U.S. patent application number 10/570566 was filed with the patent office on 2007-02-22 for novel metod for the synthesis of perindopril and the pharmaceutically-acceptable salts thereof.
Invention is credited to Thierry Dubuffet, Jean-Pierre Lecouve.
Application Number | 20070043103 10/570566 |
Document ID | / |
Family ID | 29724623 |
Filed Date | 2007-02-22 |
United States Patent
Application |
20070043103 |
Kind Code |
A1 |
Dubuffet; Thierry ; et
al. |
February 22, 2007 |
NOVEL METOD FOR THE SYNTHESIS OF PERINDOPRIL AND THE
PHARMACEUTICALLY-ACCEPTABLE SALTS THEREOF
Abstract
A process for the synthesis of perindopril of formula (I):
##STR1## and its pharmaceutically acceptable salts.
Inventors: |
Dubuffet; Thierry;
(Autretot, FR) ; Lecouve; Jean-Pierre; (Le Havre,
FR) |
Correspondence
Address: |
THE FIRM OF HUESCHEN AND SAGE
SEVENTH FLOOR, KALAMAZOO BUILDING
107 WEST MICHIGAN AVENUE
KALAMAZOO
MI
49007
US
|
Family ID: |
29724623 |
Appl. No.: |
10/570566 |
Filed: |
August 27, 2004 |
PCT Filed: |
August 27, 2004 |
PCT NO: |
PCT/FR04/02196 |
371 Date: |
February 27, 2006 |
Current U.S.
Class: |
514/419 ;
548/492 |
Current CPC
Class: |
Y02P 20/55 20151101;
A61P 9/12 20180101; A61P 43/00 20180101; C07K 5/06026 20130101;
A61P 9/04 20180101; A61P 9/10 20180101 |
Class at
Publication: |
514/419 ;
548/492 |
International
Class: |
A61K 31/405 20070101
A61K031/405; C07D 209/42 20060101 C07D209/42 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 29, 2003 |
EP |
03292131.4 |
Claims
1-6. (canceled)
7. A process for the synthesis of compounds of formula (I):
##STR8## and pharmaceutically acceptable salts thereof, wherein a
compound of formula (II): ##STR9## wherein R.sub.1 represents a
hydrogen atom, a benzyl group or a linear or branched
(C.sub.1-C.sub.6)alkyl group, is reacted with a compound of formula
(III) having the S configuration: ##STR10## wherein X represents a
halogen atom and R.sub.2 represents a protecting group for the
amino function, in the presence of a base, to yield, after
deprotection of the amino function, a compound of formula (IV):
##STR11## which is reacted with a compound of formula (V):
##STR12## wherein G represents a chlorine, bromine or iodine atom
or a p-toluenesulphonyloxy, methanesulphonyloxy or
trifluoromethanesulphonyloxy group, in the presence of a base, to
yield a compound of formula (VI): ##STR13## which is hydrogenated
in the presence of a catalyst to yield, after deprotection where
necessary, the compound of formula (I).
8. The process of claim 7, wherein the protecting group for the
amino function is a tert-butoxycarbonyl or benzyl group.
9. The process of claim 8, wherein R.sub.1 represents a benzyl
group, and the protecting group for the amino function is a
tert-butoxycarbonyl group.
10. The process of claim 7, wherein the base used for the reaction
between the compounds of formula (II) and (III) is an organic amine
selected from triethylamine, pyridine, N-methylmorpholine and
diisopropylethylamine, or a mineral base.
11. The process of claim 10, wherein the mineral base is selected
from NaOH, KOH, Na.sub.2CO.sub.3, K.sub.2CO.sub.3, NaHCO.sub.3, and
KHCO.sub.3.
12. The process of claim 7, wherein the base used for the reaction
between the compounds of formulae (IV) and (V) is an organic amine
selected from triethylamine, pyridine, N-methylmorpholine and
diisopropylethylamine, or a mineral base.
13. The process of claim 12, wherein the mineral base is selected
from NaOH, KOH, Na.sub.2CO.sub.3, K.sub.2CO.sub.3, NaHCO.sub.3, and
KHCO.sub.3.
14. The process of claim 7, wherein the hydrogenation catalyst is
selected from palladium, platinum, rhodium and nickel.
15. The process of claim 7 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 its pharmaceutically
acceptable salts.
[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 octapetide 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 the 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.
[0009] More specifically, the present invention relates to a
process for the synthesis of perindopril and its pharmaceutically
acceptable salts which is characterised in that the compound of
formula (II): ##STR3## wherein R.sub.1 represents a hydrogen atom
or a benzyl or linear or branched (C.sub.1-C.sub.6)alkyl group, is
reacted with a compound of formula (III) having the S
configuration: ##STR4## wherein X represents a halogen atom and
R.sub.2 represents a protecting group for the amino function, in
the presence of a base, to yield, after deprotection of the amino
function, a compound of formula (IV): ##STR5## wherein R.sub.1 is
as defined hereinbefore, which is reacted with a compound of
formula (V): ##STR6## wherein G represents a chlorine, bromine or
iodine atom or a p-toluenesulphonyloxy, methanesulphonyloxy or
trifluoromethanesulphonyloxy group, in the presence of a base, to
yield a compound of formula (VI): ##STR7## wherein R.sub.1 is as
defined hereinbefore, which is hydrogenated in the presence of a
catalyst such as palladium, platinum, rhodium or nickel to yield,
after deprotection where necessary, the compound of formula
(I).
[0010] Among the protecting groups for the amino function that can
be used in the process of the present invention, the groups
tert-butoxycarbonyl and benzyl may be mentioned without implying
any limitation.
[0011] R.sub.1 preferably represents a benzyl group. In that case
the protecting group for the amino function is preferably the
tert-butoxycarbonyl group.
[0012] Among the bases that can be used in the reaction between the
compounds of formulae (II) and (III) or between the compounds of
formulae (IV) and (V) there may be mentioned, without implying any
limitation, organic amines such as triethylamine, pyridine,
N-methylmorpholine 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.
EXAMPLE 1
(2S,3aS,7aS)-1-{(2S)-2-[(1S)-1-(ethoxycarbonyl)butylamino]-propionyl}-octa-
hydro-1H-indole-2-carboxylic acid tert-butylamine salt
Step A: Benzyl
(2S)-1-{(2S)-2-[(tert-butoxycarbonyl)amino]propionyl}-2,3,4,5,6,7-hexahyd-
ro-1H-indole-2-carboxylate
[0013] Introduce 200 g of benzyl
(2S)-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxylate and 1.5 litres
of dichloromethane into a reactor, then bring the temperature of
the reaction mixture to 0.degree. C. and add 107 ml of
triethylamine and then 162 g of
(2S)-2-[(tert-butoxycarbonyl)amino]propionyl chloride.
Subsequently, bring the mixture to ambient temperature. After
stirring for 1 hour at that temperature, wash the mixture with
water and then with a dilute acetic acid solution. The benzyl
(2S)-1-{(2S)-2-[(tert-butoxycarbonyl)amino]propionyl}-2,3,4,5,6,7-hexahyd-
ro-1H-indole-2-carboxylate solution so obtained is used as it is in
the following Step.
Step B: Benzyl
(2S)-1-{(2S)-2-aminopropionyl}-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxyl-
ate
[0014] Introduce the solution obtained in the above Step into a
reactor, and then add 133 g of trifluoroacetic acid. After stirring
for 1 hour 30 minutes at ambient temperature, wash the mixture with
water and then with a saturated solution of sodium hydrogen
carbonate and evaporate off the solvents to yield benzyl
(2S)-1-{(2S)-2-aminopropionyl}-2,3,4,5,6,7-hexahydro-1H-indole-2-carboxyl-
ate.
Step C: Benzyl
(2S)-1-{(2S)-2-[(1S)-1-(ethoxycarbonyl)butylamino]propionyl}-2,3,4,5,6,7--
hexahydro-1H-indole-2-carboxylate
[0015] Introduce into a reactor 200 g of the compound obtained in
the above Step, 106 ml of diisopropylethylamine and 1.5 litres of
tetrahydrofuran, and then 183 g of ethyl
(2R)-2-p-toluenesulphonyloxy-pentanoate, and subsequently heat at
70.degree. C. for 2 hours. After returning to ambient temperature,
the mixture is washed with water and then concentrated to dryness.
The residue is taken up in dichloromethane. A hydrochloric acid
solution (2M) is added until a pH of about 7.5 is obtained. After
decanting, the solvents are evaporated off to yield benzyl
(2S)-1-{(2S)-2-[(1S)-1-(ethoxycarbonyl)butylamino]propionyl}-2,3,4,5,6,7--
hexahydro-1H-indole-2-carboxylate.
Step D:
(2S,3aS,7aS)-1-{(2S)-2-[(1S)-1-(ethoxycarbonyl)butylamino]propio-
nyl}-octahydro-1H-indole-2-carboxylic acid
[0016] Introduce 200 g of the compound obtained in the above Step,
in solution in acetic acid, and then 5 g of 10% Pt/C into a
hydrogenation vessel. Hydrogenate under a pressure of 5 bars at
from 15 to 30.degree. C. until the theoretical amount of hydrogen
has been absorbed.
[0017] Remove the catalyst by filtration and then cool to from 0 to
5.degree. C. and collect the solid obtained by filtration. Wash the
cake and dry it to constant weight.
[0018] The (2S, 3aS,
7aS)-1-{(2S)-2-[(1S)-1-(ethoxycarbonyl)butylamino]propionyl}octahydro-1H--
indole-2-carboxylic acid is thereby obtained in a yield of 85% and
with an enantiomeric purity of 98%.
Step E:
(2S,3aS,7aS)-1-{(2S)-2-[(1S)-1-(ethoxycarbonyl)butylamino]propio-
nyl}-octahydro-1H-indole-2-carboxylic acid tert-butylamine salt
[0019] The precipitate obtained in the above Step (200 g) is
dissolved in 2.8 litres of acetonitrile, and then 40 g of
tert-butylamine and 0.4 litres of ethyl acetate are added.
[0020] The suspension obtained is then refluxed until dissolution
is complete, and the solution obtained is subsequently filtered hot
and cooled, with stirring, to a temperature of from 15 to
20.degree. C. The resulting precipitate is then filtered off, made
into a paste again with acetonitrile, dried and then recrystallised
from ethyl acetate to give the expected product in a yield of 95%
and with an enantiomeric purity of 99%.
EXAMPLE 2
(2S,3aS,7aS)-1-{(2S)-2-[(1S)-1-(ethoxycarbonyl)butylamino]-propionyl}-octa-
hydro-1H-indole-2-carboxylic acid tert-butylamine salt
Steps A and B: Identical to Steps A and B of Example 1
Step C: Benzyl
(2S)-1-{(2S)-2-[(1S)-1-(ethoxycarbonyl)butylamino]propionyl}-2,3,4,5,6,7--
hexahydro-1H-indole-2-carboxylate
[0021] Introduce 200 g of the compound obtained in the above Step,
106 ml of diisopropylethylamine and 1.5 litres of ethyl acetate
into a reactor, followed by 165 g of ethyl (2R)-2-chloropentanoate,
and then heat at 50.degree. C. for 3 hours. After returning to
ambient temperature, the mixture is washed with water and then
concentrated to dryness. The residue is taken up in
dichloromethane. A hydrochloric acid solution (2M) is added until a
pH of about 7.5 is obtained. After decanting, the solvents are
evaporated off to yield benzyl
(2S)-1-{(2S)-2-[(1S)-1-(ethoxycarbonyl)butylamino]propionyl}-2,3,4,5,6,7--
hexahydro-1H-indole-2-carboxylate.
Steps D and E: Identical to Steps D and E of Example 1
* * * * *