Note: Descriptions are shown in the official language in which they were submitted.
=
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TITLE OF TH~ INVENTlON
PROCESS FOR T~E PREPARATION OF AN ENDOTHELrN
ANTAGONIST
S BACK~RC)UND OF THE INVENTION
Endothelin is a 21-amino acid peptide produced by
endothelial cells~ The peptide is secreted not only by endothelial cells
but also by tracheal epithelial cells or from kidney cells. Endothelin
(ET-l) has a potent vasoconstrictor effect. The vasoconstricting effect
1 0 is caused by the binding of endothelin to its receptor on the va,scular
smooth muscle cells . ~Nature, 332, 411 -415 (1988); FEBS Letters, 231,
440-444 (1988); Biochem. Biophys. Res. Commlln 154, 868-875
(1988).]
~ndothelin-l (ET-l) i,s one of three recently identified
1 5 potent vasoconstricting peptides which also includes endothelin-2 (ET-2)
and endothelin-3 (ET-3) whose sequence,s differ from ET-l by two and
six amino acids, respectively. [TiPS, 13, 103-108, March 1992.]
Increased levels of endothelin are found in the blood of
patients with essential hypertension, acute myocardial infarction,
2 0 pulmonary hyperten,sion, Raynaud's disease or atherosclerosis or in the
washing fluids of the respiratory tract of patients with asthma compared
to normal levels. [Japan J. Hyperten~sion 12, 79 (1989); J. Vascular
Medicine Biology, 2, 207 (1990); J. Am. Med. Association, 264, 2868
(1990); and The Lancet, ii, 207 (1990) and The Lancet, ii, 747-748
2 5 (1989).]
An experimental model of cerebral vaso,spa~sm and a second
model of acute renal failure have led to the conclusion that endothelin is
one of the mediators causing cerebral vasospa,sm following a
subarachnoid hemorrhage, and renal failure. [Japan. Soc. Cereb. Blood
,. 3 0 Flow & Metabol. 1, 73 (1989); and J. Clin. Invest., 83, 1762-1767 (1989).3
Endothelin wa,s also found to control the release of many
physiological substances such as renin, atrial natriuretic peptide,
endothe}ium-derived relaxing factor (EDRF), thromboxane A2,
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prostacyclin, norepinephrine, angiotensin II and substance P. [Biochem.
Biophys. Res. Comrn. 157, 1164- 1168 (1988); Biochem. Biophys. Res.
Cornm. 155, 167-172 (1989); Proc. Natl. Acad. Sci. USA, ~5, 9797-
9800 (1989~; J. Cardiovasc. Pharmacol., 13, 589-592 (19~9); Japan. J.
Hypertension 12, 76 (1989); and Neuroscience Letters, 102, 179- 1 ~4
(1989).] Further, endothelin causes contraction of the smooth muscle of
the gastrointestinal tract and the uterine smooth muscle. [FE13S Letters,
~LZ, 337-340 (1989); ~ur. J. Pharmacol. 154, 227-228 (1988);
Biochem. Biophys. Res. Commun., 159, 317-323 (19~9). ~ Endothelin
I 0 has also been shown to promote the growth of rat vascular smooth
muscle cells which would suggest a possible relevance to arterial
hypertrophy. ~Atherosclerosis, 7~, 225-228 (1989).]
Endothelin receptors are present in high concentration in
the peripheral tissues and also in the central nervous system, and
1 5 cerebral administration of endothelin has been shown to induce
behavioral changes in ~nim:~ls, suggesting that endothelin may play an
important role in controlling neural functions. [Neuroscience Letters,
97, 276-279 (1989).]
Endotoxin has been shown to promote the release of
2 0 endothelin. This finding has suggested that endothelin is an important
mediator for endotoxin-induced disease~s. [Biochem. Biophys. Res.
Cornmun. 161, 1220-1227 ~19~9); and Acta Physiol. Scand., 137, 317-
31~ (1989)-]
A study has ,shown that cyclosporin added to a renal cell
2 5 culture, increased endothelin secretion. [Eur. J. Pharmacol., 1~0, 191-
192 (1990).] Another study has shown that ~dministration of
cyclosporin to rat.s, led to a decrease in the glomerular filtration rate
and an increase in the blood pressure, in as.sociation with a remarkable
increase in the circulating endothelin level. This cyclosporin-induced
3 0 renal failure can be suppressed by the ~lministration of anti-endothelin "
antibody. [Kidney Int. 37, 14~7-1491 (1990).] These studies sugge,st
that endothelin is significantly involved in the pathogenesis of
cyclosporin-induced renal disease.
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A recent study in patients with congestive heart failure
demonstrated a good correlation between the elevated levels of
endothelin in the plasma and the severity of the disease. ~Mayo Clinic
Proc., 67, 719-724 (1992).]
Endothelin is an endogenous substance which directly or
indirectly (through the controlled release of various other endogenous
substances) induces sustained contraction of vascular or non-vascular
smooth muscles. Its excess production or excess secretion is believed to
be one of the factors responsible for hypertension, pulmonary
I 0 hyperten.sion, Raynaud's disease, bronchial asthma, acute renal failure,
myocardial infarction, angina pectoris, arteriosclerosis, cerebral
vasospasm and cerebral infarction. See A. M. Doherty, Endothelin: A
New Challen~e. J. Med. Chem., 35, 1493-1508 (1992).
Substances which specifically inhibit the binding of
1 5 endothelin to its receptor are believed to block the physiological effectsof endothelin and are useful in treating patients with endothelin related
disorders.
The present invention relates to a stereoselective synthesis
of the compound
KO2C
~0
o~,,~" N KSO2~<
O O
which is disclosed in PCT International Publication No. WO 94/21590
published on 29 September 1994 by Merck & Co., Inc. The route
described previously by Merck & Co., Inc. was a racemic route to this
endothelin antagonist. This approach required a classical resolution of a
2 5 late stage intermediate in order to obtain the desired enantiomer. This
was deemed ine~ficient for large scale synthesis of a potential drug
candidate.
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SUMMARY OF THE INVENTION
This inventions relates to the stereoselective synthesis of
KO2C ~
~; N KS02~<
useful for the large scale preparation of the stereoisomers of this
5 compound. The synthesis involves the use of a chiral auxiliary to
enhance the stereoselectivity of the alkylation step. The enantiomeric
may be enhanced by recrystallization of a diastereomeric purity of salt.
I~ETAILEV DESCRIPTION OF T~E INVENTION
I O This invention relates to a process for the stereoselective
synthesis of
KO2C ~
~ NKS02~<
useful for the large scale preparation of the stereoisomers of this
compound.
1 5 The instant invention relates to a process for the
preparation of a compound of the structural formula I:
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KO2C ~'
O
o~ NKSO2~<
wherein the * represents a chiral center;
5 comprising the ,steps of:
a) reacting the methyl 4-hydroxy-3-n-propylbenzoate with a
base in an aprotic solvent to give a salt of methyl 4-
hydroxy-3 -n-propylbenzoate
CO2Me
~'
O-M+
1 0 wherein M+ i,s Na+, K+, or Li+;
b) acylating 1,3-benzodioxole with ethyl oxalyl chloride in the
presence of a lewis acid and an organic solvent to give an
ester
o
<O~C02Et
0
c) hydrolyzing the ester with a base in a solvent to give an
acid
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<O ~CO2H
d) reacting the acid with a chlorinating agent in a solvent to
give an acid chloride
o
<O ~CI
e) reacting the acid chloride with a chiral auxiliary, RC, and
an organic base to give a substituted ketoester derivative
o
<O ~ RC
wherein RC is
~OR13, ~N l$o;
Ra Ra R1s CH
CH3
1 0 Ra is (Cl-C6)-alkyl, phenyl, or cyclohexyl;
Rl3 is (C1-C6)-alkyl, phenyl or cyclohexyl;
R14 and R15 are independently: (Cl-Clo)-alkyl, or R14
and Rl 5 can join together to form a 5- or 6-
membered heterocyclic ring selected from the group
1 5 consisting of: piperadinyl or pyrrolidinyl;
f) reducing the substituted ketoester derivative with a
reducing agent to give a hydroxyl derivative
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OH
O ~
g) halogenating the hydroxyl derivative with a halogenating
agent in an organic solvent to give a halo derivative
X
o--~ O
wherein: X is Br, Cl, or I;
h) alkylating the salt of methyl 4-hydroxy-3-n-propylbenzoate
with the halo derivative, in an organic solvent to give a
1 0 chiral auxiliary phenoxyphenylacetic acid derivative
MeO2C ~
~0
<o~O
i) hydrolyzing the chiral auxiliary from the phenoxyphenyl-acetic acid derivative with an inorganic base in an aqueous
organic solvent mixture to give a phenoxyphenylacetic acid
MeO2C~
,. ~0
1 5 <o _~OH
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j) reacting the phenoxyphenylacetic acid with a chlorinating
agent in a solvent to give an acid chloride
MeO2C ~
~0
<O~CI
k) reacting the acid chloride with a source of ammonia to give
an amide
MeO2C ~
~~ NH2
I) alkylating the amide with 4-isopropylbenzenesulfonyl
chloride in the presence of a base and a solvent to give a
sulfonamide
MeO2C ~
I () O ~NHSO2~<
m) hydrolyzing the sulfonamide with an inorganic base in a
solvent to give a salt of the acid
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PCT/US96/1 954~i
+M-02C~
o~ NHSO2~<
n) neutralizing the salt with mineral acid to give a diacid
HO2C ~
o ~NHSO2~<
o) reacting the diacid with two equivalent.s of a-methyl-
S benzylamine in an organic solvent to give a dia~tereomeric
salt
-02C~
~o Ph
<o~3~ N -S02 ~< ~ 2 H3N+l
p) breaking the salt with mineral acid to give an optically
enriched acid
HO2C ~\/
~0
<o ¢ ~, N HSO2~<
; and
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- ~0 -
q) reacting the optically enriched acid with a base in a ,solvent
or mixture of solvents to give a dipotassium salt, the
compound of formula I
KO2C ~\/
~0
o~NKSO2~<
SThe process as recited above, wherein the base in step a is
selected from the group consisting of sodium, potassium, or lithium
carbonate, sodium, potassium, or lithium t-butoxide, sodium, potassium,
or lithium t-amylate, sodium, potassium, or lithium hydroxide, or
sodium, potassium, or lithium hydride; and the aprotic solvent in step a
is selected from the group consisting of: tetrahydrofuran, toluene and
dimethylformamide .
The process as recited above, wherein the Lewis acid in the
acylating step b is selected from the group consisting of: AIC13, FeC13,
TiC14, and ~F3-etherate; and the organic solvent in the acylating step b
is selected from the group consisting of dichloromethane and
dichlorobenzenes.
The process as recited above, wherein the base in the
hydrolysis step c i.s selected from the group consisting of: NaOH, KOH,
NaOCH3, KOCH3, KOCH2CH3, NaOCH2CH3, KOt-butyl and NaOt-
2 0 butyl; and the solvent in the hydrolysi,s step c is selected from the group
consisting of: tetrahydrofuran, methanol, ethanol, t-butanol,
dimethylformamide and dimethylsulfoxide.
The proces~ ~:,s recited above, wherein the chlorinating
agent in step d i,s selected from the group con.sisting of: oxalyl chloride,
2 5 SO2C12, POC13, PC13 and PC15; and the solvent in step d is selected
from the group consisting of: tetrahydrofuran, toluene and
dimethylformamide .
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The process as recited above, wherein the chiral auxiliary
in step e is selected from the group consisting of:
O I O I O
O~OEt, ~N\~ ~ $o;
CH3
and the organic base in step e is selected from the group consisting of:
triethylamine, pyridine and diisopropylethylamine.
The process as recited above, wherein the reducing agent in
step f is selected from the group consisting of: NaBH4, NaCNBH3 and
Na(OAc)3BH; and the solvent in step f is ,selected from the group
consisting of: tetrahydrofuran-water, ethanol, methanol,
dimethylformamide and dimethylsulfoxide.
The process as recited above, wherein the halogenating
agent in the halogenation step g is selected from the group consisting of:
PBr3, CBr4-P(C6E~5)3, NBS-DMF, PC13, CC14-P(C6H5)3 and NCS-
DMF; and the organic solvent in the halogenating step is selected from
I S the group consi,sting of tetrahydrofuran, dichloromethane and toluene.
The process as recited above, wherein the organic solvent
in step h is selected from the group consisting of: tetrahydrofuran,
toluene and dimethylformamide.
The process as recited above, wherein the inorganic base in
2 () the chiral auxiliary hydroly,sis step i is selected from the group
consisting of: LiOH-H202, LiOH, KOH or NaOH; and the aqueous
organic solvent mixture in the chiral auxiliary hydrolysis step i is
selected from the group consisting of: tetrahydro~ran, toluene-~,vater,
dimethylformarnide, methanol, ethanol and t-butanol.
2 5 The process as recited above, wherein the chlorinating
agent in the acyl chloride formation step j is selected from the group
consisting of: oxalyl chloride, S02C12, POC13, PC13 and PCls; and the
solvent in step j is selected from the group consi,sting of:
tetrahydrofuran, toluene and dimethylformamide.
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The process a~s recited above, wherein the source of
ammonia in step k is selected from the group consisting of: NH3(g),
aqueous ammonium hydroxide, amrnonium chloride-Na2C~03 and
ammonium chloride-K2CO3.
The process as recited above, wherein the base in .step I is
selected from the group consisting of: NaOt-amyl, KOt-amyl, NaOt-
butyl, KOt-butyl, NaH, and KH; and the solvent in step I is selected
from the group consisting of tetrahydrofuran and toluene.
The process as recited above, wherein the inorganic base in
1 () step m is selected from the group consisting of: NaOH, KOH and LiOI~;
and the solvent in step m is ,selected from the group consisting of:
tetrahydrofuran-water.
The process as recited above, wherein the mineral acid in
the neutralization ,step n is selected from ~ICl, H2SO4 and HNO3.
The proces,s as recited above, wherein the organic solvent
in step o is selected ~rom the group consisting of ethyl acetate, isopropyl
acetate, methanol, ethanol and t-butanol.
The process as recited above, wherein the mineral acid in
the breaking ,step p is selected from the group consisting of: H~l,
2 () H2S04 and HNO3.
The process as recited above, wherein the base in step q is
selected from the group consisting of: KO~, KOCH3, KOCH2CH3 and
KOt-butyl; and the solvent in step q is selected from the group
consisting of: methanol, ethanol, t-butanol, water, and mixtures
2 5 therefrom.
The stereogenic center represented in the instant invention
using an asterik, is optically enriched in two steps in the instant
methodology: I) the alkylation step using a chiral auxiliary; and 2) a
diastereoselective recry,stallization. The examples are believed to have
3 0 the stereochemistry indicated. The chiral auxiliary and the amine .salt
used will dictate the isomer which will predomin~te in the alkylation
step and the diastereoisomer which will crystallize out.
A chiral auxiliary is defined as an easily removable group
chiral group which is attached at a position near the site of alkylation
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- 13 -
and is capable of influencing the direction of nucleophilic attack. Some
of the chiral auxiliaries useful in this method are:
~OR, ~N , $0
Ra Ra R15 CH3
CH3
wherein:
Ra is (C1-C6)-alkyl, phenyl, or cyclohexyl;
R13 is (C1-C~)-aLkyl, phenyl or cyclohexyl; and
R 14 and R ~ ~S are independently: (C 1 -C 1 o)-aLkyl, or R 14 and R I :S
can join together to form a 5- or 6-membered heterocyclic
ring selected from the group consisting of: piperadinyl or
1 0 pyrrolidinyl.
The preferred chiral auxiliary useful in this invention is
when RC is:
~ O
~N~
CH3
The alkyl substituents recited above denote straight and
1 5 branched chain hydrocarbons of the length specified such as methyl,
ethyl, isopropyl, isobutyl, neopentyl, isopentyl, etc.
The alkenyl-substituents denote alkyl groups as described
above which are modified so that each contains a carbon to carbon
double bond such as vinyl, allyl and 2-butenyl.
2 0 Cycloalkyl denotes rings composed of 3 to ~ methylene
groups, each of which may be substituted or unsubstituted with other
hydrocarbon substituents, and include for example cyclopropyl,
" cyclopentyl, cyclohexyl and 4-methylcyclohexyl.
The alkoxy substituent represents an alkyl group as
2 5 described above attached through an oxygen bridge.
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The heteroaryl is defined a.s carbazolyl, furyl, thienyl,
pyrrolyl7 isothiazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl,
pyrazolyl, pyrazinyl, pyridyl, pyrimidyl, purinyl or quinolinyl.
The synthesis begins with the allylation of readily available
methyl-4-hydroxybenzoate (Scheme I ). The allylated phenol is then
thermally rearranged in dichlorobenzene and subsequently
hydrogenated to provide the desired Methyl-4-hydroxy-3-n-
propylbenzoate in good overall yield.
l O
SCHE~ 1
CO2Me CO2Me
¢~ K2CO3, THF
OH .~O
CO2Me
1. DCB, 180~C
2. H2, PcVC, EtOAc
3. Na2CO3 ONa
Friedel-Crafts reaction of 1,3-benzodioxole with ethyl
oxalyl chloride provides the ketoester 3 in high yield. Without
1 5 isolation, this intermediate is hydrolyzed to the corresponding ketoacid
which can be isolated as a crystalline solid. This acid is then converted
via the acid chloride to the (S)-ethyl lactate ester 5 (Scheme 2).
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SC~DE~IE 2
O O
<~~3 Cl~--OEt r < ~ C02Et
O o H2ci2 o
90%
2 3
1. NaOH~ THF <O~CI ethyl(S)-(-) lact~te
2. (COC1)2, CH2C12 O TEA
85% 4
O O
< ~ ~
Sodium borohydride reduction of the keto-ester generates a
diastereomeric mixture of hydroxyesters 6 (Scheme 3). Ratios as high
5 as 65:35 have been observed. The crude mixture of alcohols is typically
converted to a mixture of ~he corresponding diastereomeric bromides
using phosphorous tribromide. The diastereomeric mixture of
bromides is not crystalline and is typically carried onto the following
step without any purification.
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SClDE~DE 3
O O Br O
o~,o~l~ 1 NaBH4 o~,o~J~OEt
MeO2C ~~
THF
CO2Me ~ ~
< ~ OEt
ONa 8
80%
The coupling reaction of the sodium salt of methyl-4-
hydroxy-3-n-propylbenzoate with the bromide 7 is conducted in THF at
5 -35~C. Under these conditions the reaction requires ~1 ~h to go to
completion and the product is obtained in 80% yield with a
dia,stereomeric ratio of approximately 90:10. Running the reaction at
higher temperatures accelerates the rate, however, the
diastereoselectivity is lower.
The crude coupling product was treated with lithium
hydroperoxide in order to hydrolyze the lactate auxiliary (Scheme 4).
Under these conditions, little or no racemization of the chiral center was
observed. Saponification using a .stronger base such as lithium hyroxide
leads to some racemization. Reaction of the crude acid with oxalyl
15 chloride followed by ammonium hydroxide generates the amide which
is isolated as a crystalline intermediate. Results indicate that the
enantiomeric purity of this compound can be upgraded by
recryst~lli7~tion. The material is typically isolated in ~5% yield with an
enatiomeric excess of 75-80%.
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SC~M~ ~
MeO2C ~ ~ MeO2C ~~
O O LiOH,H202 0
<~ ~r' ~OEt THF-H~O <O ~OH
8 9
MeO2c I-- r
. (COCl)2
2. NH40H <O~¢~NH2
7~% o O
8~:1 2
Sulfonylation of the arnide using sodium ~ert-arnylate and
4-i,sopropylbenzenesulfonyl chloride in I~F gene~ates the desired
product in good yield without racemi~ation (Scheme ~, ~r represents 4-
isopropylbenzene). Thi,s intermediate i~s not isolated but typically
treated with potassium hydro~ide in methanol to hydrolyze the ester.
The diacid is then treated with two equivalents of (R)-a--methylbenzyl-
amine to form the diamine salt. This diastereomeric salt precipitates
I () from EtOAc. One recrystallization gives material of greater than 99%
ee after salt breaking.
The diamine salt is treated with HCl to liberate the diacid.
Diacid 14 is crystallized from methanol and water to provide pure
(>99~%, >99% ee) material. Formation of the dipotassium ,salt of 14
1 5 to generate compound I is complicated by the fact that the product
forms a variety o~ different ~olvates and hydrates. Ultimately, it was
found that the MeOH solvate of Compound I cry~tallized micely and
could be converted to the desired dihydrate through exposure to an
atmosphere of moist air.
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SCHEME S
MeO2C ~ >~ SO2CI
o~,NH2 CH3CH2(CH3)2CONa, THF
MeO2C ~
b,!l~ 1. KOH, MeOH
O ~ NHSO2Ar 2. HCI
HO2C~ 1. H2N
~~ Ph
o ~ N H SO2Ar EtOAc
O O 2. HCI
12
85:1 5
HO2C ~ KO2C
~ IPA,MeOH
o~NHSO2Ar KOH ' <~ ~ ~NKSO2Ar
14
99 1Ar= 4-isopropylphenyl
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The instant invention can be understood further by the
following examples, which do not constitute a limitation of the
invention.
~XAMPLE 1
O O
~~3 Cl~ AICI ~ 0 ,~ CO2~t
To a slurry of alllminllm chloride (150 g, 1.13 mole) in
methylene chloride (800 ml) at -SS ~C was added ethyl oxalyl chloride
(100 ml, 0.89 moles) over S min. The reaction exothermed to -48 ~C
1 0 and was cooled back down to -SS ~C over lS min. 1,3-Benzodioxole
(100 g, 94 ml, 0.82 moles) was added over lS min while the reaction
temperature was m~int~ined between -45 ~C and-55 ~C using dry ice /
acetone. The red solution was aged for 20 min. The batch was
carefully ~uenched into 700 ml of ice water and the mixture agitated for
1 5 10 min. The layers were separated and the organic layer was washed
with water (500 ml). Concentration in vacuo provided the product as a
brown oil ~lg4 g) which was used in the next step without purification.
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EXAMPLE 2
Synthesis of Ketoacid
O O
<O~J~co2Et NaOH < ~CO2H
To a solution of ketoester 3 (182 g, 0.82 mole) in methanol
(~sOO ml) was added a mixture of SN sodium hydroxide (300 ml) and
water (300 ml) while maintaining the temperature below 35 ~C using an
1 0 ice bath. The batch was aged for 20 min. during which time a
precipitate formed. Methylene chloride (500 ml) was added and the
mixture was acidified to pH 3.0 using concentrated HCI. The layers
were separated and the organic phase was concentrated in vacuo to 100
ml. Toluene (300 ml) was added and concentration was continued to a
15 final volume of 300 ml. The resulting slurry was aged for lh and
filtered. The wet cake was washed with hexane and air dried to provide
120 g of ketoacid a.s a tan solid.
EXAMPLE 3
2()
Lactate Ester Formation
O O O
O~OH 1- oxalyl chloride o~O~l~OEt
<o ~ o 2. ethyl-~S)-lactate <O ~ o
2 5 To a slurry of ketoacid (~0 g, 0.41 moles) in methylene
chloride (~00 ml) at 20-25 ~C was added DMF (3 ml). Oxalyl chloride
(37 ml, 0.42 moles, d=1.45 g/ml) was added over 10 min.
-
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- 21 -
Within 20 min the reaction mixture turned to a clear
solution. NMR assay of a small sample indicated <5% ketoacid
rem~ining. The reaction mixture was then added via cannula over 15
min to a solution of ethyl-(S)-lactate (44 ml, 0.39 mole, d=1.042 g/ml),
and TEA (143 ml, d = 0.72 g/ml) in methylene chloride (600 ml) while
maintaining the temperature <30 ~C using an ice bath. The mixture was
aged for lh. The batch was quenched into water (500 ml) and the
layers separated. The organic layer was washed with water (500 ml)
and then with sat'd sodium bicarbonate (2x300 ml). Concentration in
1 () vacuo provided 100 g of product as an oil. The material is used in the
next step without purification.
EXAMPLE 4
1 5 Lactate ester Reduction
~ o OH O
<~~ O~l'OEt NaBH4 <O~O~ OEt
To a solution of lactate ester (100 g, 0.34 mole) in THF
(600 ml) at 10-15 ~C was added water (65 ml). Sodium borohydride (5
g, 0.14 mole) was added in 5 portions over 25 min.
2 0 The addition of the sodium borohydride was moderately
exothermic. The reaction temperature was m~int~ined < 25 ~C using an
ice bath.
The mixture was aged for 20 min and poured into brine
~300 ml) and ethyl acetate (600 ml). The layers were cut and the
2 5 aqueous was back extracted with ethyl acetate (300 ml). The combined
organic extract~s were washed with water (200 ml) and the layer.s were
separated. Concentration in vacuo yielded 100 g of product as an oil
which was used in the next step without purification.
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.
EXAMPL13 5
Preparation of Bromide
OH O Br O
o~~~JI~ pBr3 o~o~JI~OEt
To a solution of the hydroxyester (100 g, 0.34 mole) in
methylene chloride (500ml) at 10-15 ~C was addedphosphorous
tribromide (12.8 ml, 0.13 moles, d=2.~S5 g/ml) over 5 min.
The mixture was allowed to warm to 20 ~C and aged for
1.5 h. The batch was quenched into water ~250 ml) and fhe organic
layer was washed with aqueous sodium bicarbonate (250 ml).
Concentration of the organic layer in vacuo provided 111 g of bromide
as a dark oil which was used in the next step without purification.
I S EXAMPLE 6
Phenoxide Couplin~
Br o MeO2C ~
<~~ ~OEt ~ ~ OEt
ONa
2 0 To a solution of methyl 4- hydroxy-3-n-propylbenzoate
(23.7 g, 0.12 mole) in T~F (175 ml) at 5-10 ~C was added sodium t-
butoxide (11.7 g, 0.12 mole) in 3 portions over lS min while
m~in~ining the temperature <20 ~C using an ice bath.
The mixture was aged for 20 min and then added via a
2 5 cannula to a solution of the bromide (55.0 g, 0.15 mole) in THF (400
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ml) at -35 ~C. The reaction was aged at -35 ~C for 20 h. The mixture
was poured into a mixture of brine (200 ml), water (200 ml), and ethyl
acetate (400 ml). The layers were cut and the organic layer was
concentrated in vacuo to yield 69.0 g of product as an oil.
The product was isolated as a 9Q:10 mixture of
diastereomers, determined by HPLC.
HPLC assay: Column: Zorbax Rx-C8 4.6mm x 25cm; solvent:
CH3CN:H2O(0.1% H3PO4) 60:40; flow rate: 1 ml/min; wavelength:
220 nm; column temperature: 25 ~C; retention time: major isomer, 20.2
min.; minor isomer 1~.~ min.; and bromide, 7.g min.
l~XAMPLE 7
Lactate Ester Hydrolysis
1 5
MeO2C ~ MeO2C
~ LiOH, H2~2 ~/
o ~ ~O~I~o THF-H2~ o ~,lD,OH
Hydrogen peroxide (3.5 1, 133.8 mole) was added to a
solution of lithium hydroxide (709 g, 16.9 mole) in water (3.5 1) and
the mixture was aged i~or 20 min at 20-25 ~C. This solution was then
2 0 slowly added over 30 min to a cold (0-5 ~C) solution of lactate e,ster
(3.1 kg, 6.76 mole) in THF (2~S 1).
The reaction mixture was aged for 30 min, cooled to 0-5
~C and quenched with sat'd aqueous sodium bisulfite ~61).
Sat'd aqueous ammonium chloride (4 1) and methyl t-buthyl
2 5 ether (36 1) was added and after agitation the layers were separated.
The organic layer was dried over MgSO4 (1 kg) and then
concentrated in vacuo to yield 2.6 kg of crude product as a dark oil
which was used without futher purification.
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EXAMPLE
Preparation of Amide 10
-- MeO2C ~ MeO2C 1~
o~ ~OH 2)CNHH4cOl H/ O ~ NH2
To a solution of the acid 9 (725 g, l.9 mole) in methylene
chloride (91) at 20 ~C was added DMF (20 ml). Oxalyl chloride (203
ml, 2.38 mole, d=1.45 g/ml) was added over 20 min and the mixture
1 û was aged for 60 min. Gas evolution was evident during the addition and
continued throughout the reaction. The acid chloride solution was then
slowly transfered over 20 min into a cold (0-5 ~C) mixture of
amrnonium hydroxide (2.6 1), water (3 l) and methylene chloride (101).
The layers were separated and the organic phase was
concentrated in vacuo and the residual dichloromethane was displaced
with methanol. The final volume of methanol was 51. Water (S 1) was
added over 2 h at 20 ~C and the slurry was aged for 30 min.
Crystallization initiated after 2 1 of water had been added. The product
was isolated by filtration and the cake was washed with water ( l 1).
2 0 Drying under a nitrogen sweep yielded 606 g of an off-white solid.
HPLC assay of the product indicated an ~S8:12 mixture of diastereomers.
HPLC assay: Column: Zorbax Rx-C~ 4.6mrn x 25cm; solvent:
CH3CN:H2O(0. 1% H3PO4) 60:40; flow rate: l ml/min; wavelength:
2 S 220 nrn; column temperature: 25 ~C; retention time: product, 5.6 min.;
statring material, 6.9 min.
Chiral HPLC assay: Column: Regis (R,R) -Whelk -O 4.6 mm x 250
mm; solvent: hexane:isopropylalcohol (0.5% HOAc) 30:70; flow rate: 1
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ml/min; wavelength: 220 nm; column temperature: 25 ~C; retention
time: minor isomer, 6.74 min.; major isomer 19.~4 min.
EX~MPLE 9
Sulfonylation of Arnide
MeO2C ~ MeO2C ~0 H
<0~ ~ --ONa, THF < ~,~--b N-SO2Ar
To a solution of amide (578 g, 1.56 moles) and 4-
1 0 isopropylbenzenesulfonyl chloride (409 g, 1.9 moles) in THF (6 l) at 0-
5 ~C was added a solution of sodium t-amylate (37~s g, 3.43 moles) in
TH~ (3 l) over a 1 h period. The temperature was maintained at 0-5 ~C
by controlling the rate of addition and by using an external cooling
bath. The mixture was aged for 0.5 h and quenched with sat'd ac~ueou~
ammonium chlorlde (3 l) and water (3.51). Methylene chloride (181)
was added and the phases were separated. Concentration of the organic
phase in vacuo yielded the product as a dark oil which was used without
purification.
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EXAMPLE~ 10
Methyl ester Hydrolysis
MeO2C ~ ~ HO2C
O KOH O
o~N~SO2Ar MeOH <O~N-SO2Ar
To a solution of the methyl ester (~s62 g, 1.56 mole) in
methanol (51) was added 2N KOH (21). The mixture was heated to
reflux for 1.5 h. The mix'cure was cooled to 25 ~C and quenched into a
1 () mixture of lN HCI (91) and methylene chloride (101). The phases
were separated and the organic phases was concentrated in vacuo to
provide 615 g of product as a dark oil.
E~AMPLE 11
1 5
Diamine Salt Formation and Recrystalization
HO2C ~ RO2C ~,~
W~o H - ~O R
0 ~ N-SO2Ar EtOAc ~ <~ l~N-SO2Ar
O ~ 0 2. MeOH:H20 ~~
R= NH
To a solution of the acid (615 g, 1.14 moles) in ethyl
2 0 acetate (1 1 1) was added (R)-(2)-methylbenzylamine (350 ml, 2.71
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moles) in one portion. The solution was seeded wi~h 5 g of ~i~mine salt
and the mixture was aged for 16 h. The resulting slurry was filtered
and the cake was dried under a nitrogen sweep for 18 h to provide ~S00
g of the cli~mine salt as an off -white solid. HPLC assay of the material
on an (R,R)-WheLk-O column eluting with lPA / hexane 50:50 (0.5 %
HOAc) indicated 93% ee. The tlizlmin~ salt (~00 g) was dissolved in
methanol (7 1) and water (6 1) was added over 30 min. Methanol ( 1.5 1)
was removed by vacuum distillation at 20-30 ~C and water (5 1) was
added to the resulting slurry over 30 min. The slurry was aged for 30
1 0 min and filtered. The product was dried under a nitrogen sweep for 1
h to provide 430 g of product as a off- white solid. HPLC assay under
the same conditions indicated >99~Oee.
EXAMPLE 12
1 5
Dissociation of the Diamine Salt:
RO2C ~,/ HO2C ~
R 1. HCI, EtOAc O
< ~ 2. MeOH:H20 <O~~N-SO2Ar
R= NH3 --"
Ph
To a mixture of ethyl acetate (15 1) and lN HCI (101) was
added diamine salt (g37 g, 1.07 mole). The mixture was agitated for 20
min and the layers were settled. The organic layer was treated with
Darco KB (60 g) for 1 h and then filtered through Celite to remove the
carbon. The ethyl acetate solution was concentrated in vacuo to an oil
2 5 which was dissolved in methanol (6 l). Water (1.5 1) was added over 30
min. at 20 ~C and an additional 1.5 1 of water was then added (30 min)
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to the resulting slurry. After a 30 min age the batch was filtered and
the cake was washed with MeOH: Water (l l of 50:50). The product
was dried for 16 h under a nitrogen sweep to yield 495 g of product a,s
a white solid. HPLC assay indicated the material to be >99 A% pure.
5 Chiral HPLC assay indicated the material to be > 99% ee.
Chiral HPLC assay: Column: Regis (R,R) -Whelk -O 4.6 mm x 250
mm; solvent: hexane:isopropylalcohol (0.5% HOAc) 50:50; flow rate: I
ml/min; wavelength: 220 nm; column temperature: 25 ~C; retention
time: minor isomer, 7.9 min.; major isomer 10.5 min.
1 0
EXAMPLE~ 13
Synthesis of Compound I
~'H KO2C ~O /K
0~,~, N--SO2Ar o ~3~SN 2
A suspension of diacid (45 I .5 g, 0.84 mole) in IPA (6.3 1)
and MeOH (903 ml) was heated to 45 ~C to form a clear solution. To
thi,s solution was added a KOH solution (l.9 l of a 0.97M ~olution in
IPA) over lS min while the temperature was maintained 45-50 ~C. The
clear solution was slowly cooled over 1 h to 20 ~C. Cryst:~11i7~tion
spontaneously initiates at ~4~ ~C. The batch was aged at 20 ~C for 2 h
and filtered. The cake wa,s washed with IPA (l.0 l) and dried under a
nitrogen sweep for ~ h. NMR and TGA indicated the presence of
~5.6% MeOH. The methanol was removed and the cake hydrated by
2 5 sweeping moi,st air through the batch for l.5 h. to provide 490 g of
compound I a.s a white solid.NMR and TGA at this point indicated no
MeOH. TGA and KF indicated ~5.7 % water.
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Chiral HPLC assay: Column: Regis (R,R) -Whelk -O 4.6 mrn x 250
mm; solvent: hexane:isopropylalcohol (0.5% HOAc) 50:50; flow rate: 1
ml/min; wavelength: 220 nm; column temperature: 25 ~C; retention
time: minor isomer, 7.9 min.; major isomer 10.5 min.
s
