The invention relates to a novel method for the preparation of perindopril erbumine by synthesis of esters of (S,S , S) -octahudroindole-2-carboxylic acid and its conversion to perindopril erbumine.
Background of the Invention and relevant prior art;
As known in the art, the chemical entity (2S) -2- [ (S) -1-carbethoxybutylamino]-1-oxopropyl- (2S,3aS,7aS) - perhydroindole-2-carboxylic acid tertiary butylamine salt of formula VIII, known generically as perindopril erbumine, is widely used valuable ACE inhibitor, useful for the treatment of hypertension.
The preparation of a compound of formula VIII can be achieved by any of the well know methods described in several patents viz., EP
0,037, 231, EP 0,084, 164, EP 0,115, 345, EP 0,173, 199 AND EP 0,132, 58 0.
Several methods, for example EP 00371231, use indole-2-carboxylic acid as starting material. Indole-2-carboxylic is subjected to hydrogenation using Rh/C to get a mixture of two endo isomers of (2S,3aS,7aS) and (2R,3aR,7aR). The separation of (2S,3aS,7aS) octahydroindole-2-carboxylic acid, which is required for the synthesis of perindopril from this mixture is arduous.
EP 0115345 discloses synthesis of the product of formula I, employing several stages, requiring esterification of the carboxyl group with benzyl alcohol, conversion of the aminoester to a salt with N-benzyloxycarbonyl-S-phenylalanine, separation of the (2S,3aS,7aS) isomer by fractional crystallization and the

deprotection of amino group, optionally followed by, the liberation of the carboxylic acid group.
EP 0308341 discloses in the invention, the preparation of the (2S, 3aS, 7aS)-2-carboxyperhydroindole as the benzyl ester p-toluene sulphonate salt and its further conversion to perindopril.
Vincent et. al. in US patent 4508729 disclose a method for the preparation of perindopril monoaramonium salt, as a mixture of two diastereomers, involving reductive amination of (2S)-1- [ (S)-alanyl]-2-carboxyperhydroindole with pyruvic acid in the presence of sodium cyanoborohydride. (2S)-1-[(S)-Alanyl]-2-carboxyperhydroindole, in turn is prepared by reaction of (2S)-2-ethoxycarbonylperhydroindole with t-boc alanine to give (2S)-N- [ (S)-boc alanyl]-2-ethoxycarbonylperhydroindple, which on step-wise removal of the carboxyl and amino protecting groups, gives the desired product.
However, this method gives perindopril as a mixture of diastereomers and the inventors do not disclose any methodology to get the product with desired stereochemistry viz. , S-configuration at all the five chiral centers. Moreover the method involves protection of the amino group of the alanine moiety as the t-boc group, which requires use of corrosive trifluoroacetic acid for deprotection.
US patent 4902817 by Vincent et. al discloses an industrial process for the stereoselective synthesis of N- [ (S)-1-carbethoxybutyl]-(S)-alanine, comprising of catalytic reductive amination of pyruvic acid with ethyl-1-norvalinate hydrochloride and this is in turn converted to perindopril.

In another US patent 4 914 214 Vincent et. al. disclose an industrial process for the manufacture of perindopril erbumine in which ethyl or benzyl (2S, 3aS, 7aS)-2- perhydroindole-2-carboxylate is coupled with N- [ (S)-1-carbethoxybutyl]-(S)- alanine using a reagent like DCC in combination with l-hydroxybenzotriazole to yield, protected perindopril. This in turn, on deprotection and reaction with tertiary butylamine, yields perindopril erbumine.
A similar chemistry is disclosed by Vincent et.al. in EP 0129461.
In yet another EP 0309324 by Vincent et. al, they have disclosed
the synthesis of N- [ (S)-1-carbethoxybutyl]- (S)-alanine, by condensing benzyl-S-alaninate with ethyl-2-bromovalerate and separating the required diastereomer viz., benzyl-N-[(S)-1-carboethoxybutyl]-(S)-alninate, which is deprotected and converted to perindopril erbumine. '
Meizei et, al. in EP 1256590 disclose a process in which (2S)-2, 3-
dihydroindole-2-carboxylic acid is coupled with t- boc-S-alaninate
the product on hydrogenation yielded (2S, 3aS, 7aS)-1-(S)-
yl-octahydro-lH-indole-2-carboxylie acid. This product on
"iter synthetic protocol yielded perindopril erbumine.
Langlois et. al. in PCT application No. WO 01/58868 disclose yet another method for preparation of the of N-[(S)-1-carbethoxybutyl]-(S)-alanine, which is coupled with benzyl (2S, 3aS, 7aS)-2-carboxyperhydroindole-2-carboxylate using 0.4 to 0.6 mole proportion of 1- hydroxybenzotriazole, 1 to 1.2 mole proportion of dicyclohexylcarbodiimide at and 1 mole of triethylamine at 77 °C to give benzylester of perindopril. On debenzylation and treatment with tertiary butyl amine, perindopril erbumine is obtained.

Serra et. al. in PCT application. No. WO 96/33984 disclose a novel process for several ACE inhibitors by using N-sulfoxy anhydrides of ECPPA or N-[1- (S)-ethoxycarbonyl-3-phenylpropyl/butyl-S-alanine. The N-sulfoxy derivative is prepared by reacting N- [1- (S)-ethoxycarbonyl-3~phenylpropyl/butyl-S-alanine with N-(chlorosulfonyl) heterocycle, wherein the heterocycle is an alkyl imidazole, benzimidazole, tetrazole or other similar derivatives.
The utilization of N-carboxyanhdyride of N-[1-(S)-ethoxycarbonyl-3-phenylpropyl/butyl-S-alanine for the preparation of perindopril has been disclosed by Cid et. al. in EP 1279665.
However, this method utilizes toxic and hazardous phosgene for preparation of the N- carboxyanhydride compound, thereby rendering it unsuitable for commercial exploitation.
Palomo et. al. in DE patent 19721290 disclose a methodology for synthesizing several ACE inhibitors including perindopril, using silylating reagent. Reaction of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid with HMDS, followed by treatment with thionylchloride gives the silylated acid chloride derivative, which in turn, on reaction with N- [1-(S)-ethoxycarbonyl-3-phenylpropyl/butyl-S-alanine yields perindopril. This method, however, is lengthy and not cost-effective as it is uses costly silylating reagent and further step of desilylation.
It is apparent from the above description that there are several methods for the synthesis of perindopril. However all these methods use indole-2-carboxylie acid, which apart from being not a cheap starting material, will also involve additional step to prepare the (2S.3aS,7aS) perhydroindole-2-carboxylie acid. Additionally, methods for peptide coupling use corrosive reagents

like phosgene, thionylchloride etc., which is not eco-friendly. The use of costly reagents like carbodiimide in combination with 1-
hydroxybenzotriazole for peptide coupling makes the process uneconomical. Hence there is every need to find a process, which is economical and eco-friendly.
Summary of the Invention:

The present invention provides a novel process for the preparation of (2S, 3aS,7aS)-octahydrindole-2-carboxylic acid derivative of formula I and its conversion to perindopril erbumine of formula VIII by the reduction of hexahydroindole-2-carboxylic acid of formula-II

Formula-VII The product of formiila-VII on deprotection and treatment with tertiary butyl amine is converted to perindopril erbumine of formula-VlII


The above description briefly outlines the preferred embodiments of the present invention, which enables those skilled in the art to understand the detailed description that follows. Additional features of the invention will be described hereinafter that form the subject of claims of the invention. Those skilled in the art should appreciate that they can readily use the disclosed concept and specific embodiment as a basis for preparation of similar derivatives• Those skilled in the art should realize such equivalent concept do not depart from the spirit and scope of the invention in its broadest sense.
Objectives and advantages of the invention:
Considering the short comings of the processes described in the prior art, there is every need to develop a method for the synthesis of (2S,3aS,7aS)-octahydrindole-2-carboxylic acid and its conversion to perindopril by a novel process, which is economical and eco-friendly.

of the (2S,3aS,7aS)-octahydrindole-2-carboxylic acid to perindopril. These objectives have been achieved by this invention.
The following are the advantages gained by this invention
a) synthesis of (2S,3aS>7aS)-octahydroindole-2-carboxylic acid by a newer technique
b) peptide coupling using alkane phosphonic anhydride, which gives good yield
Detailed description of the invention;
The above and other objects features and advantages will be clear from the following description.
The product of formula-II has been prepared by utilizing a new reagent viz., N-acyl-3-acyloxy alaninate. This is described in our pending PCT WO patent.
Previous report for the synthesis of a bieyelie system like octahydroindole-2-carboxylic acid uses methyl-N-acetyl-3-chloro alaninate (US4 9 633 61/EP084164) , This is prepared utilizing phosphorus pentachloride which is a corrosive and toxic reagent. Our method, described in pending PCT patent, has avoided the use of
PC15.
The synthesis of the product of formula IV has utilized the product of formula II as the starting material. The product of formula-II is catalytically hydrogenated using Pd, Pt, Rh, Ru etc. It is preferable to use Pd or Pt as catalyst. It is more preferable to Pd/C, Pd-Al203, Pt/C, Pt- AI2O3 as catalysts. The reaction is preferably conducted using solvents like acetic acid, propionic

acid, butyric acid, isobutyric acid, pivalic acid etc or dimethyl formamide, dimethyl acetamide, N-methyl 2-pyrrolidone etc. It is more preferable to use acetic acid or dimethyl formamide as solvents. The hydrogenation is preferably at 0"c to 100r,c. It: Li more preferable to conduct the hydrogenation at 10 to 80°C. It is still more preferable to perform the catalytic hydrogenation at 60-7 0 °C.
The product of formula-II on hydrogenation gives (2R/2S, 3aS, 7aS)-octahydroindole-2-carboxylic acid of formula-III as its hydrochloride. The product of formula-Ill is esterfied to give a product of formula-IV. Esterification is carried out using alcohols in the presence of dehydrating agents. The alcohols used are methanol, ethanol. n-propanol, isopropanol, tertiarybutanol, benzyl alcohol, 4-chloro benzyl alcohol, 4-methoxy benzyl alcohol, 4-nitro benzylalcohol etc. The dehydrating agents used are hydrogen chloride, sulphuric acid, methane sulfonic acid, benzene sulfonic acid, paratoluene sulfonic acid, thionylchloride, phosphoryl chloride etc. The reaction is conducted preferably using the respective alcohol as solvent in the presence of the dehydrating agent. The reaction is more preferably conducted using alcohol in a solvent medium like hexanes, heptane, cyclohexane, benzene, toluene, xylenes etc, in the presence of a dehydrating agent or combination of dehydrating agents. The reaction is preferably conducted at 20°C to 120 °C, It is more preferably conducted at 30 °C to 100 °C.
The ester of formula-IV obtained as given above, is subjected to chemical resolution in order to get the product of formula-V. This is preferably achieved by forming a salt of the product of formula-IV with an acid like S-tartaric acid, diacyl-S-tartaric acid, S-mandelic acid, N-benzyloxy-S-phenyl alanine, a variety of N-acyl-S-

amino acids, lOd camphor sulfonic acid etc. The salt f omation is carriedout in solvents like acetone, acetonitrile, ethylacetate, isopropylacetate, butylacetate, alone or in combination with Diethylether, diisopropylether, tetrahydrofuran, 1,4-dioxane, 1,1-dimethoxyethane etc. It is preferable to form the diasteromeric salt in the combination of two solvents viz., a polar solvent and an anti solvent. It is more preferable to form the salt in a combination of solvents at 10°C to 20°C. The salt formed, as per the preceding description, is converted to the product of formula-Va by conventional methods.
Several peptide coupling reagents have been used for forming the peptide using (2S,3aS, 7aS)-octahydroindole-2-carboxylic ester and N- [ (S)-1-carbethoxybutyl]-(S)-alanine. The prior art describes the shortcomings of these methodologies. Hence the second objective of the invention is to utilize a coupling reagent, which is effective in terms of yield, quality as well as the environmental aspects. All these aspects can be fulfilled by using alkane phosphopnic anhydride. The reaction is preferably conducted in solvents like ethyl acetate, propyl acetate, isopropyl acetate, acetonitrile, dimethyl f ormamide, etc. It is more preferable to conduct the reaction in a single solvent or a mixture of solvents at a temperature of 0 °C to 30°C in the presence of an organic base like triethylamine, diisopropylethyl amine, N-methyl morpholine etc. for a duration of 8 to 12 hours. The progress of the reaction is monitored by TLC and on completion is worked up by traditional method.
The peptide, thus obtained, is subjected to debenzylation using catalyst like Pd/C. The debenzylation is studied in the presence of tertiary butylamine as well as in the absence of tertiary butylamine. The observation is that debenzylation in the presence

of tertiary butylamine gives a more pure product than in the absence of it, The reason could be that perindopril formed insitu is trapped by tertiary butyl amine and this prevents formation of some unwanted impurities. The debenzylation is carried out preferably in alkanols like methanol, ethanol, propanol etc. in the presence of tertiary butyl amine using Pd/C as catalyst at a temperature of 25 °C to 30°C. On completion of absorption of hydrogen, the reaction is worked up by filtering off the catalyst, concentrating the alkanol solution under reduced pressure and treating the residue with a solvent like acetone, methylethylketone, methyl isobutylketone, acetonitrile, diisopropylether, diethylether etc. It is preferable to use one of the solvents given above. It is more preferable to use a mixture of solvents. On trituration of the residue with the solvent, perindopril erbumine slowly crystallizes out. The product is obtained in very good yield and excellent purity.
It will be understood that the above description is only illustrative of the present invention and is not intended that the present invention is limited thereto. Any other specific embodiment of the present invention will be apparent to one skilled in that art from the above disclosure. Any modifications of the present invention which comes within the scope of claims are to which the present invention is readily susceptible without departing from the spirit of the invention.
EXAMPLE
In the following example, the preferred embodiments of the present invention is described only by way of illustrating the process of the invention. However, this do not limit the scope of the present invention in any way.

I - Preparation of Octahydroindole-2-carboxylic acid hydrochloride
lOkgs of hexahydroindoline-2-carboxylic acid hydrochloride charged into 501ts of glacial acetic acid in a hydrogenator kettle. 0.5kg of 10% platinum black was charged and temperature was raised to 60-7 0°C. Hydrogen was supplied till the consumption ceased. The catalyst was filtered and filtrate concentrated under reduced pressure. After complete removal of the solvent, lOlts of n-butanol was added, cooled to 20-25°C and stirred for 30min. The precipitated crystals were centrifuged and dried. The product obtained was 8.2kgs (characterized by 1H NMR) 1.28 (m, 2H; -CH2) ; 1.68 (m, 2H; -CH2) ; 1-72 (m, 2H; -CH2) ;
2.02 (m, 2H; -CH2) 2.21 (m, 1H;-CH); 2.41 (m, 2H;-CH2); 3.04 (m,1H -CH); 3.91 (m, 1H;-CH)
II - Preparation of Phenylmethyl octahydroindole-2-carboxylate hydrochloride
8. 0kg of octahydroindole-2-carboxylic acid hydrochloride, 351ts of toluene and 6.5kgs of benzyl alcohol was charged into 2001ts glass lined reactor. 8kgs of paratoluene sulfonic acid was added and water removed azeotropically. After the required quantity of water was collected, the temperature was lowered to 25-30°C. 2 51ts of water was added and pH was adjusted to 10.5. The organic layer was separated and aqueous layer discarded. The organic layer was distilled off completely. After the distillation, 251ts of methanol and 1.8kgs of 10% methanolic hydrochloric acid was added. The mass was cooled to 10-15°C and centrifuged. The product

obtained was 11.Okgs. with a melting point of 14 3-14 5°C. 2.0 (-NH); 3.58 (-CH) ; 1.9 (-CH2); 1.66 (-CH) ; 1.40 (-CH2) ; 1.44 (2 X-CH2); 1.52 (-CH2); 2.56 (-CH); 5.34 (-CH2) ; 7.19 (5 H aromatic
protans)
III - Preparation of
A) (2S, 3aS, 7aS) Phenylmethyl octahydroindole-2-carboxylate
hydrochloride
(Resolution with dibenzoyl-L-tartaric acid)
lOkgs of phenylmethyl octahydroindole-2-carboxylate hydrochloride and 401ts of water was charged into a lOOlts glass reactor. The pH was adjusted to 10.5 using aqueous sodium hydroxide. 501ts of diisopropylether was added and organic layer was separated. The organic phase was dried. 3.5kgs of dibenzoyl-L-tartaric acid was added to the organic layer and stirred for one hour at room temperature. The crystallized salt was centrifuged and wet cake was taken in another reactor, which contained 301ts of water. The pH was adjusted to 9.5 with sodium hydroxide and 251ts of dichloromethane was added. The organic layer was separated and dried with magnesium sulphate. The organic layer was distilled off completely and after complete removal of the solvent, 2kgs of methanolic hydrochloride and 2 0Its of methanol was added to residue. The crystallized solid was stirred at 0-5°C for one hour. The reaction mass was centrifuged and dried to get 4.7kgs of (2S, 3aS, 7aS) phenylmethyl octahydroindole-2-carboxylate hydrochloride with an optical rotation of -32°
B) (2S, 3aS, 7aS) Phenylmethyl octahydroindole-2-carboxylate
hydrochloride

(Resolution with benzyloxycarbonyl-S-phenylalanine)
100gm3 of racemic phenylmethyl octahydroindole-2-carboxylate hydrochloride was dissolved in 2 60ml of 10% sodium hydroxide aqueous solution and extracted into 400ml of diisopropylether. The organic layer was washed with water and dried over sodium sulphate-, 55gms of benzyloxycarbonyl-S-phenylalanine was added and subsequently stirred for 3 hours at 15-20°C. The precipitated salt was filtered and washed with diisopropylether. The salt was basified and extracted into the solvent and precipitated hydrochloride as same manner described in example-Ill A to get 4 6.5gms (2S, 3aS, 7aS) phenylmethyl octahydroindole-2-carboxylate hydrochloride with an optical rotation of -33.2°
IV - Preparation of Perindopril erbumine
4.5kgs of (2S, 3aS, 7aS) phenylmethyl octahydroindole-2-carboxylate hydrochloride was taken in 451ts of isopropyl acetate and cooled to 10-15°C. 3.3kgs of carbethoxy butyl alanine was added. Triethylamine 3.9kgs was added and stirred for 15min. The reaction mass was further cooled to -10°C and 6.0kgs of propane phosphoric anhydride (50% solution in isopropyl acetate) was added. The temperature was maintained for 6 hours at 25-30°C. The reaction was monitored using thin layer chromatography. After completion of the reaction, 25Its of water was added and organic layer was separated. The organic layer was washed with lOlts of 10% sodium bicarbonate solution. The separated organic layer was distilled off completely. 5kgs of tertiary butylamine was added to the residue followed by 201ts of ethanol. The ethanolic solution was charged into hydrogenator. 0.3kgs of 5% palladium charcoal was charged and hydrogen gas was supplied till the consumption ceased.

The catalyst was filtered and filtrate was distilled off completed. 25kgs of methylethylketone added and cooled to 10-15"C. The reaction mass was stirred for 2 hours and then centrifuged to give 5kgs of perindopril with a melting range of 154~156°C, optical rotation of -68,4°,
:H NMR 0. 9 6 (-CH3) ; 1.33(-CH2) ; 1.7 6 (-CH2) ; 3.45(-CH); 2.00(-NH); 3.93(-CH); 2.21(-CH2); 1.66(-CH)1.98(-CH ); 3.11(-CH ); 1.40(-CH2); 1.44 (-CH2) ;1.44 (-CH2) ; 1.40 (-CH2) ; 1.14 (-CH3) ; 4 .12 (-CH2) ; 1.3 (-CH3) ; ll.O(-OH); 2.0 (-NH2); 1.1 (-CH3); 1.1 (-CH3) ; 1.1(-CH3);

We claim,
1.An industrially viable process of preparation of
perindopril erbumine by
a)reducing hexahydroindole-2-carboxylic acid of formula II to a product of formula III,
b)esterifying the product of formula III to give racemic ester of octahydroindole-2-carboxylic acid of formula IV,
c)resolving the product of formula-IV to give an ester of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid of formula V,
d)converting the product of formula V to the hydrochloride salt of formula Va,
e)coupling the product of formula-V a with a product of formula-VI to give a product of formula-VII,
f)deprotecting the product of formula VII and converting it to erbumine salt of formula VIII.
2.A claim, as claimed in claim la, wherein the reduction of the product of formula-II is carried out using catalyst like Pd/C, Pt/C, Rh/C or their oxides at a temperature of 0-100°C using solvents like acetic acid, propionoic acid, pivalic acid.
3.A claim, as claimed in claim lb, wherein the esterification is carried out using the respective alcohol in the presence of a condensing agent like thionyl chloride, phosphoryl chloride, PTSA, sulfuric acid, methane sulfonic acid.
4.A claim, as claimed in claim lc, wherein the resolution of product of formula IV is achieved using reagents like N-benzyloxy carbonyl-s-phenyl alanine, O,O' dibenzoyl-S-tartaric acid, S-mandelic acid.
5.A claim, as claimed in claim Id, wherein, the (S, S, S) -octahydroindole-2-carboxylate of formula-V is converted to a product of formula Va.
6.A claim, as claimed in claim le, wherein the product of formula Va is coupled with the alanine derivative of formula VI, using n-propane phosphoric anhydride to give a product of formula VII.
7.A claim, as claimed in claim If, wherein the product of formula VII, is deprotected, converted into tertiary butyl amine salt and purified to give the product of formula-VIII in good yield and high purity.