FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of (2S,3aR,7aS)-Octahydro-lH-indole-2-carboxylate hydrochloride of Formula I

wherein R represents H, benzyl or substituted benzyl
which is an intermediate used in the preparation of Trandolapril of Formula II

BACKGROUND OF THE INVENTION
Trandolapril, also known as (2S53aR57aS)-l-[(S)-N-[(S)-l-carboxy-3-
phenylpropyl]alanyl]hexahydro-2-indolinecarboxylic acid 1 -ethyl ester belongs to antihypertensive class of drugs known as ACE inhibitors. Generally, trandolapril undergoes hydrolysis to the diacid metabolite, trandolaprilat, which is an active inhibitor of Angiotensin-converting enzyme ("ACE") activity. ACE is a peptidyl dipeptidase that catalyzes the conversion of Angiotensin I to the vasoconstrictor, Angiotensin II. Angiotensin II is a potent peripheral vasoconstrictor that also stimulates secretion of aldosterone by the adrenal cortex and provides negative feedback for renin secretion. The effect of trandolapril in hypertension appears to result primarily from the inhibition of circulating and tissue ACE activity thereby reducing Angiotensin II formation, decreasing

vasoconstriction, decreasing aldosterone secretion, and increasing plasma renin. Trandolapril is indicated for use in treating hypertension. Trandolapril is sold under the trade name MAVIK.
(2S,3aR,7aS)-Octahydro-lH-indole-2-carboxylic acid is a key intermediate in the synthesis of (ACE) inhibitor Trandolapril. This indole carboxylic acid is characterized by a trans-fused ring junction and an epimerization center at C2.
One of the most important steps in the preparation of Octahydroindole intermediate is the selective formation of the trans fused ring which is difficult to isolate from the cis-equivalent. However, this was subsequently made pure and possible without generating significant quantities of the cis-product. But such methods were severely limited because the synthesis involved was long or required dangerous reagents like mercury compounds. These methods are summarized below :
US 4,933,361 provides an apparently effective method for the synthesis of the octahydroindole intermediate in relatively few steps, starting from trans-octahydroindole as the starting material. The preparation is shown below :


US 6,559,318 relies on enzymatic resolution of 2-(2\2'-dimethoxyethyl)cyclohexamine with Novozyme over 25 hrs to provide the N-acetylated (1R,2S) enantiomer which is then separated by column chromatography from the required (lS,2R)-l-amino-2(2',2'-dimethoxyethyl)cyclohexamine. Neither the enzymatic resolution nor the chromatography steps are well suited to industrial scale preparations.
Drug Design and Discovery 1992, Vol 9 PP 11-28 also describes the synthesis of the octahydroindole carboxylic acid as shown below:


Tetrahedron Letters Vol 24, No 48, PP 5343-5346,1983 describes the synthesis of octahydroindole ring as depicted below:

This synthesis utilizes mercuric nitrate that is undesirable in the preparation of pharmaceuticals.
The prior-art literature described above provides varied preparations of Octahydro-indole carboxylic acids. However, there are a number of disadvantages in using the prior-art methods which are listed below :
1) The methods are not industrially feasible as hazardous reagents are used
2) Many of the processes involve chromatography that needs to be avoided in large-
scale commercial manufacture.
3) In many of prior-art references the required isomer of Octahydroindole carboxylic
acid is resolved after the Trandolapril is prepared which makes the process
susceptible to generation of many unwanted side products. This also makes the
process laborious and expensive in view of subsequent purification steps.

The inventors have now developed a new improved process which does not require laborious purification steps and avoids chromatography altogether yielding the required trans (2S,3aR,7aS)octahydroindole-2-carboxylic acid ester hydrochloride that can be readily coupled to the appropriate alanine derivative resulting in Trandolapril.
OBJECTIVES OF INVENTION
The objective of the present invention is to develop an improved process for the preparation of Trandolapril intermediate (2S,3aR,7aS)-octahydro-lH-indole-2- carboxylate hydrochloride of Formula I and its further conversion to Trandolapril of Formula II
SUMMARY OF INVENTION
Accordingly, the present invention relates to an improved process for the preparation of (2S, 3aR, 7aS)-octahydro-lH-indole-2-carboxylate hydrochloride of Formula I

wherein R represents H, benzyl or substituted benzyl which comprises subjecting the compound of Formula III

to Favorsky rearrangement to obtain an intermediate comprising a mixture of two racemates of compounds of Formula IV


which on recrystallization from alcohol gives a single racemate consisting of pair of compounds of Formula V

which are esterified with an alcohol of Formula ROH wherein R is benzyl or substituted benzyl group in the presence of a suitable acid to provide a racemic benzyl ester acid addition salt of compound of Formula VI


wherein R is as defined above and treating the racemic benzyl ester acid addition salt of Formula VI with a base and subsequently resolving the racemic benzyl octahydroindole-2-carboxylate with dibenzoyl-L-tartaric acid or di-p-toluoyl-L-tartaric acid to precipitate the compound of Formula VII

wherein R is as defined above and R1 represents H or CH3 and finally treating the compound of Formula VII with a base in a suitable organic solvent followed by acidification with hydrochloric acid to provide a compound of Formula I.
DETAILED DESCRIPTION OF THE INVENTION
The present invention describes an improved process for the preparation of benzyl (2S, 3aR,7aS)-octahydroindolecarboxyIate hydrochloride of Formula I and its further conversion to Trandolapril of Formula II in higher yields.
The aim of the present invention is to provide an efficient process for the preparation of compound of Formula I in optically pure form.

Also the present invention aims at simplifying the crystallizations in various stages so that the desired compounds can be isolated by conventional techniques like filtration and drying.
The Favorsky rearrangement of compound of Formula III gives two racemates of compound of Formula IV. The compound of Formula IV is separated by refluxing in alcohol more preferably methanol, wherein the desired racemic mixture of compound of Formula V is collected by filtration. The use of methanol as single solvent is advantageous as it can be readily recycled. Also methanol as choice of solvent facilitated good yields of the desired racemic mixture when compared with prior art solvent mixture.
The racemic mixture of Formula V has to be resolved, which is normally achieved by converting the compound of Formula V to corresponding esters using benzyl alcohol and thionyl chloride. However, the inventors instead utilized benzenesulfonic acid and benzyl alcohol for esterification in toluene to isolate the compounds of Formula VI as benzenesulfonic acid addition salt. By this combination the inventors avoided the usage of thionyl chloride which is hazardous in industrial scale preparations and tedious workup procedure for isolation of compound of Formula VI.
Finally in order to resolve the compound of Formula VI to a single enantiomer, the compound of Formula VI is treated with base and resolved with dibenzoyl-L-tartaric acid or di-p-toluoyl-L-tartaric acid in an alcohol to precipitate the compound of Formula VII.
The compound of Formula VI is treated with aqueous sodium carbonate solution in methylene chloride. The organic layer was separated and reacted with resolving agent like Di-p-toluoyl-L-tartaric acid or Di-benzoyl-L-tartaric acid. The reaction mixture was concentrated completely and treated with ethanol at 40-45 °C. The precipitated product was filtered, washed with ethanol and ethyl acetate and dried to yield compound of Formula VII.
The compound of Formula VII is basified with aqueous sodium carbonate in methylene chloride. The organic layer was separated and acidified with hydrochloric acid. The reaction

mass is concentrated under reduced pressure and treated with alcohol to obtain compound of Formula I as a hydrochloride salt.
The compounds of Formula I are converted to compounds of Formula II by known methods in the literature.
The present invention is exemplified by the following examples which are provided for illustration purposes and do not limit the scope of invention.
Example 1
Preparation of 3-ChIoro-trans-octahydro-lH-quinolin-2-one
3,3-Dichloro-trans-octahydro-lH-quinolin-2-one (50 g, 0.223 m.) was hydrogenated in the presence of triethylamine (23.6 g) in methanol (50 ml) using raney nickel catalyst (5 g, Wet) at 1-3 Kg / Cm pressure of hydrogen at 20-30°C. After completion of reaction, catalyst was filtered and the filtrate was dried in vacuum. The residue obtained was dissolved in ethyl acetate (500 ml), washed with aqueous sodium chloride and evaporated the solvent in vacuum. The solid mass obtained was slurried in n-heptane (100 ml), filtered the product, washed with n-heptane and dried to yield 3-Chloro-trans-octahydro-lH-quinolin-2-one (30.1
g).
Example 2
Preparation of Racemic mixture of Octahydro-lH-indoIe-2-carboxyIic Acid
3-Chloro-trans-octahydro-lH-quinolin-2-one (200 g, 1.067 m.) was reacted with to 15% w/w
aqueous barium hydroxide solution at 95-100°C and acidified with sulfuric acid. The
reaction mass was cooled to 20-30°C and neutralized with aqueous sodium hydroxide
solution. The insolubles were filtered and the filtrate was heated with toluene (1.4 Lt)
to reflux temperature. Water was removed azeotropically from the reaction mass, cooled to 20-30°C, filtered the product, washed with toluene and dried to yield mixture of pair of racemic Octahydro-lH-indole-2-carboxylic acid (180 g).

Example 3
Isolation of Racemic mixture of (2S,3aR,7aS) and (2R,3aS,7aR)-octahydro-lH-indole-2-carboxylic acid
Racemic mixture of Octahydro-lH-indole-2-carboxylic acid (180 g) as obtained in example 2 was added to methanol (2.16 Lt) and heated to reflux temperature. The reaction mass was maintained at reflux temperature for 30 min, filtered and washed with methanol (90 ml). Methanol was distilled off partially from the filtrate at reflux temperature and cooled to 20-25°C to crystallize the product. The solid product was filtered, washed with methanol (90 ml) and dried to yield racemic mixture of (2S,3aR,7aS)(2R,3aS,7aR) octahydro-lH-indole-2-carboxylic acid (74 g).
Example 4
Preparation of Racemic mixture of benzyl (2S,3aR,7aS) and (2R,3aS,7aR)-octahydro-lH-indole-2-carboxylate benzenesulfonic acid salt
To a mixture of racemic (2S53aR,7aS)(2R,3aS,7aR)octahydro-lH-indole-2-carboxylic acid (90 g, 0.532 m.), benzyl alcohol (63.2 g) and toluene (1.35 Lt), benzenesulfonic acid (129.7 g) was added and heated to reflux. The reaction mixture was maintained at 100-118°C for 8 h and separated water azeotropically. The reaction mixture was concentrated to dryness and the residue was treated with ethyl acetate (720 ml). The reaction mass was cooled to 0-5°C, filtered the product, washed with ethyl acetate (90 ml) and dried to yield racemic benzyl (2S,3aR,7aS)(2R,3aS,7aR) octahydro-lH-indole-2-carboxylate benzenesulfonic acid salt (170.7 g).

Example 5
Preparation of benzyl (2S,3aR,7aS)octahydro-lH-indole-2-carboxylate di-p-toluoyl-1-tartrate
To a mixture of methylene chloride (853 ml) and DM water (1.02 Lt), racemic mixture of benzyl (2S53aRJaS)(2R53aS57aR)octahydro-lH-indole-2-carboxylate benzenesulfonic acid salt (170.7 g) was added and treated with 8% w/w aqueous sodium carbonate solution (550 ml). The organic layer was separated, washed with DM water and concentrated under reduced pressure. The residue was dissolved in ethanol (728 ml) and resolved with Di-p-toluoyl-L-tartaric acid (154.8 g) at 25-40°C. The product was filtered, washed with ethanol (104 ml), followed by ethyl acetate (104 ml) and dried to yield benzyl (2S,3aR,7aS)Octahydro-lH-indole-2-carboxylate Di-p-toluoyl-L-tartrate (121.6 g).
Example 6
Preparation of benzyl (2S,3aR,7aS)octahydro-lH-indoIe-2-carboxyIate hydrochloride
To a mixture of methylene chloride (150 ml) and DM water (240 ml), benzyl (2S,3aR,7aS)octahydro-lH-indole-2-carboxylate Di-p-toluoyl-L-tartrate (30 g, 0.0465 m.) was added and treated with 8% w/w aqueous sodium carbonate solution (70 ml). The organic layer was separated, washed with DM water, dried over sodium sulfate and treated with hydrochloric acid. Methylene chloride was distilled completely from the reaction mixture and the residue was treated with ethyl acetate (60 ml). The resulting slurry was cooled to 0°C, filtered the product, washed with ethyl acetate and dried to yield pure benzyl (2S,3aR,7aS)-octahydro-lH-indole-2-carboxylate hydrochloride 8.94 g).

WE CLAIM
1) A process for the preparation of (2S, 3aR, 7aS) octahydro-lH-indole-2-carboxylate hydrochloride of Formula I

wherein R represents hydrogen, benzyl and substituted benzyl which comprises subjecting the compound of Formula III

to favorsky re-arrangement to obtain an intermediate comprising a mixture of pair of


which on recrystallization with alcohol gives racemic mixture of compound of Formula V

which is esterified with an alcohol of formula ROH wherein R is benzyl or substituted benzyl group in the presence of a suitable acid to provide a racemic benzyl ester acid addition salt of compound of Formula VI

treating the racemic benzyl ester acid addition salt of Formula VI with a base and subsequently resolving the racemic benzyl octahydroindole-2-carboxylate with dibenzoyl-Z-tartaric acid or di-p-toluoyl-L-tartaric acid in a solvent or solvent mixture to precipitate the compound of Formula VII

wherein R is defined as above and R1 represents H or CH3 and finally treating the compound of Formula VII with a base in a suitable organic solvent followed by acidification with hydrochloric acid to provide a compound of Formula I.
2) The process according to claim 1, wherein the alcohol used for recrystallization of compound of Formula IV is methanol.
3) The process according to claim 1, wherein the alcohol of Formula ROH is benzyl or substituted benzyl alcohol.
4) The process according to claim 1, wherein the suitable acid is sulfonic acid.
5) The process according to claim 4, wherein the sulfonic acid is benzenesulfonic acid.
6) The process according to claim 1, wherein the compound of Formula VI is resolved with di-p-toluoyl-L-tartaric acid to give compound of Formula VII.
7) The process according to claim 1, wherein the compound of Formula I is converted to Trandolapril or a pharmaceutically acceptable salt thereof.
Dated this 11th day of september 2006.