WO2006014916A2

WO2006014916A2 - Preparation of trandolapril

Info

Publication number: WO2006014916A2
Application number: PCT/US2005/026423
Authority: WO
Inventors: Pratap Padi Reddy; Saurabh Shashikant Chitre; Srinivas Polavarapu; Varaprasad Vakamudi Sri Naga Venkata Laxmi
Original assignee: Dr. Reddy's Laboratories Ltd.; Dr. Reddy's Laboratories, Inc.
Priority date: 2004-07-26
Filing date: 2005-07-26
Publication date: 2006-02-09
Also published as: WO2006014916A3

Abstract

A process for preparing trandolapril, (2S,3aR,7aS)-1-[(S)-N-[(S)-1-Carboxy-3-phenylpropyl]alanyl]hexahydro-2-indolinecarboxylic acid, 1-ethyl ester, and intermediates that are useful in the process.

Description

PREPARATION OF TRANDOLAPRIL

INTRODUCTION TO THE INVENTION

The present invention relates to a process for preparing trandolapril. Trandolapril has the chemical name (2S,3aR,7aS)-1-[(S)-N-[(S)-1-Carboxy-3- phenylpropyl]alanyl]hexahydro-2-indolinecarboxylic acid, 1 -ethyl ester, or N-[I S- carboethoxy-3-phenylpropyl]-S-alanyl-2S,3aR,7aS-octahydroindole-2-carboxylic acid, and is represented by formula (Ia).

Formula (Ia)

Trandolapril is the ethyl ester prodrug of trandolaprilat, an inhibitor of angiotensin converting enzyme. Pharmaceutical products containing trandolapril are sold for treating hypertension, using the trademark MAVIK.

Processes for preparing trandolapril are taught in U.S. Patent 4,933,361. Processes for preparing octahydropentapyrrole carboxylates and their analogs are disclosed in U.S. Patents 5,068,351 and 5,055,591. Another process for preparing trandolapril is disclosed in International Published Application WO 96/33984.

SUMMARY OF THE INVENTION

A process for preparing trandolapril comprises condensing (±)- Benzyloctahydroindole-2-carboxylate with N-[1 (S)-ethoxycarbonyl-3- phenylpropyl]-L-alanine to form an intermediate product, and debenzylating the intermediate product to form a mixture of diastereomers of N-[1 (S)-Carboethoxy- 3-phenylpropyl]-S-alanyl-octahydroindole-2-carboxylic acid.

A process for preparing N-[1 S-carboethoxy-3-phenylpropyl]-S-alanyl- 2R,3aS,7aR-octahydroindole-2-carboxylic acid comprises condensing Benzyl- 2R,3aS,7aR-octahydroindole-2-carboxylate, or an acid addition salt thereof, with N-[1S-ethoxycarbonyl-3-phenylpropyl]-L-alanine to form an intermediate product, and debenzylating the intermediate product.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a schematic diagram of a process for preparing trandolpril.

Fig. 2 is a schematic diagram of a process for preparing Benzyl- 2R,3aS,7aR-octahydroindole carboxylate hydrochloride. Fig. 3 is a schematic diagram of a process for preparing N-[IS-

Carboethoxy-3-phenylpropyl]-S-alanyl-2R,3aS,7aR-octahydroindole-2-carboxylic acid.

Fig. 4 is a schematic diagram of a process for preparing (±)-trans- Octahydroindole-2-carboxyIic acid. Fig. 5 is a schematic diagram of a process for preparing Benzyl-2S,3aR,

7aS-octahydroindole carboxylate.

Fig. 6 is a schematic diagram of processes for preparing Benzyl-N-[1S- carboethoxy-S-phenylpropy^-S-alanyl^S.SaRJaS-octahydroindole^-carboxylate.

DETAILED DESCRIPTION

The present invention provides a commercially feasible process for the preparation of trandolapril, which in an aspect involves condensation of (±)- BenzyI-octahydroindoIe-2-carboxylate, or an acid addition salt thereof such as the hydrochloride of formula (II), with N-[1 (S)-ethoxycarbonyl-3-phenylpropyl]-S- alanine of formula (III). This reaction results in a mixture of two diastereomers of benzyl-N-[1S-carboethoxy-3-phenyIpropyl ]-S-alanyl-octahydroindole-2- carboxylate having formula (IVa) and formula (IVb), and their debenzylation gives two diastereomers of N-[1 S-carboethoxy-3-phenylpropyl]-S-alanyl- octahydroindole-2-carboxylic acid having formula (Ia) and formula (Ib). These diastereomers are separated by crystallization to afford the desired isomer N-[IS- carboethoxy-3-phenylpropyl]-S-alanyl-2S,3aR,7aS-octahydroindole-2-carboxylic acid, i.e. trandolapril, of formula (Ia). The overall process is represented schematically by Fig. 1. In this figure, and in the other figures of the application, the abbreviation "Et" means an ethyl group and the abbreviation "Ph" means a phenyl group.

Another aspect of the present invention provides a process for the preparation of benzyl-2R,3aS,7aR-octahydroindole carboxylate hydrochloride of formula (V) comprising resolution of (±)-trans-benzyIoctahydroindole-2- carboxylate hydrochloride of formula (II) by forming a salt with (1S)-(+)-camphor- 10-sulfonic acid as a resolving agent and subsequently hydrolyzing the resultant diastereomer salt to afford the desired optically pure benzyl-2R,3aS,7aR- octahydroindole-2-carboxylate hydrochloride of formula (V). This process is schematically represented in Fig. 2.

A further aspect of the present invention is a process for the preparation of N-[1S-carboethoxy-3-phenylpropyl]-S-alanyl-2R,3aS,7aR-octahydroindole-2- carboxylic acid, i.e. the isomer of trandolapril having formula (Ib) which involves condensation of benzyl-2R,3aS,7aR-octahydroindole carboxylate hydrochloride of formula (V) with N-[1 (S)-ethoxycarbonyl-3-phenylpropyl]-S-alanine and a subsequent hydrogenation of the resulting optically active compound, benzyl-N- [1 S-carboethoxy-3-phenyl propyl]-S-alanyl-2R,3aS,7aR-octahydroindole-2- carboxylate of formula (IVb) to yield the N-[1S-carboethoxy-3-phenylpropyl]-S- alanyl^R.SaSJaR-octahydroindole^-carboxylic acid isomer of trandolapril having formula (Ib). The process is represented schematically in Fig. 3.

In another aspect, the invention provides a process for the preparation of compound (+)-trans-octahydroindole-2-carboxylic acid of formula (II) comprising condensation of cyclohexanone with acrylonitrile in presence of cyclohexylamine and hydroquinone to afford 3,4,5,6,7,8-hexahydro-1 H-quinolin-2-one of Formula (X). Reaction of (X) with sodium formate and formic acid gives (±)-trans- octahydro-1 H-quinolin-2-one of Formula (XI) which on chlorination with sulfuryl chloride and phosphorus pentachloride yields (±)-3,3-dichloro-trans-octahydro-1 H- quinolin-2-one of Formula (XII). Dehalogenation of XII in the presence of Raney nickel to give (±) 3-chloro-trans-octahydro-i H-quinolin-2-one of Formula (XIII) and subsequent reaction of (XIII) with barium hydroxide octahydrate yields the desired compound (±)-trans-octahydro-indole-2-carboxylic acid of Formula (II). The process is represented schematically in Fig. 4. In yet another aspect, the present invention provides a process for the preparation of Benzyl-2S,3aR,7aS-octahydroindole carboxylate hydrochloride of Formula (Ha), an intermediate of trandolapril, which comprises conversion of (±)- 3,3a,4,5,6,7-2H-hexahydroindole-2-carboxylic acid hydrochloride (Formula Vl) into (±)-trans-octahydroindole-2-carboxylic acid hydrochloride (Formula (VII), which upon benzylation gives (±)-trans-benzyloctahydroindole-2-carboxylate hydrochloride of Formula (VIII), followed by resolution with (1 R)-(-)-camphor-10- sulfonic acid and hydrolyzing the resultant compound to afford the desired optically pure Benzyl-2S,3aR,7aS-octahydroindole-2-carboxylate hydrochloride of Formula (Ha). The process is represented schematically in Fig. 5.

In a still further aspect, the present invention provides a process for the preparation of compound Benzyl-N-[1S-carboethoxy-3-phenylpropyl]-S-alanyl- 2S,3aR,7aS-octahydroindole-2-carboxylate of Formula (IVa), which involves condensation between benzyl-2S,3aR,7aS-octahydroindole -2-carboxylate hydrochloride of formula (Ma) and N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-S- alanylchloride hydrochloride having formula (IX) or N-[1 (S)-ethoxycarbonyl-3- phenylpropyl]-S-alanine of Formula (III). The process is schematically represented in Fig. 6.

The following examples are included to illustrate certain aspects of the invention, and are not intended to limit the scope of the claimed invention.

EXAMPLE 1

PROCESS FOR THE PREPARATION OF N-[1S-CARBOETHOXY-3- PHENYLPROPYL]-S-ALANYL-2S,3aR,7aS-OCTAHYDROINDOLE-2-

CARBOXYLIC ACID (TRANDOLAPRIL)

15O g of (±)-Benzyloctahydroindole-2-carboxylate hydrochloride of formula

Il was taken in 1000 ml of methylene dichloride (also denoted herein as "MCC," or dichloromethane). The pH was adjusted to 9-11 with 1050 ml of 8% sodium carbonate solution at 25-35°C. The organic layer and the aqueous layer were separated. The aqueous layer was extracted twice with 400 ml of methylene dichloride. Combined organic layer was dried over 10 g of sodium sulfate. The organic layer was distilled under vacuum below 60⁰C. To the crude residue material, 1200 ml of methylene dichloride was added at 25-35°C and 129.5 g of N-[1 (S)-ethoxycarbonyl-3-phenylpropyl]-S-alanine of formula III was added with stirring at 25-35°C. The reaction mass was cooled to 0-5⁰C and 32 g of hydroxybenzotriazole, and 95.5 g. of dicyclohexylcarbodiimide were added at 0-5⁰C, then the temperature of the reaction mass was raised to 20- 25⁰C and maintained at 20-25°C for 3 hours. Insoluble solid was filtered off and the filtrate was washed three times with 5% sodium bicarbonate solution. Filtrate was distilled off completely under vacuum below 70⁰C. Residue was taken up in 1160 ml of isopropanol, and hydrogenated under 2-3 kg/cm² hydrogen pressure in the presence of 85.2 gm of 10% palladium-charcoal (50 % wet) at 25-35°C until the consumption of hydrogen ceased. The catalyst was filtered off and washed with 150 ml of isopropanol. The filtrate was evaporated under vacuum below 40⁰C and 250 ml of diisopropyl ether was added to the crude material and distilled off completely under vacuum below 40°C. To the residue, 1485 ml of diethyl ether was added and the mixture was stirred for 5-10 minutes. Precipitated solid was filtered and washed with 150 ml of diethyl ether and dried at 50-60⁰C to afford 64.1 g of N-[1S-carboethoxy-3-phenylpropyl]-S-alanyl-2S,3aR,7aS- octahydroindole-2-carboxylic acid (trandolapril).

EXAMPLE 2

PROCESS FOR RECRYSTALLIZATION OF N-[1S-CARBOETHOXY-3- PHENYLPROPYL]-S-ALANYL-2S,3aR,7aS-OCTAHYDROINDOLE-2- CARBOXYLIC ACID (TRANDOLAPRIL) 6.3 g. of N-[1 S-Carboethoxy-3-phenylpropyl]-S-alanyl-2S,3aR,7aS- octahydroindole-2-carboxylic acid was dissolved in 63 ml of ethyl acetate at the reflux condition. The solution was maintained at reflux for 10-15 minutes, then was filtered hot and the filtrate was cooled to 25-35⁰C and stirred at that temperature for 30-60 minutes. Precipitated solid was filtered and washed with 5 ml of ethyl acetate, then was dried at 50-60°C to get 5.0 g of pure N-[1 S-

Carboethoxy-3-phenylpropyl]-S-alanyl-2S,3aR,7aS-octahydroindole-2-carboxylic acid (trandolapril ). EXAMPLE 3

PROCESS FOR RECRYSTALLIZATION OF N-[I S-CARBOETHOXY-S-PHENYL PROPYLl-S-ALANYL^S.SaRJaS-OCTAHYDROINDOLE^-CARBOXYLIC ACID (TRANDOLAPRIL)

3.0 g. of N-[1S-Carboethoxy-3-phenylpropyl]-S-alanyl-2S,3aR,7aS- octahydroindole-2-carboxylic acid was dissolved in a mixture of 40 ml of ethyl acetate and 3 ml of methanol at the reflux condition. The solution was maintained at reflux for 10-15 minutes, was filtered hot, and the filtrate was cooled to 25-35°C and then to 0-5⁰C. The solution was stirred at 0-5⁰C for 30-45 minutes.

Precipitated solid was filtered and washed with 3 ml of chilled ethyl acetate, then was dried at 60-70⁰C to get 2.6 g of pure N-[1S-Carboethoxy-3-phenylpropyl]-S- alanyl-2S,3aR,7aS-octahydroindole-2-carboxylic acid (trandolapril).

EXAMPLE 4

PROCESS FOR RECRYSTALLIZATION OF N-[1S-CARBOETHOXY-3- PHENYLPROPYL]-S-ALANYL-2S,3aR,7aS-OCTAHYDROINDOLE-2- CARBOXYLIC ACID (TRANDOLAPRIL) 2.0 g. of N-[1 S-Carboethoxy-3-phenylpropyl]-S-alanyl-2S,3aR,7aS- octahydroindole-2-carboxylic acid was dissolved in 40 ml of diethyl ether at the reflux condition. The solution was maintained at reflux for 10-15 minutes and then was cooled to 25-35⁰C and stirred at that temperature for 15-20 minutes. Precipitated solid was filtered and washed with 10 ml of diethyl ether, then was dried at 50-60°C to get 1.6 g. of pure N-[1 S-Carboethoxy-3-phenylpropyl]-S- alanyl-2S,3aR,7aS-octahydroindole-2-carboxylic acid (trandolapril).

EXAMPLE 5

PROCESS FOR RECRYSTALLIZATION OF N-[1 S-CARBOETHOXY-3- PHENYLPROPYL]-S-ALANYL-2S,3aR,7aS-OCTAHYDROINDOLE-2- CARBOXYLIC ACID (TRANDOLAPRIL)

3.0 g. of N-[1S-Carboethoxy-3-phenylpropyl]-S-alanyl-2S,3aR,7aS- octahydroindole-2-carboxylic acid was dissolved in 30 ml of isopropanol at the reflux condition. The solution was maintained at reflux for 5-10 minutes, then was filtered hot and the filtrate was cooled to 25-35°C and stirred at that temperature for 30-45 minutes. Precipitated solid was filtered and washed with 6 ml of isopropanol, then was dried at 60-70⁰C to get 2.1 g of pure N-[1 S-Carboethoxy-3- phenylpropyl]-S-alanyl-2S,3aR,7aS-octahydroindole-2-carboxylic acid (trandolapril).

EXAMPLE 6

PROCESS FOR RECRYSTALLIZATION OF N-[1S-CARBOETHOXY-3- PHENYLPROPYL]-S-ALANYL-2S,3aR,7aS-OCTAHYDROINDOLE-2- CARBOXYLIC ACID (TRANDOLAPRIL)

3.0 g. of N-[1S-Carboethoxy-3-phenylpropyl ]-S-alanyl-2S,3aR,7aS- octahydroindoIe-2-carboxylic acid was dissolved in 12 ml of methanol at the reflux condition. The solution was maintained at reflux for 5-10 minutes then was filtered hot, and the filtrate was cooled to 25-35°C and stirred at that temperature for 30- 45 minutes. Precipitated solid was filtered and washed with 1.5 ml of methanol, then dried at 50-60⁰C to get 0.9 g of pure N-[1S-Carboethoxy-3-phenylpropyl ]-S- alanyl-2S,3aR,7aS-octahydroindole-2-carboxylic acid (trandolapril).

EXAMPLE 7

PROCESS FOR RECRYSTALLIZATION OF N-[1 S-CARBOETHOXY-3- PHENYL PROPYLl-S-ALANYL^S.SaRJaS-OCTAHYDROINDOLE^-CARBOXYLIC ACID (TRANDOLAPRIL)

3.0 g of N-[1S-Carboethoxy-3-phenylpropyl]-S-alanyl-2S,3aR,7aS- octahydroindole-2-carboxylic acid was dissolved in a mixture of 30 ml of isopropanol and 6 ml of methanol at the reflux condition. The solution was maintained at reflux for 5-10 minutes, then was filtered hot and the filtrate was cooled to 25-35⁰C and stirred at that temperature for 30-45 minutes. Precipitated solid was filtered and washed with 6 ml of isopropanol, then was dried at 60-70⁰C to get 0.9 g. of pure N-[1S-Carboethoxy-3-phenylpropyl]-S-alanyl-2S,3aR,7aS- octahydroindole-2-carboxylic acid (trandolapril). EXAMPLE 8

PROCESS FOR THE PREPARATION OF A CAMPHOR SULFONATE OF BENZYL^R^aSJaR-OCTAHYDROINDOLE^-CARBOXYLATE 80.0 g. of (±)-Benzyl-octahydroindole-2-carboxylate hydrochloride (II) was taken in 800 ml of dichloromethane. Reaction mass pH was adjusted to 9-11 with 800 ml of 8% aqueous sodium carbonate solution below 30⁰C. The aqueous layer was separated and extracted with 160 ml of dichloromethane. Combined organic layers were distilled under reduced pressure and the residue was taken in 305 ml acetone and 45.7 g of (1S)-(+)-Camphor-10-sulfonic acid was added to the mixture at 20-25⁰C. The reaction mass was stirred at 20-25⁰C for 10-15 minutes. The precipitated solid was filtered and washed with 25 ml of chilled acetone and dried at 50-60⁰C, to afford 24 grams of the camphor sulfonate of benzyl-2R,3aS,7aR-octahydroindole carboxylate hydrochloride.

EXAMPLE 9

PROCESS FOR PREPARATION OF BENZYL-2R, 3aS, 7aR- OCTAHYDROINDOLE-2-CARBOXYLATE HYDROCHLORIDE 43.0 g of the camphor sulfonate of benzyl-2R,3aS,7aR-octahydroindole carboxylate were dissolved in 430 ml of dichloromethane and pH of the mixture was adjusted to 9-11 with 215 ml of 8% aqueous sodium carbonate solution. The aqueous layer was separated and extracted with 85 ml of dichloromethane. Combined organic layer was distilled under reduced pressure and the residue was taken in 215 ml acetone, then dry HCI gas was passed through the reaction mass until the pH of reaction mass was approximately 2. The reaction mass was cooled to 0-10⁰C and stirred for 20-30 minutes. Precipitated solid was filtered, washed with 20 ml of chilled acetone and dried at 50-60⁰C to yield 20.8 g of benzyl- 2R,3aS,7aR-octahydroindole-2-carboxylate hydrochloride. EXAMPLE 10

PROCESS FOR PREPARATION OF N-[IS- CARBOETHOXY-3- PHENYL PROPYL]-S-ALANYL-2R,3aS7aR-OCTAHYDROINDOLE-2-CARBOXYLIC ACID, AN ISOMER OF TRANDOLAPRIL

17.0 g of benzyl-2R,3aS,7aR-octahydroindolθ-2-carboxylate hydrochloride of formula (V) was taken in 170 ml of methylene dichloride. Reaction mass pH was adjusted to 9-11 with 102 ml of 8% sodium carbonate solution at 25-35°C. Organic layer and aqueous layer were separated. Aqueous layer was extracted twice with 85 ml of methylene dichloride. Combined organic layer was dried over 5 g. sodium sulfate. Organic layer was distilled under vacuum below 60⁰C. To the crude material 140.0 ml of methylene dichloride was added at 25-35°C. To this reaction mass 15.1 g. of N-[1 (S)-ethoxycarbonyl-3-phenylpropyl]-S-alanine of formula III was added under stirring at 25-35°C. Reaction mass was cooled to 0- 5°C and 3.8 g of hydroxybenzotriazole and 12 g. of dicyclohexyl carbodiimide - were added at 0-5⁰C. Temperature of the reaction mass was raised to 20-25⁰C and maintained at 20-25⁰C for 3 hours. Insoluble solid was filtered off and the filtrate was washed three times with 170 ml of 5% sodium bicarbonate solution. Filtrate was distilled completely under vacuum below 7O⁰C. Residue was taken up in 240 ml of isopropanol, and hydrogenated under 2-3 kg/cm² hydrogen pressure in the presence of 8.6 g of 10% palladium-charcoal (50 % wet) at 25- 35°C until consumption of hydrogen ceased. The catalyst was filtered out and washed with 17 ml of isopropanol. The filtrate was evaporated under vacuum below 40⁰C to afford 17.3 g of N-[1S-carboethoxy-3-phenylpropyl]-S-alanyl- 2R,3aS,7aR-octahydroindole-2-carboxylic acid, an isomer of trandolapril.

EXAMPLE 11

PROCESS FOR THE PREPARATION OF BENZYL-2S,3aR,7aS- OCTAHYDROI N DOLE-2-CARBOXYLATE HYDROCHLORIDE OF FORMULA (Na).

STAGE (A): PREPARATION OF (±VTRANS OCTAHYDROlNDOLE-2- CARBOXYLIC ACID HYDROCHLORIDE (VIh 73.0 grams of 3,3a,4,5,6,7-2H-hexahydroindole-2-carboxylic acid hydrochloride (Vl) was hydrogenated under normal pressure in 730 ml of water in the presence of 18.2 grams of rhodium on carbon (50% wet) at 20-25⁰C for 16-18 hours. The catalyst was filtered off and the filtrate was evaporated to dryness. The residue was taken in acetone and stirred at 25-30⁰C for 20-30 minutes. Solids were filtered and washed with acetone to afford 62.6 grams of (±) octahydroindole-2-carboxylic acid hydrochloride.

STAGE (B): PREPARATION OF f±VBENZYL-OCTAHYDROINDOLE-2- ' CARBOXYLATE HYDROCHLORIDE (Vl)

Thionyl chloride (28 ml) was added dropwise to a mixture of (±)- octahydroindole-2-carboxylic acid hydrochloride (VII) (23.0 grams) and benzyl alcohol (138 ml) at 0-10⁰C for 2-3 hours. The reaction mass was maintained at 25-35°C for 14-16 hours. The reaction mass was slowly added to 897 ml of diethyl ether and stirred at 25-35°C for 30-40 minutes. The solid was filtered and washed thoroughly with 115 ml diethyl ether, then dried at 50-60⁰C to obtain 21.6 grams of the title compound.

STAGE (C): PREPARATION OF CAMPHOR-SULFONATE OF BENZYL-2S. 3aR, 7aS-OCTAHYDROINDOLE-2-CARBOXYLATE

(±)-Benzyl-octahydroindole-2-carboxylate hydrochloride (VIII) (31 grams) was taken in dichloromethane (310 ml) and pH was adjusted to 9-11 with 130 ml of 8% aqueous sodium carbonate solution at below 3O⁰C. The aqueous layer was separated and extracted with 100 ml of dichloromethane. Combined organic layers were distilled under reduced pressure, then the residue was taken in acetone (158.5 ml) and (1 R)-(-)-Camphor-10-sulfonic acid (21.34 grams) was added to the mixture at 20-25 ⁰C. The reaction mass was stirred at 20-25⁰C for 20-30 minutes. The precipitated solid was filtered and washed with chilled acetone (30 ml), then dried at 50-60⁰C to afford 16 grams of the camphor- sulfonate of benzyl-2S,3aR,7aS-octahydroindole carboxylate hydrochloride.

STAGE (D): PREPARATION OF BENZYL-2S, 3aR, 7aS-OCTAHYDROINDOLE- 2-CARBOXYLATE HYDROCHLORIDE (Na) The camphor sulfonate of Benzyl-2S,3aR,7aS-octahydroindole carboxylate (15 grams) was dissolved in dichloromethane (150 ml) and the pH of the mixture was adjusted to 9-11 with 70 ml of 8% aqueous sodium carbonate solution. The aqueous layer was separated and extracted with dichloromethane (40 ml). The combined organic layer was distilled under reduced pressure, the residue was taken in 150 ml of acetone, and dry HCI gas was passed through the reaction mass to adjust the pH of the reaction mass to about 2. The reaction mass was cooled to 0-10⁰C and stirred for 20-30 minutes. Precipitated solid was filtered, washed with 10 ml of chilled acetone, and dried at 50-60⁰C to yield 7.0 grams of Benzyl-2S,3aR,7aS-octahydroindole-2-carboxylate hydrochloride.

EXAMPLE 12

PROCESS FOR THE PREPARATION OF COMPOUND BENZYL-N-[I S- CARBOETHOXY -3-PHENYLPROPYL]-S-ALANYL-2S,3aR,7aS- OCTAHYDROINDOLE-2-CARBOXYLATE OF FORMULA (IVa):

Benzyl-2S,3aR,7aS-octahydroindole-2-carboxylate hydrochloride (2.5 g) of Formula (Ha) was taken in 70 ml of methylene chloride. 7.28 ml of triethylamine was added to the reaction mass at 25-30⁰C and the reaction mass was stirred at 25-30°C for 25-30 minutes under a nitrogen atmosphere. 4.75 g of N-[1 (S)- ethoxycarbonyl-3-phenylpropyl]-S-alanoylchloride hydrochloride of Formula (IX) in 70 ml of methylene dichloride was added to the reaction mass over 1-2 hours at 0- 5⁰C, and the mixture was maintained for 16-18 hours under the nitrogen atmosphere. The reaction mass was quenched with 62.5 ml of water. The organic layer washed twice with 62.5 ml of 5% aqueous sodium carbonate solution, followed by 62.5 ml of water. The organic layer was further washed with 10% hydrochloric acid solution, then was diluted with 70 ml of methylene chloride and washed with water (4 x 62.5 ml) until the pH of the water washings was 5.5- 6.5. Methylene chloride was distilled under reduced pressure to afford 4.4 grams of the title compound. EXAMPLE 13

ALTERNATIVE PROCESS FOR THE PREPARATION OF BENZYL-N-[I S- CARBOETHOXY^-PHENYLPROPYL]-S-AI-AN YL-2S,3aR,7aS- OCTAHYDROINDOLE^-CARBOXYLATE OF FORMULA (IVa):

To the suspension of N-[1 (S)-ethoxycarbonyl-3-phenylpropyl]-S-alanine (Formula III) (6.2 grams) in dimethylformamide (25 ml), 1-Hydroxybenzotriazole (3.02 grams), Benzyl-2S,3aR,7aS-octahydroindole carboxylate hydrochloride (Formula Na) (6.5 grams), N-ethylmorpholine (3.02 ml) and dicyclohexyl carbodiimide (4.87 grams) were added at 0-5⁰C. The mixture was stirred at 20- 25°C for 4.5 hours and 55 ml of ethyl acetate was added to the reaction mass. The unwanted solid was removed by filtration. Solvent was distilled from the filtrate and the residue was taken up in diethyl ether (109 ml), and washed with saturated aqueous sodium carbonate (2 x 109 ml) followed by water (2 x 100 ml). To the organic layer dichloromethane (150 ml) was added and washed with (5 x 185 ml) of dilute HCI solution, then further washed with water (23 x 100 ml). The organic layer was dried over sodium sulfate and solvent was distilled off under reduced pressure below 40⁰C to afford 10.3 grams of Benzyl-N-[1 S-carboethoxy- 3-phenylpropyl]-S-alanyl-2S,3aR,7aS-octahydroindoIe-2-carboxylate.

EXAMPLE 14

PROCESS FORTHE PREPARATION OF (I)-TRANS-OCTAHYDROINDOLE^-

CARBOXYLICACID OF FORMULA(II):

STAGE(A): PREPARATIONOF 3,4,5,6,7,8-HEXAHYDRO-IH-QUINOLIN^-

ONE(X)

A mixture of cyclohexanone (392 g), acrylonitrile (212 g), cyclohexylamine

(20 g), hydroquinone (0.4 g) and glacial acetic acid (4 g) was heated to 200°C and maintained for 5 hours. The reaction mass was cooled to 50-60⁰C followed by addition of isopropanol (250 ml) and stirring at 25-35⁰C for 30-60 minutes. The separated solid was filtered and washed with isopropanol (50 ml) then dried at 50-

60°C to yield 232.5 grams of the title compound. STAGE (B): PREPARATION OF f±VTRANS-OCTAHYDRO-I H-QUINOLIN-Σ- ONE (Xl)

A mixture of 3,4,5,6,7,8-Hexahydro-1 H-quinolin-2-one (165 g) of Formula (X), sodium formate (46.1 g) and formic acid (795 g), was heated to reflux and maintained for18 hours, then cooled to 0-10⁰C, pH of the reaction mass was adjusted to 8-9 with 20% aqueous NaOH solution followed by extraction of the reaction mass with ethyl acetate (3 x 1000 ml). The organic layer was separated and dried over dry sodium sulfate, then solvent was distilled off below 5O⁰C under reduced pressure. Cyclohexane (500 ml) was added to the residue and stirred for 1 hour at 25-35°C. The separated solid was filtered and washed with cyclohexane (50 ml), then dried at 50-60⁰C to yield 117 grams of the title compound.

STAGE (C): PREPARATION OF ^-3,3-DICHLORO-TRANS-OCTAHYDRO-I H- QUINOLIN-2-ONE (XII)

(±)-Trans-octahydro-1 H-quinolin-2-one (Xl) (110.0 grams) and phosphorus pentachloride (138 grams) were taken into chloroform (2200 ml), and a solution of sulfuryl chloride (206.5 grams) in chloroform (220 ml) was added at 20-30⁰C over 30 minutes, then the mixture was heated to reflux for 6 hours. The reaction mass was cooled to 20-25⁰C and maintained for 8 to 10 hours. The pH was adjusted to about 7 at 0-10⁰C with saturated potassium carbonate solution, then the reaction mass was extracted with dichloromethane and solvent was distilled under reduced pressure. The residue was dissolved in methanol (700 ml) at reflux temperature followed by a carbon treatment and removal of the solids. Cooled the filtrate to 0- 5°C and stirred for 15 minutes, then filtered the precipitated solid and washed with chilled methanol (55ml). Dried the solid at 50-60⁰C to yield 77.7 grams of the title compound.

STAGE (D): PREPARATION OF (±) 3-CHLORO-TRANS-OCTAHYDRO-I H- QUINOLIN-2-ONE (XIII)

(±)-3,3-Dichloro-trans-octahydro-1H-quinolin-2-one (58 grams) (XII) and triethylamine (36.2 ml) were taken into methanol (1450 ml) followed by the addition of Raney nickel (29 grams). The mixture was cooled to 20-25⁰C, followed by passing dry hydrogen gas for 1 to 2 hours. Filtered the reaction mass and distilled off the filtrate completely under reduced pressure at below 60⁰C. Dissolved the residue in ethyl acetate (150 ml), then water (200 ml) was added, followed by separation of the organic layer and aqueous layer. Washed the organic layer with water (50 ml) and distilled off the solvent under reduced pressure at below 60⁰C. The residue was dissolved in diisopropyl ether and stirred at 0-5⁰C for 15-30 minutes. Filtered the separated solid and dried at 50- 60⁰C to yield 38.2 grams of the title compound.

STAGE (E): PREPARATION OF (±VTRANS-OCTAHYDROINDOLE-2- CARBOXYLIC ACID ΠD

Barium hydroxide octahydrate (58.25 g), water (1055 ml) and (±)-3-Chloro- trans-octahydro-1 H-quinolin-2-one (XIII) (33.0 g) were heated to reflux and stirred for 4 hours. Cooled the reaction mass to 20-25°C and sulfuric acid (7.9 ml) was slowly added at below 30°C. Heated the reaction mass to reflux for 1 hour, cooled to 25-35⁰C, and filtered the resultant salt. Adjusted the pH of filtrate to 6.5 with 20% aqueous sodium hydroxide solution, distilled off water completely under reduced pressure at below 70°C. Residue was dissolved in ethanol (250 ml) at reflux, filtered the separated salt. Distilled ethanol from the filtrate completely under reduced pressure at below 40⁰C. Acetone (100 ml) was added to the residue and stirred for 10 minutes, filtered the separated solid and dried at 50- 60°C. The solid was slurried in methanol (80 ml) at 25-30°C for 15-30 minutes and filtered further washed with methanol (5 ml). Dried the solid at 50-60°C to yield 9.6 grams of the title compound, which can be subsequently converted to trandolapril.

Claims

CLAIMS:

1. A process for preparing trandolapril, comprising condensing (±)- Benzyloctahydroindole-2-carboxylate with N-[1 (S)-ethoxycarbonyl-3- phenylpropyl]-L-alanine to form an intermediate product, and debenzylating the intermediate product to form a mixture of diastereomers of N-[1 (S)-Carboethoxy- 3-phenylpropyl]-S-alanyI-octahydroindole-2-carboxylic acid.

2. The process according to claim 1 , wherein the condensing and debenzylating steps are conducted without isolating the intermediate product.

3. The process according to claim 1 , wherein debenzylating comprises hydrogenating.

4. The process according to claim 1 , further comprising crystallizing trandolapril from a solution containing the mixture of diastereomers of N-[I (S)- Carboethoxy-3-phenylpropyl]-S-alanyl-octahydroindole-2-carboxyIic acid.

5. The process according to claim 4, further comprising purifying trandolapril by dissolving crystals in a solvent and re-crystallizing.

6. The process according to claim 1 , wherein the (±)-Benzyloctahydroindole- 2-carboxylate is used in the form of an acid addition salt.

7. A process for preparing N-[1S-carboethoxy-3-phenylpropyl]-S-alanyl- 2R,3aS,7aR-octahydroindole-2-carboxylic acid, comprising condensing Benzyl- 2R,3aS,7aR-octahydroindole-2-carboxylate, or an acid addition salt thereof, with N-[1S-ethoxycarbonyl-3-phenylpropyl]-L-alanine to form an intermediate product, and debenzylating the intermediate product.

8. A compound N-[1 S-carboethoxy-3-phenylpropyl]-S-alanyl-2R,3aS,7aR- octahydroindole-2-carboxylic acid.

9. A compound Benzyl-2R,3aS,7aR-octahydroindole-2-carboxylate, or an acid addition salt thereof.

10. A process for preparing 3,4,5,6,7,8-hexahydro-1 H-quinolin-2-one, comprising condensing cyclohexanone with acrylonitrile, in the presence of cyclohexylamine and hydroquinone.

11. A process for preparing Benzyl-2S,3aR,7aS-octahydroindole-2-carboxylate hydrochloride, comprising reacting (±)-trans-Benzyloctahydroindole-2-carboxylate hydrochloride with (1 R)-(-)-camphor-10-sulfonic acid to form a salt, and hydrolyzing the isolated salt.

12. A process for preparing Benzyl-2S,3aR,7aS-octahydroindole-2-carboxylate hydrochloride, comprising reacting (±)-trans-Benzyloctahydroindole-2-carboxylate hydrochloride with (1S)-(+)-camphor-10-sulfonic acid to form a salt, and hydrolyzing the isolated salt.

13. A process for preparing trandolapril, comprising: a) condensing (±)-Benzyloctahydroindole-2-carboxylate with N-[I(S)- ethoxycarbonyl-3-phenylpropyl]-L-alanine to form an intermediate product; b) hydrogenating the intermediate product to form a mixture of diastereomers of N-[1 (S)-Carboethoxy-3-phenylpropyl]-S-alanyl-octahydroindoIe- 2-carboxylic acid; and c) crystallizing trandolapril from a solution containing the mixture of diastereomers of N-[1 (S)-Carboethoxy-3-phenylpropyl]-S-alanyl-octahydroindole- 2-carboxylic acid.

14. The process according to claim 13, wherein the condensing and hydrogenating steps are conducted without isolating the intermediate product.