The invention relates to a novel method for the preparation of esters of (S,S,S)-octahydroindole-2-carboxylic acid.
Background of the Invention and relevant prior art:
The chemical entity (2S)-2- [ (S)-1-carbethoxybutylamino]-1-oxopropyl-(2S,3aS,7aS)- perhydroindole-2-carboxylic acid tertiary butylamine salt, known generically as perindopril erbumine, is widely used valuable ACE inhibitor, useful for the treatment of hypertension. The synthesis involves perhydroinhdole-2-carboxylic acid as one of the component. There are a few methods described for the preparation of this compound.
The process described in EPO0371231, uses indole-2-carboxylic acid as starting material. This on hydrogenation using Rh/C gives a mixture of two enantiomers viz. , (2S,3aS7aS) and (2R, 3aR,7aR) . The separation of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid from the mixture is arduous.
EP0308341 discloses a process, in which, N-acyl indole-2-carboxylic acid is hydrogenated using R-Ni and indoline-2-carboxylic acid, obtained on hydrolysis, is resolved to give 2S indole-2-carboxyic acid. This on hydrogenation gives the (2S,3aS,7aS) perhydroindole-2-carboxylic acid.
Both the processes described have their shortcoming. As per the process described in EP00371231, the separation of the required enantiomer is arduous. The second process described in EP0308341 involves additional steps, which makes it less economical. Additionally both the processes, use of indole-2-carboxylic acid, which is not a cheap raw material.

Hence there is a requirement to develop an economical and eco-friendly novel method of making (S,S,S)-perhydroindole-2-carboxylic acid
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 by the reduction of hexahydroindole-2-carboxylic acid of formula-II
I
using a catalyst like Pd/C, Pt/C or their oxides and hydrogen to give a product of formula-Ill,

and then resolved to get a product of formula-V, which is converted to a product of formula-I

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 by a novel process, which is economical and eco-friendly.
One of the main objectives of the present invention is to develop a novel synthesis for the preparation of (2S,3aS, 7aS)-octahydrindole-2-carboxylic acid. This objective has been achieved by this invention.
The main advantage gained by this invention is synthesis of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid by a newer technique, which is economical and eco-friendly.
Detailed description of the invention:
The product of formula-II has been prepared by utilizing a new reagent viz., N-acyl-3-acyloxy alaninate of formula VI.

Previous report describes the preparation using methyl-N-acetyl-3~ chloroalaninate (US Patent No, 4963361/EP No. 084164), which is prepared utilizing phosphorus pentachloride 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 100°C. It is more preferable to conduct the hydrogenation at 10 to 80°C. It is still more preferable to perform the catalytic hydrogenation at 60-70 °C.
The product of formula-II on hydrogenation gives (2R/2S, 3aS, 7aS)-octahydroindole-2-carboxylie 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-propahol, 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 subj ected 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 fomation 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, thus obtained, is neutralized and converted into the required (2S,3aS,7aS)-octahydroindole-2-carboxylate hydrochloride by conventional method in excellent yield and high purity.
EXAMPLE:
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of

the invention. However, these 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 lH 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,lH-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. 251ts 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 ll.Okgs. with a melting point of 143-145°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 protons )
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 40Its of water was charged into a 10 0Its 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 30Its of water. The pH was adjusted to 9.5 with sodium hydroxide and 2 51ts 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 01ts 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)
lOOgms of racemic phenylmethyl octahydroindole-2-carboxylate hydrochloride was dissolved in 260ml 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°

We claim;
01. An industrially viable preparation of esters of
(2S,3aS,7aS)-octahydroindole-2-carboxylic acid 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 product of
formula-I
02, 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.
03. 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,
04, A claim, as claimed in claim 1c, wherein the resolution of
product of formula IV is achieved using reagents like N-
benzyloxy carbonyl-s-phenyl alanine, O,0' dibenzoyl-S-tartaric
acid, S-mandelic acid.

05. A claim, as claimed in claim Id, wherein the conversion of the product of formula-V to formula-1 achieved by treatment with an alkanolic solution of hydrogen chloride.