U.S. patent application number 10/580148 was filed with the patent office on 2007-04-12 for process for synthesis of perindopril and pharmaceutically acceptable salts thereof..
Invention is credited to Thierry DuBuffet, Pascal Langlois.
Application Number | 20070083052 10/580148 |
Document ID | / |
Family ID | 32116380 |
Filed Date | 2007-04-12 |
United States Patent
Application |
20070083052 |
Kind Code |
A1 |
DuBuffet; Thierry ; et
al. |
April 12, 2007 |
PROCESS FOR SYNTHESIS OF PERINDOPRIL AND PHARMACEUTICALLY
ACCEPTABLE SALTS THEREOF.
Abstract
Process for the synthesis of perindopril of formula (I):
##STR1## and pharmaceutically acceptable salts thereof.
Inventors: |
DuBuffet; Thierry;
(Autretot, FR) ; Langlois; Pascal; (Saint Jean De
La Neuville, FR) |
Correspondence
Address: |
THE FIRM OF HUESCHEN AND SAGE
SEVENTH FLOOR, KALAMAZOO BUILDING
107 WEST MICHIGAN AVENUE
KALAMAZOO
MI
49007
US
|
Family ID: |
32116380 |
Appl. No.: |
10/580148 |
Filed: |
November 18, 2004 |
PCT Filed: |
November 18, 2004 |
PCT NO: |
PCT/FR04/02936 |
371 Date: |
May 18, 2006 |
Current U.S.
Class: |
548/492 |
Current CPC
Class: |
C07C 309/73 20130101;
C07C 233/47 20130101; A61P 9/04 20180101; Y02P 20/55 20151101; C07K
5/06026 20130101; A61P 43/00 20180101; A61P 9/12 20180101 |
Class at
Publication: |
548/492 |
International
Class: |
C07D 209/42 20060101
C07D209/42 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 19, 2003 |
EP |
03292864.0 |
Claims
1-12. (canceled)
13. A process for the synthesis of a compound of formula (I):
##STR9## and pharmaceutically acceptable salts thereof, wherein a
compound of formula (II), of configuration (S): ##STR10## wherein R
represents a hydrogen atom or a protecting group, is reacted with a
compound of formula (III), of configuration (R): ##STR11## wherein
G represents chlorine, bromine, hydroxy, p-toluenesulphonyloxy,
methanesulphonyloxy or trifluoromethanesulphonyloxy, in the
presence of a base to yield a compound of formula (IV): ##STR12##
which is subjected to an intramolecular coupling reaction to yield
a compound of formula (V): ##STR13## which is reacted with a
compound of formula (VI): ##STR14## to yield a compound of formula
(VII): ##STR15## which is subjected to a catalytic hydrogenation
reaction to yield, after deprotection where appropriate, the
compound of formula (I).
14. The process of claim 13, wherein R represents a benzyl or
linear or branched (C.sub.1-C.sub.6)alkyl group.
15. The process of claim 13, wherein the intramolecular coupling
reaction is carried out either in the presence of a base and a
catalyst based on palladium or using sodium hydride and copper(I)
iodide or copper(I) bromide.
16. The process of claim 15, wherein the intramolecular coupling
reaction is carried out in the presence of a base and a catalyst
based on palladium and an arylphosphine or bisphosphine.
17. The process of claim 16, wherein the base used for the
intramolecular coupling reaction is selected from Cs.sub.2CO.sub.3,
NaOtBu, Na.sub.2CO.sub.3, NaOAc and KOAc.
18. The process of claim 16, wherein the catalyst based on
palladium and an arylphosphine or bisphosphine is selected from
Pd(0)/PPh.sub.3, Pd(0)/P(o-tolyl).sub.3, Pd(0)/P(1-naphthyl).sub.3,
Pd(0)/P(o-methoxyphenyl).sub.3, Pd.sub.2(dba).sub.3/PPh.sub.3,
Pd.sub.2(dba).sub.3/P(o-tolyl).sub.3,
Pd.sub.2(dba).sub.3/P(1-naphthyl).sub.3,
Pd.sub.2(dba).sub.3/P(o-methoxyphenyl).sub.3,
Pd.sub.2(dba).sub.3/P(2-furyl).sub.3, Pd.sub.2(dba).sub.3/dppp,
Pd.sub.2(dba).sub.3/(.+-.)-BINAP and
(DPPF)PdCl.sub.2.CH.sub.2Cl.sub.2/DPPF, it being understood that:
BINAP means 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, dba means
dibenzylideneacetone, DPPF means
1,1'-bis(diphenylphosphino)ferrocene and dppp means
1,3-bis(diphenylphosphino)propane.
19. The process of claim 13, wherein G represents chlorine,
bromine, p-toluenesulphonyloxy, methanesulphonyloxy or
trifluoromethanesulphonyloxy.
20. The process of claim 19, wherein the reaction between the
compounds of formulae (V) and (VI) is carried out in the presence
of an organic amine selected from triethylamine, pyridine and
diisopropylethylamine or a mineral base selected from
Na.sub.2CO.sub.3, K.sub.2CO.sub.3, NaHCO.sub.3 and KHCO.sub.3.
21. The process of claim 13, wherein G represents hydroxy.
22. The process of claim 21, wherein the reaction between the
compounds of formulae (V) and (VI) is carried out in the presence
of N-methyl-N-phenyl-aminotriphenylphosphonium iodide or, when R is
other than a hydrogen atom, under Mitsunobu reaction
conditions.
23. A compound of formula (IV): ##STR16## wherein R represents a
hydrogen atom or a protecting group, and G represents chlorine,
bromine, hydroxy, p-toluenesulphonyloxy, methanesulphonyloxy or
trifluoromethanesulphonyloxy.
24. A process according to claim 13 for the synthesis of
perindopril in the form of its tert-butylamine salt.
Description
[0001] The present invention relates to a process for the synthesis
of perindopril of formula (I): ##STR2## and pharmaceutically
acceptable salts thereof.
[0002] Perindopril and its pharmaceutically acceptable salts, and
more especially its tert-butylamine salt, have valuable
pharmacological properties.
[0003] Their principal property is that of inhibiting angiotensin I
converting enzyme (or kininase II), which allows, on the one hand,
prevention of the conversion of the decapeptide angiotensin I to
the octapeptide angiotensin II (a vasoconstrictor) and, on the
other hand, prevention of the degradation of bradykinin (a
vasodilator) to an inactive peptide.
[0004] Those two actions contribute to the beneficial effects of
perindopril in cardiovascular diseases, more especially in arterial
hypertension and heart failure.
[0005] Perindopril, its preparation and its use in therapeutics
have been described in European patent specification EP 0 049
658.
[0006] In view of the pharmaceutical value of this compound, it has
been important to be able to obtain it by an effective synthesis
process, readily transposable to an industrial scale, that leads to
perindopril in a good yield and with excellent purity starting from
reasonably priced starting materials.
[0007] Patent specification EP 0 308 341 describes the industrial
synthesis of perindopril by the coupling of
(2S,3aS,7aS)-octahydroindole-2-carboxylic acid benzyl ester with
N--[(S)-1-carboxybutyl]-(S)-alanine ethyl ester, followed by
deprotection of the carboxylic group of the heterocycle by
catalytic hydrogenation.
[0008] The Applicant has now developed a new process for the
synthesis of perindopril that uses readily obtainable starting
materials.
[0009] More specifically, the present invention relates to a
process for the synthesis of perindopril and pharmaceutically
acceptable salts thereof, which process is characterised in that
the compound of formula (II), of configuration (S): ##STR3##
wherein R represents a hydrogen atom or a protecting group for the
acid function, is reacted with a compound of formula (III), of
configuration (R): ##STR4## wherein G represents a chlorine or
bromine atom or a hydroxy, p-toluenesulphonyloxy,
methanesulphonyloxy or trifluoromethanesulphonyloxy group, in the
presence of a base to yield the compound of formula (IV): ##STR5##
wherein R and G are as defined hereinbefore, which is subjected to
an intramolecular coupling reaction to yield the compound of
formula (V): ##STR6## wherein R and G are as defined hereinbefore,
which is reacted with the compound of formula (VI): ##STR7## to
yield the compound of formula (VII): ##STR8## wherein R is as
defined hereinbefore, which is subjected to a catalytic
hydrogenation reaction to yield, after deprotection where
appropriate, the compound of formula (I).
[0010] Among the protecting groups for the acid function there may
be mentioned, without implying any limitation, the groups benzyl
and linear or branched (C.sub.1-C.sub.6)alkyl.
[0011] Among the bases that can be used for the reaction between
the compounds of formula (II) and (III) there may be mentioned,
without implying any limitation, organic amines, such as
triethylamine, pyridine or diisopropylethylamine, and mineral
bases, such as NaOH, KOH, Na.sub.2CO.sub.3, K.sub.2CO.sub.3,
NaHCO.sub.3 or KHCO.sub.3.
[0012] The intramolecular coupling reaction is preferably carried
out either in the presence of a base and a catalyst based on
palladium or using sodium hydride and copper(I) iodide or copper(I)
bromide.
[0013] The catalysts based on palladium which are preferably used
in the coupling reaction are catalysts based on palladium and on an
arylphosphine or bisphosphine.
[0014] Among those catalysts there may be mentioned, without
implying any limitation, Pd(0)/PPh.sub.3, Pd(0)/P(o-tolyl).sub.3,
Pd(0)/P(1-naphthyl).sub.3, Pd(0)/P(o-methoxyphenyl).sub.3,
Pd.sub.2(dba).sub.3/PPh.sub.3,
Pd.sub.2(dba).sub.3/P(o-tolyl).sub.3,
Pd.sub.2(dba).sub.3/P(1-naphthyl).sub.3,
Pd.sub.2(dba).sub.3/P(o-methoxyphenyl).sub.3,
Pd.sub.2(dba).sub.3/P(2-furyl).sub.3, Pd.sub.2(dba).sub.3/dppp,
Pd.sub.2(dba).sub.3/(.+-.)-BINAP and
(DPPF)PdCl.sub.2.CH.sub.2Cl.sub.2/DPPF,
BINAP being understood to be
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl,
dba being understood to be dibenzylideneacetone,
DPPF being understood to be
1,1'-bis(diphenylphosphino)ferrocene
and dppp being understood to be
1,3-bis(diphenylphosphino)propane.
[0015] Among the bases that can be used for the coupling reaction
in the presence of a catalyst based on palladium there may be
mentioned, without implying any limitation, Cs.sub.2CO.sub.3,
NaOtBu, Na.sub.2CO.sub.3, NaOAc and KOAc.
[0016] When G represents a chlorine or bromine atom or a
p-toluenesulphonyloxy, methanesulphonyloxy or
trifluoromethanesulphonyloxy group, the reaction between the
compounds of formulae (V) and (VI) is preferably carried out in the
presence of a base, preferably an organic amine, such as
triethylamine, pyridine or diisopropylethylamine, or a mineral
base, such as Na.sub.2CO.sub.3, K.sub.2CO.sub.3, NaHCO.sub.3 or
KHCO.sub.3.
[0017] When G represents a hydroxy group, the reaction between the
compounds of formulae (V) and (VI) is preferably carried out in the
presence of an activation reagent, such as
N-methyl-N-phenyl-aminotriphenylphosphonium iodide, or, when R is
other than a hydrogen atom, by a Mitsunobu reaction.
[0018] The compounds of formula (IV) are new products which are
useful as synthesis intermediates in the chemical or pharmaceutical
industry, especially in the synthesis of perindopril, and as such
form an integral part of the present invention.
[0019] The compounds of formula (II) can be prepared according to
the procedure described in the publication J. Am. Chem. Soc. 1994,
116, 10847-10848.
EXAMPLE 1
(2S,3aS,7aS)-1-{(2S)-2-[(1S)-1-(Ethoxycarbonyl)-butylamino]-propionyl}-oct-
ahydro-1H-indole-2-carboxylic acid tert-butylamine salt
Step A: Benzyl
(2S)-3-(2-bromophenyl)-2-{[(2R)-2-bromopropanoyl]amino}-propanoate
[0020] Introduce 25.7 g of benzyl (S)-2-bromophenylalaninate and
150 ml of dichloromethane into a reactor, then bring the
temperature of the reaction mixture to 0.degree. C. and add 20 ml
of diisopropylethylamine followed by 13.2 g of
(2R)-2-bromopropionyl chloride. Subsequently, bring the mixture to
ambient temperature. After stirring for 1 hour at that temperature,
wash the mixture with water and then with dilute acetic acid
solution, and evaporate off the solvents to yield the title
compound.
Step B Benzyl
(2S)-1-[(2R)-2-bromopropanoyl]-2-indolinecarboxylate
[0021] Introduce 15.5 g of the compound obtained in the Step above,
dissolved in toluene, 1.57 g of Pd.sub.2(dba).sub.3, 1.83 g of
P(o-tolyl).sub.3 and 21.5 g of Cs.sub.2CO.sub.3 into a reactor.
Then bring the reaction mixture to 100.degree. C. After stirring
for 15 hours at that temperature, the mixture is brought back to
ambient temperature and purified by chromatography over silica to
yield the title compound.
Step C: Benzyl
(2S)-1-((2S)-2-{[(1S)-1-(ethoxycarbonyl)butyl]amino}-propanoyl)-2-indolin-
ecarboxylate
[0022] Introduce 12.3 g of ethyl (2S)-2-aminopentanoate, 16 ml of
triethylamine and 16 ml of acetonitrile into a reactor; then bring
the mixture to 60.degree. C., slowly add a solution of 19.4 g of
the compound obtained in the Step above, dissolved in
dichloromethane, and reflux for 4 hours. After returning to ambient
temperature, wash the mixture with water and with dilute acetic
acid solution; then evaporate off the solvents to yield the title
compound.
Step D:
(2S,3aS,7aS)-1-{(2S)-2-[(1S)-1-(Ethoxycarbonyl)-butylamino]-prop-
ionyl}-octahydro-1H-indole-2-carboxylic acid
[0023] Introduce 20 g of the compound obtained in the Step above,
dissolved in acetic acid, and then 0.5 g of 10% Pd/C into a
hydrogenator. Hydrogenate under a pressure of 0.5 bar between 15
and 30.degree. C., until the theoretical amount of hydrogen has
been absorbed.
[0024] Remove the catalyst by filtration and then cool to between 0
and 5.degree. C. and collect the resulting solid by filtration.
Wash the cake and dry it to constant weight to yield the title
compound with an enantiomeric purity of 99%.
Step E:
(2S,3aS,7aS)-1-{(2S)-2-[(1S)-1-(Ethoxycarbonyl)-butylamino]-prop-
ionyl}-octahydro-1H-indole-2-carboxylic acid tert-butylamine
salt
[0025] The precipitate obtained in the Step above (20 g) is
dissolved in 280 ml of ethyl acetate, and then 4 g of
tert-butylamine and 40 ml of ethyl acetate are added.
[0026] The resulting suspension is then refluxed until dissolution
is complete; then the resulting solution is filtered whilst hot and
cooled to a temperature of 15-20.degree. C., with stirring.
[0027] The precipitate obtained is then filtered off, made into a
paste again using ethyl acetate, dried and then ground to yield the
expected product in a yield of 95%.
EXAMPLE 2
(2S,3aS,7aS)-1-{(2S)-2-[(1S)-1-(Ethoxycarbonyl)-butylamino]-propionyl}-oct-
ahydro-1H-indole-2-carboxylic acid tert-butylamine salt
Step A:
(2S)-3-(2-Bromophenyl)-2-{[(2R)-2-bromopropanoyl]amino}-propanoi- c
acid
[0028] Introduce 28.8 g of (S)-2-bromophenylalanine, 7.5 ml of
water and 15 ml of toluene into a reactor; then bring the mixture
to between 0 and 5.degree. C. and add 25 ml of 5M sodium hydroxide
solution and then a solution of 20.2 g of (2R)-2-bromopropionyl
chloride in toluene, whilst keeping the temperature below
10.degree. C. and maintaining the pH of the mixture at 10 by adding
5M sodium hydroxide solution. After stirring for a further 1 hour
at 10.degree. C., add concentrated hydrochloric acid to bring the
pH of the mixture to 6.
[0029] Separate off the toluene phase and then add concentrated
hydrochloric acid to the aqueous phase to bring the pH to 2.
[0030] The precipitate formed is then filtered off and dried to
yield the title compound.
Step B: Identical to Step B of Example 1
Step C:
(2S)-1-((2S)-2-{[(1S)-1-(Ethoxycarbonyl)-butyl]-amino}-propanoyl-
)-2-indolinecarboxylic acid
[0031] Introduce 10.5 g of ethyl (2S)-2-aminopentanoate, 13.5 ml of
triethylamine and 13.5 ml of acetonitrile into a reactor; then
bring the mixture to 60.degree. C. and slowly add a solution of
19.3 g of the compound obtained in the Step above in 130 ml of
dichloromethane, and then reflux for 4 hours. After returning to
ambient temperature, wash the mixture with water and with dilute
acetic acid solution; then evaporate off the solvents to yield the
title compound.
Steps D and E: Identical to Steps D and E of Example 1
EXAMPLE 3
(2S,3aS,7aS)-1-{(2S)-2-[(1S)-1-(Ethoxycarbonyl)-butylamino]-propionyl}-oct-
ahydro-1H-indole-2-carboxylic acid tert-butylamine salt
Step A: Benzyl
(2S)-3-(2-bromophenyl)-2-{[(2R)-2-(p-toluenesulphonyloxy)-propanoyl]-amin-
o}-propanoate
[0032] Introduce 25.7 g of benzyl (R)-2-bromophenylalaninate and
150 ml of dichloromethane into a reactor; then bring the
temperature of the reaction mixture to 0.degree. C. and add 20 ml
of diisopropylethylamine and then 20.2 g of
(1R)-2-chloro-1-methyl-2-oxoethyl-p-toluenesulphonate chloride.
Then bring the mixture to ambient temperature. After stirring for 1
hour at that temperature, wash the mixture with water. The solvents
are then evaporated off to yield the title compound.
Steps B to E: Identical to Steps B to E of Example 1
* * * * *