Note: Descriptions are shown in the official language in which they were submitted.
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Process for the Preparation of Amidino Phenyl
Pyrrolidine ~-Alanine Urea Analogs
BACKGROUND OF THE INVENTION
The invention herein is directed to the cyclization
of a methionine analog to a lactam using new reaction
reagents and conditions. The invention herein is further
directed to the enantioselective synthesis of ethyl 3-
t[ttl-t4-(aminoiminomethyl)phenyl]-2-oxo-3(s)-
pyrrolidinyl]amino]carbonyl]amino]propionate acetate and
related ~-alanine analogs. Such compounds are useful as
antithrombotic agents.
More specifically the invention herein is directed to
the conversion of a methionine analog such as
\~
Z~ ~
(Z = H, -CN, -CONH2 or -CO2Me)
to a lactam such as
~ ~NR
using reagent and reaction conditions which are beneficial
in comparison to previously disclosed methodology for
achieving such a conversion.
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Friedinger et al., J. Org. Chem ., 47, (104-109), 1982
disclose general methods for the synthesis of lactam-
constrained dipeptide analogs using three different paths
from protected chiral ~-amino acids to lactams. Included
within this disclosure is a method for cyclizing
methionine analogs to lactams via an alkylative
cyclization involving a two step procedure using highly
volatile and toxic methyl iodide and highly reactive
sodium hydride as reagents.
It would be desirable to provide a process for
conversion of a methionine analog to a lactam via
conditions which do not employ volatile, toxic or highly
reactive reagents and which produces a lactam having high
enantiomeric purity.
lS
SU~IARY OF THE INVENTION
The invention herein is directed to a process for
producing a lactam of the formula
r-~
Z 3~N~''NHR
wherein R is a protecting group such as t-butoxycarbonyl
(BOC) or carbobenzyloxy (CBZ) and Z is H, -CN, -CONH, or
CO2alkyl, from a methionine analog of the formula
S
H ~¦
z~ O
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by treating the methionine analog with trimethylsulfonium
halide or trimethylsulfoxonium halide in the presence of
an inorganic or aminergic base, such as alkali metal
hydroxides, alkoxides or carbonates or a tertiary amine,
diazabicycloundecane (DBU), or Hunig's base
[diisopropylethylamine (DIEA)], in a suitable aprotic
solvent.
The invention herein is further directed to the
preparation of amidinophenyl pyrrolidinyl ~-alanine urea
analogs using such methionine and lactam compounds as
intermediates, which ~-alanine urea analogs are useful as
antithrombotics.
DETAILED DESCRIPTION OF THE INVENTION
The invention herein is directed to a process for
producing a lactam of the formula
1~
Z ~ N ~ NHR
wherein R is a protecting group such as t-butoxycarbonyl
(BOC) or carbobenzyloxy (CBZ) and Z is H, -CN, -CONH2 or
CO2alkyl from a methionine analog of the formula
S
H ~
3 o ,~' --~NR
by treating the methionine analog with trimethylsulfonium
halide or trimethylsulfoxonium halide (such as
trimethylsulfonium iodide or trimethylsulfoxonium
CA 02207102 1997-06-0~
9S/14948
~VO g6/17827
chloride) in the presence of an inorganic or aminergic
base in a suitable aprotic solvent.
The invention herein is further directed to the
preparation of amidinophenyl pyrrolidinyl ~-alanine urea
analogs using such methionine and lactam compounds as
intermediates, which ~-alanine urea analogs are useful as
anti-thrombotics. Such process includes treating a
methionine analog of the formula
H r
Z~ O
(wherein Z is -CN or -CONH2) with trimethylsulfonium
halide or trimethylsulfoxonium halide in the presence of a
base, preferably potassium carbonate, in an aprotic
solvent, preferably DMS0, to afford a lactam of the
formula
r~
Z~ O
dehydrating when Z is -CONH2 and deprotecting the lactam,
reacting the resulting product with a ~-amino ester in the
presence of CDI to produce a urea of the formula
o
O ~ OR6
~N/~N~NlR
NC--~J O H H
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W O g6117827 PCTnUS9S/14g48
treating the urea with hydroxylamine to produce an
amidoxime, hydrogenating the amidoxime; and isolating a
compound of the formula
o
H2N~N~N~N~
wherein Rl is hydrogen, alkyl, aryl, arylalkyl, a
heterocyclyl radical containing 1 to 3 heteroatoms or a
heterocyclylalkyl and ~ is selected from alkyl, aryl,
arylalkyl or acyloxymethyl.
The general synthetic scheme is outlined in Scheme 1.
15 Starting from commercially available materials, a suitably
protected methionine (R = BOC, CBZ) is condensed with a
substituted or unsubstituted aniline in the presence of a
suitable amino acid coupling reagent (e.g. isobutyl
chloroformate, 2-chloro-1-methylpyridinium iodide, 1,1'-
carbonyldiimidazole (CDI) or 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride) and a tertiary amine base
(e.g. N-methylmorpholine, N-methylpiperazine or
triethylamine) in a suitable aprotic solvent (e.g.
dimethylformamide (DMF), tetrahydrofuran (THF) or CH~Cl2)
at a temperature ranging from -15~C to 25OC to give the
methionine analog 1.
Methionine analog 1 is cyclized to lactam 2 via a
novel set of reaction conditions. Treatment of compound 1
with trimethylsulfonium halide or trimethylsulfoxonium
halide in the presence of an inorganic or aminergic base
(e.g. alkali metal hydroxide, alkali metal alkoxides,
- alkali metal carbonates or tertiary amines such as DBU or
Hunig's base), preferably in the presence of potassium
carbonate in a suitable aprotic solvent (e.g. DMF,
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dimethylacetamide (DMA), DMSO or THF) at a temperature
ranging from 35~C to 90~C affords lactam 2. Historically,
this conversion was accomplished by an alkylative
cyclization in a two step procedure requiring highly
S volatile and toxic methyl iodide and highly reactive
sodium hydride respectively as the principle reagents
[c.f. Freidinger, R.M. et al., J. Orq. Chem., 47, 104-109
(1982); Kottirsch, G. et al., Bioorq. Med. Chem. Letters,
3, 167S-1680 (1993)]. Further, the extent of racemization
in the later process was dependant upon the workup
conditions. In the present invention, neither strong
alkylators nor strong bases are required and the product
is produced having high enantiomeric purity.
The lactam 2 can be dehydrated when Z is -CONH2 to
lS the nitrile 3 using standard reagents (e.g.
trifluoroacetic anhydride (TFAA), trichloroacetic
anhydride or thionyl chloride) in the presence of an amine
base (e.g. Et3N, pyridine, N-methylmorpholine or N,N-
diisopropylethylamine) in an aprotic solvent (e.g. THF,
EtOAc, pyridine or DME).
Aromatic analogs of methionine undergo cyclization as
illustrated in Table 1. For example, the nitrile compound
lb, prepared by dehydrating la (TFAA, Et3N), was cyclized
to lactam 10. Also, the carbomethoxyanilides ld and le
2S undergo cyclization without subsequent hydrolysis of the
ester function. This is important to note since ester
containing intermediates cyclized under the Freidinger
conditions undergo hydrolysis of the ester.
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TABLE 1
H ~
"NBOC Me3S X /K2Co3 ~N~""'NBOC
Me3SO X /K2CO3 Z O H
1 a-e
2 a-e
compound compound, ~neld
1 a, Z = 4-CONH2 2a, 75%
1 b, Z = 4-CN 1 O, 88%
1c, Z = 4-H 2c, 38%
1 d, Z = 3-CO2Me 2d, 53%
1 e, Z = 4-CO2Me 2e, 79%
-
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DeprotectiOn of the protecting group R with HCl or
trifluoroacetic acid (TFA) (R = BOC) or H2, Pd/C (R = CBZ)
affords aminolactam 4. For R = BOC, excess anhydrous HCl
or concentrated HCl (2.0 - 5.0 equivalents) in solvent
(e.g. EtOAc, MeO-t-Bu, 1,4-dioxane or THF) at 5 to 50~C
for 0.5 - 23 hours affords product as the hydrochloride
salt. Additionally the free base could be isolated as a
precipitate by adding 1 equivalent of base (e.g. lN NaOH)
to an aqueous solution of the hydrochloride salt.
Synthesis of the urea product 5 is accomplished by
sequential addition of an appropriate ~-amino ester and
aminolactam 4 to a suitable phosgene equivalent (e.g.
triphosgene, diphosgene, phosgene, 1,1'-
carbonyldiimidazole) in a suitable solvent (e.g. CH2Cl2,
CHC13, ClCH2CH2Cl, DMF, DMA, pyridine, dioxane, THF,
benzene, toluene). Reaction of 5 with hydroxylamine
hydrochloride in the presence of a suitable base (e.g.
Et3N, (i-Pr)2NEt, NaOAc, NaOEt, NaOH) in a suitable solvent
(e.g. MeOH, EtOH, H2O, DMF, DMA) provides the amidoxime
intermediate 6. This material is hydrogenolyzed in the
presence of a suitable catalyst (e.g. Pd/C, Pt/C, Pd(OH)2)
in a suitable solvent (e.g. MeOH, EtOH, i-PrOH or HOAc) in
the presence of an acid counterion (e.g. HOAc, HCl, HBr,
methanesulfonic acid (MsOH), succinic acid, citric acid,
H3PO4, malic acid) affording the target compound 7 as the
corresponding acid salt.
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SCHEME 1
~S ~S
~NH2 ~cou~irq ro~g~, H
/[W HO~R ~ BOC, CBZ ~ NR
Me3S X/K2C03 ~ ~N/~NHR whonZis-CONH~
Me3SO X /K2C03 Z
NC~N/~>~NR d~tprotect, { 3~ ~ H2N R~
O ~OEt H~OH HCI
pho~g~ ~ NC~ ~H H
0 5
~0
HO-NH~N~NJ~N~
6 HN~ ~NJ~NJ~
H2N O
HY
(x- is l . cr, Br')
Yis a p~,.,.~ ceF~ salt
Rt iS H, alk~4, alkenyl, alkynyl, ar~, or a
",onoc~lic heterocyclyl cu. ' ~ing 1 to 3 OINJS)
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-- 10 --
The preferred method of preparing a preferred
antithrombotic agent, namely, ethyl 3-[[[[1-[4-
(aminoiminomethyl)phenyl]-2-oxo-3(S)-
pyrrolidinyl]amino]carbonyl]amino]propionate acetate is
illustrated in Scheme 2 and Scheme 2a. Treatment of
commercially available N-BOC-L-methionine and 4-
aminobenzamide with 2-chloro-1-methylpyridinium iodide
(CMPI) and N-methylmorpholine (NMM) in DMF affords the
methionine amide lA.
In the novel cyclization step, heating a mixture of
lA, trimethylsulfonium iodide and powdered K2C03 (potassium
carbonate) in DMSO at 70~C gives the chiral lactam 2A.
Formation of the nitrile 10 is carried out by
dehydrating the primary amide with a standard reagent
(trifluoroacetic anhydride/Et3N) in THF. Removal of the
BOC protecting group with HCl/EtOAc affords the amine
hydrochloride 11. Sequential addition of ~-alanine ethyl
ester hydrochloride and compound 11 to 1,1'-
carbonyldiimidazole in DMF/pyridine (1:1) affords the
unsymmetrical urea 12.
Treatment of 12 with hydroxylamine
hydrochloride/triethylamine in ethanol gives the
benzamidoxime 13. Hydrogenolysis of 13 with 4% palladium
on carbon in acetic acid gives the target compound 14 as
the acetate salt.
In Scheme 2B another preferred method is illustrated,
wherein intermediate lA is dehydrated to intermediate 1B.
Subsequent cyclization of lB to 10 is accomplished as
described for the conversion of lA to 2A. Intermediate 1o
is then utilized further as demonstrated in Scheme 2 and
2a.
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-- 11 --
SCHEME 2
H N ~ N Boc O f W O H
Me3S r/1<2CO3 ~p ''N Boc
DMSO/70~C o~ H TFAAlEt3N
H2N
NCJC~N/~""'N E30C conc. HCUEtOAc ~3~ 0 HCI
11
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- 12 -
SCHEME 2 a
"NH2 CDUH2CH2CH2CO2Et HC
NCJ~ o HCI DMF/pyr (1:1 )
N/~ H2NOH HCUEt3N
~ "'N N EtOH/65 C
NC 12
/--\ ~ _~OEt 4%Pd/C, H2 60psi
HI~N~ ............................... 60 CIHOAC
Ho,N O
HN~,~ ? H H
H2N HOAc 14
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-- 13 --
SCHEME 2 b
H r
1A TFA~VEt3N, ~0~N~I'"'N BOC
Me3S I A<2C~3 . 10
DMSO/70~C
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As illustrated in Scheme 3, classical resolution of
commercially available ethyl 3-aminobutanoate with (R)-
mandelic acid affords enantiomerically pure mandelate salt
1s after three recrystallizations from EtOAc. Sequential
treatment of a suspension of 1,1'-carbonyldiimidazole with
11 then 15 affords the unsymmetrical urea 16. Treatment
of 16 with hydroxylamine hydrochloride/triethylamine gives
the benzamidoxime 17 which undergoes hydrogenolysis in
HOAc to give the target compound 18.
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SCHEME 3
~OEt (P)-mandelicacid ~C0
H2N EtOAc H3N--
~3~N~ H CDU15
~ NC 11 DMFlpyr(1:1)
NCJ3~N? J~ ~ H~NOH HCVEt3N .
o ~OEt 4% Pd/C. H260 psi
"NJ~NJ~ 60~C/HOAc
HO HN~N~."
H2N HOAc L8
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WO96/17827 PCT~S9S114948
- 16 -
The Arndt-Eistert homologation (Scheme 4) of N-BOC-D-
phenylglycine affords the chiral ~-amino ester 19.
Treatment of 19 with dry HCl affords the amine
hydrochloride 20. Elaboration of 20 as outlined in Scheme
2a affords the target compound 21.
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-- 17 --
SCHEME 4
.
1~l
,~02H 1) IBCF/NMM ~OEt
BOC-N ~ 2) CH2N2 BOC-N~
~ 3) Agbenzoate/EtOH H
19
HCI fJ~OE~
HCI/EtOAc I Scheme 2a
H2N~
N~0~N?"""
H2N HOAc
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- 18 -
The ~-amino acids and esters can be purchased or
prepared from commercially available starting materials
using known methods as illustrated in Scheme 5. The
racemic ~-heteroaryl ~-amino acids can be prepared from
the appropriate aryl aldehyde, malonic acid, and ammonium
acetate (Method 1) [Johnson and Livak, J. Am. Chem. Soc.,
Z29 (1936)]. The racemic ~-alkyl ~-amino acids can be
prepared from the corresponding alkene and chlorosulfonyl
isocyanate (CSI) which goes through the ~-lactam as shown
in Method 2 [W. A. Szabo, Aldrichimica Acta, 23 (1977); R.
Graf, Angew. Chem. Int. Ed., 172 (1968)]. The ~-lactam
can be opened to the ethyl ester by treatment with
anhydrous HCl in ethanol. An alternative method to form
racemic ~-amino esters is shown in Method 3. Nucleophiles
can be added to 4-benzoyloxy-2-azetidinone to afford a
variety of 3-substituted ~-amino esters after treatment
with anhydrous HCl in ethanol tK. Prasad et al., Vol. 19,
Heterocvcles, 2099 (1982)]. The racemic ~-amino acids and
esters can be resolved using classical methods described
in the literature [E. Fischer, H. Scheibler, R. Groh,
Ber., 2020 (1910); E. Fischer, H. Scheibler, Annalen, 337
(1911) ] .
Chiral ~-amino acids and esters can also be prepared
using many different approaches including the following
methods: 1) homologation of suitably protected ~-amino
acids using the Arndt-Eistert reaction as shown in Method
4 [Meier and Zeller, Anqew. Chem. Int. Ed., 32-43 (1975);
M. Rodriguez et al., Tetrahedron Lett., 5153 (1990); W. J.
Greenlee, J. Med. Chem. 434 (1985) and references
therein], 2) through the addition of an amine to ~
unsaturated esters bearing a chiral auxiliary as shown in
Method 5 [J. d'Angelo, J. Maddaluno, J. Am. Chem. Soc.,
8112-14, (1986)], 3) through an enantioselective
hydrogenation of a dehydroamino acid as shown in Method 6
[see: Asymmetric Synthesis, Vol 5, (J. D. Morrison, Ed.)
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WOg6117827 PCT~S9S114948
- 19 -
Academic Press, New York, 1985], and 4) through the
addition of enantiomerically pure amines to ~
unsaturated esters as shown in Method 7 [S. G. Davies, o.
Ich;hAra, Tetrahedron: AsYmmetr~, 183-186 (1991)].
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-- 20 --
SCHE~SE 5
Method 1
~CO2H
CH2(CO2H)2 + R1CHO ~ NH40Ac ~
(R1 is a~yl or heteroary~ H2N R1
Method 2 0 ~CO2Et
CISO2N=C=O + ~R~ ~,R1 H2N R~
Method 3
)R1 ~ ~ EHtCOH '
OCOPh R~ H2N R
(R1 is alkyl, aryl, heterocyclyl, alkenyl, alkynyl)
Method 4
CO2H 1) Fommmixed COCHN2 ~ CO2Et
anhydride ¦ A~
BOC-N~R1 2) CH2N2 H EtOH BOC-N~R~
~ Indicates Chiral Center Retention of
stereoche, l I,~t
(R~ is alkyl, aryl, heterocyclyl, arylalkyl, heteroaryblkyl)
Method 5
CO2-Xc CO2Et
1~ Ph2cHNH2 1 1 ) Hydrogenolysis
R~ Ph2CHN ~ R1 2) NaOH
Xc = 8-(p-phenoxyphenyl)-
menthyl CO2H
H2N~R
(R1 is alk~l, aryl, arylalkyl, heterocyclyl, heteroarylalkyl~
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WO g6/17827 rcrlusssll4s4s
SCHEME 5 f Cont ' d
Method 6
CO2Et ~CO2Et
Enantioselective .
R4COHN R~ HydrogenaUon R4CON R~
~ Indicates Chiral Center (R4 is alkyl or alkoxy)
(R~ is alkyl, aryl, arylalkyl)
Method 7 CO2Et
)~ + PhlN' ~ PhlN~R,
R1 PhJ
CO2H
1) Hydrogenolysis
2) NaOH H2N~R,
(R~ is alkyl, aryl, heterocyclyl, arylalkyl, heteroarylalkyl)
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- 22 -
As used herein the term "lower alkyl" refers to a
straight or branched chain hydrocarbon radical having from
1 to about 6 carbon atoms. Examples of such "lower alkyl"
radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, t-butyl, pentyl, neo-pentyl, hexyl,
isohexyl and the like.
As used herein the term "lower alkenyl" refers to
unsaturated acyclic hydrocarbon radicals containing at
least one double bond and 2 to about 6 carbon atoms.
Examples of such groups include, ethenyl, propenyl,
butenyl, isobutenyl, pentenyl, hexenyl and the like.
As used herein the term "lower alkynyl" refers to
unsaturated acyclic hydrocarbon radicals containing one or
more triple bonds and 2 to about 6 carbon atoms. Examples
of such groups are ethynyl, propynyl, butynyl, pentynyl,
hexynyl and the like.
The term aryl as used herein denotes carbocyclic
aromatic ring systems composed of one or more aromatic
rings. Preferred aryl groups are those consisting of one,
two or three benzene rings. The term embraces aromatic
radicals such as phenyl, naphthyl and biphenyl.
The term acyloxymethyl embraces groups of the formula
o
~ wherein R7 is alkyl or aryl as defined
R7~-~ocH
above.
As used herein the phrase "heterocyclyl radical
containing 1 to 3 heteroatoms" refers to monocyclic or
bicyclic radicals wherein 1 to 3 carbon atoms have been
replaced with a heteroatom selected from oxygen, nitrogen
or sulfur. Such rings can be saturated or unsaturated and
include heteroaromatics.
The following non-limiting examples describe and
illustrate methods for carrying out the process of the
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- -- 23 --
present invention, as well as other aspects of the present
invention, and the results achieved thereby in further
detail. Both an explanation of, and the actual procedures
for, the various aspects of the present invention are
described where appropriate. These examples are intended
to be merely illustrative of the present invention, and
not limiting thereof in either scope or spirit. Those of
skill in the art will readily understand that known
variations of the conditions and processes described in
these examples can be used to perform the process of the
present invention.
Unless otherwise indicated all starting materials and
equipment employed were commercially available.
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- 24 -
Exam~le 1
Preparation of N-~(4-aminocarbonYl)phenyll-4-methylthio-
2~S) -r r (1 .1-dimethYlethox~)carbonyllaminolbutanamide rlA).
H - ~ CH3
H2N~N~NJ~o~cH3
A. To a solution of L-BOC-methionine (100.0 g, 0.40
mol), 4-aminobenzamide (57.3 g, 0.42 mol) and CMPI (102.6
g, 0.40 mol) in 250 ml of DMF at 0~C, under nitrogen, was
added NMM (88 mL, 0.8 mol) over two minutes. The reaction
mixture was stirred and allowed to gradually warm to room
temperature while stirring for 4 hours. The reaction was
quenched by the addition of 0.1 N HCl (750 mL) over about
10 minutes. After stirring for about 30 minutes, the
white precipitate was filtered, washed with H2O and dried
affording 123.3 g (84%) of product [m.p. 193.5-195~C
(dec.)].
[~]D25 = -23.0~ (MeOH, c=10.85 mg/ml)
Anal. calc'd. for C~7H25N3O4S-0.33H20:
Calc'd.: C, 54.67; H, 6.93; N, 11.25; S, 8.59.
Found: C, 54.63; H, 7.02; N, 11.05; S, 8.63.
B. The following compounds were made in a like manner
substituting other anilines for 4-aminobenzamide:
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- 25 -
N-phenyl-4-methylthio-2(S)-[t(1,1-dimethylethoxy)-
carbonyl]amino]~utanamide (~c),
H-NMR (300 MHz, CD30D) ~ 1.44 (s, 9H), 1.90-2.05 (m, 2H),
2.08 (s, 3H), 2.S8 (m, 2H), 4.34 (m, lH), 7.08 (t, J = 8
Hz, lH), 7.29 (t, J = 8 Hz, 2H), 7.57 (d, J = 8 Hz, 2H).
N-[(3-methoxycarbonyl)phenyl]-4-methylthio-2(s)-[[(
dimethylethoxy)carbonyl]amino]butanamide (ld),
IH-NMR (300 MHz, CDCl3) ~ 1.43 (s, 9H), 2.00-2.25 (m, 2H),
2.08 (s, 3H), 2.63 (m, 2H), 3.82 (s, 3H), 4.65 (m, lH),
6.18 (d, J = 7 Hz, lH, exchangeable), 7.24 (t, J = 8 Hz,
lH), 7.71 (m, 2H), 8.19 (s, 2H), 9.58 (s, lH,
exchangeable).
N-[(4-methoxycarbonyl)phenyl]-4-methylthio-2(s)-[[(
dimethylethoxy)carbonyl]amino]butanamide (le),
H-NMR (300 MHz, CDCl3) ~ 1.42 (s, 9H), 2.00-2.25 (m, 2H),
2.10 (s, 3H), 2.64 (m, 2H), 3.90 (s, 3H), 4.62 (m, lH),
6.03 (d, J = 7 Hz, lH, exchangeable), 7.58 (d, J = 8 Hz,
2H), 7.88 (d, J = 8 Hz, 2H), 9.53 (s, lH, exchangeable).
C. Preparation of N-(4-cyanophenyl)-4-methylthio-2(S)-
[[(1,1-dimethylethoxy)carbonyl]amino]butanamide (lb),
To an ice cooled, stirred suspension of compound la
(10.00 g, 27.23 mmol) and triethylamine (16.5 g, 0.163
mol) in 40 mL of THF was added TFAA (7.88 g, 37.53 mmol)
at a rate to keep the internal temperature between 5-10~C.
The resulting solution was stirred at 0~C for 20 minutes
then quenched at 0~C by slowly adding 45 mL of 2N HCl.
After the subsequent addition of 40 mL of saturated NaCl,
the mixture was extracted with EtOAc, washed with
saturated NaHCO3, dried (MgSO4), treated with decolorizing
charcoal (ca. lg) and filtered through a bed of silica gel
using EtOAc as eluent. Removal of the solvent under
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- 26 -
reduced pressure produced a golden yellow oil which was
dried to 9.50 g of a gummy foam under high vacuum.
H-NMR (300 MHz, CDCl3) ~ 1.47 (s, 9H), 2.02 (m, 2H), 2.13
(s, 3H), 2.18 (m, lH), 2.63 (t, J = 7 Hz, 2H), 4.44 (m,
lH), 5.34 (broad, lH, exchangeable), 7.57 (d, J = 8 Hz,
2H), 7.63 (d, J = 8 Hz, 2H), 9.07 (s, lH, exchangeable).
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- 27 -
Example 2
Preparation of 1-~(4-aminocarbonYl)~henyll-3(S)- r r
dimethylethoxY)carbonyllaminolpyrrolidin-2-one (2~)
H2N~ ? " ~
A. To a solution of the product of example la (3.00 g,
8.16 mmol) in DMSO (6 mL) was added trimethylsulfonium
iodide (5.00 g, 24.48 mmol) and powdered K2CO3 (1.69 g,
12.24 mmol). The reaction mixture was stirred at 80~C
under nitrogen for 3 hours, cooled to room temperature and
diluted with H2O (30 mL). The white precipitate was
filtered, washed with H2O and dried affording 1.94 g (75%)
of product which was used directly in the preparation of
the compound of Example 3. An analytical sample was
prepared by recrystallizing the product from 1 part hot i-
PrOH and diluting with 3 parts H2O [m.p. 225-226~C (dec)].
[~]D25 - -14.1~ (MeOH, c=9.90 mg/mL)
Anal. calc'd. for C~6H2~N3O4-1 H20:
Calcd.: C, 56.96; H, 6.87; N, 12.46.
Found: C, 56.78; H, 6.56; N, 12.36.
B. The following compounds were made in a like manner
substituting other products of Example 1 (lb-le) for
Compound 1~:
N-(4-cyanophenyl)-3(S)-[t(1,1-dimethylethoxy)carbonyl]-
amino]pyrrolidin-2-one (3),
H-NMR (300 MHz, CDC13) ~ 1.47 (s, 9H), 2.08 (m, J = lH),
2.80 (m, lH), 3.82 (m, 2H), 4.38 (m, lH), 5.20 (broad s,
CA 02207102 1997-06-0~
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- 28 -
lH, exchangeable), 7.68 (d, J = 8 Hz, 2H), 7.82 (d, J = 8
Hz, 2H).
N-phenyl-3(S)-[[(l,l-dimethylethoxy)carbonyl]amino]-
pyrrolidin-2-one (2c),
H-NMR (300 MHz, CDCl3) ~ 1.43 (s, 9H), 2.00 (m, lH), 2.80
(m, lH), 3.81 (m, 2H), 4.36 (m, lH), 5.23 (broad, lH,
exchangeable), 7.18 (t, J = 8 Hz, lH), 7.39 (t, J = 8 Hz,
2H), 7.64 (d, J = 8 Hz, 2H).
N-[(3-methoxycarbonyl)phenyl]-3(S)-[[(l,l-
dimethylethoxy)carbonyl]amino]pyrrolidin-2-one (2d),
H-NMR (300 MHz, CDC13) ~ 1.47 (s, 9H), 2.04 (m, lH), 2.80
(m, lH), 3.85 (m, 2H), 3.93 (s, 3H), 4.38 (m, lH), 5.23
(broad, lH, exchangeable), 7.47 (t, J = 8 Hz, lH), 7.86
(m, lH), 8.10 (m, 2H).
N-[(4-methoxycarbonyl)phenyl]-3(S)-[[(l,l-
dimethylethoxy)carbonyl]amino]pyrrolidin-2-one (2e),
IH-NMR (300 MHz, CDCl3) ~ 1.48 (s, 9H), 2.04 (m, lH), 2.80
(m, lH), 3.83 (m, 2H), 3.92 (s, 3H), 4.38 (m, lH), 5.20
(broad, lH, exchangeable), 7.75 (d, J = 8 Hz, 2H), 8.06
(d, J = 8 Hz, 2H).
CA 02207102 1997-06-0~
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WO96/17827
- 29 -
Exam~le 3
PreDaration of 1-(4-cYano~henYl~-3(S)-[ r ~
dimethYlethoxy~carbonyllamino1p~rrolidin-2-one.
NC~ ? " $
To a suspension of the product of example 2a (2.0 g,
6.27 mmol) and triethylamine (5.23 mL, 37.6 mmol) in THF
(20 mL) at 0~C was added neat trifluoroacetic anhydride
(3.87 g, 18.8 mmol) dropwise over 5 minutes. The solution
was stirred at 0~C for an additional 1 hour, warmed to
room temperature then quenched by adding 20 mL of water.
The reaction mixture was partially concentrated to
approximately 1/2 the volume of THF whereupon the product
precipitated. The precipitate was filtered, washed with
water and dried affording 1.60 g (8S%) of product (m.p.
152-153.5~C).
[~]D25 = -11.4~ (MeOH, c=9.65 mg/mL)
Anal. calc'd. for Cl6HIgN3O-l H20:
Calc'd.: C, 60.17; H, 6.63; N, 13.16.
Found: C, 59.75; H, 6.30; N, 13.14.
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- 30 -
Exam~le 4
Pre~aration of 1-(4-cyano~henvl)-3(S)-aminoPYrrolidin-2-
one H~drochloride.
~
NC~N~..""NH HCI
HCl gas was bubbled through a solution of the product
of example 3 (62.0 g, 206 mmol) in EtOAc (750 mL) at
ambient temperature for 15 minutes. After an additional
30 minutes, the precipitated product was filtered, washed
with EtOAc and dried affording 46.7 g (96%) [m.p. 253-
254.5~C (dec.), >99.9% e. e.]. Enantiomeric purity was
determined by chiral HPLC analysis using a Crownpak CR(-)
column (15 cm x 4.0 mm) and isocratic elution with 1%
aqueous HCl04 at 1.2 mL/min. The detector was set at 254
nm.
[~]D25 = -20.8~ (MeOH, c = 10.63 mg/mL)
Anal. calc'd. for Cl~H~2N3OCl-l/4H20:
Calculated: C, 54.55; H, 5.20; N, 17.35.
Found: C, 54.51; H, 4.98; N, 17.40.
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- 31 -
Exam~le S
Pre~aration of Ethyl 3-~ r ~ ~l-r4-cyanOphenyl)-2-Oxo-3 rs)-
~rrolidinYllaminolcarbonYllamino1propionate.
s O
~ ~ t~ H
To a suspension of 1,1'-carbonyldiimidazole (572 mg,
3.55 mmol) in pyridine (2.5 mL) at 5~C under nitrogen was
added solid ethyl 3-amino-propionate hydrochloride (545
mg, 3.55 mmol). The resulting solution was stirred at 5~C
for 15 minutes, diluted with 2.5 mL of DMF and removed
from the ice bath. The product of example 4 (700 mg, 2.96
mmol) was added all at once and the reaction mixture was
stirred at 7S-80~C for 2 hours. After cooling to room
temperature, the resulting solution was diluted with 15 mL
of 1 N HCl. The white precipitate was filtered, washed
with H2O and dried. Trituration and filtration from
methyl t-butyl ether afforded 844 mg of product (m.p.
168.5-169~C). Extractive work up of the filtrate with
EtOAc afforded an additional 110 mg of product (94%
overall).
[~]D25 = +9.5~ (MeOH, c=9.45 mg/mL)
Anal. calc'd- for C~7H20N4O4:
Calculated: C, 59.29; H, 5.85; N, 16.27.
Found: C, 58.94; H, 5.71; N, 16.13.
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- 32 -
ExamPle 6
PreParation of EthYl 3-~ r rl-r4-(amino(hYdroxYimino~-
methYl)~henyll-2-oxo-3(S)-Pyrrolidinyllaminolcarbon
aminolProPionate.
o
HzN~ ~ 'NJ~Ng~
To a suspension of the product of example 5 ( 104 g
304 mmol) and hydroxylamine hydrochloride (42 g, 607 mmol)
in EtOH (900 mL) was added triethylamine (61 g, 607 mmol).
The reaction mixture was heated to 60-65~C and stirred for
2 hours. The reaction mixture was concentrated under
reduced pressure and diluted with H2O. The precipitate
was filtered, washed with H2O and dried affording 110 g
(96%) of product (m.p. 188-190~C).
~Cr]D25 = -2.8 (MeOH, c = 10. 53 mg/mL)
Anal. calc'd. for Cl6Hl9N3O: C, 54.10; H, 6.14; N, 18.56.
Found: C, 53.76; H, 6.14; N, 18. 52.
CA 02207102 1997-06-0~
3~ 4g48
WO g6/17827
- 33 -
Exam~le 7
Preparation of EthYl 3-~ r r rl-~4-(aminoiminOmethYl)~henyl~-
2-oxo-3(S)-pyrrolidinYllamino1carbonYllaminolpro~ionate
Acetate.
O
H2N~N~"""N~N
NH
To a suspension of the product of example 6 (250 g,
663 mmol) in HOAc (1 L) was added 100 g of 4% Pd/C (50%
wet). The mixture was hydrogenated at 60~C using 60 psi
H2 for 1.37 hours. The catalyst was filtered and the
solvent evaporated under reduced pressure. The syrupy
product was diluted sequentially while stirring with 500
mL MeOH, 1.5 L EtOH and 800 mL of CH3CN. The white solid
was filtered, washed with CH3CN and dried affording 219 g
of product. The mother liquor was concentrated and the
residue dissolved in H2O and treated with decolorizing
charcoal (5 g). After filtration and removal of the
solvent under reduced pressure, the residue was dissolved
in a minimal amount of HOAc and diluted sequentially with
150 mL of i-PrOH and 150 mL of CH3CN. The precipitate was
filtered, washed with i-PrOH/CH3CN (1:1) and dried
affording an additional 35 g of product (91% overall)
[m.p. 213-214~C (dec.)]. Enantiomeric purity was
determined by chiral HPLC using a Chiralcel-OD column and
EtOH/Heptane/TFA (20:80:0.1) as the mobile phase and was
determined to be >99.9% e. e
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[~]D25 = +13.2 (MeOH, c = 9.43 mg/mL)
Anal. calc'd. for C~9H2~N5O~: C, 54.15; H, 6.46; N, 16.62.
Found: C, 54.08~ H, 6.57; N, 16.57.
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WO g6/17827 1 ~ S/l4948
- 35 -
ExamPle 8
Preparation of Eth~l 3(R)-aminobutanoate (R)-mandelate.
OH
(~ H3N~
A solution of ethyl 3-aminobutyrate hydrochloride
(4.5 g, 26.8 mmol) in 27 mL of lN NaOH was extracted 2X
with EtOAc. The organic fraction was dried (Na2S04) and
concentrated under reduced pressure. Recrystallization of
the residue 3X from EtOAc afforded 1.93 g (51%) of product
as a single chiral diastereomer as determined by NMR
spectroscopy (m.p. 125-125~C). IH-NMR (300 MHz, CDCl3)
1.00 (d, J = 7Hz, 3H), 1.27 (t, J = 7Hz, 3H), 2.23-2.45
(m, 2H), 3.13 (m, lH), 4.13 (q, J = 7Hz, 2H), 4.85
(s, lH), 7.17-7.33 (m, 3H), 7.41 (d, J = 8Hz, 2H).
Anal. calc'd. for C~4H2lNO5: C, 59.35; H, 7.47; N, 4.94.
Found: C, 59.03, H, 7.51; N, 4.83.
CA 02207102 1997-06-0~
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Exam~le 9
Preparation of EthYl 3(R)-~ r ~ r 1- (4-cYanoPhenYl)-2-oxo-
3(S)-~YrrolidinYll-aminolcarbonYllaminolbutanoate.
~ ? NlN--
To a suspension of 1,1'-carbonyldiimidazole (178 mg,
1.1 mmol) in pyridine (2.5 mL) at 5~C under nitrogen was
added the product of example 4 (260 mg, 1.1 mmol). The
resulting solution was stirred at 5~C for 15 minutes,
diluted with 2.5 mL of DMF and removed from the ice bath.
The product of example 8 (375 mg, 1.32 mmol) was added all
at once and the reaction mixture stirred at 75-80~C for 2
hours. After cooling to room temperature, the resulting
solution was diluted EtOAc and washed with lN HCl,
saturated NaHCO3 and dried (MgSO4). Evaporation of the
solvent afforded 295 mg (73%) of product (m.p. 177.5-
179~C). IH-NMR (300 MHz, CDCl3) ~ 1.20-1.30 (m, 6H), 2.05
(m, lH), 2.53 (m, 2H), 2.83 (m, lH), 3.83 (m, 2H), 4.15
(q, J = 7Hz, 2H), 4.19 (m, lH), 4.48 (m, lH), 7.68 (d, J =
8Hz, 2H), 7.82 (d, J = 8Hz, 2H).
Anal. calc'd. for C~8H22N4O4-0.1 H20:
Calculated: C, 60.02; H, 6.21; N, 15.56.
Found: C, 60.29; H, 6.21; N, 15.06.
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W O g6/17827 ~ S114948
- 37 -
Exam~le 10
Pre~aration of Ethvl 3rR)-~ r 4-(aminorhydroxvimino)-
methyl)~henyl~-2-oxo-3rS)-pYrrolidinYllaminolcarbonyll-
aminolbutanoate.
o
Il
~ /~ "NlN
H2N~ O
,N
H0
The title compound was prepared from the product of
example 9 (250 mg, 0.63 mmol) in a manner similar to
example 6 affording 203 mg (83%) of product [m.p. 165-
167~C (dec.)]. IH-NMR (300 MHz, d6-DMSO) ~ 1.06 (d, J =
7Hz, 3H), 1.28 (t, J = 7Hz, 3H), 1.88 (m,- lH), 2.30-2.53
(m, 3H), 3.75 (m, 2H), 3.95 (m, lH), 4.05 (q, J = 7Hz,
2H), 4.40 (m, lH), 7.56 (s, 4H).
Anal. calc'd. for CI~H25N505-1/3H20:
Calculated: C, 54.40; H, 6.51; N, 17.64.
Found: C, 54.76; H, 6.71; N, 17.21.
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WO g6/17827 rcrlusssll4s4s
- 38 -
ExamPle 11
Pre~aration of EthYl 3 rR) - r r r r 1- r 4-(aminoiminomethYl~-
~henyl~-2-oxo-3rS)-pyrrolidinYl~amino1carbonvllamino~-
butanoate Acetate
o
H2N~N/~ ............ ,
NH
The title compound was prepared from the product of
example 10 (150 mg, 0.38 mmol) in a manner similar to
example 7 affording 131 mg (77~) of product [m.p. 208-
209~C (dec.)].
IH-NMR (300 MHz, d6-DMSO) ~ 1.08 (d, J = 7Hz, 3H), 1.19 (t,
J = 7Hz, 3H), 1.39 (s, 3H), 1.94 (m, lH), 2.30-2.53 (m,
3H), 3.80 (m, 2H), 3.95 (m, lH), 4.06 (q, J = 7Hz, 2H),
4.43 (m, lH), 7.86 (d, J = 8Hz, 2H), 7.91 (d, J = 8Hz,
2H).
Anal. calc'd. for C2oH29N506-3/4 H20:
Calculated: C, 53.50; H, 6.85; N, 15.60.
Found: C, 53.34; H, 6.46; N, 15.35.
CA 02207102 1997-06-0~
WOg6/17827 PCT~S9Stl4948
- 39 -
ExamPle 12
Pre~aration of EthYl ~(S)-r r (l.l-dimethYlethOxy)carbOnYl~-
~ aminolbenzene~roDanoate.
O
CH3 O ~ OEt
H C ~ O ~ N
To a stirred solution of N-BOC-D-phenylglycine
(5.02 g, 20 mmol), N-methylmorpholine (2.02 g, 20 mmol) in
EtOAc (100 mL) at 0~C was added isobutyl chloroformate
15 (2.73 g, 20 mmol). After 15 minutes the reaction mixture
was filtered to remove the amine salts then an ethereal
solution of diazomethane (60 mL, 30 mmol) was added. The
cooling bath was removed and the reaction mixture stirred
at ambient temperature for 2 hours. The reaction mixture
was purged with nitrogen for 15 minutes to remove the
excess diazomethane. The reaction mixture was diluted
with EtOAc, washed with lN HCl, saturated NaHCO3, and
dried (MgSO4). Evaporation of the solvent afforded the
crude diazoketone which was dissolved in EtOH (100 mL) and
then treated sequentially with AgO2CPh (1.6 g, 7 mmol) and
triethylamine (6.06 g, 60 mmol). After 20 hours the
reaction mixture was concentrated and chromatographed
(silica gel, 15% EtOAc/hexanes) affording 4.90 g (85%) of
product as a colorless oil. IH-NMR (300 MHz, CDCl3) ~ 1.17
30 (t, J = 7 Hz, 3H), 1.43 (s, 9H), 2.73-2.92 (m, 2H), 4.07
(q, J = 7 Hz, 2H), 5.10 (m, lH), 5.48 (m, lH), 7.22-7.39
(m, 5H).
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-- 40 --
Exam~le 13
Preparation of EthYl ~(S)-aminobenzene~ro~anoate
HYdrochloride .
O
~OEt
H2N~ ~ HCI
Dry HCl gas was bubbled through a solution of the
product of example 12 (3.0 g, 10.2 mmol) in EtOAc (50 mL)
at ambient temperature for 15 minutes. After stirring for
15 an additional 30 minutes, the solvent was removed under
reduced pressure affording 2.30 g (98%) of product as a
yellow oil. IH-N~ (300 MHz, d6-DMSO) ~ 1.03 (t, J = 7Hz,
3H), 3.02 (dd, J = 10Hz, J = 15Hz, lH), 3.25 (dd, J = 6Hz,
J = 15Hz, lH), 3.96 (m, 2H), 4.55 (m, lH), 7.3-7.6
(m, 5H), 8.93 (s, 3H).
CA 02207102 1997-06-05
PCT~S9S/149
WO96/17827
- 41 -
Exam~le 14
Preparation of Ethyl ~(s)-r r r rl-r4-cYanOphenyl)-2-oxo-
3 r S ~ -~Yrrol idinYllaminolcarbonYl~amino~benzeneproDanoate.
0
~N?"""N~N~
The title compound was prepared from the product of
example 13 (685 mg, 2.9 mmol) and the product of example 4
(600 mg, 2.9 mmol) in a manner similar to example 5
affording 1.09 g (91%) of product (m.p. 108-109~C).
H-NMR (300 MHz, CDCl3) ~ 1.16 (t, J = 7Hz, 3H), 2.00 (m,
lH), 2.77-2.93 (m, 3H), 3.81 (m, 2H), 4.05 (q, J = 7Hz,
2H), 4.50 (m, lH), 5.26 (m, lH), 7.20-7.35 (m, 5H), 7.66
(d, J = 8Hz, 2H), 7.80 (d, J = 8Hz, 2H).-
Anal. calc'd. for C23H24N4O4 1/3H2O:
Calculated: C, 64.79; H, 5.83; N, 13.14
Found: C, 64.65; H, 5.58; N, 13.18.
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- 42 -
ExamPle 15
PreParation of Ethyl ~(S)-~rl-r4-(amino(hydroxyimino~-
methYl)~henY11-2-oxo-3(S)-PYrrolidinyllamino]carbon
aminolbenzenePro~anoate.
o
H2N~ H H--
,N
HO
The title compound was prepared from the product of
example 14 (450 mg, 1.07 mmol) in a manner similar to
example 6 affording 431 mg (89%) of product [m.p. 192-
193~C (dec.)]. IH-NMR (300 MHz, d6-DMSO) ~ 1.10 (t, J =
7Hz, 3H), 1.87 (m, lH), 2.49 (m, lH), 2.77 (m, 2H), 3.74
(m, 2H), 4.00 (q, J = 7Hz, 2H), 4.41 (m, lH), 5.10 (m,
lH), 7.20-7.40 (m, 5H), 7.69 (s, 4H).
Anal. calc'd. for C23N2~N5O5-1/2H2O:
Calculated: C, 59.73; H, 6.10; N, 15.14
Found: C, 59.67; H, 6.38; N, 14.85.
CA 02207102 1997-06-05
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- 43 -
ExamPle 16
Preparation of EthYl ~(S)-r r r rl-~4-(aminoiminomethyl)-
phen~ll-2-oxo-3(S)-PYrrolidin~llaminolcarbonyllaminol-
benzenePropanoate Acetate.
H2N ~ ~ H H
NH
The title compound was prepared from the product of
example 15 (400 mg, 0.88 mmol) in a manner similar to
example 7 affording 335 mg (76%) of product [m.p. 210-
211~C (dec.)]. IH-NMR (d6-DMSO) ~ 1.14 (t, J = 7Hz, 3H),
1.93 (s, 3H), 2.03 (m, lH), 2.47 (m, lH), 2.80 (m, 2H),
3.84 (m, 2H), 4.04 (m, 2H), 4.50 (m, lH), 5.05 (t, J =
7Hz, lH), 7.23-7.44 (m, 5H), 7.92 (d, J = 8Hz, 2H), 7.97
(d, J = 8Hz, 2H).
Anal. calc'd. for C,5H3~NsO6-1/2H70:
Calculated: C, 59.28; H, 6.37; N, 13.83
Found: C, 58.96; H, 6.21; N, 13.92.
