CDC13) 1.06 (m, 3H), 1.87-2.06 (m, 2H), 2.11-
2.28 (m, 2H), 2.33 (m, 3H), 2.96 (m, 1 H), 3.53 (m, 1 H), 3.62 (s, 3H), 3.78
(m,
1 H), 5.48 (m, 1 H), 6.69 (m, 1 H),7.03 (m, 2H), 7.14 (m, 2H), 7.21-7.38 (m,
4H), 7.41 (s, 1 H), 7.56 (m, 1 H) .
EXAMPLE 41
(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1 -(4-(2-oxo-1,2-
dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one
O O
OAN OAN
F HO N F O N
OH OH H
The title compound was prepared from (R)-6-allyl-6-(4-fluorophenyl)-
3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-
oxazinan-2-one and 3-bromo-2-hydroxypyridine using a procedure
analogous to that described in Example 3 Step 2, followed by a procedure
analogous to that described in Example 29 Step 2. LC-MS Method 1 tR =
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1.24, m/z = 452(M+1); 1H NMR (CDC13) 7.76(d, 1 H), 7.52(d, 1 H), 7.42(dd,
2H), 7.24(m, 2H), 7.08-7.00(m, 4H), 6.75(t, 1 H), 5.70(m, 1 H), 3.58(t, 1 H),
2.94(m, 1 H), 1.54(d, 3H).
EXAMPLE 42
(R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-
dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one
O O
ON 0 ON
H Mel, NaH
DMF
FO F C O N
H
O O
ON disiamyl ON I \
borane
F O N F I O N
I I
OH
1o Step 1
(R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1 -(4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (18 mg, 0.039 mmol), 3-
bromo-2-hydroxypyridine (14 mg, 2 equiv), Pd(dppf)C12 (3mg, 10%mol), 2M
aq Na2CO3 solution (800 pL) and 1,4-dioxane (1.5mL) were mixed. The
mixture was evacuated and refilled with N2 gas (3 x) before being heated
overnight at 85 C. After being cooled to rt, the mixture was filtered and
acidified with 5% aq HCI solution before being purified by prep HPLC to
afford (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(2-oxo-1,2-dihydropyridin-3-
yl)phenyl)ethyl)-1,3-oxazinan-2-one (7.2mg, 43% yield). LC-MS Method 1
tR=1.57min, m/z 433 (M+1).
Step 2
A solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1 -(4-(2-oxo-1,2-
dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (15.5 mg, 0.036 mmol)
in dry DMF (1 mL) was cooled to 0 C. Sodium hydride (60% in mineral oil,
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3 mg, 2 equiv) was added. After 20 min, iodomethane (4.5 pL, 2 equiv) was
added. The mixture was stirred another 20 min before being warmed to rt
slowly and stirred for 2 h. LC-MS found the reaction completed. The
mixture was quenched with satd aq NH4CI (1 mL) and purified by prep HPLC
to afford (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(l-methyl -2-oxo-1,2-
dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (13.3 mg, 83% yield).
LC-MS Method 1 tR=1.63min, m/z 447 (M+1).
Step 3
A solution of (R)-6-allyl-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-2-oxo-
1,2-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (13.3mg,
0.030mmol) in dry THE (1.5mL) was cooled to 0 C. Disiamyl borane (0.5M
in THF, 500pL, excess) was added. After 10 min, the mixture was warmed
to rt and stirred for 1 h. The mixture was cooled to 0 C again, quenched
with water (1 mL) and NaBO3 (10mg). The mixture was concentrated and
purified by prep HPLC to afford (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-
((S)-1-(4-(1-methyl -2-oxo-1,2-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-
2-one (4.2mg, 30% yield). LC-MS Method 1 tR = 1.33 min, m/z = 487(M+1);
1H NMR (CD3CI) 6 7.47(dd, 1 H), 7.38(m, 3H), 7.24(m, 2H), 7.07(t, 2H),
6.96(d, 2H), 6.39(t, 1 H), 5.65(m, 1 H), 4.26(t, 1 H), 3.66(s, 3H), 2.91(m, 1
H),
2.40-2.14(m, 3H), 1.54(d, 3H).
EXAMPLE 43
(R)-3-((S)-1-(4-(1-ethyl -6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(3-
hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one
O
OAN
N O
OH
The title compound was prepared following procedures analogous to
those described in Example 30 using ethyl iodide in Step 1, to afford 5-
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bromo-1-ethyl pyridin-2(1 H)-one which was used in Step 2. LC-MS Method 2
tR = 1.297 min, m/z = 461.1; 1H NMR (CDCI3) 1.31 (m, 1 H), 1.36 (t, 3H),
1.51 (d, 3H), 1.68 (m, 1 H), 1.86-2.01 (m, 2H), 2.18 (m, 1 H), 2.27 (m, 2H),
2.91 (m, 1 H), 3.52 (m, 2H), 4.18 (m, 2H), 5.13 (m, 1 H), 5.62 (m, 1 H), 6.91
(m, 3H), 7.08 (m, 2H), 7.18-7.33 (m, 5H), 7.41 (s, 1 H), 7.61 (d, 1 H).
EXAMPLE 44
(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-
yl)phenyl)propyl)-6-phenyl-1,3-oxazinan-2-one
O
OAN
N O
OH
The title compound was prepared from (R)-6-(3-hydroxypropyl)-6-
phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-
yl)phenyl)propyl)-1,3-oxazinan-2-one following procedures analogous to
those described in Example 30 Step 2. LC-MS Method 2 tR = 1.113 min, m/z
= 461.1; 1H NMR (CDCI3) 0.95 (t, 3H), 1.30 (m, 1 H), 1.68 (m, 1 H), 1.81-1.99
(m, 2H), 2.11-2.32 (m, 3H), 2.88 (m, 1 H), 3.50 (m, 2H), 3.58 (m, 2H), 5.43
(m, 1 H), 6.49 (d, 1 H), 6.98 (d, 2H), 7.08 (d, 2H), 7.19 (m, 1 H), 7.25 (m,
4H),
7.32 (s, 1 H), 7.47 (m, 1 H).
EXAMPLE 45
(R)-6-(3-hydroxypropyl)-3-((S)-1 -(4-(2-hydroxypyridin-4-yl)phenyl)ethyl)-6-
phenyl-1,3-oxazinan-2-one
O O
OAN O'1, N
\ \ OH O
N I / \ tH
OH OH
The title compound was prepared from (R)-6-(3-hydroxypropyl)-6-
phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-
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1,3-oxazinan-2-one and 4-bromo-2-hydroxypyridine following a procedure
analogous to that described in Example 30 Step 2. LC-MS Method 2 tR =
1.019 min, m/z = 865.4; 1H NMR (CDCI3) 1.29-1.40 (m, 1 H), 1.49 (d, 3H),
1.60-1.72 (m, 1 H), 1.83-2.01 (m, 3H), 2.18 (m, 1 H), 2.21-2.37 (m, 2H), 2.88
(m, 1 H), 3.51 (m, 2H), 5.63 (m, 1 H), 6.41 (d, 1 H), 6.68 (s, 1 H), 6.90 (d,
2H),
7.21-7.33 (m, 7H), 7.39 (d, 1 H).
EXAMPLE 46
(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-2-
yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
O
OAN "ay
OH O
The title compound was prepared from (R)-6-(3-hydroxypropyl)-6-
phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-
1,3-oxazinan-2-one and 6-bromo-1-methylpyridin-2(1 H)-one following a
procedure analogous to that described in Example 30 Step 2. LC-MS
Method 2 tR = 1.088 min, m/z = 447; 1H NMR (CDCI3) 1.38 (m, 1 H), 1.56 (d,
3H), 1.70 (m, 1 H), 1.95-2.08 (m, 2H), 2.23 (m, 1 H), 2.37 (s, 2H), 3.05 (m,
1 H), 3.33 (s, 3H), 3.58 (m, 2H), 5.73 (m, 1 H), 6.29 (d, 1 H), 6.89 (d, 1 H),
7.01-7.09 (m, 4H), 7.21-7.39 (m, 5H), 7.53 (t, 1 H).
6-Bromo-1-methylpyridin-2(1 H)-one was prepared from 6-
bromopyridin-2(1 H)-one following a procedure analogous to that described
in Example 59 Step 1.
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EXAMPLE 47
(R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-
yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
Br OH Mel Br O
N NaH \ N~
O O
Br O
O N I\ \ N 0 N I\
g~~
\ ~~ Pd(PPh3)2CI2, Cs2CO3
O I / \ N,
OH OH
Step 1
To a suspension of NaH (80 mg, 2 mmol) in THE (10 mL) was added
4-bromopyridin-2-ol (80 mg, 0.46 mmol) at 0 C. The resulting mixture was
stirred for 1 h. Then CH3I (355 mg, 2.5 mmol) was added to the above
mixture, and the mixture was stirred overnight. The reaction was quenched
with aqueous NH4CI solution. The organic phase was concentrated to give
the crude product, which was purified by column to give 4-bromo-1-
methylpyridin-2(1 H)-one (42.3 mg, 50%).
Step 2
A mixture of (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-
tetramethyl -1,3,2- dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (50
mg, 0.11 mmol) and 4-bromo-1- methylpyridin-2(1 H)-one (30 mg, 0.16
mmol), Pd(Ph3P)2CI2 (10 mg), and aq. Cs2CO3 solution (4 mL, 2 M) in 1,4-
dioxane (10 mL) was stirred and heated to reflux for 2 h. When the reaction
was over, the mixture was washed with water and extracted with EtOAc.
The organic phase was washed with brine, dried over Na2SO4, filtered and
concentrated to give the crude product, which was purified by preparative
TLC to give (R)-6-(3-hydroxypropyl)-3-((S)-1-(4-(1-methyl -2-oxo-1,2-
dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (25 mg ,
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51%). 1H NMR (CDC13): 6=1.35 (m, 1H), 1.47 (d, 3H), 1.63 (m, 2H), 1.94 (m,
2H), 2.18 (m, 1 H), 2.39 (m, 2H), 2.86 (m, 1 H), 3.51 (m, 5H), 5.63 (m, 1 H),
6.31 (m, 1 H), 6.70 (m, 1 H), 6.91 (m, 2H), 7.20-7.32 (m, 8H).
EXAMPLE 48
(S)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(l-methyl -2-oxo-1,2-
dihydropyridin-4-y1)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
Method 1
Br OH
Br NH2 H2SO4 / Mel Br O
\ N~
N NaNO2 N NaH
O O
Br O
O N \ \ N O N I\
Pd(PPh3)2C12, Cs2CO3 O I / \ N
OH OH
Step 1
A solution of 4-bromopyridin-2-amine (600 mg, 3.5 mmol) in a mixture
of 2 M H2SO4 (20 mL) and 2 M Na2NO2 (10 mL) was stirred at 0-5 C for 2 h.
The reaction mixture was extracted with CH2C12, and the organic layer was
washed with a saturated NaCl solution, dried over anhydrous Na2SO4 and
concentrated. The residue was purified by preparative TLC to give 4-
bromopyridin-2-ol (303 mg, 50%).
Step 2
To a suspension of NaH (300 mg, 7.5 mmol) in THE (10 mL) was
added 4-bromopyridin-2-ol (303 mg, 1.73 mmol) at 0 C. After the resulting
mixture was stirred for 1 h, CH3I (491 mg, 3.46 mmol) was added, and the
mixture was stirred overnight. The reaction was quenched with aqueous
NH4CI solution. The organic phase was concentrated to give the crude
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product, which was purified by column to give 4-bromo-1-methylpyridin-
2(1 H)-one (161 mg, 50 %).
Step 3
A mixture of (S)-6-(2-hydroxy-2-methyl propyl)-6-phenyl-3-((S)-1-(4-
(4,4,5,5- tetramethyl- 1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-
one (200 mg, 0.42 mmol), 4-bromo-1 - methyl pyridin-2(1 H)-one (118 mg,
0.63 mmol), Pd(Ph3P)2C12 (20 mg), and 2 M aq Cs2CO3 solution (5 mL, 10
mmol) in 1,4-dioxane (20 mL) was stirred and heated to reflux for 2 h. When
the reaction was finished, the mixture was washed with water and extracted
with EtOAc. The organic phase was washed with brine, dried over Na2SO4,
filtered, and concentrated to give the crude product, which was purified by
preparative TLC to give (S)-6-(2-hydroxy-2-methylpropyl)- 3-((S)-1-(4-(1-
methyl -2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-
one (83 mg, 43%). LC-MS Method 2 tR = 1.16 min, m/z = 921.5; 1H NMR
(CDC13) 1.11 (s, 3H), 1.18 (s, 3H), 1.22 (t, 1 H), 1.52 (m, 3H), 2.21 (s, 2H),
2.22-2.34 (m, 2H), 2.34-2.46 (m, 1 H), 2.85 (m, 1 H), 3.57 (s, 3H), 5.59 (m,
1 H), 6.33 (d, 1 H), 6.68 (s, 1 H), 7.01 (d, 2H), 7.29-7.41 (m, 8H); 1H NMR
(CD3OD) 0.98 (s, 3H), 1.29 (s, 3H), 1.58 (d, 3H), 2.17 (s, 2H), 2.22 (m, 1 H),
2.50 (m, 2H), 3.08 (m, 1 H), 3.59 (s, 3H), 5.59 (m, 1 H), 6.61 (d, 1 H), 6.66
(s,
1 H), 7.08 (m, 2H), 7.30-7.40 (5H), 7.42 (d, 2H), 7.70 (d, 1 H).
Method 2
Mel I I \
NH ~Iy N'~'
0 0
O)LN ~'~ O~N
I O
/ PdC12(PPh3)2/CS2CO3 / ` I N
HO HO O
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Step 1
To a solution of 4-iodopyridin-2(1 H)-one (3 g, 0.013 mol) and K2CO3
(3.55 g, 0.026 mol) in DMF (30 mL) was added iodomethane (4.7 g, 0.033
mmol). The mixture was stirred at room temperature overnight. Water and
EtOAc were added. The organic phase was dried over Na2SO4 and
concentrated to give 4-iodo-1 -methylpyridin- 2(1 H)-one (1.6 g, 53%).
Step 2
A mixture of 4-iodo-1-methylpyridin-2(1 H)-one (0.909 g, 3.76 mmol),
(S)-6-(2-hydroxy-2-methyl propyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -
1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (1.5 g, 3.13 mmol),
2 M aq Cs2CO3 (3 mL, 6 mmol), and PdC12(PPh3)2 (0.201 g, 0.282 mmol) in
1,4-dioxane (15 mL) was refluxed under N2 for 2 hours. The reaction
mixture was filtered, and the filtrate was extracted with EtOAc. The
combined organic layer was washed with brine, dried over Na2SO4 and
concentrated to obtain the crude compound, which was purified by
preparative HPLC and chiral HPLC to obtain (S)-6-(2-hydroxy -2-
methyl propyl)-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)
phenyl)ethyl) -6-phenyl-1,3-oxazinan-2-one (399 mg, 28%). LC-MS and 1H
NMR (CD3OD) were the same as those of product made by Method 1. The
compound was recrystallized using below methods.
The compound was obtained as a crystalline monohydrate by
dropwise addition of 60 mL of water to a solution of 7.6 g of compound in 15
mL of methanol. After stirring for 1 h, the solid is filtered by suction,
washed
with water and diethylether and dried in an exsiccator over conc. sulphuric
acid/potassium hydroxide. The compound was also recrystallized from
water/ethanol (80:20) to also yield the monohydrate. Melting point: 118-
122 C.
The compound was recrystallized from isopropyl acetate following a
procedure analogous to that described for Example 37 in Recrystallization
Method B to give a crystalline solid with mp 106-116 C. The compound
was also recrystallized by this method from EtOAc (mp 90-93 C), from
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EtOAc/iPr2O (mp 102-122 C) from isobutyl acetate (mp 108-126 C), from
EtOH/TBME (mp 108-126 C) and from 2-butanone.
This crystalline form may be characterized by means of its
characteristic X-ray powder diffraction (XRPD) patterns.
The crystalline form is characterised by an X-ray powder diffraction
pattern that comprises peaks at 8.71, 12.93 and 19.16 degrees 20 ( 0.05
degrees 2Q, wherein said X-ray powder diffraction pattern is made using
CuKai radiation.
In particular said X-ray powder diffraction pattern comprises peaks at 8.71,
12.93, 19.16, 19.45 and 21.06 degrees 20 ( 0.05 degrees 2Q, wherein said
X-ray powder diffraction pattern is made using CuKai radiation.
More specifically, the crystalline form is characterised by following
lattice parameters: orthorhombic symmetry, space group P212121 with the
cell parameters, a=9.28(1) A, b=11.06(2) A, c=25.52(2) A, and cell
volume=2616(5) A3 obtained by indexing of the X-ray powder diagram
measured at room temperature using CuKai radiation, which comprises
peaks at degrees 20 ( 0.05 degrees 2E) as contained in Table 1.
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Table 1 Indexed XRPD peaks up to 30 0 20 including intensities
(normalised) of the monohydrate of Example 48
20 dhk, Intensity Indexing 20obs - 20ca,c
[0] [A] I/Io [%] h k I [0]
6.90 12.80 13 0 0 2 -0.024
8.71 10.14 100 0 1 1 0.003
10.13 8.73 12 1 0 1 -0.012
10.58 8.36 32 0 1 2 -0.004
11.78 7.51 1 1 0 2 -0.007
12.45 7.10 42 1 1 0 0.004
12.93 6.84 91 1 1 1 0.007
13.86 6.39 29 0 0 4 -0.016
14.26 6.21 52 1 1 2 0.002
16.05 5.52 39 0 2 0 0.035
16.26 5.45 41 1 1 3 0.015
16.42 5.39 49 0 2 1 0.030
17.48 5.07 2 0 2 2 0.014
18.68 4.75 39 1 2 0 0.013
19.16 4.63 76 2 0 0 0.041
19.45 4.56 70 2 0 1 0.010
19.96 4.44 44 1 2 2 0.028
20.37 4.36 52 2 0 2 0.006
20.77 4.27 18 2 1 0 0.016
21.06 4.22 57 2 1 1 0.011
21.43 4.14 38 1 2 3 0.012
21.87 4.06 54 2 1 2 -0.038
22.38 3.97 18 0 1 6 < 0.001
23.36 3.81 4 1 2 4 0.023
23.73 3.75 16 2 0 4 0.027
24.39 3.65 17 1 1 6 0.013
25.18 3.53 13 0 3 2 0.046
25.69 3.46 13 0 1 7 -0.023
26.31 3.38 8 0 3 3 -0.026
26.41 3.37 7 0 2 6 -0.009
27.21 3.28 32 2 2 3 0.027
27.48 3.24 5 1 1 7 0.003
28.14 3.17 4 1 2 6 -0.011
28.77 3.10 7 2 2 4 0.030
29.10 3.07 2 3 0 1 0.032
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29.34 3.04 5 0 2 7 0.017
29.71 3.00 19 3 0 2 0.004
29.95 2.98 13 3 1 0 -0.037
The X-ray powder diffraction patterns are recorded, within the scope
of the present invention, using a STOE - STADI P-diffractometer in
transmission mode fitted with a position-sensitive detector (PSD) and a Cu-
anode as X-ray source and a Germanium monochromator (CuKai radiation,
X = 1,54056 A, 40kV, 40mA). In the Table 1 above the values "20 [ ]"
denote the angle of diffraction in degrees and the values " dhk, [A]" denote
the specified distances in A between the lattice planes. The intensity shown
in the Figure 1 is given in units of cps (counts per second).
The crystalline form is characterised by an X-ray powder diffraction
pattern, made using CuKai radiation, which comprises peaks at degrees 20
( 0.05 degrees 20 as shown in Figure 1.
In order to allow for experimental error, the above described 2 O
values should be considered accurate to 0.05 degrees 20. That is to say,
when assessing whether a given sample of crystals of the compound A is
the crystalline form I in accordance with the invention, a 2 O value which is
experimentally observed for the sample should be considered identical with
a characteristic value described above if it falls within 0.05 degrees 2 O
of
the characteristic value.
X-ray Structure Determination of the Monohydrate of Example 48
The monohydrate of Example 48, C29H34NO5, crystallizes in the
orthorhombic space group P212121 (systematic absences h00: h=odd, OkO:
k=odd, and 001: 1=odd) with a=9.2099(11)A, b=11.0051(11)A, c=25.456(3)A,
V=2580.1(5)A3, Z=4 and dcalc=1.227 g/cm3. X-ray intensity data were
collected on a Rigaku Mercury CCD area detector employing graphite-
monochromated Mo-Ku radiation (X=0.71073 A) at a temperature of 170K.
Preliminary indexing was performed from a series of twelve 0.5 rotation
images with exposures of 30 seconds. A total of 350 rotation images were
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collected with a crystal to detector distance of 35 mm, a 20 swing angle of -
12 , rotation widths of 0.5 and exposures of 20 seconds: scan no. 1 was a
~-scan from 150 to 300 at w = 10 and = 20 ; scan no. 2 was an w-scan
from -20 to 5 at x = -90 and 4 = 135 . Rotation images were processed
using CrystalClear (CrystalClear (CrystalClear: Rigaku Corporation, 1999),
producing a listing of unaveraged F2 and 6(F2) values which were then
passed to the CrystalStructure (CrystalStructu re: Crystal Structure Analysis
Package, Rigaku Corp. Rigaku/MSC (2002)) program package for further
processing and structure solution on a Dell Pentium III computer. A total of
11320 reflections were measured over the ranges 5.46 <_20<_ 50.04 , -8<_h
<_10, -13<_ k<_10, -30<_l <_24 yielding 4448 unique reflections (R;nt =
0.0192).
The intensity data were corrected for Lorentz and polarization effects and for
absorption using REQAB (minimum and maximum transmission 0.822,
1.000).
The structure was solved by direct methods (SIR97) (SIR97:
Altomare, A., M. Burla, M. Camalli, G. Cascarano, C. Giacovazzo, A.
Guagliardi, A. Moliterni, G. Polidori & R. Spagna (1999). J. Appl. Cryst., 32,
115-119). Refinement was by full-matrix least squares based on F2 using
SHELXL-97(SHELXL-97: Program for the Refinement of Crystal Structures,
Sheldrick, G.M. (1997), University of Gottingen, Germany). All reflections
were used during refinement. The weighting scheme used was w=1/[62(Fo
)+ 0.0501 P2 + 0.2402P] where P = (Fo + 2F2
)/3 . Non-hydrogen atoms
were refined anisotropically and hydrogen atoms were refined using a
"riding" model. Refinement converged to R1=0.0357 and wR2=0.0873 for
4119 reflections for which F > 46(F) and R1=0.0399, wR2=0.0917 and GOF
= 1.080 for all 4448 unique, non-zero reflections and 323 variables:
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R1 = IIIFOI - IF,II/ I IFOI
wR2 = { I w (F2 - F2 )2 / I w(F0 )2}v2
GOF = { w (Fo - Fc )2 / (n - p)}'/2
where n = the number of reflections and p = the number of parameters
refined.
The maximum 4/6 in the final cycle of least squares was 0.000 and the two
most prominent peaks in the final difference Fourier were +0.142 and -0.137
lo e/A3.
Table 1A. lists cell information, data collection parameters, and
refinement data. Final positional and equivalent isotropic thermal
parameters are given in Table 1B. Anisotropic thermal parameters are in
Table 1 C.
Table 1A. Summary of Structure Determination of the Monohydate of
Example 48
Formula: C29H34NO5
Formula weight: 476.57
Crystal class: orthorhombic
Space group: P212121 (#19)
Z 4
Cell constants:
a 9.2099(11)A
b 11.0051(11)A
c 25.456(3)A
V 2580.1(5)A3
0.83 cm-'
crystal size, mm 0.32 x 0.22 x 0.20
Dcalc 1.227 g/cm3
F(000) 1020
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Radiation: Mo-K0,(X=0.71073A)
20 range 5.46 - 50.04
hkl collected: -8<_h<_10; -11<_k<_10;
- 30<_I <_24
No. reflections measured: 11320
No. unique reflections: 4448 (R;nt=0.0192)
No. observed reflections 4119 (F>46)
No. reflections used in refinement 4448
No. parameters 323
R indices (F>46) R1=0.0357
wR2=0.0873
R indices (all data) R1=0.0399
wR2=0.0917
GOF: 1.080
Final Difference Peaks, e/A3 +0.142, -0.137
Table 1 B. Refined Positional Parameters for The Monohydrate of
Example 48
Atom X Y Z U Cl 0.5301(2) 0.5918(2) 0.334967 0.0916(4)
C2 0.7452(2) 0.7096(2) 0.35792(6) 0.0323(4)
C3 0.5174(2) 0.7392(2) 0.40836(7) 0.0367(4)
H3a 0.4759 0.8163 0.4191 0.049
H3b 0.5014 0.6810 0.4364 0.049
C4 0.4434(2) 0.6956(2) 0.35879(7) 0.0351(4)
H4a 0.4365 0.7618 0.3338 0.047
H4b 0.3459 0.6681 0.3669 0.047
C5 0.7598(2) 0.8066(2) 0.44350(7) 0.0374(4)
H5 0.8622 0.8025 0.4332 0.050
C6 0.7410(2) 0.7237(2) 0.49076(7) 0.0352(4)
C7 0.6725(2) 0.7583(2) 0.53701(7) 0.0364(4)
H7 0.6425 0.8384 0.5412 0.048
C8 0.6482(2) 0.6754(2) 0.57705(7) 0.0371(4)
H8 0.6030 0.7011 0.6078 0.049
C9 0.6902(2) 0.5544(2) 0.57218(7) 0.0352(4)
C10 0.7651(2) 0.5206(2) 0.52640(7) 0.0391(4)
H10 0.7984 0.4413 0.5227 0.052
C11 0.7899(2) 0.6036(2) 0.48700(7) 0.0389(4)
H11 0.8403 0.5794 0.4571 0.052
C12 0.6520(2) 0.4631(2) 0.61269(7) 0.0377(4)
C13 0.6253(2) 0.3449(2) 0.59925(8) 0.0424(4)
H13 0.6319 0.3232 0.5640 0.056
014 0.5880(2)1 0.2537(2)1 0.63613(7) 0.0405(4)1
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C15 0.6009(2) 0.4096(2) 0.70166(8) 0.0471(5)
H15 0.5916 0.4315 0.7368 0.063
C16 0.6388(2) 0.4956(2) 0.66659(7) 0.0441(5)
H16 0.6562 0.5749 0.6774 0.059
C17 0.7240(3) 0.9403(2) 0.45250(8) 0.0525(5)
H 17a 0.7381 0.9846 0.4204 0.079
H17b 0.7866 0.9725 0.4792 0.079
H 17c 0.6247 0.9478 0.4635 0.079
C18 0.5347(3) 0.2018(2) 0.72771(7) 0.0497(5)
H18a 0.5388 0.2382 0.7619 0.075
H18b 0.6008 0.1344 0.7262 0.075
H 18c 0.4378 0.1736 0.7210 0.075
C19 0.5527(2) 0.4858(2) 0.37321(7) 0.0337(4)
C20 0.6853(2) 0.4263(2) 0.37745(7) 0.0396(4)
H2O 0.7643 0.4537 0.3580 0.053
C21 0.7016(2) 0.3261(2) 0.41037(8) 0.0493(5)
H21 0.7910 0.2872 0.4129 0.066
C22 0.5851(3) 0.2846(2) 0.43922(8) 0.0528(5)
H22 0.5958 0.2181 0.4614 0.070
C23 0.4521(3) 0.3421(2) 0.43508(8) 0.0532(5)
H23 0.3732 0.3139 0.4544 0.071
C24 0.4359(2) 0.4415(2) 0.40230(8) 0.0442(5)
H24 0.3459 0.4792 0.3996 0.059
C25 0.4685(2) 0.5389(2) 0.28381(7) 0.0338(4)
H25a 0.3889 0.4858 0.2936 0.045
H25b 0.5434 0.4875 0.2689 0.045
C26 0.4127(2) 0.6206(2) 0.23918(7) 0.0375(4)
C27 0.3582(3) 0.5387(2) 0.19492(8) 0.0537(6)
H27a 0.2852 0.4847 0.2083 0.081
H27b 0.4377 0.4921 0.1812 0.081
H27c 0.3175 0.5877 0.1674 0.081
C28 0.5254(2) 0.7077(2) 0.21787(8) 0.0465(5)
H28a 0.4840 0.7543 0.1897 0.070
H28b 0.6072 0.6626 0.2050 0.070
H28c 0.5565 0.7615 0.2454 0.070
N l 0.6739(2) 0.75380 12 0.39953(6) 0.0332(3)
N2 0.5755(2) 0.29203 14 0.68795(6) 0.0408(4)
01 0.67306 12 0.64280 10 0.32157(4) 0.0337(3)
02 0.87528 13 0.72746 12 0.34976(5) 0.0419(3)
03 0.2937(2) 0.69479 12 0.25654(5) 0.0482(3)
H3 0.2391 0.6541 0.2750 0.072
04 0.5655(2) 0.14473 13 0.62470(6) 0.0549(4)
05 1.1026(2) 0.57570 12 0.32703(7) 0.0597(4)
H5a 1.0135 0.6229 0.3334 0.037
H5b 1.0862 0.5012 0.3412 0.037
Ue = 1/ [Ull(aa*) +U22(bb*) +U33(cc*)
+2U12aa*bb*cosy+2U13aa*cc*cos(3+2U23bb*cc*cosa]
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Table 1 C. Refined Thermal Parameters (U's) for the Monohydrate of
Example 48
Atom U11 U22 U33 U23 U13 U12
C1 0.0268(8) 0.0321(9) 0.0359(9) -0.0022(7) 0.0012(7) 0.0000(7)
C2 0.0299(9) 0.0324(9) 0.0345(9) 0.0001(7) -0.0011(8) 0.0013(7)
C3 0.0273(9) 0.0436 10 0.0392 10 -0.0095(8) 0.0011(7) 0.0002(7)
C4 0.0290(8) 0.0384 10 0.0379 10 -0.0052(8) -0.0019(7) 0.0035(7)
C5 0.0351(9) 0.0422 10 0.0350(9) -0.0019(8) -0.0048(8) -0.0074(8)
C6 0.0288(8) 0.0424 11 0.0345(9) -0.0039(8) -0.0049(8) -0.0037(8)
C7 0.0309(9) 0.0381 10 0.0402 10 -0.0053(8) -0.0036(8) 0.0023(8)
C8 0.0300(9) 0.0455 11 0.0359 10 -0.0068(8) -0.0006(8) 0.0018(8)
C9 0.0322(9) 0.0385 10 0.0350(9 -0.0051(8) -0.0021(8) -0.0001 8
C10 0.0398 10 0.0366 10 0.0409 10 -0.0048(8) -0.0008(8) 0.0049 8
C11 0.0364 10 0.0451 11 0.0354 10 -0.0072(8) 0.0014(8) 0.0009(8)
C12 0.0329(9) 0.0425 10 0.0376 10 -0.0020(8) -0.0018(8) 0.0021(8)
C13 0.0471 11 0.0457 11 0.0344 10 -0.0038(9) -0.0001(9) -0.0022 9
C14 0.0390 10 0.0440 11 0.0385 10 -0.0010(9) -0.0012(8) -0.0004(8)
C15 0.0561 13 0.0486 12 0.0365 10 -0.0047(9) 0.0020 10 0.0049 10
C16 0.0517 12 0.0426 11 0.0379 10 -0.0054(9) 0.0006(9) 0.0022(9)
C17 0.0699 14 0.0414 11 0.0462 11 -0.0014(9) -0.0082(11) -0.0139(10)
C18 0.0620 14 0.0480 11 0.0392 11 0.0064(9) 0.0059 10 0.0066 10
C19 0.0361(9) 0.0336(9) 0.0315(9) -0.0042(7) -0.0042(8) 0.0008(8)
C20 0.0400 10 0.0351 10 0.0436 10 -0.0033(8) -0.0024(9) 0.0037(8)
C21 0.0540 12 0.0405 11 0.0535 12 -0.0036(9) -0.0105(10) 0.0083(9)
C22 0.075(2) 0.0377 10 0.0460 11 0.0038(9) -0.0098(11) 0.0008(l 1
C23 0.0603(13) 0.0492(11) 0.0500(12) 0.0069(10) 0.0089(11) -0.0064(11)
C24 0.0426 11 0.0445 11 0.0455 11 0.0020(9) 0.0023(9) 0.0016(9)
C25 0.0356 10 0.0302(9) 0.0356 10 -0.0023(8) -0.0005(8) 0.0009 7
C26 0.0422 11 0.0372 10 0.0331 10 -0.0020(8) -0.0034(8) 0.0031(8)
C27 0.070(2) 0.0486 12 0.0426 11 -0.0030(10) -0.0159(11) -0.0034(10)
C28 0.0509 12 0.0432 11 0.0454 11 0.0082(9) -0.0030(9) -0.0005(9)
N1 0.0273(7) 0.0387(8) 0.0338(8 -0.0034(7) -0.0014(6) -0.0014 6
N2 0.0431(9) 0.0445(9) 0.0349(8) -0.0006(7) 0.0012(7) 0.00387
01 0.0291(6) 0.0383(7) 0.0338(6) -0.0045(5) 0.0011(5) -0.00055
02 0.0293(7) 0.0523(8) 0.0442(7) -0.0029(6) 0.0047(5) -0.0046(6)
03 0.0423(8) 0.0510(8) 0.0513(8 0.0028(7) -0.0043(6) 0.01146
04 0.0706 10 0.0446(8) 0.0494(8) -0.0035(7) 0.0011(8) -0.00967
05 0.0511(9) 0.0428(8) 0.0850 11 0.0016(8) 0.0162(8) 0.0038 7
The form of the anisotropic displacement parameter is:
exp[-2m2 a*2U11h2+b*2U22k2+c*2U3312+ 2b*c*U23k1+2a*c*U13h1+2a*b*U12hk ].
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To investigate the stability of the monohydrate of Example 48, a slurry
experiment was performed. In this study, a suspension of the monohydrate
of Example 48 was suspended in water for up to seven days. After the
treatment, the mixtures were filtered and an x-ray powder diffraction of the
filtration residue was measured. No polymorphic change was observed for
the monohydrate of Example 48. In contrast, the anhydrous form of Example
48 did not remain in the anhydrous state during the measurement by XRPD
(30 minutes).
Method 3
0
O lt~ ON Pd(dppf)CIZ N
B \ 0 2M aq Na2CO3 \ I / \ O
\ Br +
I A N wave, dioxane OH N
OH 130 C, 2h
O
O~N \
Mel, K2CO3, CH3CN O
reflux OH N,
Step 1
A mixture of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-hydroxy-2-
methylpropyl)-6-phenyl-1,3-oxazinan-2-one (100 mg, 0.23 mmol), 2-
methoxy-4-(4,4,5,5-tetram ethyl- 1, 3,2-dioxaborolan-2-yl)pyridine (68 mg,
1.25
equiv), Pd(dppf)C12.CH2CI2 (19 mg, 10%mol), 2M aq Na2CO3 (1 mL), 1,4-
dioxane (3mL) was degassed, refilled with N2 gas for 3 times before being
put into microwave oven for 2 h at 130 C. LC-MS found the reaction was
completed. The mixture was diluted with EtOAc (50 mL), washed with water
(10 mL) and brine (8 mL), and dried over Na2SO4. After filtration and
concentration, the residue was purified by chromatography on a 12-g silica
gel column, eluted with a 0 to 10% MeOH in CH2CI2 gradient to afford (S)-6-
(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(2-methoxypyridin-4-yl)phenyl)ethyl)-
6-phenyl-1,3-oxazinan-2-one (112 mg, quant yield). LC-MS Method 1 tR =
1.66min, m/z = 461(M+1).
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Step 2
(S)-6-(2-hyd roxy-2-m ethyl propyl)-3-((S)-1-(4-(2-methoxypyridin-4-
yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (28 mg, 0.061 mmol),
potassium carbonate (17 mg, 2equiv), and lodomethane (40 pL, 10 equiv)
were mixed with acetonitrile (2.5 mL) and heated at reflux for 4 h. After
being
cooled to rt, the mixture was acidified with 5% aq HCl and purified by prep
HPLC to afford (S)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(1-methyl-2-
oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (14.4
mg. 52%). LC-MS and 1H NMR (CD3OD) were the same as those of product
made by Method 1.
EXAMPLE 49
2,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl -6-oxo-1,6-dihydropyridin-3-
yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanenitrile
O
OAN
O
N O
N
Method 1
The title compound was prepared from 2,2-dimethyl-3-((R)-2-oxo-6-
phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-
1,3-oxazinan-6-yl)propanenitrile and 5-bromo-1-methylpyridin-2(1 H)-one
following a procedure analogous to that described in Example 6 Step 1. LC-
MS Method 2 tR = 1.231 min, m/z = 470.1; 1H NMR (CDCI3) 1.28 (s, 3H),
1.40 (s, 3H), 1.47 (d, 3H), 2.09 (s, 2H), 2.21 (m, 1 H), 2.41 (m, 2H), 2.83
(m,
1 H), 3.52 (s, 3H), 5.56 (m, 1 H), 6.58 (d, 1 H), 6.82 (d, 2H), 7.02 (d, 2H),
7.30
(m, 6H), 7.43 (m, 1 H).
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Method 2
O O
OAN Mel, THE OAN
NaH
CNN
IN O 600C CN IN O
H
A solution of 2,2-dimethyl -3-((R)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-
dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-6-yl)propanenitrile
(202 mg, 0.444 mmol) and Mel (110 pL, 4equiv) in dry THE (5 mL) was
cooled to 0 C. NaH (60% in mineral oil, 36mg, 2equiv) was added. After
10min, the mixture was warmed to rt slowly and stirred for 3 h. LC-MS
showed about 50% conversion. The mixture was heated for 1 h at 60 C.
LC-MS found the reaction completed. After cooling to rt, the mixture was
cooled to 0 OC and quenched with satd aq NH4CI (3 mL). The mixture was
then diluted with CH2CI2 (20mL), washed with 1 % aq HCI (5 mL) and brine (4
mL), and dried over Na2SO4. After filtration and concentration, the residue
was purified by prep HPLC to afford 2,2-dimethyl-3-((R)-3-((S)-1-(4-(1-
methyl -6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-
oxazinan-6-yl)propanenitrile (177.4 mg, 85% yield) product as a light brown
oil.
Method 3
ON O)~ N \ O11 N -"'~
QOH N CL O / I N O I/ ON N O
Mass spectrum (ESI+); m/z = 443 [M+H]+ Mass spectrum (ESI+); m/z = 470 [M+H]+
2,2-Dimethyl-3-(3-{(S)-1-[4-(1-methyl -6-oxo-1,6-dihydro-pyridin-3-yl)-
phenyl]-ethyl}-2-oxo-(S)-6-phenyl-[1,3]oxazinan-6-yl)-propionitrile was
prepared from (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-
1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one following
procedures analogous to those described Example 71 Method 2 to prepare
3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-
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dimethylpropanenitrile. (S)-6-(2-hydroxy-2-methyl -propyl)-3-{(S)-1-[4-(1-
methyl -6-oxo-l,6-dihydro-pyridin-3-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-
2-one, is obtained from coupling (S)-6-(2-hydroxy-2-methyl propyl)-6-phenyl-
3-[(S)-1-(4-(4,4,5,5- tetra methyl -1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-
oxazinan-2-one with 5-iodo-1 -methyl-1 H-pyridin-2-one by the action of
Pd(PPh3)4 and 2 M aqueous Na2CO3 solution in a mixture of methanol and
dioxane (1:3) at 80 C. The compound that had been obtained as a foam
was dissolved in a small amount of ethyl acetate and stirred overnight at rt.
The solid was filtered by suction, washed with a small amount of diethylether
and dried. Melting point: 143-145 C
EXAMPLE 50
2,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl -2-oxo-l,2-dihydropyridin-4-
yl)phenyl)ethyl)-2-oxo-6-phenyl-l,3-oxazinan-6-yl)propanenitrile
O
OAN
N NI
IVI
Method 1
The title compound was prepared from 2,2-dimethyl-3-((R)-2-oxo-6-
phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-
1,3-oxazinan-6-yl)propanenitrile and 4-bromo-1 -methylpyridin-2(1 H)-one
following a procedure analogous to that described in Example 6 Step 1. LC-
MS Method 2 tR = 1.103, m/z = 470.4; 1H NMR (CDCI3) 1.26 (s, 3H), 1.41 (s,
3H), 1.49 (d, 3H), 2.09 (s, 2H), 2.24 (m, 1 H), 2.53 (m, 2H), 2.88 (m, 1 H),
3.56 (s, 3H), 5.59 (m, 1 H), 6.38 (d, 1 H), 6.78 (s, 1 H), 6.84 (d, 2H), 7.19
(m,
2H), 7.31 (m, 6H).
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Method 2
O1~1 N Oa, N O1~1 N
/ OH I N~ / I N~ / CN
O O O
Mass spectrum (ESI+): m/z = 443 [M+H]+ Mass spectrum (ESI+): m/z = 470 [M+H]+
(S)-2,2-Dimethyl -3-(3-{1-[(S)-4-(1-methyl-2-oxo-1,2-dihydro-pyridin-4-
yl)-phenyl]-ethyl}-2-oxo-6-phenyl-[1,3]oxazinan-6-yl)-propionitrile was
prepared from (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-2-oxo-
1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one following
procedures analogous to those described in Example 71 Method 2 to
prepare 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-
6-yl)-2,2-dimethylpropanenitrile. The starting compound, (S)-6-(2-hydroxy-2-
methyl -propyl)-3-{(S)-1-[4-(1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-phenyl]-
ethyl}-6-phenyl-[1,3]oxazinan-2-one, is obtained from coupling (S)-6-(2-
hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1 -(4-(4,4,5,5- tetramethyl-1,3,2-
dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one with trifluoro-
methanesulfonic acid 1 -m ethyl -2-oxo- 1, 2-d i hyd ro-pyrid in -4-yl ester
employing the standard conditions, Pd(dppf)C12*CH2CI2, 2 M aqueous
Na2CO3 solution, DMF, 90 C, 2 h. The compound that had been obtained
as a resin was dissolved in a small amount of EtOAc and stirred overnight at
rt. The solid was filtered by suction, washed with a small amount of
diethylether and dried. Melting point: 195-198 C.
EXAMPLE 51
2,2-dimethyl-3-((R)-3-((S)-1-(4-(1-methyl -2-oxo-1,2-dihydropyridin-4-
yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide
O
OAN
Nz~
N
O NH2 O
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The title compound was prepared from 2,2-dimethyl-3-((R)-2-oxo-6-
phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-
1,3-oxazinan-6-yl)propanenitrile and 4-bromo-1-methylpyridin-2(1 H)-one
following a procedure analogous to that described in Example 6 Step 1,
followed by treatment with H202, K2CO3. LC-MS Method 2 tR = 1.133 min,
m/z = 488.1; 1H NMR (CDCI3) 1.12 (s, 3H), 1.19 (s, 3H), 1.49 (d, 3H), 2.09-
2.28 (m, 3H), 2.32-2.58 (m, 2H), 2.89 (m, 1 H), 3.59 (s, 3H), 5.61 (m, 1 H),
6.54 (m, 1 H), 6.88 (m, 1 H), 6.97-7.10 (m, 2H), 7.28 (m, 6H), 7.42 (m, 1 H),
7.53 (m, 1 H).
EXAMPLE 52
(S)-3-((S)-1-(4-(1-ethyl -6-oxo-1,6-dihydropyridin-3-yl)phenyl)propyl)-6-(2-
hydroxy-2-m ethyl propyl)-6-phenyl-1,3-oxazinan-2-one
O
OAN
014; OH N O
The title compound was prepared from (R)-6-allyl-3-((S)-1-(4-
bromophenyl)propyl)-6-phenyl-1,3-oxazinan-2-one following a procedure
analogous to that described in Example 32 Method 2 using 5-bromo-1-
ethyl pyridin-2(1 H)-one in Step 4. LC-MS Method 2 tR = 1.732 min, m/z =
475.1; 1H NMR (CDCI3) 0.95 (s, 3H),1.01 (t, 3H), 1.26 (s, 3H), 1.38 (t, 3H),
2.06 (m, 2H), 2.18-2.31 (m, 3H), 2.36 (m, 1 H), 2.55 (m, 1 H), 3.04 (m, 1 H),
4.11 (m, 2H), 5.37 (m, 1 H), 6.66 (d, 1 H), 7.11 (m, 2H), 7.20-7.33 (m, 7H),
7.76 (d, 1 H), 7.88 (s, 1 H).
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EXAMPLE 53
(S)-3-((S)-1-(4-(1-ethyl -6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(2-
hydroxy-2-m ethyl propyl)-6-phenyl-1,3-oxazinan-2-one
O
OAN
O
OH nN O
The title compound was prepared from (S)-6-(2-hydroxy-2-
methyl propyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-
2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 5-bromo-1-ethyl pyridin-2(1 H)-one
following a procedure analogous to that described in Example 6 Step 1. LC-
MS Method 2 tR = 1.224 min, m/z = 475.1; 1H NMR (CDC13) 1.11 (s, 3H),
1.19 (s, 3H), 1.39 (t, 3H), 1.56 (d, 3H), 2.20 (s, 2H), 2.26 (m, 1 H), 2.36-
2.57
(m, 2H), 2.87 (m, 1 H), 4.03 (m, 2H), 5.69 (m, 1 H), 6.62 (d, 1 H), 7.00 (d,
2H),
7.17 (d, 2H), 7.28-7.51 (m, 6H), 7.50 (d, 1 H). Recrystallization from
isopropyl acetate following a procedure analogous to that described for
Example 37 in Recrystallization Method B afforded a crystalline solid with
mp 167-168 C.
EXAMPLE 54
(S)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(1-methyl -6-oxo-1,6-
dihydropyridin-3-yl)phenyl)propyl)-6-phenyl-1,3-oxazinan-2-one
O
OA N
O
N O
OH 1
The title compound was prepared from (R)-6-allyl-3-((S)-1-(4-
bromophenyl)propyl)-6-phenyl-1,3-oxazinan-2-one following a procedure
analogous to that described in Example 32 Method 2 using 5-bromo-1-
methylpyridin-2(1 H)-one in Step 4. LC-MS Method 2 tR = 1.746 min, m/z =
475.2; 1H NMR (CD3OD) 1.04 (t, 3H), 1.11 (s, 3H), 1.24 (s, 3H), 1.95-2.04
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(m, 2H), 2.13-2.26 (m, 4H), 2.44 (m, 1 H), 2.91 (m, 1 H), 3.61 (s, 3H), 5.36
(m,
1 H), 6.67 (d, 1 H), 7.10-7.33 (m, 8H), 7.42(s, 1 H), 7.55 (d, 1 H).
EXAMPLE 55
(S)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(l-methyl -2-oxo-1,2-
dihydropyridin-4-yl)phenyl)propyl)-6-phenyl-1,3-oxazinan-2-one
O
OAN HN
OH
O
The title compound was prepared from (S)-6-(2-hydroxy-2-
methyl propyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-
2-yl)phenyl)propyl)-1,3-oxazinan-2-one and 4-bromo-1-methylpyridin-2(1 H)-
one following a procedure analogous to that described in Example 59 Step
2. LC-MS Method 2 tR = 1.203 min, m/z = 971.4; 1H NMR (CDCI3) 0.97 (t,
3H), 1.12 (s, 3H), 1.19 (s, 3H), 1.79-2.02 (m, 2H), 2.11-2.24 (m, 4H), 2.29-
2.42 (m, 1 H), 2.81 (m, 1 H), 3.50 (s, 3H), 5.40 (m, 1 H), 6.28 (d, 1 H), 6.64
(s,
1 H), 7.02 (d, 2H), 7.18 (m, 3H), 7.20 (m, 2H), 7.28 (m, 3H).
EXAMPLE 56
(R)-6-ethyl-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-
yl)phenyl)propyl)-6-phenyl-1,3-oxazinan-2-one
O
OAN
O
N O
1
The title compound was prepared from (R)-3-((S)-1-(4-
bromophenyl)propyl)-6-ethyl -6-phenyl-1,3-oxazinan-2-one following
procedures analogous to those described in Example 32 Method 2 Steps 3
and 4. LC-MS Method 1 tR = 1.6 min, m/z = 431 (M+1).
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(R)-3-((S)-1-(4-bromophenyl)propyl)-6-ethyl-6-phenyl-1,3-oxazinan-2-
one was prepared from 1 -chloro-3-phenylpentan-3-ol and (S)-1 -(4-
bromophenyl)propan-1 -amine following a procedure analogous to that
described in Example 71 Step 2.
1-chloro-3-phenylpentan-3-ol was prepared from 3-chloro-1-
phenylpropan-1-one and ethylmagnesium bromide following a procedure
analogous to that described in Preparation 1 Method 1 Step 2.
EXAMPLE 57
(R)-6-ethyl-3-((S)-1-(4-(1-ethyl -6-oxo-1,6-dihydropyridin-3-yl)phenyl)propyl)-
6-phenyl-1,3-oxazinan-2-one
O
OAN
O
N O
The title compound was prepared from (R)-3-((S)-1-(4-
bromophenyl)propyl)-6-ethyl -6-phenyl-1,3-oxazinan-2-one following
procedures analogous to those described in Example 32 Method 2 Steps 3
and 4 using 5-bromo-1-ethyl pyridin-2(1 H)-one in Step 4. LC-MS Method 1 tR
= 1.68 min, m/z = 445 (M+1).
EXAMPLE 58
(R)-6-ethyl-3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-
yl)phenyl)propyl)-6-phenyl-1,3-oxazinan-2-one
O
OAN
/ I N
O
The title compound was prepared from (R)-3-((S)-1-(4-
bromophenyl)propyl)-6-ethyl -6-phenyl-1,3-oxazinan-2-one following
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procedures analogous to those described in Example 32 Method 2 Steps 3
and 4 using 4-iodo-1-methylpyridin-2(1 H)-one in Step 4. LC-MS Method 1 tR
= 1.58 min, m/z = 431 (M+1); 1H NMR (CDC13) 7.33 (1 H, d, J = 7.03 Hz),
7.29 - 7.21 (7H, m), 7.01 (2H, d, J = 8.20 Hz), 6.75 (1 H, d, J = 2.05), 6.39
(1 H, dd, J = 2.05, 7.03), 5.48 (1 H, ap dd, J = 6.44, 9.66), 3.58 (3H, s),
2.95-
2.87 (1 H, m), 2.37-2.14 (3H, m), 2.06-1.81 (m, 4H), 1.00 (3H, t, J = 7.32),
082 (3H, t, J = 7.61).
EXAMPLE 59
(S)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(1-isopropyl-6-oxo-1,6-
dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
OH BrO
Br
Z~-
K2CO3, DMF
O
O Br -(\- O
0 N N O N /
O 0 Pd(PPh3)2C12 N O
OH Cs2CO3 OH
Step 1
To a solution of 5-bromopyridin-2-ol (1 g, 5.75 mmol) in DMF (10 mL)
were added 2-iodopropane (4.9 g, 28.75 mmol) and K2CO3 (4 g, 28.75
mmol). The mixture was stirred at rt overnight. The mixture was diluted with
water (20 mL) extracted with EtOAc (3 x 25 mL), the combined organic
phase was washed with brine, dried over Na2SO4, concentrated and purified
by prep TLC to give 5-bromo-1-isopropylpyridin-2(1 H)-one (380 mg, 31 %).
1H NMR (CDC13): 1.35 (d, 6H), 5.65-5.75 (m, 1 H), 6.48 (d, 1 H), 7.30 (m, 1
H),
7.41 (d, 1 H).
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Step 2
To a solution of (S)-6-(2-hydroxy-2-methyl propyl)-6-phenyl-3-((S)-1-
(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-
one (100 mg, 0.21 mmol) in 1,4-dioxane (2 mL) was added 5-bromo-1 -
isopropylpyridin-2(1 H)-one (54.2 mg, 0.25 mmol). Then catalysts of
Pd(PPh3)2CI2 (14 mg, 0.02 mmol), Cs2CO3 (1 mL, 2 M ) were added. The
vessel was sealed with a septum and placed into the microwave cavity.
Microwave irradiation of 100 W was used, the temperature being ramped
from room temperature to 120 C. Once this temperature was reached, the
reaction mixture was held at this temperature for 30 min. After the mixture
cooled to rt, the mixture was filtered. The filtrate was extracted with EtOAc
(20 mLx4), the organic layer was washed with brine, dried over Na2SO4 and
concentrated to give the crude product which was purified by preparative
HPLC to give (S)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(1-isopropyl-6-
oxo-1,6- dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (22
mg, 21%). 1H NMR (CDC13): 1.13 (s, 3H), 1.19 (s, 3H), 1.40 (6H), 1.53 (d,
3H), 2.18-2.30 (m, 4H), 2.40 (m, 1 H), 2.88 (m, 1 H), 5.31 (m, 1 H), 5.70 (m,
1 H), 6.73 (d, 1 H), 7.02 (d, 2H), 7.15 (d, 2H), 7.27-7.38 (m, 5H), 7.43 (d, 1
H),
7.50 (d, 1 H).
EXAMPLE 60
(R)-6-ethyl-3-((S)-1-(4-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-
yl)phenyl)propyl)-6-phenyl-1,3-oxazinan-2-one
O
OAN
O
N O
The title compound was prepared from (R)-3-((S)-1-(4-
bromophenyl)propyl)-6-ethyl -6-phenyl-1,3-oxazinan-2-one following
procedures analogous to those described in Example 32 Method 2 Steps 3
and 4 using 5-bromo-1-isopropylpyridin-2(1 H)-one in Step 4. LC-MS Method
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1 tR = 1.75 min, m/z = 459 (M+1); 1H NMR (CDC13) 7.49, (1 H, dd, J = 2.34,
9.37 Hz), 7.42 (1 H, d, J = 2.34 Hz), 7.32-7.24 (5H, m), 7.13 (1 H, d, J =
8.20),
7.04 (1 H, d, J =8.49), 6.66 (1 H, d, J =9.37), 5.49 (1 H, aq q, J = 6.44,
9.37),
5.33 (1 H, m), 2.96-2.91 (1 H, m), 2.39-2.32 (1 H, m), 2.29-2.17 (2H, m), 2.05-
1.85 (m, 4H), 1.41 (6H, dd, J = 1.17, 6.73), 1.01 (3H, t, J = 7.32 Hz), 0.832
(3H, t, J = 7.32 Hz).
5-bromo-1-isopropylpyridin-2(1 H)-one was prepared from 5-
bromopyridin-2(1 H)-one and isopropyl iodide following a procedure
analogous to that described in Example 59 Step 1.
EXAMPLE 61
(S)-3-((S)-1-(4-(1,5-dimethyl -6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-
(2-
hydroxy-2-m ethyl propyl)-6-phenyl-1,3-oxazinan-2-one
O
OAN
OH N O
The title compound was prepared following a procedure analogous to
that described in Example 59 using 1 5-bromo-3-methylpyridin-2(1 H)-one
and methyl iodide in Step 1. LC-MS Method 2 tR = 1.197 min, m/z = 475.1;
1H NMR (CDC13) 1.04 (s, 3H), 1.11 (s, 3H), 1.46 (d, 3H), 2.18 (m, 5H), 2.21
(m, 1 H), 2.29-2.40 (m, 1 H), 2.80 (m, 1 H), 3.41 (s, 3H), 3.56 (s, 3H), 5.60
(m,
1 H), 6.91 (d, 2H), 7.07 (d, 2H), 7.21-7.40 (m, 7H).
EXAMPLE 62
(S)-3-((S)-1-(4-(1-ethyl -6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-(4-
fluorophenyl)-6-(2-hydroxy-2-methyl propyl)-1,3-oxazinan-2-one
O
OAN
F OH O
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The title compound was prepared following a procedure analogous to
that described in Example 59, using 5-bromopyridin-2(1 H)-one and ethyl
iodide in Step 1 and (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methyl propyl)-3-
((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-
oxazinan-2-one in Step 2. LC-MS Method 2 tR = 1.205 min, m/z = 493.2; 1H
NMR (CDC13) 1.16 (d, 6H), 1.39 (t, 3H), 1.52 (d, 3H), 2.19 (s, 4H), 2.20-2.31
(m, 2H), 2.38-2.50 (m, 1 H), 2.90 (m, 1 H), 4.04 (m, 2H), 5.69 (m, 1 H), 6.66
(d,
1 H), 7.00 (m, 4H), 7.18 (d, 2H), 7.30 (m, 2H), 7.41 (s, 1 H), 7.51 (d, 1 H).
Recrystallization from isopropyl acetate following a procedure analogous to
that described for Example 37 in Recrystallization Method B afforded a
crystalline solid with mp 172-173.6 C.
EXAMPLE 63
(R)-6-methyl -3-((S)-1-(4-(1-methyl-2-oxo-1,2-dihydropyridin-4-
yl)phenyl)propyl)-6-phenyl-1,3-oxazinan-2-one
0
OAN
CE ): "i~ I N
0
The title compound was prepared from (R)-3-((S)-1-(4-
bromophenyl)propyl)-6-methyl -6-phenyl-1,3-oxazinan-2-one following
procedures analogous to those described in Example 32 Method 2 Steps 3
and 4 using 4-iodo-1-methylpyridin-2(1 H)-one in Step 4. LC-MS Method 1 tR
= 1.55 min, m/z = 417 (M+1); 1H NMR (CDC13) 7.41 (1 H, d, J = 7.03 Hz),
7.33 (2H, d, J = 8.20 Hz), 7.29-7.19 (5H, m), 7.10 (1 H, d, J = 8.20), 6.95 (1
H,
d = 1.76), 6.55 (1 H, dd, J = 2, 7.03 Hz), 5.51 (1 H, q, J =6.49, 9.66 Hz),
3.65
(3H, s), 3.00-2.95 (1 H, m), 2.44-2.36 (1 H, m), 2.33-2.15 (2H, m), 2.06-1.86
(2H, m), 1.64 (3H, s), 1.02 (3H, t, J = 7.32 Hz).
(R)-3-((S)-1-(4-bromophenyl)propyl)-6-methyl -6-phenyl-1,3-oxazinan-
2-one was prepared from 4-chloro-2-phenylbutan-2-ol and (S)-1 -(4-
bromophenyl)propan-1 -amine following a procedure analogous to that
described in Example 71 Step 2.
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4-chloro-2-phenylbutan-2-ol was prepared from 3-chloro-1-
phenylpropan-1-one and methylmagnesium bromide following a procedure
analogous to that described in Preparation 1 Method 1 Step 2.
EXAMPLE 64
(S)-3-((S)-1-(4-(1,6-dimethyl -2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-
(2-
hydroxy-2-m ethyl propyl)-6-phenyl-1,3-oxazinan-2-one
O
OAN
/ I N:
OH O
The title compound was prepared from (S)-6-(2-hydroxy-2-
methyl propyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-
2-yl)phenyl)propyl)-1,3-oxazinan-2-one and 4-bromo-1,6-dimethylpyridin-
2(1 H)-one following a procedure analogous to that described in Example 6
Step 1. LC-MS Method 2 tR = 1.173 min, m/z = 475.2; 1H NMR (CDC13) 1.10
(s, 3H),1.16 (s, 3H), 1.51 (d, 3H),2.18 (m, 3H), 2.21 (m, 1 H), 2.42 (m, 4H),
2.86 (m,1 H), 3.54 (s, 3H), 5.66 (m, 1 H), 6.21 (s, 1 H), 6.60 (s, 1 H), 6.97
(m,
2H), 7.23-7.34(m, 7H).
4-bromo-1,6-dimethylpyridin-2(1 H)-one was prepared by methylation
of 4-bromo-6-methylpyridin-2(1 H)-one with methyl iodide using K2CO3
following a procedure analogous to that described in Example 59 Step 1.
EXAMPLE 65
(S)-3-((S)-1-(4-(1-ethyl -2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-(2-
hydroxy-2-methyl propyl)-6-phenyl-1,3-oxazinan-2-one
O
OAN
Nom/
OH
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The title compound was prepared from (S)-6-(2-hydroxy-2-
methyl propyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-
2-yl)phenyl)propyl)-1,3-oxazinan-2-one and 1-ethyl -4-iodopyridin-2(1 H)-one
following a procedure analogous to that described in Example 6 Step 1. LC-
MS Method 2 tR = 1.228 min, m/z = 971.4; 1H NMR (CDC13) 1.10 (s, 3H),
1.14 (s, 3H), 1.36 (m, 3H), 1.53 (d, 3H), 2.17 (s, 2H), 2.21-2.32 (m, 2H),
2.32-2.48 (m, 1 H), 2.88 (m, 1 H), 4.00 (m, 2H), 5.68 (m, 1 H), 6.39 (d, 1 H),
6.78 (s, 1 H), 6.99 (d, 2H), 7.27-7.38 (m, 8H).
1-ethyl -4-iodopyridin-2(1 H)-one was prepared from 4-iodopyridin-
2(1 H)-one and ethyl iodide following a procedure analogous to that
described in Example 59 Step 1.
EXAMPLE 66
(S)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(2-oxo-1-(2,2,2-trifluoroethyl)-
1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
O
OA N I
N ~F
OH O
The title compound was prepared from (S)-6-(2-hydroxy-2-
methyl propyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-
2-yl)phenyl)propyl)-1,3-oxazinan-2-one and 4-iodo-1 -(2,2,2-
trifluoroethyl)pyridin-2(1 H)-one following a procedure analogous to that
described in Example 6 Step 1. LC-MS Method 2 tR = 1.871 min, m/z =
471.1; 1H NMR (CDC13) 1.11 (s, 3H), 1.17 (s, 3H), 1.53 (d, 3H), 2.16-2.33
(m, 4H), 2.35-2.47 (m, 1 H), 2.89 (m, 1 H), 4.58-4.70 (m, 2H), 5.69 (m, 1 H),
6.71 (s, 1 H), 7.00 (d, 2H), 7.19-7.38 (m, 8H). Recrystallization from
isopropyl acetate following a procedure analogous to that described for
Example 37 in Recrystallization Method B afforded a crystalline solid with
mp 144-145.5 C.
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4-iodo-1 -(2,2,2-trifluoroethyl)pyridin-2(1 H)-one was prepared from 4-
iodopyridin-2(1 H)-one and 2,2,2-trifluoroethyl trifluoromethanesulfonate
following a procedure analogous to that described in Example 59 Step 1.
EXAMPLE 67
(S)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(6-oxo-1-(2,2,2-trifluoroethyl)-
1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
O
OAN I \
O
OH O
Y
F F
The title compound was prepared from (S)-6-(2-hydroxy-2-
methyl propyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-
2-yl)phenyl)propyl)-1,3-oxazinan-2-one and 5-bromo-1-(2,2,2-
trifluoroethyl)pyridin-2(1 H)-one following a procedure analogous to that
described in Example 6 Step 1. LC-MS Method 2 tR = 1.323 min, m/z =
471.1; 1H NMR (CDC13) 1.13 (s, 3H), 1.19 (s, 3H), 1.53 (d, 3H), 2.19-2.30
(m, 4H), 2.40 (m, 1 H), 2.89 (m, 1 H), 4.67 (m, 2H), 5.69 (m, 1 H), 6.70 (d, 1
H),
7.03 (d, 2H), 7.13 (d, 2H), 7.29-7.38 (m, 6H), 7.55 (d, 1 H).
5-bromo-1 -(2,2,2-trifluoroethyl)pyridin-2(1 H)-one was prepared from
5-bromopyridin-2(1 H)-one and 2,2,2-trifluoroethyl trifluoromethanesulfonate
following a procedure analogous to that described in Example 59 Step 1.
EXAMPLE 68
(S)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(1-isopropyl-2-oxo-1,2-
dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
O
OA N I \
N
OHII-I
O
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The title compound was prepared from (S)-6-(2-hydroxy-2-
methyl propyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-
2-yl)phenyl)propyl)-1,3-oxazinan-2-one and 4-iodo-1-isopropylpyridin-2(1 H)-
one following a procedure analogous to that described in Example 6 Step 1.
LC-MS Method 2 tR = 1.846 min, m/z = 489.2; 1H NMR (CDCI3) 1.10 (s, 3H),
1.24 (s, 3H), 1.39 (d, 6H), 1.52 (d, 3H), 2.17-2.31 (m, 4H), 2.35-2.46 (m, 1
H),
2.88 (m, 1 H), 5.27 (m, 1 H), 5.69 (m, 1 H), 6.49 (d, 1 H), 6.88 (s, 1 H),
7.00 (d,
2H), 7.29-7.38 (m, 7H), 7.40 (d,1 H). Recrystallization from isopropyl acetate
following a procedure analogous to that described for Example 37 in
Recrystallization Method B afforded a crystalline solid with mp 134-139 C.
4-iodo-1-isopropylpyridin-2(1 H)-one was prepared from 4-iodopyridin-
2(1 H)-one and isopropyl iodide following a procedure analogous to that
described in Example 59 Step 1.
EXAMPLE 69
3-((R)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-
yl)phenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile
O
OA N
F ~~ N O
N
The title compound was prepared from 3-((R)-6-(4-fluorophenyl)-2-
oxo-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-
1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile and 5-bromo-1-methylpyridin-
2(1 H)-one following a procedure analogous to that described in Example 3
Step 2. LC-MS Method 1 tR = 1.45 min, m/z = 488; 1H NMR (CDCI3)
7.68(dd, 1 H), 7.52(d, 1 H), 7.32(q, 2H), 7.17(d, 2H), 7.06(t, 2H), 6.97(d,
2H),
6.91(d, 1 H), 5.66(q, 1 H), 3.72(s, 3H), 2.99(dt, 1 H), 2.48(dd, 2H), 2.27(m,
1 H), 2.11(s, 2H), 1.55(d, 3H), 1.44(s, 3H), 1.34(s, 3H).
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EXAMPLE 70
(S)-3-((S)-1-(4-(1-ethyl -5-methyl -6-oxo-1,6-dihydropyridin-3-
yl)phenyl)ethyl)-
6-(2-hydroxy-2-methyl propyl)-6-phenyl-1,3-oxazinan-2-one
O
OAN
O
OH N O
The title compound was prepared from (S)-6-(2-hydroxy-2-
methyl propyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-
2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 5-bromo-1-ethyl-3-methylpyridin-
2(1 H)-one following a procedure analogous to that described in Example 6
Step 1. LC-MS Method 2 tR = 1.314 min, m/z = 489; 1H NMR (CDC13) 1.09
(s, 3H), 1.15 (s, 3H), 1.35 (t, 3H), 1.50 (d, 3H), 2.15-2.25 (m, 7H), 2.35 (m,
1 H), 2.86 (m, 1 H), 4.03 (m, 2H), 5.66 (q, 1 H), 6.96 (d, 2H), 7.13 (d, 2H),
7.25-7.36 (m, 7H).
5-Bromo-1-ethyl-3-methylpyridin-2(1 H)-one was prepared by
alkylation of 5-bromo-3-methylpyridin-2(1 H)-one with ethyl iodide following a
procedure analogous to that described in Example 59 Step 1.
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EXAMPLE 71
2,2-d imethyl -3-((R)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-d ihyd ropyrid in-3-
yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-6-yl)propanenitrile
Method 1
O ~mgcl OH H2N OH
Br
CI . I \ CI I \ H I \
CeCl3 KI, K2CO3 / /
McCN Br
O
H
MeOCOCI 04 NaH O~N \ TsCN
aoo~ Br THE \ / Br Ph3SiH
Co cat
O O
ON Oi H Pd(dppf)C12, dioxane
+ HOB ajC,~~ CS2CO3 ON Br O 900C CN
H / I\
CN H O
Step 1
A 250 mL flask was charged with anhydrous CeC13 (7.1890 g, 29.2
mmol) and THE (55 mL). The mixture was vigorously stirred for 2 h at rt.
The suspension was then cooled to -78 C and a solution of 2-
methylallylmagnesium chloride (0.5 M in THF, 56 mL, 28.0 mmol) was
added. After stirring for 2 h at -78 C, a solution of 3-chloropropiophenone
(3.350 g, 19.8 mmol) in THE (30 mL) was added via cannula. The reaction
mixture was allowed to slowly warm to 8 C while stirring overnight (18 h).
The reaction was then quenched with satd aq NaHCO3, extracted with
EtOAc, and dried over Na2SO4. After the solvents were evaporated, the
crude 1-chloro-5-methyl-3-phenylhex-5-en-3-ol was directly used in the next
step without further purification. LC-MS Method 1 tR = 1.91 min, m/z 248,
207 (M-OH)+; 1H NMR (400 MHz, CDC13) 6 7.39-7.22 (m, 5H), 4.92 (m, 1 H),
4.77 (m, 1 H), 3.60-3.53 (m, 1 H), 3.17-3.10 (m, 1 H), 2.67 (d, J = 13.2 Hz,
1 H), 2.55 (d, J = 13.2 Hz, 1 H), 2.41-2.25 (m, 2H), 1.29 (s, 3H); 13C NMR
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(100 MHz, CDC13) 6 144.55, 141.72, 128.32, 126.88, 125.07, 116.50, 74.44,
51.46, 46.34, 40.19, 24.22.
Step 2
1 -ch loro-5-m ethyl -3-ph enyl h ex-5-en -3-ol (1.28 g, 5.7 mmol), (S)-1 -(4-
bromophenyl)ethanamine (1.37 g, 1.2 equiv), KI (995 mg, 1.05 equiv),
K2CO3 (1.57 g, 2 equiv) were mixed with acetonitrile (15 mL) and heated to
reflux (oil bath 96 C) for overnight. After being cooled to rt, the mixture
was
filtered, concentrated, and purified by chromatography on a 40-g silica gel
column, eluted with 0-8% MeOH in CH2CI2, to afford 1-((S)-1-(4-
bromophenyl)ethylamino)-5-methyl-3-phenylhex-5-en-3-ol (1.33 g, 60%).
Step 3
To a solution of 1-((S)-1-(4-bromophenyl)ethylamino)-5-methyl -3-
phenylhex-5-en-3-ol (1.33 g, 3.43 mmol) in CH2CI2 (100 mL) was added
pyridine (277 pL, 1 equiv) and triethylamine (717 pL, 1.5equiv). The mixture
was cooled to 0 C. Methyl chloroformate (397 pL, 1.5 equiv) was added
slowly. After 15 min, the mixture was warmed to rt slowly and stirred for 3 h.
The mixture was then diluted with ether (200 mL), washed with 5% aq HCI (2
x 25 mL), satd aq NaHCO3 (25 mL) and brine (20 mL), and dried over
Na2SO4. After filtration and concentration, the crude methyl (S)-1-(4-
bromophenyl)ethyl(3-hydroxy-5-methyl-3-phenylhex-5-enyl)carbamate was
used for next steps without further purification.
Step 4
The crude methyl (S)-1-(4-bromophenyl)ethyl(3-hydroxy-5-methyl -3-
phenylhex-5-enyl)carbamate from above procedure was dissolved in dry
THE (75 mL), NaH (60% in mineral oil, 274 mg, 2 equiv) was added slowly at
rt. After 10 min, the mixture was heated to reflux for 2 h. LC-MS found
reaction completed. The mixture was cooled to 0 C, quenched with satd aq
NH4CI (10 mL), diluted with ether (100 mL), washed with 1 % aq HCI (25 mL)
and brine (15 mL), and dried over Na2SO4. After filtration and concentration,
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the crude product was purified by by chromatography on a 40-g silica gel
column, eluted with 10-35% EtOAc in hexanes. The second UV active peak
was collected to afford (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methyl allyl)-
6-phenyl-1,3-oxazinan-2-one (490mg 34.5% overall yield for Steps 3 and 4).
Step 5
A mixture of (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-methyl aIlyl)-6-
phenyl-1,3-oxazinan-2-one (490 mg, 1.18 mmol), TsCN (257 mg, 1.2 equiv),
PhSiH3 (157 pL, 1.07 equiv) and the cobalt N,N'-bis(3,5-di-tert-
butylsalicylidene)-1,1,2,2-tetramethylethenediamine catalyst prepared as
described in Preparation 3 (7.5 mg, 0.01 equiv) and ethanol (20 mL) was
stirred 4 h at rt. LC-MS found the reaction completed. The mixture was
concentrated and purified by ISCO (40g column, 25-80% EtOAc in
Hexanes) to afford 267mg product (51 % yield). LC-MS Method 1 tR =
1.89min., m/z 441, 443 (M+1).
Step 6
To a solution of 3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-
1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile (208mg, 0.47mmol) in 1,4-
dioxane (5 mL) were added 6-oxo-1,6-dihydropyridin-3-ylboron ic acid (98mg,
1.5 equiv), 2.0 M aq Cs2CO3 solution (500 pL), and Pd(dppf)C12 (20mg, 0.06
equiv). The mixture was degassed and refilled with N2 gas 3 times, before
being heated to 90 C (oil bath) for 3 h. LC-MS found the reaction was
complete. The mixture was cooled to rt, diluted with EtOAc (25 mL), and
washed with water (10 mL). The aqueous layer was extracted with EtOAc (2
x 10 mL). The combined organic layers were washed with water (10 mL)
and brine (8 mL), and dried over Na2SO4. After filtration and concentration,
the residue was purified by chromatography (12-g silica gel cartridge, 0
-10% MeOH in CH2C12, major UV peak) to afford 2,2-dimethyl-3-((R)-2-oxo-
3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-
oxazinan-6-yl)propanenitrile (202 mg, 94%) as a brown oil. LC-MS Method
1 tR = 1.34 min, m/z = 456 (M+1); 1H NMR (CDC13) 8.01 (d, 1 H), 7.80 (s, 1 H),
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7.36 (dt, 6H), 7.19 (d, 2H), 6.98 (m, 3H), 5.65 (d, 1 H), 2.98 (d, 1 H), 2.50
(m,
2H), 2.32 (m, 1 H), 2.17 (s, 2H), 1.57 (d, 3H), 1.40 (s, 3H), 1.32 (s, 3H).
Method 2
I
O 0 SN\/ O O
NH OOH_ II TsCN II
O N O O N Ph3SiH O N
\ '' Br \ `' Br Co cat I Br
OH O CN '!:~ ' Step 1. 3-[(S)-1-(4-Bromo-phenyl)-ethyl]-(S)-6-(2-methyl -
allyl)-6-phenyl-
[1,3]oxazinan-2-one
(Methoxycarbonylsulfamoyl)triethylammonium hydroxide (1.38 g) was
added to 3-[(S)-1-(4-bromo-phenyl)-ethyl]-(S)-6-(2-hydroxy-2-methyl -propyl)-
6-phenyl-[1,3]oxazinan-2-one (2.0 g) dissolved in tetrahydrofuran (30 mL)
and toluene (15 mL). The resulting solution was stirred at room temperature
for 0.5 h and at 75 C for 1 h. After cooling to room temperature, the
solution was concentrated and ethyl acetate was added to the residue. The
resulting mixture was washed with aqueous NaHCO3 solution and brine and
dried (MgS04). The title compound was obtained after removal of the
solvent. Yield: 1.9 g (quantitative). Mass spectrum (ESI+): m/z = 414/416
(Br) [M+H]+
Step 2. 3-{3-[(S)-1-(4-Bromo-phenyl)-ethyl]-2-oxo-(S)-6-phenyl-
[1,3]oxazinan-6-yl}-2,2-dimethyl-propionitrile
3-[(S)-1-(4-Bromo-phenyl)-ethyl]-(S)-6-(2-methyl -allyl)-6-phenyl-
[1,3]oxazinan-2-one (0.21 g), p-toluenesulfonyl cyanide (143 mg), tert-
BuOOH (5.5 M in decane, 27 pL), and phenylsilane (64 pL) were added in
the given order to a flask charged with a stir bar, (1 R,2R)-(-)-1,2-
cyclohexanediamino-N,N'-bis(3,5-di-tert-butylsalicyliden)cobalt(II) (3 mg) and
ethanol (15 mL) in argon atmosphere. The resulting solution was stirred at
room temperature for 3 h and then concentrated under reduced pressure.
The residue was purified by chromatography on silica gel (cyclohexane/ethyl
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acetate 60:40->0:100) to afford the title compound as a resin-like solid.
Yield: 0,16 g (70% of theory). Mass spectrum (ESI+): m/z = 441/443 (Br)
[M+H]+
EXAMPLE 72
(S)-3-((S)-1-(4-(1-ethyl -6-methyl -2-oxo-1,2-dihydropyridin-4-
yl)phenyl)ethyl)-
6-(2-hydroxy-2-methyl propyl)-6-phenyl-1,3-oxazinan-2-one
O
OAN
OH O
The title compound was prepared from (S)-6-(2-hydroxy-2-
methyl propyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-
2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-bromo-1-ethyl-6-methylpyridin-
2(1 H)-one following a procedure analogous to that described in Example 6
Step 1. LC-MS Method 2 tR = 1.211 min, m/z = 489.2; 1H NMR (CDC13) 1.10
(s, 3H), 1.17 (s, 3H), 1.49 (s, 9H), 1.57 (d, 3H), 2.22 (m, 4H), 2.37 (m, 1
H),
2.84 (m, 1 H), 5.60 (m, 1 H), 5.91 (s, 1 H), 7.06 (d, 2H), 7.27-7.40 (m, 5H),
7.68 (d, 1 H), 7.24 (d, 2H), 8.09 (d, 1 H), 8.90 (s, 1 H).
4-bromo-1-ethyl-6-methylpyridin-2(1 H)-one was prepared by
alkylation of 4-bromo-6-methylpyridin-2(1 H)-one with ethyl iodide using
K2CO3 following a procedure analogous to that described in Example 59
Step 1.
EXAMPLE 73
(S)-6-(2-hydroxy-2-methyl propyl)-6-phenyl-3-((S)-1-(4-(1,5,6-trimethyl -2-oxo-
1,2-dihydropyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one
O
OA N
N
OH O
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The title compound was prepared from (S)-6-(2-hydroxy-2-
methyl propyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-
2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-bromo-1,5,6-trimethylpyridin-
2(1 H)-one following a procedure analogous to that described in Example 6
Step 1. LC-MS Method 2 tR = 1.187 min, m/z = 489.2; 1H NMR (CDC13) 1.10
(s, 3H),1.15 (s, 3H), 1.32 (m, 3H),1.52 (m, 3H), 1.72 (s, 1 H),2.18 (m, 3H),
2.19 (m, 1 H), 2.42 (m, 4H), 2.86 (m, 1 H), 4.12 (m, 2H), 5.66 (m, 1 H), 6.16
(s,
1 H), 6.53 (s, 1 H), 6.98 (m, 2H), 7.23-7.34 (m, 7H).
4-bromo-1,5,6-trimethylpyridin-2(1 H)-one was prepared by alkylation
of 4-bromo-5,6-dimethyl pyrid in-2(1 H)-one with methyl iodide using K2CO3
following a procedure analogous to that described in Example 59 Step 1. 4-
bromo-5,6-dimethyl pyrid in-2(1 H)-one was prepared following the procedure
described in McElroy, W. T. and DeShong, P. Org. Lett. 2003, 5, 4779.
EXAMPLE 74
3-((R)-3-((S)-1-(4-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-
oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-dimethylpropanenitrile
O
OIN OAN
Cs2CO3
N Q_N O
N \
O
H
2,2-dim ethyl -3-((R)-2-oxo-3-((S)-1-(4-(6-oxo-1,6-dihydropyridin-3-
yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-6-yl)propanenitrile (6 mg, 0.013
mmol) was dissolved in DMF (2.5 mL). Cs2CO3 (c.a. 15 mg, excess) and i-
Pr1 (100pL, excess) were added. The mixture was stirred for 3 h at rt. LC-MS
found the reaction was complete. The mixture was purified by prep HPLC to
afford 3-((R)-3-((S)-1-(4-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-
yl)phenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)-2,2-dimethyl propanenitrile
(1.99 mg, 30%). LC-MS Method 1 tR = 2.03 min, m/z = 498; 1H NMR
(CDC13) 8.35(d, 1 H), 7.80(dd, 1 H), 7.37(m, 5H), 7.22(d, 2H), 6.92(d, 2H),
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6.83(d, 1 H), 5.66(q, 1 H), 5.22(m, 1 H), 2.93(m, 1 H), 2.16(s, 2H), 1.55(d,
3H),
1.46(s, 3H), 1.40(d, 6H), 1.33(s, 3H).
EXAMPLE 75
3-{(S)-1-[4-(1-Cyclopropyl-2-oxo-1,2-dihydro-pyridin-4-yl)-phenyl]-ethyl}-(S)-
6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one
O
01N
OH N
Method 1
2 M aqueous Na2CO3 solution (0.23 mL) was added to a solution of
(S)-6-(2-hydroxy-2-methyl propyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5- tetramethyl-
1,3,2-dioxaborolan-2- yl)phenyl)ethyl]-1,3-oxazinan-2-one (0.11 g) and
trifluoro-methanesulfonic acid 1-cyclopropyl-2-oxo-1,2-dihydro-pyridin-4-yl
ester (74 mg; alternatively, 4-bromo-1 -cyclopropyl-1 H-pyridin-2-one was
used) in dimethylformamide (3 mL). The resulting mixture was sparged with
argon for 15 min, before [1,1'-bis(diphenylphosphino)-ferrocene]-
dichloropalladium(II) dichloromethane complex (10 mg) was added. The
mixture was heated to 100 C and stirred at this temperature overnight.
After cooling to ambient temperature, water was added and the resulting
mixture was extracted with ethyl acetate. The combined organic extracts
were washed with brine, dried (MgSO4), and concentrated. The residue was
purified by chromatography on silica gel (CH2CI2/MeOH 99:1->90:10) to
afford the title compound as a foam-like solid which was crystallized with
little ethyl acetate. Yield: 30 mg (27% of theory); Mass spectrum (ESI+): m/z
= 487 [M+H]+. The compound (1.3 g) was recrystallized from 30 mL of
isopropyl acetate. The hot solution, while being stirred, was slowly cooled
down to room temperature overnight in the oil bath to yield the crystalline
monohydrate. Mp 108-110 C.
The crystalline monohydrate was also obtained by recrystallization of
10.6 g of compound of Example 75 from 170 mL of isopropyl acetate that had
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been saturated with water. The hot solution, while being stirred, was slowly
cooled down to room temperature, stirred for 2 hours at room temperature
and 1 hour in an ice-bath. The solid was filtered by suction and dried
overnight at 50 C. Yield 10.2 g. Mp 112-114 C.
The compound of Example 75 (2.0 g) was also recrystallized from a
mixture of 30 mL of tert.butyl methylether and 15 mL of isopropanol. The
solid was filtered by suction, washed with tert.butyl methylether and dried at
45 C and then at 65 C overnight. 100 mg of this solid was stirred in 3 mL of
water to first form a resinous material that later on converts into a white
solid. This was stirred for another hour, filtered by suction and dried
overnight at room temperature and then at 65 C for 3 hours in a circulating
air drier to yield a crystalline monohydrate. Mp 102-108 C.
This crystalline form of the monohydrate may be characterized by
means of its characteristic X-ray powder diffraction (XRPD) pattern.
The crystalline form is characterised by an X-ray powder diffraction
pattern that comprises peaks at 21.00, 21.72, 23.98 degrees 20 ( 0.05
degrees 2Q, wherein said X-ray powder diffraction pattern is made using
CuKai radiation.
In particular said X-ray powder diffraction pattern comprises peaks at
14.25, 21.00, 21.72, 23.10, 23.98, 27.04 degrees 20 ( 0.05 degrees 2Q,
wherein said X-ray powder diffraction pattern is made using CuKai radiation.
More specifically, the crystalline form is characterised by following
lattice parameters: orthorhombic symmetry, space group P212121 with the
cell parameters, a=8.65(1) A, b=1 5.46(2) A, c=20.35(2) A, and cell
volume=2720(7) A3 obtained by indexing of the X-ray powder diagram
measured at room temperature using CuKai radiation, which comprises
peaks at degrees 20 ( 0.05 degrees 2E) as contained in Table 2.
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Table 2 Indexed XRPD peaks up to 30 0 20 including intensities
(normalised) of the monohydrate of Example 75
20 dhk, Intensity Indexing 2 Oobs - 2 Ocalc
[0] [A] I/Io [%] h k I [0]
7.19 12.29 4 0 1 1 0.011
8.66 10.21 2 0 0 2 -0.027
11.14 7.94 20 1 0 1 0.032
11.40 7.76 18 0 2 0 -0.046
11.74 7.53 15 1 1 0 0.027
12.50 7.07 28 1 1 1 0.004
14.25 6.21 32 0 1 3 0.004
14.59 6.07 24 1 1 2 -0.013
15.38 5.76 7 1 2 0 0.014
17.58 5.04 29 1 1 3 0.015
17.68 5.01 13 1 2 2 0.003
18.34 4.83 17 0 1 4 -0.009
19.32 4.59 2 0 3 2 0.029
20.21 4.39 14 1 2 3 0.006
20.51 4.33 22 1 3 1 -0.012
20.88 4.25 22 0 2 4 -0.011
21.00 4.23 97 2 0 1 0.015
21.30 4.17 6 2 1 0 -0.017
21.72 4.09 100 2 1 1 -0.041
22.51 3.95 18 0 1 5 -0.061
23.10 3.85 57 2 1 2 0.046
23.57 3.77 6 2 2 0 0.016
23.98 3.71 65 2 2 1 0.013
24.41 3.64 12 2 0 3 0.023
24.86 3.58 6 1 1 5 0.026
25.08 3.55 15 2 1 3 0.013
26.68 3.34 7 1 3 4 0.005
26.92 3.31 25 0 1 6 0.029
27.04 3.29 48 2 2 3 0.028
27.20 3.28 5 2 3 1 -0.057
27.66 3.22 26 2 1 4 0.005
28.28 3.15 3 1 0 6 0.034
28.52 3.13 2 1 4 3 0.030
28.85 3.09 5 1 1 6 0.011
29.40 3.04 2 2 2 4 -0.042
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30.00 2.98 3 2 3 3 -0.001
30.18 2.96 3 2 0 5 0.056
The X-ray powder diffraction patterns are recorded, within the scope
of the present invention, using a STOE - STADI P-diffractometer in
transmission mode fitted with a position-sensitive detector (PSD) and a Cu-
anode as X-ray source and a Germanium monochromator (CuKal radiation,
X = 1,54056 A, 40kV, 40mA). In the Table 1 above the values "20 [0]"
denote the angle of diffraction in degrees and the values " dhkl [A]" denote
the specified distances in A between the lattice planes. The intensity shown
in the Figure 1 is given in units of cps (counts per second).
The crystalline form is characterised by an X-ray powder diffraction
pattern, made using CuKal radiation, which comprises peaks at degrees 20
( 0.05 degrees 20) as shown in Figure 2.
In order to allow for experimental error, the above described 2 O
values should be considered accurate to 0.05 degrees 20. That is to say,
when assessing whether a given sample of crystals of the compound A is
the crystalline form I in accordance with the invention, a 2 O value which is
experimentally observed for the sample should be considered identical.
X-ray Structure Determination of the Monohydrate of Example 75
The monohydrate of Example 75, 031H36N205, crystallizes in the
orthorhombic space group P212121 with a=8.4940(17) A, b=15.480(3) A,
c=20.200(4)A, V=2656.0(9) A3, Z=4 and dcalc=1.257 g/cm3. X-ray intensity
data were collected on a Rigaku Saturn944 CCD area detector employing
Cu-Ka, radiation (X=1.54178A) at a temperature of 100(1)K. Data were
collected by the rotation method. Rotation images were processed using
D*trek Pflugrath, JW (1999) Acta Cryst. D55, 1718-1725.A total of 24559
reflections were measured yielding 4381 unique reflections (R;nt = 0.061).
The structure was solved by direct methods and refined by full-matrix
least squares based on F2 (SHELX-97 Sheldrick, G.M. (2008). Acta Cryst.
A64, 112-122.. All reflections were used during refinement. The weighting
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scheme used was w=1/[62(F2O) + 0.1542P2 + 1.3034P] where P = (Fo +
2F2
c )/3 . Non-hydrogen atoms were refined anisotropically and hydrogen
atoms were refined using a "riding" model. Refinement converged to
R1=0.0772 and wR2=0.2096 for 4204 reflections for which F > 46(F) and
R1=0.0823, wR2=0.2234 and GOF = 1.092 for all 4381 unique, non-zero
reflections and 356 variables. The maximum 0/6 in the final cycle of least
squares was 0.001 and the two most prominent peaks in the final difference
Fourier were +0.68 and -0.34 e/A3.
Table 2A lists cell information, data collection parameters, and
refinement data. Final positional and equivalent isotropic thermal
parameters are given in Table 2B. Anisotropic thermal parameters are in
Table 2C.
The molecule crystallises as a monohydrate. The water molecule lies within
a cavity lined by polar functional groups of the title compound. The terminal
N-cyclopropyl moiety is statically disordered and was modelled in three
conformations symmetrically rotated around the N30-C33 bond.
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Table 2A. Summary of Structure Determination of the Monohydrate of
Example 75
Formula: C30H34N205
Formula weight: 502.59
Crystal class: orthorhombic
Space group: P212121 (#19)
Z 4
Cell constants:
a 8.4940(17)A
b 15.480(3)A
c 20.200(4)A
V 2656.0(9)A3
0.69 cm-1
crystal size, mm 0.2 x 0.2 x 0.2
Dcaic 1.257 g/Cm3
F(000) 1072
Radiation: Cu-Ka,(X=1.54178A)
hkl collected: -9<_h<_9; -17<_k<_17;
-
23<_I <_23
No. reflections measured: 24599
No. unique reflections: 4381 (R;nt=0.061)
No. observed reflections 4204 (F>46)
No. reflections used in refinement 4204
No. parameters 356
R indices (F>46) R1=0.0772
wR2=0.2096
GOF: 1.092
Final Difference Peaks, e/A3 +0.68, -0.34
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Table 2B. Refined Positional Parameters for the Monohydrate of
Example 75
Atom Atomtype X Y Z Ueq, A
06 0 0.2810(3) 0.85690 15 0.18748 11 0.0286 6
07 0 0.5346(3) 0.86676 17 0.16786 14 0.0350(D
018 0 0.0932(4) 1.00778 17 0.17024 14 0.0394(7)
H18 H 0.1679 0.9869 0.1481 0.059
N2 N 0.4438(4) 0.73979 19 0.20957 16 0.0296(D
C19 C 0.6042(5) 0.7014(2) 0.20666 19 0.0298(8)
H19 H 0.6704 0.7408 0.1790 0.036
036 0 0.5819(5) 0.14643 17 0.09269 14 0.0541 10
C4 C 0.1732(5) 0.7407(2 0.25110 18 0.0294(8
H4A H 0.1922 0.7735 0.2924 0.035
H413 H 0.0808 0.7028 0.2581 0.035
C32 C 0.5863(5) 0.2991(2 0.09586 19 0.0360(9)
H32 H 0.5663 0.3002 0.1421 0.043
C12 C -0.0284(5) 0.6427(2 0.0703(2) 0.0369(9)
H12 H -0.1058 0.5984 0.0698 0.044
C3 C 0.3166(5) 0.6862(2 0.23465 19 0.0325(9)
H3A H 0.3523 0.6555 0.2749 0.039
H313 H 0.2880 0.6425 0.2010 0.039
C8 C 0.1127(5) 0.7544(2 0.12992 17 0.0281(8)
C5 C 0.1402(4) 0.8032(2 0.19446 17 0.0257(8)
C25 C 0.5407(5) 0.5339(2 0.0723(2) 0.0366 10
H25 H 0.5012 0.5330 0.0283 0.044
C21 C 0.5986(5) 0.6149(2 0.17143 18 0.0305(8)
Cl C 0.4262(5) 0.8216(2 0.18703 18 0.0286(8)
C26 C 0.5401(5) 0.6099(2 0.10768 19 0.0353(9)
H26 H 0.4981 0.6605 0.0877 0.042
C17 C -0.1619(5) 0.9948(3 0.2117(2) 0.0373(9)
H 17A H -0.1209 1.0138 0.2546 0.056
H17B H -0.2516 0.9560 0.2186 0.056
H 17C H -0.1961 1.0452 0.1861 0.056
010 C 0.1735(5) 0.7218(3 0.01594 19 0.0370 10
H10 H 0.2357 0.7327 -0.0222 0.044
C23 C 0.6562(6) 0.4632(2 0.1648(2) 0.0378(10)
H23 H 0.6976 0.4126 0.1850 0.045
C20 C 0.6764(5) 0.7000(3 0.27568 19 0.0353(9)
H2OA H 0.6852 0.7592 0.2924 0.053
H2OB H 0.7813 0.6737 0.2736 0.053
H20C H 0.6092 0.6661 0.3054 0.053
N30 N 0.6253(8) 0.2210(2 -0.00457(18) 0.0733 16
011 C 0.0600(5) 0.6587(3 0.0139(2) 0.0379 10
H11 H 0.0424 0.6266 -0.0255 0.046
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C31 C 0.5949(7) 0.2169(3) 0.0636(2) 0.0455 11
C15 C -0.0319(5) 0.9467(2) 0.17352 19 0.0316(T
C24 C 0.5991(5) 0.4585(2) 0.10070 19 0.0327(T
C27 C 0.6052(6) 0.3760(2) 0.0640(2) 0.0370(10)
C16 C -0.0946(5) 0.9249(3 0.10498 19 0.0374 10
H 16A H -0.1370 0.9772 0.0843 0.056
H16B H -0.1781 0.8816 0.1088 0.056
H16C H -0.0089 0.9019 0.0777 0.056
C13 C -0.0048(5) 0.6906(2 0.12734 18 0.0315(9)
H13 H -0.0687 0.6803 0.1651 0.038
C14 C 0.0091(5) 0.8662(2 0.21457 18 0.0298(9)
H 14A H 0.0348 0.8867 0.2597 0.036
H14B H -0.0887 0.8318 0.2183 0.036
C9 C 0.1989(5) 0.7701(2 0.07326 17 0.0322(9)
H9 H 0.2764 0.8144 0.0733 0.039
C28 C 0.6334(9) 0.3748(3) -0.0051(2) 0.0661(18)
H28 H 0.6437 0.4274 -0.0290 0.079
C22 C 0.6543(5) 0.5402(2) 0.2003(2) 0.0360 10
H22 H 0.6916 0.5413 0.2447 0.043
C29 C 0.6454 12 0.2984(3 -0.0368(2) 0.094(3)
H29 H 0.6685 0.2980 -0.0828 0.112
C33 C 0.6453 15 0.1402(3 -0.0380(3) 0.105(3)
C34 C 0.6533(9) 0.1275(4) -0.1038(3) 0.0431(16)
C35 C 0.5373 14 0.0926(7 -0.0556(4) 0.074(3)
C36 C 0.7109 14 0.0797(7 -0.0330(5) 0.085(3)
080 0 0.3853(4) -0.0013(2 0.09418 16 0.0473(8)
H81 H 0.443(5) 0.044(2) 0.099(3) 0.046 14
H82 H 0.429(9) -0.040(4) 0.119(4) 0.12(3)
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Table 2C. Refined Thermal Parameters (U's) for the Monohydrate of
Example 75
U11 U22 U33 U23 U13 U12
Atom
06 0.0281 15 0.0252(12) 0.0325(13) -0.0002(10) 0.0002(11) -0.0020(10)
07 0.0308(16) 0.0298(13) 0.0443(15) 0.0040(11) 0.0000(13) -0.0037(12)
018 0.0381 17 0.031314 0.048917 0.0009(12) -0.0004(13) -0.0007(12)
N2 0.0271 18 0.0280(15) 0.0338(16) 0.0012(12) 0.0034(13) -0.0005(13)
C19 0.028(2) 0.0268 18 0.0344 19 -0.0007(14) 0.0022 15 0.0040 16
036 0.101(3) 0.0258(13) 0.0356(15) 0.0019(11) -0.0057(17) -0.0051(16)
04 0.032(2) 0.0281 17 0.0286 18 0.0034 15 0.0021 15 -0.0020(15)
C32 0.046(3) 0.0340 19 0.0281 18 0.0032 15 0.0033 17 0.0018 18
C12 0.031(2) 0.0324 19 0.047 2 -0.0099(17) -0.0052(18) -0.0029(16)
03 0.035(2) 0.0299 18 0.0326 18 0.0051 15 0.0048 16 0.0009 16
08 0.029(2) 0.0266 17 0.0282 18 -0.0023(14) -0.0014(15) 0.0000 15
05 0.025(2) 0.0232 16 0.0293 18 0.0024 14 0.0026 14 -0.0041(15)
C25 0.048(3) 0.0340 19 0.0277 18 0.0038 15 -0.0034 18 0.0021 18
C21 0.030(2) 0.0308 18 0.0305 19 0.0017 15 0.0019 16 0.0033 16
Cl 0.029(2) 0.0244 17 0.0318 18 -0.0017(15) -0.0010(16) -0.0018(16)
C26 0.046(3) 0.0314 19 0.0285 19 0.0038 15 -0.0007(17) 0.0012 18
C17 0.038(2) 0.036(2) 0.038(2) -0.0063(17) -0.0023(18) 0.0096 18
C10 0.044(2) 0.039 2 0.0286 19 -0.0019(15) 0.0039 17 0.0074 19
C23 0.048(3) 0.0284 19 0.036 2 0.0048 16 -0.0088(19) 0.0060 18
C20 0.032(2) 0.038 2 0.037 2 -0.0034(16) -0.0009(17) -0.0022(17)
N30 0.161(5) 0.0313 19 0.0279 18 0.0022 16 0.010 3 0.017 3
C11 0.038(2) 0.039 2 0.037 2 -0.0091(16) -0.0071(18) 0.0073 18
C31 0.075(3) 0.033 2 0.028 2 0.0016 16 -0.004(2) 0.004(2)
C15 0.029(2) 0.0300 18 0.036 2 -0.0021(15) 0.0018 16 0.0008 15
C24 0.035(2) 0.0329 19 0.0299 18 -0.0030(15) 0.0026 16 -0.0009(16)
C27 0.049(3) 0.0249 18 0.037(2) 0.0026 15 0.0045 19 0.0042 17
C16 0.041(3) 0.040(2) 0.031(2) 0.0006 16 -0.0028(18) 0.0087 19
C13 0.032(2) 0.0318 18 0.0304 18 -0.0008(15) 0.0049 16 0.0012 16
C14 0.033(2) 0.0298 19 0.0268 18 -0.0015(14) 0.0000 16 -0.0005(16)
09 0.039(2) 0.0307 18 0.0273 18 -0.0005(15) -0.0018(16) 0.0031 16
C28 0.130(5) 0.031 2 0.037 2 0.0065 18 0.024(3) 0.017(3)
C22 0.046(3) 0.0293 19 0.033 2 0.0008 15 -0.0074(18) 0.0013 17
C29 0.218(9) 0.032 2 0.030 3 0.0057 19 0.030(4) 0.018(4)
C33 0.235(8) 0.029 3 0.052 3 -0.005(2) 0.010(4) 0.019(4)
C34 0.075(5) 0.031 3 0.024 3 -0.018(2) 0.018(3) -0.018(3)
C35 0.097(6) 0.069 5 0.057 4 0.004(4) -0.002 4 -0.015 5
C36 0.091(6) 0.085 6 0.078 6 -0.002(5) 0.007(5) 0.023(5)
080 0.052(2) 0.0401 17 0.0499 18 0.0081 15 0.0030 16 -0.0011(15)
To investigate the stability of the monohydrate of Example 75, a slurry
experiment was performed. In this study, a suspension of the monohydrate
of Example 75 was suspended in water for up to seven days. After the
treatment, the mixtures were filtered and an x-ray powder diffraction of the
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filtration residue was measured. No polymorphic change was observed for
the monohydrate of Example 75. In contrast, the anhydrous form of Example
75 did not remain in the anhydrous state during the measurement by XRPD
(30 minutes).
Intermediate XX
1 -Cyclopropyl-4-(4-methoxy-benzyloxy)-1 H-pyridin-2-one
O
io
IN O
X
A microwave-suited vessel charged with a stir bar, 4-(4-methoxy-
benzyloxy)-1 H-pyridin-2-one (0.60 g), cyclopropylboronic acid (0.45 g),
pyridine (1.50 mL), triethylamine (1.50 mL), and toluene (4 mL) was sparged
with argon for 5 min. Then, Cu(OAc)2 (0.94 g) was added and the mixture
was stirred in a microwave oven under microwave irradiation at 140 C for
45 min. Then, the solvent was evaporated and water was added. The
resultant mixture was extracted with ethyl acetate and the combined organic
extracts were washed with water and aqueous NaHCO3 solution. After
drying (MgSO4) and removing the solvent, the residue was purified by
chromatography on silica gel (CH2CI2/MeOH 99:1->95:5) to afford the title
compound as a solid. Yield: 0.17 g (25% of theory); Mass spectrum (ESI+):
m/z = 272 [M+H]+.
Intermediate XXI
1 -Cyclopropyl-4-hydroxy-1 H-pyridin-2-one
OH
N O
X
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Trifluoroacetic acid (1 mL) was added to a flask charged with a stir
bar and 1 -cyclopropyl-4-(4-methoxy-benzyloxy)-1 H-pyridin-2-one (0.17 g)
and chilled in an ice/EtOH bath. The resulting mixture was stirred with
cooling for 1.5 h and at ambient temperature for another 4.5 h. Then, the
solution was concentrated under reduced pressure and the residue was
triturated with tert-butyl methyl ether and dried to give the title compound
as
a solid. Yield: 0.10 g (quantitative). Mass spectrum (ESI+): m/z = 152
[M+H]
Intermediate XXII
Trifluoro-methanesulfonic acid 1-cyclopropyl-2-oxo-1,2-dihydro-pyridin-4-yl
ester
0
D:S11
F
F
F
N 0
X
Trifluoromethanesulfonic anhydride (0.12 mL) was added to a flask
charged with a stir bar, 1-cyclopropyl-4-hydroxy-1 H-pyridin-2-one (0.10 g),
NEt3 (0.24 mL), and dichloromethane (8 mL) and chilled in an ice/EtOH bath.
The resulting mixture was stirred with cooling for 2 h and at ambient
temperature for another 2 h. Then, the solution was diluted with
dichloromethane and washed in succession with water, aqueous NaHCO3
solution, and water. The organic solution was dried (MgSO4), the solvent
was removed, and the residue was purified by chromatography on silica gel
(dichloromethane/methanol 99:1->90:10) to afford the title compound as a
resin-like solid. Yield: 0.07 g (36% of theory). Mass spectrum (ESI+): m/z =
284 [M+H]
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Intermediate XXIII
4-Bromo-1 -cyclopropyl-1 H-pyridin-2-one
Br
N O
A
A flask charged with a stir bar, 4-bromo-1 H-pyridin-2-one (1.80 g),
cyclopropylboronic acid (2.00 g), Cu(OAc)2 (2.00 g), 2,2'-bipyridine (1.70 g),
Na2CO3 (2.47 g), and 1,2-dichloroethane (75 ml-) was heated to 70 C and
the mixture was stirred at this temperature in air overnight. Then, another
portion of cyclopropylboronic acid (0.50 g) and Na2CO3 (0.55 g) were added
and the mixture was further stirred at reflux temperature for another 4 h.
After cooling to ambient temperature, aqueous NH4CI solution was added
and the resultant mixture was extracted with dichloromethane. The
combined organic extracts were dried (MgSO4) and the solvent was
evaporated. The residue was purified by chromatography on silica gel
(cyclohexane/ethyl acetate 50:50->35:65) to afford the title compound as an
oil that crystallized on standing. Yield: 0.82 g (37% of theory); Mass
spectrum (ESI+): m/z = 214/216 (Br) [M+H]+.
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Method 2
I l
Formic acid
C \ I \
N CI 38% N 0
O O
PdC12(dppf)
O N Cs2CO3, Dioxane 0 N
71% NH 71/0
OH OH
85% >-B(OH)2, Cu(OAc)2, BiPy
Na2CO3, air, dichloroethane, 70 C
O
OAN
N
OH
Step 1. 4-Iodopyridin-2(1 H)-one
A mixture of 2-chloro-4-iodopyridine (4.943 g, 20.6 mmol) and formic
acid (88%, 10 mL) was stirred at 105 C for 21 h. The excess of formic acid
was removed in vacuo, and the mixture was quenched with 2 M aq Na2CO3,
extracted with CH2CI2, dried over Na2SO4. After the solvent was removed
under reduced pressure, the residue was purified by chromatography on
silica gel eluted with CH2CI2/MeOH to afford 1.716 g (38%) of 4-iodopyridin-
2(1 H)-one as a solid. LC-MS Method 1 tR = 0.82 min, m/z = 222 (MH+); 1H
NMR (400 MHz, (CD3)2SO) 6 7.14 (d, J = 6.5 Hz, 1 H), 6.87 (s, 1 H), 6.49 (d, J
= 7.0 Hz, 1 H).
Step 2. (S)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(2-oxo-1,2-
dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
To a solution of (S)-6-(2-hydroxy-2-methyl propyl)-6-phenyl-3-((S)-1-
(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-
one (2.646 g, 5.52 mmol) in 1,4-dioxane (60 mL) were added 4-iodopyridin-
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2(1 H)-one (1.200 g, 5.43 mmol), 2 M Cs2CO3 (14.5 mL), and
PdC12(dppf).CH2CI2 (0.230 g, 0.28 mmol). The mixture was degassed and
heated, under a nitrogen atmosphere, at 120 C for 15 h. The mixture was
diluted with CH2CI2, dried over Na2SO4. After the solvents were evaporated,
the residue was purified by chromatography on silica gel eluted with
MeOH/CH2CI2 to afford 1.717 g (71 %) of (S)-6-(2-hydroxy-2-methyl propyl)-3-
((S)-1-(4-(2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-
2-one. LC-MS Method 1 tR = 1.23 min, m/z 389, 447 (MH+); 1H NMR (400
MHz, CD3OD) 6 7.40 (d, J = 6.7 Hz, 1 H), 7.31 (d, J = 8.2 Hz, 2H), 7.29-7.20
(m, 5H), 6.96 (d, J = 8.2 Hz, 2H), 6.57-6.52 (m, 2H), 5.49 (q, J = 7.0 Hz, 1
H),
2.98-2.93 (m, 1 H), 2.47-2.34 (m, 2H), 2.16-2.09 (m, 1 H), 2.07 (s, 2H), 1.45
(d, J = 7.0 Hz, 3H), 1.19 (s, 3H), 0.87 (s, 3H).
Step 3. (S)-3-((S)-1-(4-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-
yl)phenyl)ethyl)-6-(2-hydroxy-2-methyl propyl)-6-phenyl-1,3-oxazinan-2-one
A mixture of (S)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(2-oxo-1,2-
dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (1.683 g, 3.77
mmol, 1.0 equiv), Cu(OAc)2 (0.692 g, 3.81 mmol, 1.01 equiv), bipyridine
(0.599 g, 3.83 mmol, 1.02 equiv), cyclopropylboronic acid (0.681 g, 7.93
mmol, 2.10 equiv) and Na2CO3 (0.890 g, 8.40 mmol, 2.23 equiv) in
dichloroethane (40 mL) was stirred at 70 C for 22 h under air. The reaction
mixture was quenched with satd aq NH4CI, diluted with CH2CI2, dried over
Na2SO4. After the solvent was removed under reduced pressure, the residue
was purified by chromatography on silica gel eluted with MeOH/CH2CI2 to
afford 1.560 g (85%) of (S)-3-((S)-1-(4-(1-cyclopropyl-2-oxo-1,2-
d ihydropyrid in-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-methyl propyl)-6-phenyl-1,3-
oxazinan-2-one. LC-MS tR = 1.41 min in 3 min chromatography, m/z 429,
487 (MH+); 1H NMR (400 MHz, CD3OD) 6 7.52 (d, J = 7.0 Hz, 1 H), 7.29-7.18
(m, 7H), 6.92 (d, J = 8.2 Hz, 2H), 6.54 (d, J = 1.8 Hz, 1 H), 6.47 (dd, J =
7.3,
1.8 Hz, 1 H), 5.47 (q, J = 7.0 Hz, 1 H), 3.27-3.21 (m, 1 H), 2.95-2.91 (m, 1
H),
2.48-2.33 (m, 2H), 2.15-2.08 (m, 1 H), 2.07 (s, 2H), 1.42 (d, J = 7.0 Hz, 3H),
1.20 (s, 3H), 1.05-1.00 (m, 2H), 0.87 (s, 3H), 0.83-0.79 (m, 2H); 13C NMR
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(100 MHz, CD3OD) 6 166.17, 155.63, 152.88, 144.03, 142.27, 138.90,
136.91, 129.71, 128.70, 128.58, 127.67, 126.09, 116.08, 107.10, 85.19,
71.49, 55.13, 54.62, 37.44, 33.24, 32.71, 31.86, 30.03, 15.60, 7.27. (S)-3-
((S)-1-(4-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-(2-
hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one (ca. 1.5 g) and
isopropyl acetate (30 mL) was heated in a 120 C oil bath, affording a
homogeneous solution. Heating was discontinued and the resulting solution
was slowly stirred while slowly cooling to rt in the oil bath overnight. The
solids were filtered and washed with isopropyl acetate, dried at room
temperature under high vacuum affording crystalline solid Mp 91-94 C.
EXAMPLE 76
3-{(S)-1-[4-(1-Cyclopropylmethyl -6-oxo-1,6-dihydro-pyridin-3-yl)-phenyl]-
ethyl}-(S)-6-(2-hydroxy-2-methyl -propyl)-6-phenyl-[1,3]oxazinan-2-one
O
ON
/ OH
N O
VI-I
2 M aqueous Na2CO3 solution (0.84 mL) was added to a solution of
(S)-6-(2-hydroxy-2-methyl propyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5- tetramethyl-
1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3- oxazinan-2-one (0.40 g) and 5-
bromo-1-Cyclopropylmethyl -1H-pyridin-2-one (0.24 g) in dimethyl-formamide
(4 mL). The resulting mixture was sparged with argon for 10 min, before
[1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(I I)
dichloromethane complex (34 mg) was added. The mixture was heated to
100 C and stirred at this temperature for 4 h. After cooling to ambient
temperature, water was added and the resulting mixture was extracted with
ethyl acetate. The combined organic extracts were washed with brine, dried
(MgSO4), and concentrated. The residue was purified by chromatography
on silica gel (dichloromethane/methanol 99:1->95:5) to afford the title
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compound that was crystallized with little ethyl acetate. Yield: 0.19 g (46%
of theory); Mass spectrum (ESI+): m/z = 501 [M+H]+.
Intermediate XXIV
5-Bromo-1-cyclopropylmethyl -1 H-pyridin-2-one
Brnc1-
N
O
KOtBu (0.68 g) was added to a solution of 5-bromo-1 H-pyridin-2-one
(1.00 g) in tetrahydrofuran (20 ml-) at room temperature. After stirring for
30
min, cyclopropylmethyl bromide (0.77 ml-) and dimethy1formamide (3 ml-)
were added to the suspension and the resulting mixture was warmed to 70
C. After stirring the mixture at 70 C for 2 h, the reaction was complete.
The mixture was cooled to room temperature, diluted with ethyl acetate (50
mL), and washed with water (2x 20 ml-) and brine (20 mL). Then, the
solution was dried (MgSO4) and the solvent was removed to give the title
compound as a colorless oil. Yield: 1.18 g (90% of theory). Mass spectrum
(ESI+): m/z = 228/230 (Br) [M+H]+
EXAMPLE 77
(R)-6-Methoxymethyl -3-{(S)-1-[4-(1-methyl -6-oxo-1,6-dihydro-pyridin-3-yl)-
phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one
O
ON
O N O
The title compound was prepared from (R)-6-(methoxymethyl)-6-
phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-
1,3-oxazinan-2-one and 5-bromo-1-methylpyridin-2(1 H)-one following a
procedure analogous to that described in Example 76. Mass spectrum
(ESI+): m/z = 433 [M+H] +
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EXAMPLE 78
(R)-6-Methoxymethyl -3-{(S)-1-[4-(1-methyl -2-oxo-1,2-dihydro-pyridin-4-yl)-
phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one
O
OAN
O N
O
The title compound was prepared from (R)-6-(methoxymethyl)-6-
phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-
1,3-oxazinan-2-one and trifluoro-methanesulfonic acid 1 -methyl-2-oxo-1,2-
dihydro-pyridin-4-yl ester following a procedure analogous to that described
in Example 76. Mass spectrum (ESI+): m/z = 433 [M+H]+.
EXAMPLE 79
3-{(S)-1-[4-(5-Fluoro-1-methyl-2-oxo-1,2-dihydro-pyridin-4-yl)-phenyl]-
ethyl}-(S)-6-(2-hydroxy-2-methyl -propyl)-6-phenyl-[1,3]oxazinan-2-one
O
OAN F
/ OH N
O
The title compound was prepared from (S)-6-(2-hydroxy-2-
m ethyl propyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-
2- yl)phenyl)ethyl]-1,3- oxazinan-2-one and 4-bromo-5-fluoro-1-methyl-1 H-
pyridin-2-one following a procedure analogous to that described in Example
76. Mass spectrum (ESI+): m/z = 479 [M+H]+. The compound that had been
obtained as an oil crystallized on standing. The solid was dried at 80 C
under vacuum. Melting points: 120-125 C with evolution of gas followed by
recrystallization and melting at 183-184 C.
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Intermediate XXV
4-Bromo-5-fluoro-1 -methyl-1 H-pyridin-2-one
F
\
Br.
N",
0
Methyl iodide (0.9 ml-) was added to a mixture of potassium
carbonate (2.34 g) and 4-bromo-5-fluoro-1 H-pyridin-2-one (2.50 g) in
dimethylformamide (25 ml-) at room temperature. The mixture was stirred at
room temperature overnight and then water was added. The resulting
mixture was extracted with ethyl acetate and the combined extracts were
washed with brine and dried (MgSO4). The solvent was evaporated to afford
the crude title compound that was recrystallized from Et20. Yield: 1.22 g
(45% of theory); Mass spectrum (ESI+): m/z = 206/208 (Br) [M+H]+.
EXAMPLE 80
(S)-6-(2-Hydroxy-2-methyl -propyl)-3-((S)-1-{4-[1-(2-hydroxy-2-methyl -
propyl)-2-oxo-l,2-dihydro-pyridin-4-yl]-phenyl}-ethyl)-6-phenyl-[1,3]oxazinan-
2-one
O
OAN I \
/ OH \ N,-40H
The title compound was prepared from (S)-6-(2-hydroxy-2-
m ethyl propyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-
2- yl)phenyl)ethyl]-1,3- oxazinan-2-one and 4-bromo-1 -(2-hydroxy-2-methyl-
propyl)-1 H-pyridin-2-one following a procedure analogous to that described
in Example 75. Mass spectrum (ESI+): m/z = 519 [M+H]+.
Intermediate XXVI
4-Bromo-l-(2-hydroxy-2-methyl -propyl)-1 H-pyridin-2-one
Br / O
\ N N OH
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A mixture of 4-bromo-1 H-pyridin-2-one (0.25 g), 2,2-dimethyl-oxirane
(0.26 mL), and potassium carbonate (0.40 g) in dimethylformamide (2.5 mL)
was stirred under microwave irradiation at 120 C for 30 min. After cooling to
ambient temperature, the mixture was concentrated and purified by HPLC
on reversed phase (acetonitrile/water) to afford the title compound. Yield:
0.34 g (96% of theory); Mass spectrum (ESI+): m/z = 246/248 (Br) [M+H]+.
EXAMPLE 81
(S)-6-(2-Hydroxy-2-methyl -propyl)-3-((S)-1-{4-[1-(3-methoxy-2-methyl -
propyl)-2-oxo-1,2-dihydro-pyridin-4-yl]-phenyl}-ethyl)-6-phenyl-[1,3]oxazinan-
2-one
O
O'k N
/ OH N
The title compound was prepared from (S)-6-(2-hydroxy-2-
m ethyl propyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-
2- yl)phenyl)ethyl]-1,3- oxazinan-2-one and 4-bromo-1-(3-methoxy-2-methyl-
propyl)-1 H-pyridin-2-one following a procedure analogous to that described
in Example 75 Method 1. Mass spectrum (ESI+): m/z = 533 [M+H]+.
Intermediate XXVII
3-(4-Bromo-2-oxo-2H-pyridin-1-yl)-2-methyl -prop ionic acid methyl ester
B O
O
A mixture of 4-bromo-1 H-pyridin-2-one (0.50 g), methyl 2-
bromoisobutyrate (0.45 mL), and potassium carbonate (0.68 g) in
dimethylformamide (5 mL) was stirred at 60 C for 3 h. After cooling to
ambient temperature, water was added and the resulting mixture was
extracted with ethyl acetate. The combined extracts were washed with
brine, dried (MgSO4), and concentrated. The residue was purified by
chromatography on silica gel (cyclohexane/ethyl acetate 70:30->50:50) to
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afford the title compound. Yield: 0.53 g (67% of theory); Mass spectrum
(ESI+): m/z = 274/276 (Br) [M+H]+. Additionally 2-(4-bromo-pyridin-2-yloxy)-
2-methyl-propionic acid methyl ester was obtained {Yield: 0.15 g; Mass
spectrum (ESI+): m/z = 274/276 (Br) [M+H]+}
Intermediate XXVIII
4-Bromo-1 -(3-hyd roxy-2-m ethyl -propyl)- 1 H-pyridin-2-one
Br O
\ N~OH
LiAIH4 (1 M solution in tetrahydrofuran, 1.16 mL) was added to a
solution of 3-(4-bromo-2-oxo-2H-pyridin-1-yl)-2-methyl -prop ionic acid methyl
ester (0.53 g) in tetrahydrofuran (6 mL) chilled in an ice bath. After
stirring
the solution with cooling for 2 h, another portion of LiAIH4 (1 M in
tetrahydrofuran, 0.29 mL) was added. After stirring with cooling for 1 more
hour, the reaction was quenched by the addition of water. The resulting
mixture was extracted with ethyl acetate and the combined organic extracts
were washed with brine and dried (MgSO4). The solvent was evaporated to
give the title compound. Yield: 0.37 g (78% of theory); Mass spectrum
(ESI+): m/z = 246/248 (Br) [M+H]
Intermediate XXIX
4-Bromo-1-(3-methoxy-2-methyl -propyl)-1 H-pyridin-2-one
Br O
\ NO~
NaH (60% in mineral oil, 57 mg) was added to a solution of 4-bromo-
1-(3-hydroxy-2-methyl-propyl)-1 H-pyridin-2-one (0.53 g) in
dimethylformamide (6 mL) chilled in an ice bath. After stirring the solution
with cooling for 0.5 h, methyl iodide (110 pL) was added. The cooling bath
was removed and the solution was stirred at room temperature overnight.
Then, the solution was concentrated under reduced pressure and the
residue was diluted with water. The resulting mixture was extracted with
ethyl acetate and the combined organic extracts were washed with brine and
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dried (MgSO4). The solvent was evaporated and the residue was purified by
HPLC on reversed phase (acetonitrile/water) to give the title compound as
an oil. Yield: 70 mg (30% of theory); Mass spectrum (ESI+): m/z = 260/262
(Br) [M+H]
EXAMPLE 82
(S)-6-(2-Hydroxy-2-methyl -propyl)-3-((S)-1-{4-[1-(3-hydroxy-2-methyl -
propyl)-2-oxo-1,2-dihydro-pyridin-4-yl]-phenyl}-ethyl)-6-phenyl-[1,3]oxazinan-
2-one
O
OAN
0 OH
/ OH OCL
The title compound was prepared from (S)-6-(2-hydroxy-2-
m ethyl propyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-
2- yl)phenyl)ethyl]-1,3- oxazinan-2-one and 4-bromo-1-(3-hydroxy-2-methyl-
propyl)-1 H-pyridin-2-one following a procedure analogous to that described
in Example 75. Mass spectrum (ESI+): m/z = 519 [M+H]+.
EXAMPLE 83
(S)-6-(2-Hydroxy-2-methyl -propyl)-3-(1-{4-[1-(2-methoxy-2-methyl -
propyl)-2-oxo-1,2-dihydro-pyridin-4-yl]-phenyl}-ethyl)-6-phenyl-[1,3]oxazinan-
2-one
O
OAN I \
/ OH \ N
,i0
The title compound was prepared from (S)-6-(2-hydroxy-2-
m ethyl propyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-
2- yl)phenyl)ethyl]-1,3- oxazinan-2-one and 4-bromo-1 -(2-methoxy-2-methyl-
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propyl)-1 H-pyridin-2-one following a procedure analogous to that described
in Example 75 Method 1. Mass spectrum (ESI+): m/z = 533 [M+H]+.
Intermediate XXX
4-Bromo-1-(2-methoxy-2-methyl -propyl)-1 H-pyridin-2-one
Br 0
N,
The title compound was prepared from 4-bromo-1-(2-hydroxy-2-
methyl-propyl)-1 H-pyridin-2-one and methyl iodide following a procedure
analogous to that described in Intermediate XXIX. Mass spectrum (ESI+):
m/z = 260/262 (Br) [M+H]+.
EXAMPLE 84
6-(3-hydroxy-3-methyl butyl)-6-isopropyl -3-((S)-1-(4-(1-methyl -2-oxo-1,2-
dihydropyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one
0
O OH 0 N
M Br
g H I \ triphosgene / Br
Br Br
O
1. BH O N / Br Jones reagent O N SOCIZ O N
3
/ Br
22. H202 Acetone Br MeOH
OH COOH COOMe
40 B BOt IOI
O .
MeMgBr ON O O O N I/ -0
1. THE Br Pd(dppf)CI2, KOAc,
2. Separation HO DMSO 0
OH
0 0
I O O N 0 N
O O + H Jam' ~/ O
Pd(PPh3)2Cl2, Cs2CO3 H
-\ \ N~ - \ N
Step 1
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To a solution of (S)-1-(1-(4-bromophenyl)ethylamino)-4-methyl pentan-
3-one (740 mg, 2.5 mmol) in THE (25 mL) was added dropwise
allylmagnesium bromide (25 mL, 25 mmol) under N2 at -78 C. The reaction
mixture was stirred at -78 C for 2 h, quenched by addition of satd aq
NH4CI,and extracted with EtOAc. The organic layer was washed with brine,
dried over Na2SO4, and filtered. The solvent was removed under vacuo to
give 1-((S)-1-(4-bromophenyl)ethylamino)-3-isopropylhex-5-en-3-ol (802 mg,
95% yield), which was used directly in the next step.
1o Step 2
To a solution of 1-((S)-1-(4-bromophenyl)ethylamino)-3-isopropylhex-
5-en-3-ol (802 mg, 2.366 mmol) and triethylamine (139 mg, 2.366 mmol) in
CH2C12 (20 mL) was added triphosgene (348 mg, 1.18 mmol) at 0 C under
N2, and the mixture was stirred at rt overnight. The reaction mixture was
quenched with water, and extracted with CH2C12. The organic layer was
washed with brine, dried over Na2SO4, filtered, concentrated, and purified by
column chromatography to give 6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-
isopropyl-1,3-oxazinan-2-one (480 mg, 56% yield),
Step 3
To a solution of 6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-1,3-
oxazinan-2-one (480 mg, 1.315 mmol) in THE (5 mL) was added BH3.THF
(5.3 mL, 5.3 mmol) at 0 C under N2. The reaction mixture was stirred for 2
h, and quenched with water, 3 M aq NaOH (1 mL), and H202 (5 mL). The
resulting mixture was stirred for 2 h, extracted with EtOAc, washed with
brine, dried over Na2SO4, filtered, and concentrated to afford the crude
product, which was purified by prep TLC to give 3-((S)-1-(4-
bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-isopropyl-1,3-oxazinan-2-one.
(110 mg, 22% yield). 1H NMR (CDC13): (50.88 (m, 6H), 1.45 (m, 3H), 1.60
(m, 4H), 1.71 (m, 1 H), 1.82 (m, 1 H), 1.99 (m, 1 H), 2.63 (m, 1 H), 3.03 (m,
1 H), 3.59 (m, 2H), 5.68 (m, 1 H), 7.13 (d, 2H), 7.40 (d, 2H),
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Step 4
To a mixture of 3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-
isopropyl-1,3-oxazinan-2-one. (41 mg, 0.1 mmol) in acetone (10 ml-) was
added Jones reagent (2.5 M, 1 ml-) at 0 C. The mixture was stirred at room
temperature for 1 h, concentrated, and extracted with EtOAc. The organic
layer was concentrated to give the crude product 3-(3-((S)-1-(4-
bromophenyl)ethyl)-6-isopropyl-2-oxo-1,3-oxazinan-6-yl)propanoic acid (51
mg, 95% yield), which was used for the next step without further purification.
1o Step 5
To a solution of 3-(3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-2-oxo-
1,3-oxazinan-6-yl)propanoic acid (41 mg, 0.1 mmol) in MeOH (10 ml-) was
added SOC12 (5 ml-) at 0 C. The reaction mixture was stirred at room
temperature for 2 h, concentrated, and purified by preparative TLC to give
methyl 3-(3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-2-oxo-1,3-oxazinan-6-
yl)propanoate (42 mg, 96% yield).
Step 6
To a solution of methyl 3-(3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-
2-oxo-1,3-oxazinan-6-yl)propanoate (42 mg, 0.1 mmol) in dry THE (5 ml-)
was added MeMgBr (2.5 mL, 2.5 mmol, 1 M in THF) at -78 C. The mixture
was stirred at rt for 0.5 h, quenched with satd aq NH4CI, and extracted with
EtOAc. The organic layer was concentrated,and to afford crude 3-((S)-1-(4-
bromophenyl)ethyl)-6-(3-hydroxy-3-methyl butyl)-6-isopropyl-1,3-oxazinan-2-
one.
The two isomers could be separated by preparative HPLC..
Isomer 1: (1.1 mg, 12% yield), 1H NMR (CDC13): (50.91 (m, 6H), 1.25
(m, 6H), 1.44 (d, 3H), 1.70 (m, 4H), 1.85 (m, 2H), 2.01 (m, 1 H), 2.74 (m, 1
H),
3.18 (m, 1 H), 5.79 (m, 1 H), 7.24 (d, 2H), 7.50 (d, 2H),
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Isomer 2: (0.9 mg, 10% yield), 1H NMR (CDC13): 50.89 (m, 6H), 1.15
(s, 6H), 1.45 (m, 5H), 1.55 (m, 3H), 1.85 (m, 1 H), 1.99 (m, 1 H), 2.64 (m, 1
H),
2.99 (m, 1 H), 5.72 (m, 1 H), 7.17 (d, 2H), 7.40 (d, 2H),
Step 7
To a solution of compound 3-((S)-1-(4-bromophenyl)ethyl)-6-(3-
hydroxy-3-methylbutyl)-6-isopropyl-1,3-oxazinan-2-one (105 mg, 0.255
mmol) in DMSO (8 ml-) was added compound 4,4,4',4',5,5,5',5'-octamethyl-
2,2'-bi(1,3,2-dioxaborolane) (198.5 mg, 0.781 mmol), KOAc (351.6 mg, 3.587
mmol), and Pd(dppf)C12 (21.9 mg, 0.027 mmol) under N2. The reaction
mixture was stirred at 90 C for 3.5 h added H2O, and extracted with ethyl
acetate. The organic layer was washed with water and brine, dried over
Na2SO4, concentrated, and purified by preparative TLC to give the two
isomers of 6-(3-hydroxy-3-methyl butyl)-6-isopropyl-3-((S)-1-(4-(4,4,5,5-
tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one
Isomer 1 (17 mg, 15 %).
Isomer 2 (10.3 mg, 9 %).
Step 8
To a solution of compound 4-iodo-1-methylpyridin-2(1 H)-one (17 mg,
0.074 mmol) in DME (4.6 ml-) was added Pd(PPh3)4 (6.7 mg, 0.007 mmol)
under nitrogen. The mixture was stirred at room temperature for 1 h, and a
solution of compound 6-(3-hydroxy-3-methyl butyl)-6-isopropyl -3-((S)-1-(4-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-
one isomer 1 (17 mg, 0.037 mmol) in EtOH (2 ml-) and satd aq NaHCO3 (1.5
ml-) were added. The mixture was stirred at 100 C for 2 h, quenched with
water, and extracted with EtOAc. The combined organic layer was dried
over anhydrous Na2SO4 and concentrated to give the compound 6-(3-
hydroxy-3-methyl butyl)-6-isopropyl -3-((S)-1-(4-(1-methyl -2-oxo-1,2-
dihydropyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one isomer 1 (10.73 mg,
65.8%). LC-MS Method 2 Method 2 tR = 1.03 min, m/z = 463, 441; 1H NMR
(CD3OD): 5 0.89 (m, 6H), 1.11 (s, 6H), 1.42 (m, 2H), 1.51(m, 3H), 1.60 (m,
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2H), 1.82-2.02 (m, 2H), 2.69 (m, 1 H), 3.03 (m, 1 H), 3.51 (s, 3H), 5.79 (m,
3H), 6.35 (d, 1 H), 6.72 (s, 1 H), 7.28 (d, 1 H),7.39 (d, 2H), 7.49 (m, 2H).
6-(3-hydroxy-3-methyl butyl)-6-isopropyl -3-((S)-1-(4-(1-methyl-2-oxo-
1,2-dihydropyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one isomer 2 was
prepared from 6-(3-hydroxy-3-methyl butyl)-6-isopropyl-3-((S)-1-(4-(4,4,5,5-
tetramethyl -1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one isomer
following a procedure analogous to that described in Step 8 immediately
above. LC-MS Method 2 Method 2 tR = 1.00 min, m/z = 463, 441;'H NMR
(CD3OD): 5 0.89 (m, 6H), 1.18 (m, 6H), 1.43 (m, 1 H), 1.51 (m,3H), 1.63 (m,
2H), 1.76 (m, 2H), 1.92 (m, 1 H), 2.61 (m, 1 H), 3.12 (m, 1 H), 3.51 (s, 3H),
5.79 (m, 1 H), 6.37 (d, 1 H), 6.72 (s, 1 H), 7.28 (d, 1 H),7.35(d, 2H), 7.51
(m,
2H).
EXAMPLE 85
(S)-3-((S)-1-(4-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-
(2-hydroxy-2-m ethyl propyl)-6-isopropyl-1,3-oxazinan-2-one
O
>-B(OH)2
HN
O / 1 Cu(OAc)2, BiPy, Na2CO3 1 N<
air, dichloroethane, 70 C
J1 ~ O O
O N I N O N
., /
N"V
O Pd(PPh3)4 HO
HO 0
satd aq NaHCO3
DME
Step 1
A mixture of 4-iodopyridin-2(1 H)-one (0.2425 g, 1.10 mmol, 1.0
equiv), Cu(OAc)2 (0.2146 g, 1.18 mmol, 1.07 equiv), bipyridine (0.1832 g,
1.17 mmol, 1.07 equiv), cyclopropylboronic acid (0.2122 g, 2.47 mmol, 2.25
equiv) and Na2CO3 (0.2638 g, 2.49 mmol, 2.27 equiv) in dichloroethane (10
mL) was stirred at 70 C for 18 h. The reaction mixture was quenched with
satd aq NH4CI, diluted with CH2CI2, and dried over Na2SO4. After the
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solvent was removed under reduced pressure, the residue was purified by
chromatography on silica gel eluted with hexanes/ethyl acetate to afford
0.2309 g (81 %) of 1-cyclopropyl-4-iodopyridin-2(1 H)-one.
Step 2
To a solution of compound 1-cyclopropyl-4-iodopyridin-2(1 H)-one
(17.60 mg, 0.067 mmol) in DME (2.5 mL) was added Pd(PPh3)4 (6.12 mg,
0.006 mmol) under nitrogen. The mixture was stirred at rt for 1 h. A solution
of compound (S)-6-(2-hydroxy-2-methyl propyl)-6-isopropyl -3-((S)-1-(4-
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-
one (15 mg, 0.034 mmol) in EtOH (1 mL) and satd aq NaHCO3 (1 mL) were
added. The mixture was stirred at 100 C for 2 h, quenched with water and
extracted with EtOAc. The combined organic layer was dried over
anhydrous Na2SO4 and concentrated to give the final crude product, which
was purified by preparative HPLC to afford the compound (S)-3-((S)-1-(4-(1-
cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-(2-hydroxy-2-
m ethyl propyl)-6-isopropyl -1,3-oxazinan-2-one (6.50 mg, 43%). LC-MS
Method 2 tR = 1.00 min, m/z = 453; 1H NMR (CD3OD): (50.82 (d, 3H), 0.89
(m, 2H), 0.99 (d, 3H), 1.17 (m, 2H), 1.35 (m, 6H), 1.58 (d, 3H), 1.62 (m, 2H),
1.85 (m, 1 H), 1.96 (d, 1 H), 2.09-2.18 (m, 2H), 2.68-2.78 (m, 1 H), 3.11 (m,
1 H), 3.37 (m, 1 H), 5.81 (m, 1 H), 6.40 (d, 2H), 6.78 (s, 1 H), 7.31-7.42(m,
3H),
7.58 (d, 2H).
EXAMPLE 86
(S)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(1-(2-hydroxyethyl)-6-oxo-1,6-
dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
O
OAN I \
O
OH N O
OH
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The title compound was prepared from (S)-6-(2-hydroxy-2-
methyl propyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-dioxaborolan-
2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 5-bromo-1-(2-
hydroxyethyl)pyridin-2(1 H)-one following a procedure analogous to that
described in Example 20 Step 2. LC-MS Method 2 tR = 1.08 min, m/z = 513,
491; 1H NMR (CD3OD) 6 0.95 (s, 3H), 1.24 (s, 3H), 1.26 (s, 1 H), 1.52 (d,
3H), 2.12 (s, 2H), 2.18 (m, 1 H), 2.40-2.53 (m, 2H), 3.02 (m, 1 H), 3.52 (m,
0.5H), 3.64 (m, 0.5H), 3.83 (t, 1 H), 4.15 (t, 1 H), 5.53(m, 1 H), 6.61(m, 1
H),
7.01(d, 2H), 7.25-7.40(m, 7H), 7.79(m, 2H).
5-Bromo-1-(2-hydroxyethyl)pyridin-2(1 H)-one was prepared from 5-
bromopyridin-2(1 H)-one and 2-iodoethanol following a procedure analogous
to that described in Example 20 Step 1.
EXAMPLE 87
(S)-3-((S)-1-(4-(1-(2-fluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-
6-(2-hydroxy-2-methyl propyl)-6-phenyl-1,3-oxazinan-2-one
Tf20, Et3N
F~\OH F~\OTf
CH2CI2, -78 C to rt
BrN 0 Br
F~~OTf H I
K2CO3 N B r
0 + F
N O
F
0
OWN
" BO /
Br 0 \
rI N
HO O
N O
Pd(PPh3)2CI2 HO N 0
CS2CO3
F
F
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Step 1
To a solution of 2-fluoroethanol (3.2 g, 50 mmol) and triethylamine
(5.5 g, 55 mmol) in dichloromethane (60 mL) was added dropwise
(CF3SO2)20 (15.5 g, 55 mmol) at -78 C under N2. The mixture was stirred
at 10-20 C for 1 h, and treated with water (100 mL). The organic layer was
washed with satd aq NaHCO3 (100 mL) and brine (100 mL), dried, and
concentrated to give 2-fluoroethyl trifluoromethanesulfonate (8 g, yield 82%).
Step 2
A solution of 5-bromopyridin-2(IH)-one (100 mg, 0.58 mmol), 2-
fluoroethyl trifluoromethanesulfonate (1.1 g, 5.8 mmol), and K2CO3 (800 mg,
5.8 mmol) in DMF (3 mL) was stirred at rt overnight. 2-Fluoroethyl
trifluoromethanesulfonate (1.1 g, 5.8 mmol) and K2CO3 (800 mg, 5.8 mmol)
were added, and the mixture was treated with ethyl acetate (20 mL) and
water (20 mL). The organic layer was washed with water (2 x 20 mL) and
brine (20 mL), dried over Na2SO4, concentrated, and purified by preparative,
TLC (1:1 petroleum ether/EtOAc) to give two isomers.
5-bromo-1-(2-fluoroethyl)pyridin-2(IH)-one (30 mg, yield 24%).'H
NMR (CD3OD): 5 4.25 (t, 1 H), 4.32 (t, 1 H), 4.62 (t, 1 H), 4.74 (t, 1 H),
6.52 (d,
1 H), 7.61 (dd, 1 H), 7.85 (s, 1 H).
5-bromo-2-(2-fluoroethoxy) pyridine (30 mg, yield 24%). 1H NMR
(CD3OD): (54.46 (t, 1 H), 4.53 (t, 1 H), 4.64 (t, 1 H), 4.76 (t, 1 H), 6.79
(d, 1 H),
7.79 (dd, 1 H), 8.18 (s, 1 H),
Step 3
To a solution of (S)-6-(2-hydroxy-2-methyl propyl)-6-phenyl-3-((S)-1-
(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-
one (20 mg, 0.041 mmol), 5-bromo-1 -(2-fluoroethyl)pyridin-2(IH)-one (9.2
mg, 0.041 mmol), and Cs2CO3 (2 N, 0.2 mL, 0.41 mmol) in 1,4-dioxane (2
mL) was added Pd(PPh3)2C12 (3 mg, 0.0041 mmol) under N2. The mixture
was refluxed for 2 h, treated with EtOAc (10 mL) and water (10 mL). The
organic layer was dried over Na2SO4, concentrated, and purified by
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preparative HPLC to give (S)-3-((S)-1-(4-(1-(2-fluoroethyl)-6-oxo-1,6-
dihydropyridin-3-yl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-
oxazinan-2-one (4.20 mg, 20%). LC-MS Method 2 tR = 1.01 min, m/z = 515,
493; 1H NMR (CD3OD): 5 0.97 (s, 3H), 1.28 (s, 3H), 1.56 (d, 3H), 2.18 (s,
2H), 2.22 (m, 1 H), 2.49 (m, 2H), 3.05 (m, 1 H), 4.37 (t, 1 H), 4.43 (t, 1 H),
4.69
(t, 1 H), 4.81 (t, 1 H), 5.59 (q, 1 H), 6.66 (d, 1 H), 7.05 (d, 2H), 7.33 (m,
7H),
7.82 (m, 2H).
EXAMPLE 88
(S)-3-((S)-1-(4-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-
(2-fluorophenyl)-6-(2-hydroxy-2-methyl propyl)-1,3-oxazinan-2-one
O
F
O lul N
0 I
N
H O O '~V
The title compound was prepared from (S)-6-(2-fluorophenyl)-6-(2-
hydroxy-2-methyl propyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 1-cyclopropyl-4-iodopyridin-2(1 H)-
one following a procedure analogous to that described in Example 23 Step
9. LC-MS Method 2 tR = 1.05 min, m/z = 505; 1H NMR (CDC13) 6 0.88 (m,
2H), 1.12 (s, 3H), 1.15 (s, 1 H), 1.17 (s, 1 H), 1.21 (s, 3H), 2.18-2.29 (m,
2H),
2.30-2.34 (m, 1 H), 2.42 (d, 1 H), 2.54 (d, 1 H), 2.90 (m,1 H), 3.35 (m, 1 H),
5.70
(m, 1 H), 6.32 (m, 1 H), 6.68 (m, 1 H), 6.98 (m, 1 H), 7.09 (d, 2H), 7.18 (t,
1 H),7.25-7.36 (m, 4H),7.50 (t,1 H).
EXAMPLE 89
(S)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(1-(2-hydroxy-2-methyl propyl)-
6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
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0
Br O EtO~, Br Br O MeMgBr, THE
-(\7N K2CO3, DMF -N O
OEt
O O
O0 N
j~~ P'O N
HO
N~
Br OH DME, Pd(PPh3)4 HO N 0
HO
Step 1
To a solution of compound 5-bromopyridin-2(1 H)-one (348 mg, 2.0
mmol) and K2CO3 (830 mg, 6.0 mmol) in DMF (15 mL) was added ethyl
bromoacetate dropwise. The mixture was stirred at room temperature for 2
h, filtered, and the filtrate was concentrated in vacuo. The residue was
purified by prep TLC (1:1 PE/EtOAc) to afford ethyl 2-(5-bromo-2-oxopyridin-
1(2H)-yl)acetate (300 mg, 57.7%). 1H NMR CDC13: 5 7.41-7.26 (m, 2H),
6.53-6.5 (d, 1 H), 4.59 (s, 2H), 4.28-4.21 (q, 2H), 1.32-1.23 (q, 3H).
Step 2
To a solution of ethyl 2-(5-bromo-2-oxopyridin-1(2H)-yl)acetate (130
mg, 0.5 mmol) in anhydrousTHF (5 mL, ) was added 1 M MeMgBr (5 mL, 5
mmol) dropwise with stirring at -78 C. The reaction mixture was stirred at -
78 C for 1 h, quenched with aq NH4CI (5 mL), and extractde with EtOAc (3 x
10 mL). The combined organic layer was dried and concentrated to give the
crude final product, which was purified by preparative TLC (1:1 PE/EtOAc) to
afford the 5-bromo-1 -(2-hyd roxy-2-m ethylpropyl)pyridin-2(1 H)-one (65 mg,
52.9%).
Step 3
To a solution of 5-bromo-1 -(2-hyd roxy-2-m ethylpropyl)pyridin-2(1 H)-
one (20 mg, 81.3 mmol) in DME (6 mL) was added Pd(PPh3)4 (10 mg) under
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nitrogen. The mixture was stirred for 1 h at rt, and a solution of (S)-6-(2-
hydroxy-2-methyl propyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-
dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (38.95 mg, 81.3 mmol)
in EtOH (2 mL) and satd aq NaHCO3 (2 mL) were added. The resulting
mixture was stirred at 100 C for 2 h, quenched with water, and extracted
with EtOAc. The combined organic layer was dried over anhydrous Na2SO4
and concentrated to give the crude product, which was purified by
preparative TLC and preparative HPLC to afford (S)-6-(2-hydroxy-2-
methyl propyl)-3-((S)-1-(4-(1-(2-hydroxy-2-methyl propyl)-6-oxo-1,6-
dihydropyridin-3-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (6.5 mg,
15.5%). LC-MS Method 2 tR = 0.99 min, m/z = 519; 1H NMR (CDC13): 5
7.60-7.57 (d, 1 H), 7.43 (s, 1 H), 7.36-7.26 (m, 5H), 7.15 (d, 2H), 7.01 (d,
2H),
6.70 (d, 1 H), 2.85 (m, 1 H), 5.69-5.66 (m, 1 H), 4.13-4.09 (s, 2H), 4.05-3.98
(s, 1 H), 2.89-2.86 (m, 1 H), 2.44-2.36 (m, 1 H), 2.28-2.16 (m, 5H), 1.58-1.53
(d, 3H) , 1.33-1.30 (s, 6H), 1.19 (s, 3H), 1.12 (s, 3H).
EXAMPLE 90
3-((S)-1-{4-[1-(3-Hydroxy-2,2-dimethyl -propyl)-2-oxo-1,2-dihydro-pyridin-4-
yl]-phenyl}-ethyl)-(S)-6-(2-hydroxy-2-methyl -propyl)-6-phenyl-[1,3]oxazinan-
2-one
O
OAN
QH N` OH
2 M aqueous Na2CO3 solution (0.32 mL) was added to a mixture of 4-
bromo-1 -(3-hyd roxy-2,2-d i m ethyl -propyl)- 1 H-pyridin-2-one (0.13 g) and
(S)-
6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl -1,3,2-
dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one (0.15 g) in N,N-
dimethylformamide (3 mL). The resulting mixture was sparged with argon for
5 min, before [1,1 '-bis(diphenylphosphino)-ferrocene]dichloro-palladium(I I)
dichloromethane complex (26 mg) was added. The mixture was heated to
100 C and stirred at this temperature for 4 h. After cooling to ambient
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temperature, water was added and the resulting mixture was extracted with
ethyl acetate. The combined organic extracts were washed with water and
brine and dried (MgSO4). The solvent was evaporated and the residue was
purified by HPLC on reversed phase (methanol/water/NH4OH) to afford the
title compound as a beige solid. Yield: 0.10 g (60% of theory); Mass
spectrum (ESI+): m/z = 533 [M+H]+.
3-(4-Bromo-2-oxo-2H-pyridin-1-yl)-2,2-dimethyl -prop ionic acid methyl ester
Br
N 0111
O O
3-Bromo-2,2-dimethyl-propionic acid methyl ester (0.75 g) was added
to a mixture of 4-bromo-1 H-pyridin-2-one (0.55 g) and potassium carbonate
(0.75 g) in N,N-dimethylformamide (10 mL) at room temperature. The
mixture was heated to 60 C and stirred at this temperature overnight. After
stirring at 80 C for another 8 h, the mixture was cooled to room temperature
and water was added. The resultant mixture was extracted with ethyl
acetate and the combined organic extracts were washed with brine and
dried (MgSO4). The solvent was evaporated and the residue was purified by
chromatography on silica gel (cyclohexane/ethyl acetate 4:1) to afford the
title compound; 3-(4-bromo-pyridin-2-yloxy)-2,2-dimethyl-propionic acid
methyl ester (0.35 g) was also obtained from this reaction. Yield: 0.29 g
(32% of theory); Mass spectrum (ESI+): m/z = 288/300 (Br) [M+H]+.
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4-Bromo-1 -(3-hyd roxy-2,2-d i m ethyl -propyl)- 1 H-pyridin-2-one
Br \
N\ OH
O
Lithium borohydride (25 mg) was added to a solution of 3-(4-bromo-2-
oxo-2H-pyridin-1-yl)-2,2-dimethyl -prop ionic acid methyl ester (0.29 g) in
tetrahydrofuran (3 mL) chilled in an ice bath. Then methanol (45 pL) was
added and the mixture was stirred in the cooling bath for 1 h and at room
temperature overnight. The mixture was diluted with tetrahydrofuran and
MgSO4 was added. The mixture was filtered and the filtrate was
concentrated. The residue was purified by chromatography on silica gel
(cyclohexane/ethyl acetate 1:1) to afford the title compound as a colorless
oil. Yield: 0.13 g (49% of theory); Mass spectrum (ESI+): m/z = 260/262 (Br)
[M+H]
EXAMPLE 91
3-((S)-1-(4-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-(2-
hydroxy-2-methyl propyl)-6-(tetrahydro-2H-pyran-4-yl)-1,3-oxazinan-2-one
O
O p11 N
N
HO O
The title compound was prepared following procedures analogous to
those described in Example 23 with the following changes. In Step 1
tetrahydro-2H-pyran-4-carboxylic acid and carbonyl diimidazole were used in
place of 2-fluorobenzoyl chloride and in Step 9 1 -cyclopropyl-4-iodopyridin-
2(1 H)-one was used in place of 5-bromo-1-methylpyridin-2(1 H)-one. Two
isomers were isolated.
Isomer 1. LC-MS Method 2 tR = 0.95 min, m/z = 495.
Isomer 2. LC-MS Method 2 tR = 0.93 min, m/z = 495.
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EXAMPLE 92
(S)-6-(2-hydroxy-2-methyl propyl)-3-((S)-1-(4-(1Arid euteromethyl -2-oxo-1,2-
dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one
O
OAN
/ ~N<D
OH O
The title compound was prepared following procedures analogous to
those described in Example 48 Method 2 with the following changes. In
Step 1 trideuteromethyl iodide was used in place of methyl iodide and in
Step 2 PdC12(dppf) was used in place of PdC12(PPh3)2. LC-MS Method 1 tR
= 1.30 min, m/z = 464.
EXAMPLE 93
3-((S)-1-(4-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-
6-(cyclopropylmethyl)-6-(2-hydroxy-2-methyl propyl)-1,3-oxazinan-2-one
O
01~1 N
N
HO 0
The title compound was prepared following a procedure analogous to
that described in Example 23 Steps 2 to 9. 2-cyclopropyl-N-methoxy-N-
methylacetamide, prepared by CDI mediated coupling of 2-cyclopropylacetic
acid and N,O-dimethylhydroxylamine, was used in Step 2. The two isomers
of 3-((1 S)-1-(4-bromophenyl)ethyl)-6-(cyclopropylmethyl)-6-(2-methylallyl)-
1,3-oxazinan-2-one prepared in Step 5 were separated by column
chromatography. The two isomers were separately carried forward through
Steps 6-9, using 1-cyclopropyl-4-iodopyridin-2(1 H)-one in Step 9, to afford
the two isomers of the title compound.
Isomer 1: LC-MS Method 2 tR = 1.04 min, m/z = 465, 447.
Isomer 2: LC-MS Method 2 tR = 1.06 min, m/z = 465, 447.
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EXAMPLE 94
3-((S)-1-(4-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-
6-(2-hydroxy-2-methyl propyl)-6-neopentyl-1,3-oxazinan-2-one
O
I
OAN ,0---
N
X O
O
The title compound was prepared following a procedure analogous to
that described in Example 23 Steps 2 to 9. N-methoxy-N,3,3-
trimethylbutanamide, prepared by HATU mediated coupling of 3,3-
dimethylbutanoic acid and N,O-dimethylhydroxylamine, was used in Step 2.
The two isomers of 3-((1 S)-1-(4-bromophenyl)ethyl)-6-(2-methyl aIlyl)-6-
neopentyl-1,3-oxazinan-2-one prepared in Step 5 were separated by column
chromatography. The two isomers were separately carried forward through
Steps 6-9, using 1-cyclopropyl-4-iodopyridin-2(1 H)-one in Step 9, to afford
the two isomers of the title compound.
Isomer 1: LC-MS Method 2 tR = 1.09 min, m/z = 503, 481, 423.
Isomer 2: LC-MS Method 2 tR = 1.16 min, m/z = 481.
EXAMPLE 95
3-((S)-1-(4-(1-cyclopropyl-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-
6-(3,3-d ifl uorocyclobutyl)-6-(2-hyd roxy-2-m ethyl propyl)- 1 , 3-oxazi n an
-2-on e
O
F O1~1 N
F
N
HO O
The title compound was prepared following a procedure analogous to
that described in Example 23 Steps 2 to 9. 3,3-difluoro-N-methoxy-N-
m ethylcyclobutanecarboxamide, prepared by CDI mediated coupling of 3,3-
difluorocyclobutanecarboxylic acid and N,O-dimethylhydroxylamine, was
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used in Step 2. The two isomers of 3-((S)-1-(4-bromophenyl)ethyl)-6-(3,3-
difluorocyclobutyl)-6-(2-methyl aIlyl)-1,3-oxazinan-2-one prepared in Step 5
were separated by column chromatography. The two isomers were
separately carried forward through Steps 6-9, using 1 -cyclopropyl-4-
iodopyridin-2(1 H)-one in Step 9, to afford the two isomers of the title
compound.
Isomer 1: LC-MS Method 1 tR = 1.08 min, m/z = 501.
Isomer 2: LC-MS Method 1 tR = 1.07 min, m/z = 501.
Examples 96-98
Intermediate 1
(S)-4-Bromo-1 -(1-isocyanato-ethyl)-2-methyl -benzene
0 0
O I \ Step S.N I \ Step S11
,H I \ 40. ~* ~ Br ~ Br ~ Br
Step 3 Step 4 0
H2N N
- __'6
Br Br
Step 1: (R)-2-Methyl-propane-2-sulfinic acid [1-(4-bromo-2-methyl-
phenyl)-ethylidene]-amide
Titanium(IV) ethoxide (10.7 mL) was added to a solution of 1-(4-
bromo-2-methyl -phenyl)-ethanon e (4.41 g) and (R)-2-methyl-2-
propanesulfinamide (2.76 g) in tetrahydrofuran (45 mL). The resulting
solution was heated to 65 C and stirred at this temperature for 20 h. Then,
the solution was cooled to ambient temperature and another portion of
titanium(IV) ethoxide (5.4 mL) and (R)-2-methyl-2-propane-sulfinamide (1.25
g) were added. After stirring the solution at 65 C for another 12 h, the
solution was cooled to ambient temperature and poured into brine. The
resulting mixture was filtered over Celite and the organic phase of the
filtrate
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was separated. The aqueous phase of the filtrate was extracted with ethyl
acetate and the extracts were combined with the separated organic phase.
The combined organic phases were washed with brine and dried (MgSO4)
and the solvent was evaporated. The residue was chromatographed on
silica gel (cyclohexane/ethyl acetate 9:1 --A:1) to afford the title compound.
Yield: 6.24 g (95% of theory); Mass spectrum (ESI+): m/z = 316/318 (Br)
[M+H]
Step 2: (R)-2-Methyl-propane-2-sulfinic acid [(S)-1-(4-bromo-2-
methyl-phenyl)-ethyl]-amide
Lithium tri-sec-butylborohydride (1 mol/L in tetrahydrofuran, 59.2 mL)
was added to a solution of (R)-2-methyl-propane-2-sulfinic acid [1 -(4-bromo-
2-methyl-phenyl)-ethylidene]-amide (6.24 g) in tetrahydrofuran (50 mL)
chilled in an ice bath. The solution was stirred for 2 h while warming to room
temperature in the cooling bath. The solution was then cooled again in an
ice bath prior to the careful addition of water. The resulting mixture was
extracted with ethyl acetate and the combined extracts were washed with
water, saturated aqueous NaHCO3 solution, and brine. After drying (MgSO4)
and evaporating the solvent, the title compound was obtained that was
directly submitted to the next reaction step. Yield: 8.85 g (ca. 75% pure);
Mass spectrum (ESI-): m/z = 318/320 (Br) [M+H]+.
Step 3: (S)-1-(4-Bromo-2-methyl -phenyl)-ethylamine
Hydrochloric acid (4 mol/L in 1,4-dioxane, 46 mL) was added to a
solution of (R)-2-methyl-propane-2-sulfinic acid [(S)-1-(4-bromo-2-methyl-
phenyl)-ethyl]-amide (crude from Step 2, 8.85 g, ca. 75% pure) in ethyl
acetate (80 mL) at room temperature. The solution was stirred at room
temperature for 1 h and then concentrated. The residue was taken up in
water and the resulting mixture was washed with diethyl ether. The aqueous
phase was basified using aqueous 1 M NaOH solution and extracted with
dichloromethane. The combined extracts were washed with brine, dried
(MgS04), and concentrated to afford the title compound. Yield: 4.04 g (905
of theory); Mass spectrum (ESI-): m/z = 214/216 (Br) [M+H]+.
Step 4: (S)-4-Bromo-1 -(1-isocyanato-ethyl)-2-methyl -benzene
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Triphosgene (2.24 g) was added at once to a vigorously stirred
mixture of NaHCO3 (3.65 g) in water (80 mL) and (S)-1-(4-bromo-2-methyl-
phenyl)-ethylamine (4.04 g) in dichloromethane (80 mL) chilled in an ice
bath. The cooling bath was removed and the mixture was stirred at room
temperature for another 30 min. Then the organic phase was separated and
dried (MgSO4) and the solvent was evaporated to afford the isocyanate as
an oil that was directly submitted to the next reaction step. Yield: 4.50 g
(99% of theory); Mass spectrum (ESI-): m/z = 240/242 (Br) [M-H]-.
Intermediate 2
(S)-1-Bromo-4-(1-isocyanato-ethyl)-2-methyl -benzene
O O
Step 1 g Step 2 g, O I\ `t' N N V
Br Br Br
Step 3 Step 4 O~
30. Fi2N I \ N I \
Br Br
Step 1: (R)-2-Methyl-propane-2-sulfinic acid [1-(4-bromo-3-methyl-
phenyl)-ethylidene]-amide
The title compound was prepared from 1-(4-bromo-3-methyl-phenyl)-
ethanone and (R)-2-methyl-2-propanesulfinamide following a procedure
analogous to that described in Step 1 of Intermediate 1. Mass spectrum
(ESI+): m/z = 316/318 (Br) [M+H]
Step 2: (R)-2-Methyl-propane-2-sulfinic acid [(S)-1-(4-bromo-3-
methyl-phenyl)-ethyl]-amide
The title compound was prepared from (R)-2-methyl-propane-2-
sulfinic acid [1-(4-bromo-3-methyl -phenyl)-ethylidene]-amide following a
procedure analogous to that described in Step 2 of Intermediatel. LC-MS
(Method 5): tR = 4.04 min; Mass spectrum (ESI+): m/z = 318/320 (Br) [M+H]
Step 3: (S)-1-(4-Bromo-3-methyl -phenyl)-ethylamine
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The title compound was prepared from (R)-2-methyl-propane-2-
sulfinic acid [(S)-1-(4-bromo-3-methyl -phenyl)-ethyl]-amid e following a
procedure analogous to that described in Step 3 of Intermediate 1. LC-MS
(Method 4): tR = 3.56 min; Mass spectrum (ESI+): m/z = 214/216 (Br) [M+H]
Step 4: (S)-1-Bromo-4-(1-isocyanato-ethyl)-2-methyl -benzene
The title compound was prepared from (S)-1-(4-bromo-3-methyl-
phenyl)-ethylamine and triphosgene following a procedure analogous to that
described in Step 4 of Intermediate 1. Mass spectrum (ESI+): m/z = 272/274
(Br) [M+H+MeOH]
Intermediate 3
5-Bromo-2-isocyanatom ethyl -1,3-d imethyl-benzene
O% N
Br
The title compound was prepared from 4-bromo-2,6-dimethyl-
benzylamine and triphosgene following a procedure analogous to that
described in Step 4 of Intermediate 1. Mass spectrum (El): m/z = 239/241
(Br) [M]
Intermediate 4
4-Bromo-1 -cyclopropyl-1 H-pyridin-2-one
Br
yv
O A flask charged with a stir bar, 4-bromo-1 H-pyridin-2-one (1.80 g),
cyclopropylboronic acid (2.00 g), Cu(O2CCH3)2 (2.00 g), 2,2'-bipyridine (1.70
g), Na2CO3 (2.47 g), and 1,2-dichloroethane (75 mL) was heated to 70 C.
The mixture was stirred at this temperature in air overnight. Then, further
portions of cyclopropylboronic acid (0.50 g) and Na2CO3 (0.55 g) were
added and the mixture was stirred at reflux temperature for another 4 h.
After cooling to ambient temperature, aqueous NH4CI solution was added
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and the resultant mixture was extracted with dichloromethane. The
combined organic extracts were dried (MgSO4) and the solvent was
evaporated. The residue was purified by chromatography on silica gel
(cyclohexane/ethyl acetate 50:5035:65) to afford the title compound as an
oil that crystallized on standing. Yield: 0.82 g (37% of theory); Mass
spectrum (ESI+): m/z = 214/216 (Br) [M+H]+.
Example 96
3-{(S)-1-[4-(1-Cyclopropyl-2-oxo-1,2-dihydro-pyridin-4-yl)-2-methyl -phenyl]-
ethyl}-(S)-6-(2-hydroxy-2-methyl -propyl)-6-phenyl-[1,3]oxazinan-2-one
O
OH
CI O~ Step 1 O +
N 0.SSNB
r
Br
Step 2
O O
O~N Step 3 ON
Br 011~11
OH CO
Step 4
O1~1 N
O ONI Step 5
B-I
a O / N
OH OH
Step 1: 3-[(S)-1-(4-Bromo-2-methyl -phenyl)-ethyl]-(R)-6-(2-methyl-
al lyl)-6-phenyl-[1,3]oxazinan-2-one
Lithium hexamethyldisilazide (1 mol/L in tetrahydrofuran, 18.7 mL)
was added dropwise (at such a rate that the solution temperature maintains
below 25 C) to a solution of 1-chloro-5-methyl -3-phenyl-hex-5-en-3-ol (3.82
g) and (S)-4-bromo-1 -(1-isocyanato-ethyl)-2-methyl -benzene (4.49 g) in
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tetrahydrofuran (140 mL) chilled in an ice bath. The solution was stirred in
the cooling bath for 30 min and at room temperature for another 60 min.
Then acetic acid (1.9 mL) in water (40 mL) was slowly added to the reaction
mixture. The resulting mixture was concentrated under reduced pressure
and the residue was taken up in tert-butyl methyl ether. The resulting
solution was washed with water, dried (MgSO4), and concentrated. The
residue was submitted to chromatography on silica gel (cyclohexane/ethyl
acetate 90:1040:60) to afford the title compound as a colorless solid.
Besides the title compound a diastereomer thereof, 3-[(S)-1-(4-bromo-2-
methyl -phenyl)-ethyl]-6-(S)-(2-methyl -allyl)-6-phenyl-[1,3]oxazinan-2-one,
was isolated as an oil {1.55 g, Mass spectrum (ESI+): m/z = 428/430 (Br)
[M+H]+}. Yield: 1.34 g (18% of theory); Mass spectrum (ESI+): m/z =
428/430 (Br) [M+H]+; 1 H NMR (400 MHz, DMSO-d6) 1.40 (d, J = 6.8 Hz, 3H),
1.53 (s, 3H), 1.71 (s, 3H), 1.81-190 (m, 1 H), 1.98-2.08 (m, 1 H), 2.43-ca.
2.51
(m, 3H), 2.86-2.94 (m, 1 H), 4.58 (hardly resolved m, 1 H), 4.77 (hardly
resolved m, 1 H), 5.30 (q, J = 6.8 Hz, 1 H), 7.15-7.19 (m, 2H), 7.24-7.35 (m,
6H). The assignment of the stereogenic centers of the title compound is
based on the comparison of the 1H NMR data with the data of the known
analog 3-[(S)-1-(4-bromo-phenyl)-ethyl]-(R)-6-(2-methyl -allyl)-6-phenyl-
[1,3]oxazinan-2-one.
Step 2: 3-[(S)-1-(4-Bromo-2-methyl -phenyl)-ethyl]-(S)-6-(2-methyl -
oxiranylmethyl)-6-phenyl-[1,3]oxazinan-2-one
3-[(S)-1-(4-Bromo-2-methyl-phenyl)-ethyl]-(R)-6-(2-methyl -allyl)-6-
phenyl-[1,3]oxazin-an-2-one (1.34 g) dissolved in dichloromethane (15 mL)
was added to a solution of 3-chloroperoxybenzoic acid (77%, 0.81 g) in
dichloromethane (15 mL) cooled to 5 C. The cooling bath was removed
and the solution was stirred at room temperature overnight. Aqueous 10%
Na2S2O3 solution (10 mL) and aqueous saturated NaHCO3 solution (25 mL)
were added and the resulting mixture was stirred for further 30 min. The
organic phase was separated and washed with aqueous Na2S2O3 solution
combined with aqueous saturated NaHCO3 solution, water, and brine. The
organic phase was dried (MgSO4) and concentrated to furnish the title
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compound. Yield: 1.55 g (ca. 85-90% pure); LC-MS (Method 4): tR = 4.28
min; Mass spectrum (ESI+): m/z = 444/446 (Br) [M+H]+.
Step 3: 3-[(S)-1-(4-Bromo-2-methyl -phenyl)-ethyl]-(S)-6-(2-hydroxy-2-
methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one
Lithium triethylborohydride (1 mol/L in tetrahydrofuran, 4.2 mL) was
added to an ice-cold solution of 3-[(S)-1-(4-bromo-2-methyl -phenyl)-ethyl]-
(S)-6-(2-methyl -oxiranylmethyl)-6-phenyl-[1,3]oxazinan-2-one (1.55 g, ca.
85-90% pure) in tetrahydrofuran (15 mL) at such a rate that the solution
temperature remained below 10 C. The resulting solution was stirred in the
cooling bath for one more hour and at room temperature for another 2 h.
Then, the solution was cooled in an ice bath and the reaction was quenched
by the careful addition of water (7 mL). After the addition of aqueous
hydrochloric acid and ethyl acetate (80 ml), the organic phase was
separated, washed with brine, and dried (MgSO4). The solvent was
evaporated to afford the title compound. Yield: 1.48 g (95% of theory); LC-
MS (Method 4): tR = 4.00 min; Mass spectrum (ESI+): m/z = 446/448 (Br)
[M+H]
Step 4: (S)-6-(2-Hydroxy-2-methyl -propyl)-3-{(S)-1-[2-methyl-4-
(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-6-phenyl-
[1,3]oxazinan-2-one
A flask charged with a stir bar, potassium acetate (1.14 g),
bis(pinacolato)diboron (1.10 g), 3-[(S)-1-(4-bromo-2-methyl-phenyl)-ethyl]-
(S)-6-(2-hydroxy-2-methyl -propyl)-6-phenyl-[1,3]oxazinan-2-one (1.48 g),
and dimethyl sulfoxide (20 mL) was sparged with argon for 10 min. Then,
[1,1 '-bis(diphenylphosphino)ferrocene]dichloro-palladium(I I) dichloro-
methane complex (0.27 g) was added and the mixture was heated to 90 C
and stirred at this temperature for 2.5 h. After cooling the mixture to
ambient
temperature, water and ethyl acetate were added and the resulting mixture
was filtered over Celite. The aqueous phase of the filtrate was separated
and extracted twice with ethyl acetate. The organic extracts and the organic
phase of the filtrate were combined and washed with water and brine and
dried (MgS04). The solvent was evaporated and the residue was
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chromatographed on silica gel (cyclohexane/ethyl acetate 1:1--AA) to afford
the title compound. Yield: 1.23 g (75% of theory); Mass spectrum (ESI+): m/z
= 494 [M+H]+.
Step 5: 3-{(S)-1-[4-(1-Cyclopropyl-2-oxo-1,2-dihydro-pyridin-4-yl)-2-
methyl -phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl -propyl)-6-phenyl-
[1,3]oxazinan-2-one
2 M aqueous Na2CO3 solution (0.41 mL) was added to a mixture of 4-
bromo-1 -cyclopropyl-1 H-pyridin-2-one (0.11 g) and (S)-6-(2-hydroxy-2-
methyl -propyl)-3-{(S)-1-[2-methyl -4-(4,4,5,5-tetramethyl -
[1,3,2]dioxaborolan-
2-yl)-phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one (0.20 g) in N,N-
dimethylformamide (2 mL). The resulting mixture was sparged with argon
for 10 min prior to the addition of [1,1'-bis(diphenylphosphino)-
ferrocene]dichloro-palladium(II) dichloromethane complex (33 mg). The
mixture was heated to 100 C and stirred at this temperature overnight.
After cooling the mixture to ambient temperature, water was added and the
resulting mixture was extracted with ethyl acetate. The combined organic
extracts were washed with water and brine and dried (MgSO4). The solvent
was evaporated and the residue was purified by HPLC on reversed phase
(methanol/water/NH4OH) to afford the title compound. Yield: 0.13 g (64% of
theory); LC-MS (Method 5): tR = 3.43 min; Mass spectrum (ESI+): m/z = 501
[M+H]
Example 97
3-{(S)-1-[4-(1-Cyclopropyl-2-oxo-1,2-dihydro-pyridin-4-yl)-3-methyl -phenyl]-
ethyl}-(S)-6-(2-hydroxy-2-methyl -propyl)-6-phenyl-[1,3]oxazinan-2-one
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O
OH
CI O Step 1 O N
+ N 0", Vr
Br
Br
I Step 2
O O
ON I Step 3 ON
~~ / Br ~~ Vrr
OH O
Step 4
~ N
O N O
I Step 5
N
a O QH o
Step 1: 3-[(S)-1-(4-Bromo-3-methyl -phenyl)-ethyl]-(R)-6-(2-methyl-
allyl)-6-phenyl-[1,3]oxazinan-2-one
The title compound was prepared from 1-chloro-5-methyl-3-phenyl-
hex-5-en-3-ol and (S)-1-bromo-4-(1-isocyanato-ethyl)-2-methyl -benzene
following a procedure analogous to that described in Step 1 of Example 96.
Mass spectrum (ESI+): m/z = 428/430 (Br) [M+H]+; 1H NMR (400 MHz,
DMSO-d6) 1.40 (d, J = 6.9 Hz, 3H), 1.55 (s, 3H), 2.13 (s, 3H) superimposed
on 2.07-2.18 (m, 2H), 2.42-2.47 (m, 1 H), 2.53 (broad s, 2H), 2.92-3.03 (m,
1 H), 4.60 (hardly resolved m, 1 H), 4.77 (hardly resolved m, 1 H), 5.33 (q, J
=
6.9 Hz, 1 H), 6.62 (dd, J = 8.2 Hz, 2.0 Hz, 1 H), 6.76 (hardly resolved d, 1
H),
7.26-7.33 (m, 4H), 7.34-7.40 (m, 2H). The assignment of the stereogenic
centers of the title compound is based on the comparison of the 1H NMR
data with the data of the known analog 3-[(S)-1-(4-bromo-phenyl)-ethyl]-(R)-
6-(2-methyl-allyl)-6-phenyl-[1,3]oxazinan-2-one.
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Step 2: 3-[(S)-1-(4-Bromo-3-methyl -phenyl)-ethyl]-(S)-6-(2-methyl -
oxiranylmethyl)-6-phenyl-[1,3]oxazinan-2-one
The title compound was prepared from 3-[(S)-1-(4-bromo-3-methyl -
phenyl)-ethyl]-(R)-6-(2-methyl -allyl)-6-phenyl-[1,3]oxazinan-2-one following
a
procedure analogous to that described in Step 2 of Example 96. LC-MS
(Method 4): tR = 4.03 min; Mass spectrum (ESI+): m/z = 444/446 (Br) [M+H]
Step 3: 3-[(S)-1-(4-Bromo-3-methyl -phenyl)-ethyl]-(S)-6-(2-hydroxy-2-
methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one
The title compound was prepared from 3-[(S)-1-(4-bromo-3-methyl-
phenyl)-ethyl]-(S)-6-(2-methyl -oxiranylmethyl)-6-phenyl-[1,3]oxazinan-2-one
following a procedure analogous to that described in Step 3 of Example 96.
LC-MS (Method 4): tR = 4.03 min; Mass spectrum (ESI+): m/z = 446/448 (Br)
[M+H]
Step 4: (S)-6-(2- Hyd roxy-2-m ethyl -propyl)-3-{(S)- 1 -[3-methyl-4-
(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-6-phenyl-
[1,3]oxazinan-2-one
The title compound was prepared from 3-[(S)-1-(4-bromo-3-methyl -
phenyl)-ethyl]-(S)-6-(2-hydroxy-2-methyl -propyl)-6-phenyl-[1,3]oxazinan-2-
one following a procedure analogous to that described in Step 4 of Example
96. Mass spectrum (ESI+): m/z = 494 [M+H]+.
Step 5: 3-{(S)-1-[4-(1-Cyclopropyl-2-oxo-1,2-dihydro-pyridin-4-yl)-3-
methyl -phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl -propyl)-6-phenyl-
[1,3]oxazinan-2-one
The title compound was prepared from (S)-6-(2-hydroxy-2-methyl-
propyl)-3-{(S)-1-[3-methyl -4-(4,4,5,5-tetramethyl -[1,3,2]dioxaborolan-2-yl)-
phenyl]-ethyl}-6-phenyl-[1,3]oxazinan-2-one and 4-bromo-1 -cyclopropyl-1 H-
pyridin-2-one following a procedure analogous to that described in Step 5 of
Example 96. LC-MS (Method 5): tR = 3.42 min; Mass spectrum (ESI+): m/z =
501 [M+H]
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Example 98
3-[4-(1-Cyclopropyl-2-oxo-1,2-dihydro-pyridin-4-yl)-benzyl]-6-(2-hydroxy-2-
methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one
O
OH
CI O~ Step 1 O N
all + N I Br 1~ Br
Step 2
O O
ON Step 3 ON
Br Br
OH O
Step 4
O N I Step 5 O N
OH / iN
V
Step 1: 3-(4-Bromo-2,6-dimethyl -benzyl)-6-(2-methyl-allyl)-6-phenyl-
[1,3]oxazinan-2-one
The title compound was prepared from 1-chloro-5-methyl-3-phenyl-
hex-5-en-3-ol and 5-bromo-2-isocyanatomethyl-1,3-dimethyl-benzene
following a procedure analogous to that described in Step 1 of Example 96.
LC-MS (Method 5): tR = 4.95 min; Mass spectrum (ESI+): m/z = 428/430 (Br)
[M+H]
Step 2: 3-(4-Bromo-2,6-dimethyl-benzyl)-6-(2-methyl-oxiranylmethyl)-
6-phenyl-[1,3]oxazinan-2-one
The title compound was prepared from 3-(4-bromo-2,6-dimethyl -
benzyl)-6-(2-methyl -allyl)-6-phenyl-[1,3]oxazinan-2-one following a
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procedure analogous to that described in Step 2 of Example 96. LC-MS
(Method 4): tR = 4.05 min; Mass spectrum (ESI+): m/z = 444/446 (Br) [M+H]
Step 3: 3-(4-Bromo-2,6-dimethyl -benzyl)-6-(2-hydroxy-2-methyl -
propyl)-6-phenyl-[1,3]oxazinan-2-one
The title compound was prepared from 3-(4-bromo-2,6-dimethyl -
benzyl)-6-(2-methyl -oxiranylmethyl)-6-phenyl-[1,3]oxazinan-2-one following
a procedure analogous to that described in Step 3 of Example 96. LC-MS
(Method 4): tR = 4.05 min; Mass spectrum (ESI+): m/z = 446/448 (Br) [M+H]
Step 4: 3-[2,6-Dim ethyl -4-(4,4,5,5-tetramethyl -[1,3,2]dioxaborolan-2-
yl)-benzyl]-6-(2-hydroxy-2-methyl -propyl)-6-phenyl-[1,3]oxazinan-2-one
The title compound was prepared from 3-(4-bromo-2,6-dimethyl -
benzyl)-6-(2-hydroxy-2-methyl -propyl)-6-phenyl-[1,3]oxazinan-2-one
following a procedure analogous to that described in Step 4 of Example 96.
Mass spectrum (ESI+): m/z = 494 [M+H]+.
Step 5: 3-[4-(1-Cyclopropyl-2-oxo-1,2-dihydro-pyridin-4-yl)-benzyl]-6-
(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one
The title compound was prepared from 3-[2,6-dimethyl -4-(4,4,5,5-
tetramethyl -[1,3,2]dioxaborolan-2-yl)-benzyl]-6-(2-hydroxy-2-methyl -propyl)-
6-phenyl-[1,3]oxazinan-2-one and 4-bromo-1 -cyclopropyl-1 H-pyridin-2-one
following a procedure analogous to that described in Step 5 of Example 96.
LC-MS (Method 5): tR = 3.53 min; Mass spectrum (ESI+): m/z = 501 [M+H]
BIOLOGICAL TEST EXAMPLE 1
The inhibition of a microsomal preparation of 11 R-HSD1 by
compounds of the invention was measured essentially as previously
described (K. Solly, S.S. Mundt, H.J. Zokian, G.J. Ding, A. Hermanowski-
Vosatka, B. Strulovici, and W. Zheng, High-Throughput Screening of 11-
Beta-Hydroxysero id Dehydrogenase Type 1 in Scintillation Proximity Assay
Format. Assay Drug Dev Technol 3 (2005) 377-384). All reactions were
carried out at rt in 96 well clear flexible PET Microbeta plates
(PerkinElmer).
The assay begins by dispensing 49 l of substrate solution (50mM HEPES,
pH 7.4, 100mM KCI, 5mM NaCl, 2mM MgCl2, 2 mM NADPH and 160 nM
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[3H]cortisone (1 Ci/mmol)) and mixing in 1 pL of the test compounds in
DMSO previously diluted in half-log increments (8 points) starting at 0.1 mM.
After a 10 minute pre-incubation, 50 pL of enzyme solution containing
microsomes isolated from CHO cells overexpressing human 11 R-HSD1 (10-
20 g/ml of total protein) was added, and the plates were incubated for 90
minutes at rt. The reaction was stopped by adding 50 pl of the SPA beads
suspension containing10 pM 18[3-glycyrrhetinic acid, 5 mg/ml protein A
coated YSi SPA beads (GE Healthcare) and 3.3 pg/ml of anti-cortisol
antibody (East Coast Biologics) in Superblock buffer (Bio-Rad). The plates
were shaken for 120 minutes at rt, and the SPA signal corresponding to
[3H]cortisol was measured on a Microbeta plate reader.
BIOLOGICAL TEST EXAMPLE 2
The inhibition of 11 R-HSD1 by compounds of this invention was
measured in whole cells as follows. Cells for the assay were obtained from
two sources: fully differentiated human omental adipocytes from Zen-Bio,
Inc.; and human omental pre-adipocytes from Lonza Group Ltd. Pre-
differentiated omental adipocytes from Zen-Bio Inc. were purchased in 96-
well plates and were used in the assay at least two weeks after
differentiation from precursor preadipocytes. Zen-Bio induced differentiation
of pre-adipocytes by supplementing medium with adipogenic and lipogenic
hormones (human insulin, dexamethasone, isobutylmethylxanthine and
PPAR-gamma agonist). The cells were maintained in full adipocyte medium
(DMEM/Ham's F-12 (1:1, v/v), HEPES pH 7.4, fetal bovine serum, penicillin,
streptomycin and Amphotericin B, supplied by Zen-Bio, Inc.) at 37 C, 5%
CO2.
Pre-adipocytes were purchased from Lonza Group Ltd. and placed in
culture in Preadipocyte Growth Medium-2 supplemented with fetal bovine
serum, penicillin, and streptomycin (supplied by Lonza) at 37 C, 5% CO2.
Pre-adipocytes were differentiated by the addition of insulin,
dexamethasone, indomethacin and isobutyl-methylxanthine (supplied by
Lonza) to the Preadipocyte Growth Medium-2. Cells were exposed to the
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differentiating factors for 7 days, at which point the cells were
differentiated
and ready for the assay. One day before running the assay, the
differentiated omental adipocytes were transferred into serum- and phenol-
red-free medium for overnight incubation. The assay was performed in a
total volume of 200 pL. The cells were pre-incubated with serum-free,
phenol-red-free medium containing 0.1 % (v/v) of DMSO and various
concentrations of the test compounds at least 1 h before [3H] cortisone in
ethanol (50Ci/mmol, ARC, Inc.) was added to achieve a final concentration
of cortisone of 100 nM. The cells were incubated for 3-4 hrs at 37 C, 5%
CO2. Negative controls were incubated without radioactive substrate and
received the same amount of [3H] cortisone at the end of the incubation.
Formation of [3H] cortisol was monitored by analyzing 25 pL of each
supernatant in a scintillation proximity assay (SPA). (Solly, K.; Mundt, S.
S.;Zokian, H.J.;Ding, G. J.; Hermanowski-Vosatka, A.; Strulovici, B.; Zheng,
W. Assay Drug Dev. Technol. 2005, 3, 377-384). Many compounds of the
invention showed significant activity in this assay.
TABLE OF BIOLOGICAL ASSAY RESULTS
Compound Biological Test Example 1
-----------------------------------------------
Average %
IC50 Rangea inhibition at
100 nM
EXAMPLE 1 ++ 90.3
EXAMPLE 2 ++ 89.1
EXAMPLE 3 ++ 95.6
EXAMPLE 4 ++ 95.2
EXAMPLE 5 ++ 95.6
EXAMPLE 6 ++ 92.6
EXAMPLE 7 ++ 75.9
EXAMPLE 8 ++ 84.5
EXAMPLE 9 ++ 86.2
EXAMPLE 10 ++ 95.8
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EXAMPLE 11 ++ 84.1
EXAMPLE 12 ++ 84.2
EXAMPLE 13 ++ 90.0
EXAMPLE 14 ++ 91.0
EXAMPLE 15 ++ 92.9
EXAMPLE 16 ++ 95.6
EXAMPLE 17 Isomer 1 ++ 54.0
EXAMPLE 17 Isomer 2 # 14.8
EXAMPLE 18 Isomer 1 # 23.7
EXAMPLE 18 Isomer 2 ++ 42.6
EXAMPLE 19 ++ 36.5
EXAMPLE 20 ++ 90.9
EXAMPLE 21 Isomer 1 ++ 103.5
EXAMPLE 21 Isomer 2 ++ 88.8
EXAMPLE 22 Isomer 1 ++ 82.5
EXAMPLE 22 Isomer 2 ++ 88.7
EXAMPLE 23 ++ 88.2
EXAMPLE 24 ++ 87.9
EXAMPLE 25 ++ 93.9
EXAMPLE 26 ++ 94.7
EXAMPLE 27 ++ 92.0
EXAMPLE 28 Isomer 1 ++ 86.9
EXAMPLE 28 Isomer 2 # 42.9
EXAMPLE 29 ++ 94.1
EXAMPLE 30 ++ 96.7
EXAMPLE 31 ++ 90.1
EXAMPLE 32 ++ 96.4
EXAMPLE 33 ++ 95.9
EXAMPLE 34 ++ 95.0
EXAMPLE 35 ++ 95.8
EXAMPLE 36 ++ 95.0
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EXAMPLE 37 ++ 96.5
EXAMPLE 38 ++ 74.3
EXAMPLE 39 ++ 99.1
EXAMPLE 40 ++ 95.9
EXAMPLE 41 ++ 88.7
EXAMPLE 42 ++ 88.4
EXAMPLE 43 ++ 96.6
EXAMPLE 44 ++ 102.0
EXAMPLE 45 ++ 97.9
EXAMPLE 46 ++ 94.8
EXAMPLE 47 ++ 100.1
EXAMPLE 48 ++ 95.0
EXAMPLE 49 ++ 97.4
EXAMPLE 50 ++ 97.1
EXAMPLE 51 ++ 93.4
EXAMPLE 52 ++ 95.4
EXAMPLE 53 ++ 96.6
EXAMPLE 54 ++ 96.0
EXAMPLE 55 ++ 96.6
EXAMPLE 56 ++ 102.8
EXAMPLE 57 ++ 102.2
EXAMPLE 58 ++ 104.7
EXAMPLE 59 ++ 95.9
EXAMPLE 60 ++ 94.5
EXAMPLE 61 ++ 96.2
EXAMPLE 62 ++ 96.9
EXAMPLE 63 ++ 96.2
EXAMPLE 64 ++ 94.9
EXAMPLE 65 ++ 96.1
EXAMPLE 66 ++ 96.0
EXAMPLE 67 ++ 97.7
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EXAMPLE 68 ++ 95.6
EXAMPLE 69 ++ 98.1
EXAMPLE 70 ++ 96.5
EXAMPLE 71 ++ 92.2
EXAMPLE 72 ++ 95.6
EXAMPLE 73 ++ 99.2
EXAMPLE 74 ++ 95.0
EXAMPLE 75 ++ 87.4
EXAMPLE 84 Isomer 1 # 16.2
EXAMPLE 84 Isomer 2 # 8.0
EXAMPLE 85 ++ 68.4
EXAMPLE 86 ++ 87.7
EXAMPLE 87 ++ 107.5
EXAMPLE 88 ++ 92.4
EXAMPLE 89 ++ 92.6
EXAMPLE 91 Isomer 1 # 22.5
EXAMPLE 91 Isomer 2 # 13.8
EXAMPLE 92 ++ 93.7
EXAMPLE 93 Isomer 1 ++ 86.4
EXAMPLE 93 Isomer 2 # 18.7
EXAMPLE 94 Isomer 1 # 41.9
EXAMPLE 94 Isomer 2 # 8.2
EXAMPLE 95 Isomer 1 # 12.8
EXAMPLE 95 Isomer 2 # 8.0
a ++ means IC50 = <100 nM, + means IC50 = 100 - 1000 nM, # means IC50 >
100 nM, - means IC5o > 1000 nM.
BIOLOGICAL TEST EXAMPLE 3
In vitro inhibition of 11 R-HSD1 by test compounds was determined
with HTRF (Homogeneous Time-Resolved Fluorescence) technology (cisbio
international, France) detecting cortisol generated from cortisterone by
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human liver microsomes. Briefly, compounds were incubated for 1 hour at
37 C in Tris buffer (20 mM tris, 5 mM EDTA, pH 6.0) containing NADPH
(200 pM) and cortisone (80 nM). Cortisol generated in the reaction was then
detected with a competitive immunoassay, involving two HTRF conjugates:
cortisol linked to XL665 and anti-cortisol antibody labeled with Europium
cryptate. The incubation period for detection reaction was typically 2 hours.
The amount of cortisol was determined by reading the time-resolved
fluorescence of the wells (Ex 320/75 nm; Em 615/8.5 nm and 665/7.5 nm).
The ratio of the two emission signals was then calculated
(Em665*10000/Em615). Each assay contained incubations with vehicle
controls instead of compound as controls for non-inhibited cortisol
generation (100% CTL; 'high values') and incubations with carbenoxolone as
controls for fully inhibited enzyme and cortisol background (0% CTL; 'low
values'). Each assay also contained a calibration curve with cortisol to
transform the fluorescent data into cortisol concentrations. Percent
inhibition
of each compound was determined relative to the carbenoxolone signal.
In following table the 11 R-HSD 1 inhibitory activities, determined as
described above, wherein 100% indicates no inhibition and a value of zero
or below zero indicates complete inhibition.
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TABLE OF BIOLOGICAL ASSAY RESULTS FOR BIOLOGICAL TEST 3
Average %
control
Example
inhibition at
100 nM
75 -14
76 17
77 59
78 58
79 15
80 37
81 11
82 -12
83 54
90 4
96 21
97 47
98 67
BIOLOGICAL TEST EXAMPLE 4
The inhibition of a microsomal preparation of 11 R-HSD1 in the
presence of 50% human plasma by compounds of the invention was
measured as follows. Microsomes from CHO cells overexpressing human
11 R-HSD1 were diluted into reaction buffer consisting of 25 mM HEPES, pH
7.4, 50 mM KCI, 2.5 mM NaCl, 1 mM MgC12, and 50% (v/v) human plasma
(BioChemed). The assay began by dispensing 49 pl of microsome solution
into 96-well polypropylene plates and adding 1 pl of the test compounds in
DMSO, previously diluted in half-log increments (8 points) starting at 1.0
mM. The reaction was initiated with the addition of 50 pl substrate solution
consisting of reaction buffer with 2 mM NADPH and 160 nM [3-H]cortisone (1
Ci/mmol). The plates were incubated for 120 minutes at rt, and the reaction
was quenched with the addition of 100p1 acetonitrile with 20 mM cortisone
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and 20 mM cortisol. After a ten minute incubation at rt, 100 pl of each well
was filtered through a MultiScreen HTS, HV filter plate (Millipore) and
diluted
with 100 pl of reaction buffer without human plasma. [3-H]cortisone and [3-
H]cortisol were separated by HPLC on a Zorbax SB-C8 column (4.6 x 250
mm, Agilent) with an isocratic elution at 25% acetonitrile in water with 0.01
%
trifluoroacetic acid, and radioactivity was quantified with an in-line R-RAM
(IN/US Systems, Inc.).
BIOLOGICAL TEST EXAMPLE 5
(Fraction Unbound in Human Plasma)
Plasma protein binding of compounds was determined with
Equilibrium Dialysis of spiked plasma against compound free dextrane buffer
using a dialysis membrane with mass cutoff of 5000 Da. Compound
concentrations in plasma and buffer after incubation were measured using
HPLC/Mass spectrometry.
BIOLOGICAL TEST EXAMPLE 6
(CYP3A4 Inhibition)
The assay was based on a method published by Moody et al.
(Xenobiotica 1999). The inhibition of cytochrome P450 3A4-isoenzyme
catalysed N-demethylation of [N-methyl-14C]-Erythromycin by the test
compound was assayed at 37 C with human recombinant cytochrome P450
3A4. All assays were carried out on a robotic system in 96 well plates. The
final incubation volume of 200 pl contained TRIS buffer (0.1 M), MgCl2 (5
mM), recombinant protein (40 pmol/ml), Erythromycin (50 pM) and the test
compound either at four different concentrations in duplicate (e.g. highest
concentration 10-50 pM with subsequent serial 1:5 dilutions) or at a
concentration of 10 pM in triplicate. Following a short preincubation period,
reactions were started with the cofactor (NADPH, 1 mM) and stopped by
addition of 50 pl aqueous trichloroacetic acid (1 0%;w/v). An aliquot of the
incubate was transferred to 96 well solid phase extraction (SPE) plates and
extracted on the cartridge. The resultant [14C]-formaldehyde/formic acid was
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not retained on the cartridge and was therefore separated from the
unmetabolized substrate by washing the SPE plates with water. An aliquot
of the eluates was transferred into well plates suitable for liquid
scintillation
counting. The rate of formation of [14C]- formaldehyde/formic acid in these
incubations was compared to a control activity containing no test compound.
If the compound was tested at four concentrations, experimental IC50 values
were calculated.
BIOLOGICAL TEST EXAMPLE 7
(CYP2C9 Inhibition)
Using a procedure similar to that described in Biological Test
Example 6, the inhibition of cytochrome P450 2C9-isoenzyme catalysed 0-
demethylation of [O-methyl-14C]-Naproxen by the test compound was
assayed at 37 C with human recombinant cytochrome P450 2C9. The
experimental IC5o was calculated based on % control at four different
concentrations.
BIOLOGICAL TEST EXAMPLE 8
(CYP2C19 Inhibition)
Using a procedure similar to that described in Biological Test
Example 6, the inhibition of cytochrome P450 2C19-isoenzyme catalysed N-
demethylation of [N-methyl-14C]-Diazepam by the test compound was
assayed at 37 C with human recombinant cytochrome P450 2C19. The
experimental IC5o was calculated based on % control at four different
concentrations.
BIOLOGICAL TEST EXAMPLE 9
(CYP2C9 Inhibition)
The inhibition of recombinant CYP2C9 by compounds of the invention
was measured using a commercial kit from Invitrogen (cat #2859). Supplied
microsomes isolated from insect cells infected with a baculovirus engineered
to express human CYP2C9 were diluted to 10 mM in reaction buffer (100
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mM potassium phosphate buffer, pH 8.0) with an NADPH generation system
(3.33 mM glucose-6-phosphate and 0.4 U/ml glucose-6-phosphate
dehydrogenase). 89 pl of this dilution were dispensed to each well of a 96-
well, black, polystyrene plate and mixed with 1 pl of test compound
previously diluted in DMSO in half log increments starting at 3 mM. The
assay was initiated by adding 10 pl of fluorogenic substrate n-
octyloxymethyl resorufin (OOMR, 20 pM.) with NADP (100 pM) diluted in
reaction buffer. The plate was immediately placed in a Perkin Elmer Fusion
plate reader. Reaction progress was monitored by measuring fluorescence
every two minutes for a total of twenty minutes (530 nM excitation filter /605
nM emission filter).
TABLE OF BIOLOGICAL ASSAY RESULTS FOR BIOLOGICAL TESTS 1, 4
AND 5
Biological Test Biological Test Biological
EXAMPLE Example 1 Example 4a Shiftb Test
IC50 (nM) IC50 (nM) Example 5
(%)
1 1.51 2.84 1.88
2 0.31 15.54 50.94
3 1.59 3.85 2.42
4 1.80 5.60 3.12
5 1.25 3.80 3.04
6 2.36 4.07 1.72
7 35.07 nt
8 18.33 nt
9 4.29 13.12 3.06
10 2.91 13.13 4.51
11 5.94 13.51 2.27
12 5.38 31.75 5.90
13 7.22 nt 0.00
14 1.11 2.88 2.59
0.58 2.15 3.70
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Biological Test Biological Test Biological
EXAMPLE Example 1 Example 4a Shiftb Test
IC5o (nM) IC5o (nM) Example 5
(%)
16 0.90 2.00 2.23
17 Isomer 1 75.98 nt
17 Isomer 2 >100.00 nt
18 Isomer 1 >100.00 nt
18 Isomer 2 97.49 nt
19 95.38 nt
20 4.28 7.61 1.78
21 Isomer 1 3.89 4.72 1.21
21 Isomer 2 7.21 9.58 1.33
22 Isomer 1 14.87 75.86 5.10
22 Isomer 2 6.60 20.11 3.05
23 1.99 4.17 2.10
24 3.70 8.28 2.24
25 2.34 5.44 2.32
26 1.49 8.05 5.39
27 3.49 8.41 2.41
28 Isomer 1 >100.00 nt
28 Isomer 2 8.89 nt
29 1.39 2.76 1.99
30 1.44 3.42 2.37 13.9
31 9.01 25.42 2.82
32 3.58 11.48 3.20 12.3
33 2.23 3.69 1.66
34 3.19 8.85 2.78
35 2.97 nt
36 2.03 13.62 6.72
37 1.67 6.44 3.85 14.6
38 5.18 nt
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Biological Test Biological Test Biological
EXAMPLE Example 1 Example 4a Shiftb Test
IC5o (nM) IC5o (nM) Example 5
(%)
39 1.31 5.10 3.89
40 1.86 7.01 3.77
41 9.28 38.06 4.10
42 6.70 53.38 7.97
43 2.23 3.51 1.57
44 1.08 5.60 5.19
45 1.58 11.85 7.52
46 4.24 16.97 4.00
47 0.96 6.75 7.03
48 1.62 5.54 3.41 8.7
49 1.03 2.96 2.86
50 0.61 1.97 3.23
51 5.46 7.89 1.45
52 3.24 14.09 4.35 9.0
53 1.35 4.19 3.10 12.8
54 2.40 7.05 2.94 9.1
55 1.66 7.18 4.31 7.1
56 1.03 13.19 12.81
57 1.26 12.45 9.92
58 0.87 8.98 10.32
59 1.53 4.02 2.63 11.7
60 0.75 7.00 9.40
61 1.40 6.99 4.99
62 2.48 11.96 4.82
63 3.85 102.97 26.73
64 1.64 9.62 5.87
65 0.80 4.64 5.82
66 1.47 6.71 4.58 5.5
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Biological Test Biological Test Biological
EXAMPLE Example 1 Example 4a Shiftb Test
IC5o (nM) IC5o (nM) Example 5
(%)
67 2.01 7.29 3.63
68 0.96 4.39 4.59
69 0.72 3.89 5.42
70 1.01 2.63 2.60
71 0.65 3.96 6.09
72 4.04 8.23 2.04
73 1.99 33.08 16.62
74 1.21 8.76 7.24
75 1.40 2.80 2.00 15.6
84 Isomer 1 >100 nt
84 Isomer 2 >100 nt
85 42.9 nt
86 12.1 24.5 2.0
87 1.4 3.2 2.2
88 1.2 2.9 2.5
89 2.8 4.6 1.7
91 Isomer 1 > 100 nt
91 Isomer 2 > 100 nt
92 1.8 6.2 3.4
93 Isomer 1 6.1 16.3 2.7
93 Isomer 2 >100
94 Isomer 1 >100
94 Isomer 2 >100
95 Isomer 1 >100
95 Isomer 2 >100
a nt means not tested; b Shift is the IC5o determined in Biological Test
Example 4 divided by the IC50 determined in Biological Test Example 1.
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TABLE OF BIOLOGICAL ASSAY RESULTS FOR BIOLOGICAL TESTS 6-9
Biological Test Biological Test Biological Test Biological Test
EXAMPLE Example 6 Example 7 Example 8 Example 9
CYP3A4, IC50 CYP2C9, IC50 CYP2C19, IC50 CYP2C9 IC5o
[pM] [pM] [pM] [uM]
1
2
3 44 38 >50
4 21 17 22
29 37 22
6
7
8
9
30.0
11 16.1
12 12.1
13
14 25 18 24
16
17 Isomer 1
17 Isomer 2
18 Isomer 1
18 Isomer 2
19
21 Isomer 1
21 Isomer 2
22 Isomer 1
22 Isomer 2
23 >50 >50 44
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Biological Test Biological Test Biological Test Biological Test
EXAMPLE Example 6 Example 7 Example 8 Example 9
CYP3A4, IC50 CYP2C9, IC50 CYP2C19, IC50 CYP2C9 IC50
[pM] [pM] [pM] [uM]
24
25 33 30 22
26 >50 >50 >50
27
28.1
28.2
29 7.5
30 >50 >50 27 14.3
31
32 >50 >50 >50 28.7
33 >50 43 17 24.6
34
36
37 48 43 >50 24.8
38 30.0
39
>50 >50 13 27.9
41
42
43 10.5
44
15.2
46
47 12.1
48 >50 >50 >50 30.0
49 32 29 46 14.8
14 11 27 5.1
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Biological Test Biological Test Biological Test Biological Test
EXAMPLE Example 6 Example 7 Example 8 Example 9
CYP3A4, IC50 CYP2C9, IC50 CYP2C19, IC50 CYP2C9 IC50
[pM] [pM] [pM] [uM]
51
52 48 14 8 20.3
53 >50 >50 >50 30.0
54 >50 >50 18
55 >50 29 13 24.3
56
57
58 8 3 2
59 >50 >50 37 17.7
61 >50 40 18
62 48 >50 38
63
64 >50 33 17
>50 >50 25
66 18 10 11
67 28 41 34
68 43 47 28
69 23 38 >50
28 >50 23
71 6 17 24
72 41 35 8
73
74
23 19 24
76 10 4 9
77 >50 >50 34
78 47 39 40
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Biological Test Biological Test Biological Test Biological Test
EXAMPLE Example 6 Example 7 Example 8 Example 9
CYP3A4, IC50 CYP2C9, IC50 CYP2C19, IC50 CYP2C9 IC50
[pM] [pM] [pM] [uM]
79 >50 >50 >50
80 >50 >50 38
81 >50 30 12
82 >50 48 29
83 >50 14 10
84 Isomer 1
84 Isomer 2
86
87
88 >50 28 >50
89
91 Isomer 1
91 Isomer 2
92
93 Isomer 1 28.5
93 Isomer 2
94 Isomer 1
94 Isomer 2
Isomer 1
95 Isomer 2
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TABLE OF BIOLOGICAL ASSAY RESULTS FOR COMPARATOR
COMPOUNDS IN BIOLOGICAL TESTS 1, 4 AND 5
Biological Biological Biological
Comparator Test Test b Test Example
Compound Example 1 Example 4a Shift 5
IC50 (nM) IC50 (nM) (%)
1 0.77 11.97 15.51
2 1.80 14.16 7.88
3 0.75 17.74 23.63 0.3
4 1.44 15.24 10.57
0.51 18.50 36.10
6 1.48 37.58 25.39
7 0.99 41.90 42.43
8 0.72 17.85 24.74
9 0.55 11.86 21.45 0.3
1.79 53.49 29.91
11 0.55 13.40 24.59 0.7
12 1.08 19.54 18.12 0.4
13 0.76 6.32 8.30
14 1.30 8.94 6.90
0.79 8.94 11.32
a nt means not ;b Shift is the IC50 determined in Biological Test
Example 4 divided by the IC50 determined in Biological Test Example 1.
5
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TABLE OF BIOLOGICAL ASSAY RESULTS FOR COMPARATOR
COMPOUNDS IN BIOLOGICAL TESTS 6-9
Biological Biological Biological Biological
Test Test Test Test Example
Comparator Example 6 Example 7 Example 8 9
Compound CYP3A4, CYP2C9, CYP2C19, CYP2C9IC5o
IC50 IC50 [pM] IC50 [pM] [uM]
[pM]
1 27.0
2 1.4
3 7.4 4.1 5.7 4.9
4 5.1
9.9 5.1 8.3 3.7
6 4.4 2.3 8.6 5.0
7 4.0
8 5.3 2.4 5.6 3.0
9 7.0 3.1 9.3 2.5
3.6
11 14.1 6.3 12.5 5.5
12 4.9 4.6 9.5 2.5
12 4.9 3.9 10.1
13 4.4 5.6 < 0.4 7.3
14 19.7 25.9 6.4 24.6
3.1 7.7 < 0.4 9.5
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O F O nN O N\ F OA N
F I \ F F
HO / OH
Comparator 1 Comparator 2
O 0
O~
N F 0A N
nN
\ I / F
F J OF
OH OH
Comparator 3 Comparator 4
0 0
O N O~N F
F / \ OH
F F F
HO
Comparator 5 Comparator 6
0 O
F / O N O N
F F
O F F
NH2 OH
Comparator 7 Comparator 8
0
0 F --O p~N
O~N -
F F
F NH
OH O~~S
0
Comparator 9 Comparator 10
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O O
O N I \ / O N
O NH2 HO
Comparator 11 Comparator 12
O O
OAN O)LN I \ F
\ / Br I \ / OF
JO C\%
F OH F OH
Comparator 13 Comparator 14
O
OAN I \
\ ``, / Br
OH
Comparator 15
The compounds of the invention are useful for ameliorating or treating
disorders or diseases in which decreasing the level of cortisol is effective
in
treating a disease state. Thus, the compounds of the invention can be used
in the treatment or prevention of diabetes mellitus (e.g., type II diabetes),
obesity, symptoms of metabolic syndrome, glucose intolerance,
hyperglycemica, hypertension, hyperlipidemia, insulin resistance,
cardiovascular disease, dyslipidemia, atherosclerosis, lipodystrophy,
osteoporosis, glaucoma, Cushing's syndrome, Addison's Disease, visceral
fat obesity associated with glucocorticoid therapy, depression, anxiety,
Alzheimer's disease, dementia, cognitive decline (including age-related
cognitive decline), polycystic ovarian syndrome, infertility and
hypergonadism. The compounds of the invention can be used as
therapeutic agents for pseudo Cushing's Syndrome associated with
alcoholic liver disease. In addition, the compounds modulate the function of
B and T cells of the immune system and can therefore be used to treat
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diseases such as tuberculosis, leprosy and psoriasis. They can also be
used to promote wound healing, particularly in diabetic patients.
Additional diseases or disorders that are related to 11 R-HSD1 activity
include those selected from the group consisting of lipid disorders,
hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels,
vascular restenosis, pancreatitis, abdominal obesity, neurodegenerative
disease, retinopathy, nephropathy, neuropathy, diabetes, coronary heart
disease, stroke, peripheral vascular disease, Cushing's syndrome,
hyperinsulinemia, viral diseases, and Syndrome X. A further disease related
to 11 R-HSD1 activity is pseudo Cushing's Syndrome associated with
alcoholic liver disease.
A pharmaceutical composition of the invention may, alternatively or in
addition to an 11 R-HSD1 inhibitor of the invention, comprise a
pharmaceutically acceptable salt of a an 11 R-HSD1 inhibitor of the invention
and one or more pharmaceutically acceptable carriers therefore.
Alternatively, a pharmaceutical composition of the invention may comprise a
compound of an 11 R-HSD1 inhibitor of the invention or a pharmaceutical salt
thereof as the only pharmaceutically active agent in the pharmaceutical
composition. The disclosed 11 R-HSD1 inhibitors can be used alone or in a
combination therapy with one or more additional agents for the treatment of
diabetes, dyslipidemia, cardiovascular disease, hypertension, obesity,
cancer or glaucoma.
The compositions of the invention are 11 R-HSD1 inhibitors. Said
compositions contain compounds having a mean inhibition constant (IC50)
against 11 R-HSD1 of below about 1,000 nM; preferably below about 100 nM;
more preferably below about 50 nM; even more preferably below about 5
nM; and most preferably below about 1 nM.
The invention includes a therapeutic method for treating or
ameliorating an 11 R-HSD1 mediated disorder in a subject in need thereof
comprising administering to a subject in need thereof an effective amount of
an 11 R-HSD1 inhibitor of the invention, or an enantiomer, diastereomer, or
pharmaceutically acceptable salt thereof or composition thereof. As used
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herein, "treating" or "treatment" includes both therapeutic and prophylactic
treatment. Therapeutic treatment includes reducing the symptoms
associated with a disease or condition and/or increasing the longevity of a
subject with the disease or condition. Prophylactic treatment includes
delaying the onset of a disease or condition in a subject at risk of
developing
the disease or condition or reducing the likelihood that a subject will then
develop the disease or condition in a subject that is at risk for developing
the
disease or condition.
An embodiment of the invention includes administering an 11 R-HSD1
inhibiting compound of the invention or composition thereof in a combination
therapy with one or more additional agents for the treatment of diabetes,
dyslipidemia, cardiovascular disease, hypertension, obesity, cancer or
glaucoma. Agents for the treatment of diabetes include insulins, such as
Humulin (Eli Lilly), Lantus (Sanofi Aventis), Novolin (Novo Nordisk), and
Exubera (Pfizer); PPAR gamma agonists, such as Avandia (rosiglitizone
maleate, GSK) and Actos (pioglitazone hydrochloride, Takeda/Eli Lilly);
sulfonylureas, such as Amaryl (glimepiride, Sanofi Aventis), Diabeta
(glyburide, Sanofi Aventis), Micronase /Glynase (glyburide, Pfizer), and
Glucotrol /Glucotrol XL and (glipizide, Pfizer); meglitinides, such as
Prandin /NovoNorm (repaglinide, Novo Nordisk), Starlix (nateglinide,
Novartis), and Glufast (mitiglinide, Takeda); biguanides, such as
Glucophase /Glucophase XR (metformin HCI, Bristol Myers Squibb) and
Glumetza (metformin HCI, Depomed); thiazolidinediones; amylin analogs,
GLP-1 analogs; DPP-IV inhibitors such as Januvia (sitagliptin, Merck) and
Galvus (vildagliptin, Novartis); PTB-1 B inhibitors; protein kinase
inhibitors
(including AMP-activated protein kinase inhibitors); glucagon antagonists,
glycogen synthase kinase-3 beta inhibitors; glucose-6-phoshatase inhibitors;
glycogen phosphorylase inhibitors; sodium glucose co-transporter inhibitors,
and alpha-glucosidase inhibitors, such as
Precose /Glucobay /Prandase /Glucor (acarbose, Bayer) and Glyset
(miglitol, Pfizer). Agents for the treatment of dyslipidemia and
cardiovascular disease include statins, fibrates, and ezetimbe. Agents for
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the treatment of hypertension include alpha-blockers, beta-blockers, calcium
channel blockers, diuretics, angiotensin converting enzyme (ACE) inhibitors,
dual ACE and neutral endopeptidase (NEP) inhibitors, angiotensin-receptor
blockers (ARBs), aldosterone synthase inhibitors, aldosterone-receptor
antagonists, or endothelin receptor antagonist. Agents for the treatment of
obesity include orlistat, phentermine, sibutramine and rimonabant.
An embodiment of the invention includes administering an 11 R-HSD1
inhibiting compound of the invention or composition thereof in a combination
therapy with one or more other 11 R-HSD1 inhibitors, or with combination
products, such as Avandamet (metformin HCI and rosiglitazone maleate,
GSK); Avandaryl (glimepiride and rosiglitazone maleate, GSK); Metaglip
(glipizide and metformin HCI, Bristol Myers Squibb); and Glucovance
(glyburide and metformin HCI, Bristol Myers Squibb).
The compounds of the present invention can be prepared and
administered in a wide variety of oral and parenteral dosage forms. Thus,
the compounds of the present invention can be administered by injection,
that is, intravenously, intramuscularly, intracutaneously, subcutaneously,
intraduodenally, or intraperitoneally. Additionally, the compounds of the
present invention can be administered intranasally or transdermally. It will
be obvious to those skilled in the art that the following dosage forms may
comprise as the active ingredient, either compounds or a corresponding
pharmaceutically acceptable salt of a compound of the present invention.
For preparing pharmaceutical compositions from the compounds of
the present invention, pharmaceutically acceptable carriers can either be
solid or liquid. Solid form preparations include powders, tablets, pills,
capsules, cachets, suppositories, and dispersible granules. A solid carrier
can be one or more substances which may also act as diluents, flavoring
agents, solubilizers, lubricants, suspending agents, binders, preservatives,
tablet disintegrating agents, or an encapsulating material. In powders, the
carrier is a finely divided solid which is in a mixture with the finely
divided
active ingredient.
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In tablets, the active ingredient is mixed with the carrier having the
necessary binding properties in suitable proportions and compacted in the
shape and size desired.
The powders and tablets preferably contain from about one to about
seventy percent of the active ingredient. Suitable carriers are magnesium
carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,
gelatin, tragacanth, methylcellulose, sodium caboxymethylcelIulose, a low-
melting wax, cocoa butter, and the like. Tablets, powders, cachets,
lozenges, fast-melt strips, capsules and pills can be used as solid dosage
forms containing the active ingredient suitable for oral administration.
For preparing suppositories, a low-melting wax, such as a mixture of
fatty acid glycerides or cocoa butter, is first-melted and the active
ingredient
is dispersed homogeneously therein, as by stirring. The molten
homogeneous mixture is then poured into convenient sized molds, allowed
to cool, and thereby to solidify.
Liquid form preparations include solutions, suspensions, retention
enemas, and emulsions, for example, water or water propylene glycol
solutions. For parenteral injection, liquid preparations can be formulated in
solution in aqueous polyethylene glycol solution.
Aqueous solutions suitable for oral administration can be prepared by
dissolving the active ingredient in water and adding suitable colorants,
flavors, stabilizing, and thickening agents as desired. Aqueous suspensions
for oral administration can be prepared by dispersing the finely divided
active
ingredient in water with viscous material, such as natural or synthetic gums,
resins, methylcellulose, sodium carboxymethylcelIulose, and other well-
known suspending agents.
The pharmaceutical composition is preferably in unit dosage form. In
such form, the composition is subdivided into unit doses containing
appropriate quantities of the active ingredient. The unit dosage form can be
a packaged preparation, the package containing discrete quantities of, for
example, tablets, powders, and capsules in vials or ampules. Also, the unit
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dosage form can be a tablet, cachet, capsule, or lozenge itself, or it can be
the appropriate amount of any of these in packaged form.
The quantity of active ingredient in a unit dose preparation may be
varied or adjusted from about 0.1 mg to about 1000.0 mg, preferably from
about 0.1 mg to about 100 mg. The dosages, however, may be varied
depending upon the requirements of the patient, the severity of the condition
being treated, and the compound being employed. Determination of the
proper dosage for a particular situation is within the skill in the art. Also,
the
pharmaceutical composition may contain, if desired, other compatible
therapeutic agents.
In therapeutic treatment or as a method-of-use as an inhibitor of 11 R-
HSD1 or an inhibitor in the production of cortisol in the cell, the active
ingredient is preferably administered orally in a solid dosage form as
disclosed above in an amount of about 0.1 mg to about 100 mg per daily
dose where the dose is administered once or more than once daily.
All publications, patents and patent applications mentioned in this
specification are herein incorporated by reference to the same extent as if
each individual publication or patent application were specifically and
individually designated as having been incorporated by reference. It is
understood that the examples and embodiments described herein are for
illustrative purposes only, and it will be appreciated that the invention is
susceptible to modification, variation and change without departing from the
proper scope or fair meaning of the appended claims.
While this invention has been particularly shown and described with
references to example embodiments thereof, it will be understood by those
skilled in the art that various changes in form and details may be made
therein without departing from the scope of the invention encompassed by
the appended claims.
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