Title of Invention	PROCESS FOR PREPARATION OF (TRANS)-OCTAHYDRO-1H-INDOLE-2-CARBOXYLIC ACID
Abstract	A process for preparation of manufacture of octahydroindole -2-carboxylic acid of formula (1). wherein the A/B ring junction is trans, its cnantiomers thereof its esters and salts thereof, and more specifically [2(3, 3ap, 7aa] or [2S, 3aR, 7aS]-octahydro-lH-indole-2-carboxylic acid, its esters and salts thereof of formula (I1) of high optical purity and substantially free of other isomers and impurities, where the diastereoselectivity in providing irons octahydroindole-lH-2-carboxylic acid is enhanced by by selection of proper pH conditions, catalyst and medium of reaction during catalytic hydrogenation of [3,3a,4,5,6,7]- hexahydro-2H-indole-2-carboxylic acid of formula (iii) The compounds of formula (I) and (I ) are valuable as intermediates in the synthesis of the therapeutically valuable Angiotensin Converting Enzyme (ACE) Inhibitor, viz. Trandolapril. To The Controller of Patents The Patent Office Mumbai

Title of Invention

PROCESS FOR PREPARATION OF (TRANS)-OCTAHYDRO-1H-INDOLE-2-CARBOXYLIC ACID

Abstract

A process for preparation of manufacture of octahydroindole -2-carboxylic acid of formula (1). wherein the A/B ring junction is trans, its cnantiomers thereof its esters and salts thereof, and more specifically [2(3, 3ap, 7aa] or [2S, 3aR, 7aS]-octahydro-lH-indole-2-carboxylic acid, its esters and salts thereof of formula (I1) of high optical purity and substantially free of other isomers and impurities, where the diastereoselectivity in providing irons octahydroindole-lH-2-carboxylic acid is enhanced by by selection of proper pH conditions, catalyst and medium of reaction during catalytic hydrogenation of [3,3a,4,5,6,7]- hexahydro-2H-indole-2-carboxylic acid of formula (iii) The compounds of formula (I) and (I ) are valuable as intermediates in the synthesis of the therapeutically valuable Angiotensin Converting Enzyme (ACE) Inhibitor, viz. Trandolapril. To The Controller of Patents The Patent Office Mumbai

Full Text	FORM -2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION (See section 10; rule 13) I. TITLE PROCESS FOR PREPARATION OF (TRANS)-OCTAHYDRO-IH-INDOLE-2-CARBOXYLIC ACID; ITS ESTERS AND SALTS THEREOF. 2. (a) LUPIN LTD. (b) 159, CST Road, Kalina, Santacruz (East), Mumbai - 400 098, State of Maharashtra, India, (c) An Indian Company. The following specification particularly describes the nature of this invention and the manner in which it is to be performed. FIELD OF THE INVENTION The present invention relates to process for manufacture of octahydroindole -2-carboxylic acid of formula (I), wherein the A/B ring junction is trans, its enantiomers thereof its esters and salts thereof, and more specifically [2p, 3ap, 7aa] or [2S, 3aR, 7aS]-octahydro-lH-indole-2-carboxylic acid, its esters and salts thereof of formula (I ) of high optical purity and substantially free of other isomers and impurities. d1) 2 The compounds of formula (I) and (I1) are valuable as intermediates in the synthesis of the therapeutically valuable Angiotensin Converting Enzyme (ACE) Inhibitor, viz. Trandolapril of formula (II). BACKGROUND OF THE INVENTION (2S,3aR,7aS)-l-[(2S)-2-[[(lS)-l-(ethoxycarbonyl)-3-phenylpropyl] amino]-l-oxopropyl] octahydro-lH-indole-2-carboxyilc acid, gcncrically known as Trandolapril of formula (II) is a therapeutically valuable ACE inhibitor. ( A key intermediate in preparation of trandolapril is the trans isomer of the octahydro-lH-indoIe-2-carboxylic acid of formula (I) or (I1), referred to hereinbefore. Taking the case of trans configuration of the hydrogen atoms on C3a and C7a of the octahydro-lH-indole-2-carboxylic acid moiety, there are two possible configurations for me Vicyc'le, namely the (3acc, ?a]V) configuration, as represented by "rormu'ia (Ti ) ana tpa'p), 7aa) configuration, represented by formula (I ), shown below. H H Taking the carboxyl group on C2 into consideration, this group can be oriented in the exo position or p position or the carboxyl group can be oriented in the endo position or the a position, which gives rise to four isomeric compounds of formula (I ), (I ), (I ), and (I ) shown below. 3 Several methods are known for preparation of the abovementioned trans octahydro-lH-indoIe-2-carboxylic acid derivatives, namely as disclosed in 1) US Patent No. 4,933,361-(Urbach et. al.), wherein four methods are disclosed for synthesis of octahydro-lH-indole-2-carboxylic acid. The first method (Method-I) comprises acylation of a compound of formula (1), followed by anodic oxidation in the presence of an aliphatic alcohol and in the presence of a conducting salt to give compound of formula (2). Reaction of compound (2) with Irimethylsilyl cyanide in the presence of a Lewis acid gives the corresponding cyano derivative (3). Hydrolysis of the cyano derivative gives compound of formula (1), along with the corresponding cis isomers (cis configuration of hydrogen atoms on C3a and C7a of the bicycle), all in the form of racemates. The second method (Method-II) comprises Beckmann rearrangement of compound (4) to give compound (5). Halogenation gives compound (6), which on catalytic reduction gives compound (7). Compound (7) is then converted to compound (I) through a Favorskii reaction. Compound (I) thus obtained is accompanied by the corresponding cis isomers (cis configuration of hydrogen atoms on C3a and C7a of the bicycle), all in the form of racemates. In the third method (Method-Ill) compound of formula (I), in which the hydrogen atoms on the bridgehead carbon have the trans configuration is prepared by first reduction of compound of formula (8) with sodium formate/formic acid to give compound (9) and reacting compound (9) as in Method-II to give compound (I). 4 The last method (Method-IV) comprises catalytic hydrogenation or reduction using complex borohydrides or boranc-aminc complexes, of enamincs of formula (10 or 11), wherein the carboxylic acid group is optionally protected as alkyl or aralkyl esters. The four methods disclosed in US Patent No. 4,933,361 are schematically represented in Scheme-I. Methods I and II as mentioned hereinearlier give compound (I) in admixture with the corresponding cis isomers. In addition, they involve the steps of anodic oxidation and cyanation reactions using expensive and hazardous compounds such as tetramethylammonium tetrafluoborate and trimethylsilyl cyanide respectively. Further, the halogenation and dehalogenation reactions utilize corrosive phosphorous pentachloride and hazardous Raney Nickel, which in general render the methods not attractive on a commercial scale. Moreover, Methods-I and II result in formation of cis octahydro1H-indole-2-carboxylic acid, rather than the trans analogue as can be seen from the description residing in Examples 1 and 4 of the US Patent No. 4,933,361. Method IV is described in Examples 48 and 89 of the US Patent No. 4,933,361. In Example 48, the imino compound (11), namely (3,3a,4,5,6,7)-2H-hexahydroindole-2-carboxylic acid hydrochloride is hydrogenated using platinum on carbon in glacial acetic acid as solvent. After the reduction the residue obtained after filtration of the catalyst and evaporation of acetic acid is caused to precipitate out from ethanol cooled to -20° C and isolated after concentration of ethanol followed by addition of isopropanol to give (2p,3a[3.7aa)-octahydroindole-2-carboxylic acid of formula (1 ). However, the description does neither provide any information on the amount ot the trans product obtained, nor it gives any details on the proportions of other isomers formed in the reaction. Further, in our hands reproduction of the conditions described in Example 48 invariably was found to give cis isomers in major amounts. In particular, the ratio of the cis : trans isomers obtained was found to be 53 : 36. In the description provided in Example-89, the imino compound (11), namely (3,3a,4,5,6,7)-2H-hexahydroindole-2-carboxylic acid hydrochloride is reduced with sodium borohydride in isopropanol as solvent at 40-50 C. Fractional crystallization of the residue obtained from a mixture of chloroform-diisopropyl ether gives the cis and trans octahydro-lH-indole-2-carboxylic acids. Furthermore, both the Examples 48 and 89 of the US Patent No. 4,933,361 do not mention the optical purity of the trans isomer obtained. 5 2) F. Brion et. al. in Tetrahedron Letters, 1992, 33(34), 4889-4892 in addition to providing a detailed account of the difficulties faced in preparation of the trans isomer (I) and (I!) have described a enantioselective synthesis of comppund (I ), starting from a meso diester, as summarized in Scheme-II. Even though, this method is reported to give the desired 2/3 isomer (I ) in a ratio of 95 over the corresponding 2a isomer, however, this method is not only lengthy but also utilizes expensive and corrosive chemicals and enzymes like 6 diethyldihydroaluminate, sodium hydride and Pig Liver Esterase, thereby rendering the method not cost-effective as well as having little commercial application. L. Belvisi et. al in Tetrahedron, 2001, 57, 6463-6473 have reported a stereo selective synthesis of both cis and trans octahydroindoIc-2-carboxyIic acid as summarized in Scheme-Ill. The method comprises conversion of N-Boc protected dimethyl glutamate (A) to the 4-allyl pyroglutamic ester (C), via (B). The imide (C) was selectively reduced to the hemiaminal (D) using lithium triethylborohydride at -78° C, which was converted to the corresponding acetoxy derivative (E). Allylation of compound (E) with a twofold excess of allyltributyltin and tert-butyldimethylsilyl trifluoromethanesuifonate gave the diallylated proline derivative as a mixture of trans and cis isomers (F and G) in a ratio of 3:1. The ring closure metathesis of the separate stereoisomers (trans and cis) using Grubbs catalyst gave the corresponding ring-closed trans and cis derivatives (H and J respectively), which on hydrogenation with 5% Pd on charcoal afforded the respective trans and cis fused octahydro-indole-2-carboxylic acid (K and L respectively). This method is also not viable on a commercial scale since it utilizes expensive, corrosive and hazardous chemicals like allyl bromide, tri fluoroacetic acid, lithium triethylborohydride, butyl lithium, allyltributyltin, tcrt-butyldimethylsilyl trifluoromethanesuifonate etc., as well as cryogenic temperatures of-780 C. PCT Application No. WOJ30/40555. {Ebel et. al.) discloses a method for producing (2S,4R,9S)-octahydro-lH-indole-2-carboxylic acid comprising reaction of a 3,3-dialkoxypropane of formula" (M) with water in the presence of an acid catalyst to give the 3,3-diaIkoxypropionaldchyde of formula (N). which on Henry reaction with nitromethane gives the 4,4-dia!koxy-l-nitro-2-butanol of( formula (0). Dehydration of compound (O) gives the nitroolefin (P), which on Diels-Alder reaction gives the corresponding irans-4-(2,2-dialkoxyethyl)-5-nitro-l-cyclohexene, which is further hydrogenated to give the corresponding cyclohexane derivative (Q) as a racemic mixture. Compound (Q) thus obtained is resolved to give (lS,2R)-l-amino-2-(2,2-dialkoxyethyl)-cyclohexane in the enantiomerically pure form (S), which is hydrolysed to the corresponding aldehyde (T). The aldehyde (T) is converted to the corresponding nitrile (U), which on hydrolysis gives the object compound. The chemistry utilized is summarized in Scheme-IV. Even though, the trans isomer is a major product of this process with the ratio of the trans to the cis isomers produced being 3:1, however, it is only lengthy, but also utilizes highly toxic sodium cyanide, which render the process of little industrial applicability. 7 From the foregoing, it is apparent that the methods available in the prior art for the synthesis of trans octahydroindole-1H-2 carboxylic acid (I) and/or (I ) suffer from the following limitations in that most of the methods : i) give the cis isomer, rather than the trans isomer in major amounts, ii) are not only lengthy but also utilize expensive, hazardous, toxic and corrosive chemicals and enzymes like dicthyldihydroaluminale, sodium hydride, allyl bromide, trifluoro acetic acid, lithium triethylborohydride, butyl lithium allyltributyltin, tert-butyldimethylsilyl trifluoromethanesulfonate, sodium cyanide. Pig Liver Esterase etc and iii) utilize cryogenic temperatures in some of the synthetic steps, which overall render the methods less cost-effective and commercially unattractive. There exists a need, therefore, for a practical method for preparation of trans isomer of octahydroindole-1H-2- carboxylic acid, (I) and/or (I1), which overcomes the shortcomings of the prior art methods mentioned hereinabove. For the foregoing reasons, the synthesis of /raws-fused octahydroindole-1-H-2 carboxylic acid was of significant interest for the present inventors, both because of the 10 inherent challenge associated with stereo selective formation of the trans isomer of octahydro-lH-indoIe-2-carboxylic acid as well as its use in synthesis of trandolapril. OBJECTS OF THE INVENTION It is, therefore, an object of the present invention to provide a method for preparation of octahydroindole-lH -2-carboxylic acid, its esters and salts thereof, predominantly as the trans isomer of the formula (I), and more specifically, [2p,3aB,7act] or [2S,3aR,7aS]-octahydro-lH-indole-2-carboxylic acid, its esters and salts thereof of formula (I1), which is convenient; simple; cost-effective; avoids use of toxic, corrosive and hazardous chemicals and which, moreover, gives the desired trans isomers (I1) in high chemical yield and optical purity. Yet another object of the present invention is to provide a convenient; simple; cost-effective and efficient method for synthesis of the therapeutically valuable ACE inhibitor, Trandolapril using trans octahydroindole-lH-2-carboxylic acid, its esters and salts thereof of formula (I), and more specifically, [2p,3ap,7acc] or [2S,3aR,7aS]-octahydro-lH-indole-2-carboxylic acid, its esters and salts thereof of formula (I1). SUMMARY OF THE INVENTION It was found with surprising effect that the hydrogenation or reduction of the mixture containing enamine (10) and imine (11) of Scheme-I in turn corresponding to compound (II) of the present invention predominantly gives the trans isomer of formula (I) and/or (I!)by i) proper selection of the pH conditions at which the reduction is carried out, ii) proper selection of the transition metal catalyst for the reductive step, and iii) proper selection of the medium in which the reduction is carried out. In particular, it was found that a ratio of trans : cis isomers greater than or equal to 1 : 1 could be achieved by carrying out the reduction of the imine compound alkaline conditions in the presence of a transition metal catalyst containing rhodium and in the presence of water or mixture of water and a water-miscible organic solvent as a medium of reaction. Such a selection of the right and proper pH conditions, catalyst and medium of reaction in giving the trans octahydro-1H-indole-2-carboxylic acids of formula (I), its enantiomers thereof and (I1) forms the basis for one aspect of the present invention. The trans isomer of formula (I), thus obtained can be separated from the corresponding cis isomers formed in the reaction, by a selective fractional crystallization method from a water-miscible organic, wherein the object compound (I) is obtained in high purity, 11 substantially free of the corresponding cis isomer and other impurities. This forms the basis for another aspect of the present invention. Finally, the trans isomer (I), and its enantiomers thereof thus obtained as a mixture of racemates can be used as such or can be resolved to give the specific isomer (I1), which collectively can be used for synthesis of trandolapril of formula (II). Thus in one aspect of the present invention, there is provided a process for preparation of [2B, 3aB 7aa] or [2S,3aR,7aS]- 2,3,3a,4,5,6,7,7a-octahydro-lH-indole-2- carboxylic acid, its esters and salts thereof of formula (I1), comprising catalytic hydrogenation of [3,3a,4,5,6,7]- hexahydro-2H-indole-2-carboxylic acid of formula (111) under alkaline conditions in the presence of a transition metal catalyst containing rhodium and in the presence of water or a mixture of water and a water-miscible orgamc""so]vent andlractibnaT crystallization of the mixture of trans and cis octahydro lH-indole-2-carboxy!ic acid thus obtained from a water-miscible organic solvent at a temperature of between 60°JZ to 80 C to give trans octahydro lH-indole-2-carboxylic acid of formula (I), its enantiomers thereof and esters and salts thereof, and resolution of compound of formula (I), after conversion to its N-acetyl derivative of formula (VII) 12 using 1-cinchonidine in organic solvent to give compound of formula (I!). In a preferred aspect of the present invention there is provided a stereoselective, simple, convenient and cost-effective method for preparation of trans octahydroindoIe-lH -2-carboxylic acid of formula (I) and its enantiomers thereof and its esters and salts thereof, and/or (I) [2B,3aB,7so] or [2S,3aR,7aS]-octahydro-lH-indole-2-carboxylic acid, its esters and salts thereof of formula (I1), in predominant amounts, comprising catalytic hydrogenation of [3,3a,4,5,6,7]-2H- hexahydroindole-2-carboxylic acid of formula III, 13 under alkaline conditions in the presence of a transition metal catalyst containing rhodium and in the presence of water or a mixture of water and a water-miscible organic solvent at a temperature of between 30° C to 35° C and at a pressure of 50-60 psi of hydrogen gas . In another aspect of the present invention there is provided a stereoselective, simple, convenient and cost-effective method for preparation of compound of formula (I) and its enantiomers thereof and its esters and salts thereof, and/or [2B,3ap,7aa] or [2S,3aR,7aS]-octahydro-lH-indole-2-carboxylic acid, its esters and salts thereof of formula (I1), in high purity, and substantially free of the corresponding cis isomers and other impurities comprising catalytic hydrogenation of [3,3a,4,5,6,7]-2H- hexahydroindole-2-carboxylic acid of formula III under alkaline conditions in the presence of a transition metal catalyst containing rhodium and in the presence of water and a mixture of water and a water-miscible organic solvent at a temperature of between 30° C to 35° C and at a pressure of 50-60 psi of hydrogen gas, followed by repeated fractional crystallization of the product thus obtained from a water-miscible organic solvent at a temperature of 60-80 C to give 14 compound of formula (I) and its enantiomers thereof and its esters and salts thereof, in high optical purity and free of the corresponding cis isomer. In yet another aspect of the present invention, there is provided a process for preparation of [2p,3ap,7aa] or [2S,3aR,7aS]-octahydro-lH-indole-2-carboxylic acid; its esters and salts thereof of formula (I1), in high purity, and substantially free of the corresponding cis isomers and other impurities comprising resolution of the N-acetyl derivative of compound of formula (I) i. e. a racemic compound of formula (VII) with 1- cinchonidine to give compound of formula (I ), comprising the steps of; a) reacting compound of formula (VII) with an equimolar or slight excess of cquimolar proportion of 1-cinchonidine in an organic solvent to give the 1-cinchonidine salt of formula (VIII), 15 b) reacting the cinchonidinc salt of formula (VIII) with an acid in an organic acid to give compound of formula (IX), and c) N-deacylation of compound of formula (IX) by treatment with an acid to give compound of formula (I1). In a further aspect of the present invention there is provided a stereoselective, simple, convenient, and cost-effective method for preparation of trandolapril of formula (II). i) utilizing compound of formula (I), free of the corresponding cis isomers and other impurities obtained by the selective method enumerated hereinabove, followed by separation of the desired diastereomer of trandolapril from a mixture obtained thereon, or ii) utilizing compound of formula (I1) obtained by the selective method enumerated hereinabove. 16 DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for preparation of trans octahydroindole-lH-2-carboxylic acid derivatives via catalytic hydrogenation of the precursor imincs. This is a methodology generally practiced for synthesis of amines. However, the stereochemical outcome of such a reductive method is largely dependent on the overall effect of number of variables acting simultaneously, which makes the method highly sensitive. Of particular significance is the extent of diastereoselectivity achieved when an angular imine compound of formula (III) is subjected to reduction, wherein the C-2 and C-3a positions of the bicycle are racemic i. e. in (R/S) configuration. Compound of formula (III) can be prepared by the methods known in the art, specially by the method disclosed in US Patent No. 4,933,361. The diastereoselectivity of the reaction in giving either the cis or trans octahydroindole-lH-2-carboxylic acid, in principle is determined by the transition metal catalyst employed, the amount of catalyst used, the medium of reaction, the substrate concentration, pH of the reaction, the hydrogen gas pressure etc. As mentioned hereinearlier, the known methods for reduction of the imine compound of formula (III) have invariably been carried out under acidic pH conditions, for example as described in Examples 48 and 89 of US Patent No. 4,933,361, which is diastereoselective in leading to formation of cis octahydroindole-lH-2-carboxylic acid in predominant amounts. Further, the known methods while acknowledging the importance of the transition metal catalyst in dictating the diastereoselectivity, however, arc vague in recommending specific catalyst(s) as well as other variables, which could bring about a reversal in the diastereoselectivity in providing trans octahydroindole-lH-2-carboxylic acid in predominant amounts. The present inventors, have found with surprising effect that such a reversal in the diastereoselectivity from production of cis octahydroindole-1 H-2-carboxylie acid to trans octahydroindole-1 H-2-carboxylic acid could be effected by selection of proper pH conditions, catalyst and medium of reaction, which is a step forward towards a practical method for manufacture of trandolapril. The effect of the abovementioned variables, either taken individually or collectively in favouring production of octahydroindole -2-carboxylic acid, its esters and salts thereof, predominantly as the trans isomer of the formula (I) and more specifically the [2p,3a(3,7aa] or [2S, 3aR, 7aS]-octahydro-lH-indole-2-carboxylic acid, its esters and salts thereof of formula (I1) are described in detail hereinbelow. 1. Effect ofpH It was found that production of compounds of formula (I) and (I1) are achieved when the imine compound of formula (III) is subjected to catalytic hydrogenation, when the pH of the reaction mixture is in a range of between 6.0 to 14.0. The most optimum results are 17 obtained when the pH is in the range of between 10.0'to 13.0, which happens to be the preferred range. The best results are obtained when the pll is specifically between 12 to 13.0, which is the most preferred pH for obtaining the trans derivatives (I) and (I1). The observed effect of pH in giving either the cis or trans octahydro-III-indolc-2-carboxylic acid is graphically represented in Fig-1 given hereinbelow. pH dependance of the invention Effect and amount of catalyst The selectivity of the method in giving either the cis or trans octahydro-lH-indole-2-carboxylic acid is also largely dependent on the type and amount of transition metal catalyst used for the reduction of the imine compound (III). After, carrying out several experiments, it was found that, while use of catalysts containing Platinum or Palladium such as PUC,Pdc. which are widely utilized in prior art favour formation of the cis octahydrr1H-indole-carboxylic acid in major amounts, even under alkaline pH conditions, the object trans isomer i. e. trans octahydro-lH-indole-2-carboxylic is formed and could only be obtained in predominant amounts when a transition metal catalyst containing Rhodium, specially those selected from Rhodium on Aluminium oxide (Rh/AI2O3) or Rhodium on carbon (Rh/C) is employed as catalyst for the reduction. Of these Rhodium on carbon (Rh/C) is the most preferred catalyst. Fig. 2 The ratio of the catalyst to the substrate i. e. the iminc compound of formula (III) also plays a significant role in dictating the amount of the cis or trans octahydro-IH-indoIe-2-carboxylic acid formed in the reaction. The amount of catalyst was varied from 10% to 100% by weight of the imine compound (III) and optimum results were obtained when the amount ofthe catalyst is between 20% to 50% by weight of the imine compound (III). The observed role of various catalysts at a pH of 12.70 in giving the cis or trans octahydro-III-indole-2-carboxylic acid is graphically represented in Fig-2, while the observed role of the amount of Rhodium on carbon (Rh/C) in dictating the proportion of the trans octahydro-lH-indole-2-carboxylic acid formed is graphically represented in Fig-3, given hereinbelow. Effect of catalyst loading Fig. 3 3. Effect of Solvent The diastereoselectivity of the reaction in giving either the cis or trans octahydro-lH-indole-2-carboxylic acid is also largely dependent on medium or solvents used for the reduction of the imine compound (III). Only when either water or a mixture of water and a water-miscible organic solvent is employed as the reaction medium, the trans octahydro-lH-indoie-2-carboxylic acid was found to be formed in major amounts. On the contrary, when a water-miscible organic solvent is employed without admixture with water as the reaction medium, it was found to give the cis octahydro-IH-indole-2-carboxylic acid in major amounts. The water-miscible organic solvents that can be utilised include those solvents that do not participate in the reaction and are selected from lower aliphatic alcohols, both straight and branched of 1-4 carbon atoms and tetrahydrofuran. Furthermore, the diastereoselectivity in giving the maximum amounts of trans octahydro-lH-indole-2-carboxylic acid is achieved when the lower aliphatic alcohol is 2-propanol. The best results are achieved when 100% water is used or a mixture of water and 2-propanol in a ratio of 1 1 is employed. The observed effect of the pH, nature and amount of the transition metal catalyst and medium of reaction in the reduction of the imino compound of formula (III) in giving either the cis or trans octahydro-lH-indole-2-carboxylic acid is further summarized in Table-I. 20 Table-I : The effect of pH, nature and amount of the transition metal catalyst, and the medium of reaction in dictating the diastereoselectivity of the reduction of the inline compound of formula (111) under identical gas pressure (50-60 psi of hydrogen) and at ambient temperature (30-35° C) Carried out hydrogen pressure of 25-35 psi Any organic or inorganic base can be used for maintaining alkaline pH during the reaction. Of these, inorganic bases are preferred because of their low cost. The inorganic bases that can be employed are selected from alkali metal carbonates, such as sodium, potassium, lithium and cesium carbonates; alkali metal hydroxides, such as sodium, potassium, lithium and cesium hydroxides etc. The preferred base is an alkali metal hydroxide and the most preferred alkali metal hydroxide is sodium hydroxide. The reaction is ideally carried out at ambient temperature, at a temperature between 30 C to35°C. The reaction can be carried out in a Parr hydrogenator as well as in industrial scale autoclaves, both giving reproducible results. However, in the later case the type of 21 agitator, agitation speed, substrate concentration etc. would need to be set to obtain the most optimum amounts of trans octahydro-lH-indole-2-carboxyIic acid. All such variations should be construed as falling within the scope of the present invention. The catalytic hydrogenation of the imino compound (III) under alkaline conditions, in presence of a transition metal catalyst containing rhodium and in aqueous medium or in a mixture of water and a water-miscible organic solvent leads to formation of a mixture of four diastereomers of trans octahydro-lH-indole-2-carboxylic acids of formula (I1), (I4), (I ), and (I ) shown below, which collectively correspond to compound of formula (I). H At the end of the reaction, the product i. e. a mixture of cis and trans octahydro-lH-indoIe-2-carboxylic acids is obtained. The product could be isolated by filtration of the catalyst, followed by acidification of the filtrate to a pH of about 6,0 to 6.5 by addition of mineral acid. The aqueous solution is concentrated under reduced pressure to dryness and traces of water and other solvents removed by azeotropic distillation with toluene. Methanol is added to the solution and the precipiated alkali metal chloride filtered off. Evaporation of the solution gives the trans octahydro-lH-indoIc-2-carboxyIic acid of formula (1) in admixture with the corresponding cis isomers and other unidentified compounds. The ratio of the trans to cis isomer can be determined by formation of the benzyl ester of each of the isomers. The trans octahydro-lH-indole-2-carboxylic acid of formula (I) can be separated from the corresponding cis isomers by classical column chromatography to get a pure compound. However, they can be separated by repeated fractional crystallization comprising heating of the mixture of isomers in a water-miscible organic solvent or mixtures thereof at 60-80 °C and filtering off the insoluble trans isomer. The pure trans 22 isomer can finally be obtained in a purity of greater than or equal to 96%, having a specification rotation of --0.56". The water-miscible organic solvent can be selected from nitriles such as acetonitrile; lower aliphatic alcohols of 1-4 carbon atoms such as methanol, elhanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol and tertiary-butanol; ethers such as tetrahydrofuran and 1,4-dioxane; ketonic solvents such as acetone; and amides such as N,N-dimethylformamide. Among these, the most preferred water-miscible solvents are acetonitrile and a lower alcohol of 1-4 carbon atoms. Methanol is the most preferred lower aliphatic alcohol. Typically, the separation to give the pure trans isomer in a purity of greater than or equal to 96% is achieved in three or four fractional crystallizations from the water-miscible organic solvent employed. The trans ring junction of compound (I) thus obtained was confirmed by comparing its 2D COSY-45 and ROSEY NMR spectra with those of the corresponding cis analogues as well as by converting it to trandolapril of formula (II). The highly selective separation of trans octahydro-lH-indole-2-carboxylic acid of formula (I) from the corresponding cis isomers in optically pure form forms another novel aspect of the present invention. The starting imino compound of formula (III) can be prepared by methods known in the art. For instance it can be prepared by the method as described in US Patent No. 4.933.361, comprising reacting an enaminc prepared from cyclohexanone. such as. for example, 1-pyrrolidinyl-cyclohcxene (IV-) with a N-protectcd 3-haIo-aIanine alkyl ester (V), where X is a halo radical selected from chloro, bromo or iodo, and PG is a nitrogen protective group selected from acetyl (COCH3), trifluoroacetyl (COCF3) or phenylacetyl (COC6H5) in presence of solvents, such as acetonitrile, dichloromethane, methanol, dimethyformamide. The N-protecting group can be acetyl, benzoyl, trifluoro acetyl or the like. Such N-protected 3-haloalanines can, in turn be prepared from L- or DL-serine as per the method described in US Patent No. 4,933,361. The alkylation is carried out by reacting 1.0-1.5 equivalent of the enamine (IV) with 1.0 equivalent of the halo alanine ester (V) at temperatures ranging from 20 C to 80 C, preferably at room temperature, over a period of 18-24 hours to give the alpha alkylated cyclohexanones VI in near quantitative yields. Carbon NMR spectrum of VI (where PG= COCH3) shows the presence of two diastereomers indicating that both the chiral centers have been racemized. The shift values in CDC13 are 212.92, 212.87 (both keto), 172.83, 172.64 (both ester CO), 170.31, 170.10 (both amide CO), 52.26, 52.20 (both OCH3), 50.96, 50.87 (both CH), 47.81, 47.42(both CH), 41.98, 41.85 (both CH2), 34.54, 34.39 (both CH2), 31.96, 31.63 (both CH2), 27.92, 27.81 (both CH2), 25.04, 25.16 (both CH2), 22.87 (CH3). 23 Hydrolysis of VI by an acid, such as, for example, hydrochloric acid, at temperature ranging from 30-100 °C, preferably at 80-85° C. affords the imino compound (III) as the hydrochloride salt. The chemistry for preparation of the imino compound (III) is summarized in Scheme-V. (HI) Scheme-V : Preparation of the Starting Imino Compound (III) As mentioned hereinbefore, the irons octahydro-III-indole-2-carboxylic acid obtained by the best mode of this invention is produced as a racemic mixture of four diastereomers of formula (I1), (I4), (I5), and (I6), which collectively correspond to compound of formula (I). The racemic acid (I) can be a) used as such as an intermediate for further elaboration to a diastereomcric mixture of trandolapril, from which the desired diastereomer of formula (11), can be separated out by methods known in the art, or b) it can be resolved into the optically pure (2S,4R,9S) octahydrolH-indole-2-carboxylic acid of formula (I1), through the intermediacy of a chiral resolving agent and converted to trandolapril of formula (II). The separation of the racemate compound (I) into the pure enantiomer (I ), can be achieved by customary methods, known in the art via salt formation with optically active acids and bases. 24 In particular, the racemate compound (I) could be resolved first converting the mixture into the corresponding benzyl ester by reaction with thionyl chloride and benzyl alcohol: the benzyl ester could be reacted with 0,0'-dibenzoyl-L-tartaric acid to give the corresponding O.O'-dibenzoyl-L-tartaric acid salt and removal of the salt would give the desired compound (I ) as per the method disclosed by M. Vincent et. al. in Drug Design and Discovery, 1992, 9, 11-28. Alternatively, the racemate compound (I) could be converted into the corresponding N-acetyl derivative of formula (VII) H and resolving the N-acetyl derivative (VII) using L-cinchonidine to give the desired compound (I ) in high optical purity. This is the preferred method of resolution and is summarized in Scheme-VI. Typically, compound (I) and its enanliomer obtained is converted to the corresponding N-acetyl derivative of formula (VII) by reaction with acetic anhydride in the presence of a base. Typically, the base is employed as an aqueous solution. Suitable bases include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. The N-acetyl derivative (VII) is found to possess the following physical and spectral characteristics. [4r]i,=+0.97(C- 0.10. methanol) Mass Spectrum : m/z at 212.2 anm (M M ) 'H NMR (CDC13, &) : 1.60-2.10 (m. 9H); 2.12 (s, 3H); 2.20-2.40 (nv 1H); 2.40-2.50 (dd. J- 11.90 & 4.80 Hz, 1H); 2.85-3.00 (dt. J= 10.50 and 3.40 Hz. 1H); 4.53 (d, J-7.80 Hz. 1H). The N-acetyl derivative (VII) is reacted with an equimolar or slight excess of 1-cinchonidine in a suitable organic solvent to give the corresponding l-cinchonidine salt of the [2p, 3aP, 7aa] or [2S, 3aR, 7aS]-N-acetyl isomer. (VIII) in greater than 98% optical purity and possessing the following physical and spectral characteristics. [a]D = -85.5° (C - 0.10, methanol) Mass Spectrum : m/z at 295.3 amu (M+l) Melting point: 156-158° C IR (KBr, v, cm"1): 3325, 2927.7,1720.4,1631.7 and 1593.1 25 The free [2p, 3ap, 7aa] or [2S, 3aR, 7aS]-N-acetyl isomer (IX) is then obtained by treatment of the N-acetyl cinchonidine salt (VIII) with an acid in an organic solvent and is found to possess the following spectral characteristics. [a]D - +18.85° (C - 0.10, methanol) Mass Spectrum : m/zat 212.1amu (M+l) IR (KBr, v, cm"1): 3398.3, 2935.5, 1708.8 and 1593.1 Finally, the [2p, 3a(3, 7aa] or [2S, 3aR, 7aS]-octahydro-lH-indole~2-carboxylic acid, of formula (I1) can be obtained by treatment of the N-acetyl derivative (IX) with an acid. Compound (I!) thus obtained was found to possess the following physical and spectral characteristics. [a]D=-75.70(C= 1.0, water) 26 Mass Spectrum : m/z at 170.2amu (M+1) Melting point : 272-274° C1 IR(KBr, v. cm"1) : 3460.1, 2935.5. 1612.4, 1596.9 and 1454.2 lH NMR (CDCh. 8) : 0.90-1.30 (m. 3H); 1.30-1.70 (m. 3H); 1.70-2.00 (m. 31!): 2.00- 2.20 (m, 2H); 2.77 (dt, J= 3.6 and 11.60 Hz, 1H); 4.15 (dd, J=2.20 and 10.50 Hz, 1H) Both the methods for synthesis of Irandolapril are within the scope of the present invention. For instance, the racemic acid (I) can be reacted with N-carboxy anhydride (NCA) of N-(lS)-2-ethoxycarbonyl-3-phenyIpropyl)-S-alanine (NEPA) as per the method disclosed in US Patent No. 4,716,235 or giving trandolapril as a mixture of diastereomers, from which the pure optical antipode (II) can be separated out. Alternatively, the pure optical antipode (I1), can be reacted with N-carboxy anhydride (NCA) of N- (lS)-2-ethoxycarbonyl-3-phenylpropyl)-S-alanine (NEPA) as per the method disclosed in US Patent No. 4,716,235 to give directly trandolapril (II) in pure optical form. The following examples serve to illustrate the invention, but however, should not be construed as limiting the scope of the invention. Example -1 To obtain the disatereomeric mixture of trans and cis octahydro 1H-indole -2-carboxylic acid. In a 500 ml Parr hydrogenation bottle was placed 0.5 g (2.4 m moles) of imino acid hydrochloride (III) dissolved in 10 ml of deionized water and the pH of the solution was adjusted to 12.70 by addition of 2.5 ml of 10% aqueous sodium hydroxide solution. To this was added 250 mg of rhodium (5%) on activated carbon and the mixture was shaken under a hydrogen atmosphere at 50-60 psi for 14-15 hours till TLC analysis showed completion of reaction. The reaction mixture was filtered through a Whatman #1 filter paper and the catalyst bed was washed with 5 m of demineralised water. The filtrate was cooled to 10° C and the pH was adjusted to 2.3-2.6 by addition 6N HC1. Again the solution was neutralized to pH 6.0-6.2 by addition of 10% NaOH. The solution was concentrated to dryness under vacuum, swapped twice with 2X5 ml toluene and toluene distilled off. Finally 20 ml of methanol was added to the residue and the precipitated NaCl was filtered off. The methanol filtrate was concentrated under reduced pressure to give 400 mg (2.4 m moles) of the diastereomeric mixture of trans and cis octahydroindole -2-carboxylic acid as a white solid. In a three-necked dry round-bottomed flask, equipped with a magnetic stirrer, thermowell and a Dean - Stark apparatus the diastereomeric mixture of trans and cis octahydro indole -2-carboxylic acid as obtained above was mixed with 20 ml of cyclohexane, 410 mg (2.4 m moles) of p-toluene sulfonic acid and I.04g (9.7 m moles) of benzyl alcohol. The resulting heterogeneous mixture was vigorously stirred for 8-10 hours at 80° C, with 27 concurrent removal of water azeotropically. The mixture was cooled to 25° C and cyclohexane was decanted out. The residual mixture was triturated with cyclohexane till excess benzyl alcohol was removed. The residual mixture was concentrated under vacuum to give 1,04g of the benzyl ester of diastereomeric mixture of octahydroindole -2-carboxylic acid (I). HPLC analysis of the benzyl ester revealed it contained 50.40% of the racemic trans octahydroindole -2-carboxylic acid (I). Example-2 To obtain the disatereomeric mixture of trans and cis octahydro W-indole -2-carboxylic acid, In a 500mL Parr hydrogenation bottle was placed 5 g (24.57 moles) of imino acid hydrochloride (III), 50 ml of demineralised water, 50 ml of isopropanol and the pH of the reaction mixture was adjusted to 12.60 by addition of 30 ml of 10% aqueous sodium hydroxide solution. To this was added 1 g of rhodium (5%) on activated carbon. The mixture was shaken under hydrogen atmosphere at 50-60 psi for twenty-four hours till TLC indicated completion of reaction. The reaction was mixture was workuped the same way as described in Example-1, to give the title compound, containing 49.9% of the racemic trans octahydroindole -2-carboxylic acid (I). Example-3 To obtain the disatereomeric mixture of trans and cis octahydro IH-indole -2-carboxylic acid, Into a 500 mL Parr hydrogenation bottle was placed 10.0 g (49.1 mmoles) of imino acid hydrochloride (III), 200 ml of demineralised water, 50 ml of 10% aqueous sodium hydroxide solution to adjust the pll to 12.5± 0.1 and 2.0 g of rhodium (5%) on activated carbon. The mixture was shaken under a hydrogen gas atmosphere of 50-60 psi pressure for 23 hours till completion of reaction as indicated by TLC. The mixture was filtered through a Whatman filter paper No. 1, the residue was washed with 10 ml of water and the filtrate was cooled to 10°C. The plI of the solution was adjusted to 6.5 by addition of 6N I1C1 and then concentrated to dryness under vacuum. Residual water was removed b\ azeotropic distillation with 2X30 ml of toluene. Thereafter 100 ml of methanol was added and the sodium chloride precipitated out and was filtered off. The filtrate was concentrated to dryness and the resulting solids were slurried with 40 ml of 2-propanol , the solid fdtered and dried to afford 5.4 g the title compound, containing 39.9% of the racemic trans octahydroindole -2-carboxylic acid (I). 28 To obtain the racemic mixture of trans octahydro 1 H-indole-2-carboxylic acid (I1 + 16) from the disater corner ic mixture of tran s and cis octahydroindole ~2-carboxylic acid, 5.4 g of the disatereomeric mixture of trans and cis octahydroindole -2-carboxyIic acid, as obtained from Example 3 was suspended in 15 ml of methanol and agitated for 0.5 hours at 60-65 C. The mixture was cooled to 30 C and the solid filtered off. The solid were washed with 2X5 ml of methanol and dried to give 4.2 g of solid. The solid thus obtained hereinabove was suspended in 12.5 ml of methanol and the slurry was agitated at 60-65 C for 0.5 hours. The solid was filtered and washed with 2X3.0 ml of methanol, dried under vacuum to give 3.0g of g of trans octahydro lH-indole-2-carboxylic acid (I), having a purity of 95-96% as shown by HPLC (as benzyl ester). Specific rotation : +0.2 (C= 1, H20) IR (KBr, v, cm"1): 3431, 3068, 2954, 1597 'H NMR (200 MHz. D20, 5): 3.96(d, 111, J=10.4 Hz), 2.70 (dt, 1H. .1=11.6.3.3 Hz), 2.15-1.90 (m. 211). 1.90-1.65 (m, 3H). 1.65-1.50 (m, 1H), 1.50-1.25 (m. 211). 1.25-0.80 (m, 311): 13 C NMR (200, MHz, D20, 5): 175.01 (COOH), 64.17 (CH), 59.37 (CH), 41.56(CII), 34.03(CH2), 28.49(CH2), 28.17(CH2), 24.08 (CH2), 23.82(CH2). Mass(m/z)= 170.5 (M+l) m.p = 270-271 °C Example-5 [2B 3aB 7aa] or [2S, 3aR, 7aS]-(23l3a,4,5,6,7,7a)octahydro-lH-indole-2-carboxylic acid, (I1) can be prepared using the following steps Step-1 : Preparation of (±)-N-acetyl- octahydro-indole-2-carboxylic acid as a mixture of [2S, 3aR, 7aS]-and [2R, 3aS, 7aR] isomers 29 To a solution of 6.9 g (40.80 mmoles) of racemic trans octahydro -lH-indole-2-carboxylic acid (I, as obtained from Example-3 and Example-4) in 51.3 ml of aqueous sodium hydroxide (128.3 mmoles), cooled to 2° C was added acetic anhydride 911.9 g, 116.7 mmoles), dropwise over a period of 15 mns, maintaining a temperature between 2 to 13 C. During the addition, the pH of the reaction mixture was maintained between 9.0 to 10.0 by addition of a 10% aqueous solution of sodium hydroxide. After the addition, the reaction mixture was cooled to 0-5° C and agitated at this temperature for 5 hrs. The pH of the reaction mixture was adjusted to 2.0 by addition of Cone. HC1 (25 ml) and extracted with dichloromethane (200 ml). The layers were separated and the organic layer was concentrated under reduced pressure to give an oily residue. The residue was stirred with n-hexane (80 ml) for 3 hrs and the solid separated out was filtered, washed with n-hexane (3x10 ml) and dried under vacuum at 45-50 C to give 8.14 g (95%) of the title compound as a white solid. [a]97(C Mass .Spectrum "HNMR(CDC J= 11.90 &4.8( 1H). IR(KBr, cm"1):-2925.8, 1728. 1708.8 and 1616.2 m.p144.1450C 0.10, methanol) m/z at 212.2 amu(M+l) , 5) : 1.60-2.10 (m, 911); 2.12 (s. 3H; 2.20-2.40 (m. 1H); 2.40-2.50 (dd. Hz, 1H); 2.85-3.00 (dt, J= 10.50 and 3.40 Hz, 1H); 4.53 (d, J- 7.80 Hz. 30 Step-2 : Preparation of (-)-N-acetyl-[2S, 3aR, /aSJ- octahydro-indole-2-carboxylic acid, l-cinchomdine salt A mixture of 9.0 g (42.6 mmoles) of (±)-N-acetyl- octahydro-indole-2-carboxylic acid as a mixture of [2S; 3aR, 7aS]-and [2R, 3aS, 7aR] isomers (as obtained in Step-1), ethyl acetate (100 ml) and 1-cinchonidine (12.54 g, 42.6 mmolcs) was heated to reflux to obtain a clear solution. The solution was cooled to 20-25° C and stirred at this temperature for 5 hrs. The solid separated out was filtered, washed with ethyl acetate (3x5 ml) and dried at 40-45° C under vacuum. The above solid was resuspended in ethyl acetate and the above procedure was repeated twice to give (-)-N-acetyI-[2S, 3aR, 7aS]- octahydro-lH-indole-2-carboxyIic acid, L-cinchonidine salt having optical purity >98%. [CC]D = -85.5° (C = 0.10, methanol) Mass Spectrum : m/z at 295.3 and 212.2 amu (M+lof cinchonidine and N-acetyl acid derivative respectively) Melting point: 156-158° C IR (KBr, v, cm"1): 3325, 2927.7,1720.4,1631.7 and 1593.1 Step-3 : Preparation of {+)-N-acetyl-[2S, 3aR, 7aS]~ octahydro-indole-2-carboxylic acid, 4.9 g (9.7 mmolcs) (-)-N-acetyl-[2S, 3aR, 7aS]- octahydro-III-ole-2-carboxylic acid. 1-cinchonidinc salt (as obtained in Stc-20 was dissolved in dichloromcthane (49 ml). The solution was washed thrice with 15 ml portions of 2N hydrochloric acid. The organic layer was separated and concentrated under vacuum to give an oily residue. The residue was stirred with n-hexane (5 ml) for 2 hrs at 25° C. The solid separated out was filtered, washed with n-hexane and dried at 40-45° C under vacuum to give the title compound having 99.7% optical purity. [a]D = +18.85° (C = 0.10, methanol) Mass Spectrum : m/z at 212.1 amu (M+1) IR (KBr, v, cm"1) : 3398.3, 2935.5, 1708.8 and 1593.1 mp. - 170-172 6C PMR: 0.1-1.6 (m, 5H); 1.6-2.1 (m, 4H); 2.2 (s, 3H); 2.25-2.4 (m, 1H), 2.4-2.6 (m, 1H); 3.0 (m, 1H) and 4.61 (d, J=8.3 Hz, 1H) 31 Step-4 : Preparation of [2/3, 3a/3, 7a a] or [2S, 3aR, 7aS]-octahydro-lH~indole-2-corboxylic acid, (I) A mixture of 0.35 g (1.79 mmoles) of (+)-N-acetyl-[2S, 3aR, 7aS]- octahydro-indole-2-carboxylic acid (as obtained in Step-3) and 3.8 ml of 5N hydrochloric acid was stirred at 90-95° C for 30 hrs. The mixture was cooled to 25 C and extracted with dichloromethane (4x5 ml). The layers were separated and the aqueous layer was concentrated under vacuum to give a residue. The residue was dissolved in water (5 ml) to which was added 1.42 ml (1.69 mmoles) of 10% aqueous sodium carbonate solution to adjust the pH to 5.60 and the mixture again concentrated under vacuum to give a residue. The residue was dissolved in methanol (40 ml) and heated to reflux. The solution was filtered hot through a 0.20 u membrane and the filtrate concentrated under reduced pressure to give 0.216 g (72%) of [2/3, 3a/3, 7aa] or [2S, 3aR, 7aS]-octahydro-lH-indoie-2-carboxylic acid, (l') as a white crystalline solid. [a]D --75.7° (C= 1.0, water) Mass Spectrum : m/z at 170.2amu (M+l) Melting point : 272-274° C 1R (KBi\ v. cm"1) : 3460.1, 2935.5. 1612.4, 1596.9 and 1454.2 !H NMR (CDC13, 5) : 0.90-1.30 (m. 3H); 1.30-1.70 (m. 311); 1.70-2.00 (m. 3H: 2.00- 2.20 (m, 2H); 2.77 (dt, J= 3.6 and 11.60 Hz, 1H); 4.15 (dd, J-2.20 and 10.50 Hz, 111) ExampIe-6 To obtain irandolapril as a mixture of diastereomers utilizing racemic trans octahydro 1 H-indole-2-carboxyhc acid (1), 32 To a solution of 0.5 g (2.96 mmoles) of racemic trans octahydro III-indoIc-2-carboxyIic acid (I.(as obtained in example IV) in 15 ml of water was added 1.3 ml (3.25 mmoles) of 10% aqueous sodium hydroxide, followed by 0.344 g (3.25 mmoles) of sodium carbonate. The reaction mixture was stirred to get a clear solution and then cooled to -5° C. A solution of 0.86 g (2.81 mmoles) of in 20 ml of acetone was added N-Carboxy anhydride of N-[l-(S)-ethoxycarbonyl-3-phenylpropyl]-(S)-alanine (NEPA-NCA) rapidly in one lot and the reaction mixture was stirred at -5 to 0 ° C for one hour, The reaction mixture was acidified to pH 4.5 withn 1.2 ml of 6Nhydrochloric acid. To the aqueous solution was added 20 mL of ethyl acetate and the solvent was concentrated under vacuum. The resulting aqueous solution was then extracted with 3X10 ml of ethyl acetate and the combined organic extract was dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The thick syrup obtained slowly solidified at 25 ° C. HPLC analysis showed two peaks, in which the peak eluting out first had the same retention time as that of authentic trandolapril (II), thereby meaning it is the (S,R?S,S,S) diastereomer and the one eluting second is the (R,S,R,S,S) diastereomer. ExampIe-7 To obtain trandolapril (II) utilizing [2B 3afi 7aa] or [2S, SaR, 7aS]-octahydro-1H- indole-2-carboxylic acid, (I) To a solution of 0.1 g (0.5917 mmoles) of [2B 3aB 7aa] or ['2S, 3aR, 7aS]-oclahydro-lH-indolc-2-carboxylic acid, (I1, as obtained in Step-4 of Example-5) in water (5 ml), cooled to 0° C was added 5% aqueous sodium carbonate solution (2.8 ml) and the mixture stirred at 0° C for 10 mns. To this was added a solution of 0.162 g (0.532 mmoles) of N-Carboxy anhydride of N-[l-(S)-ethoxycarbonyl-3-phenyIpropyl]-(S)-alanine (NEPA-NCA) in acetone (2 ml) in one lot and the reaction mixture was stirred at 0° C for 2 hrs. The pH of the mixture was adjusted to 4.0 with 2N hydrochloric acid and the solution concentrated under vacuum. The residue was dissolved in a mixture of water (5 ml) and ethyl acetate (10 ml). The organic layer was separated out and the aqueous layer was extracted twice with ethyl acetate (2x10 ml). The combined organic layer was washed with saturated solution of aqueous sodium chloride (5 ml) and concentrated under vacuum to give an gummy residue. The residue was stirred with diisoproplyl ether (30 ml) to obtain a solution. Dry hydrogen chloride gas was bubbled into the solution for 15 mns at 25 C and the reaction mixture was evaporated under vacuum. To the residue obtained was added n-hexane (5 ml) and the mixture stirred at 25° C for 1 hr. The precipitated solid was filtered, washed with n-hexane (3 ml) and dried at 40-45° C under vacuum to give 0.084 g trandolapril (II). 33 We Claim: A process for preparation of [2B, 3aB, 7aa] or [2S,3aR,7aSl- 2,3,3a,4,5,6,7,7a-octahydro-lH-indole-2-carboxylic acid for formula (I1); comprising catalytic hydrogenation of [3,3a,4,5,6,7]- hexahydro-2H-indole-2-carboxyiic acid of formula (III) under alkaline conditions in the presence of a transition metal catalyst containing rhodium and in the presence of water or a mixture of water and a water-miscible organic solvent and fractional crystallization of the mixture of trans and cis octahydro lH-indole-2-carboxylic acid thus obtained from a water-miscible organic solvent at a temperature of between 60 C to 80 C to give trans octahydro lH-indole-2-carboxylic acid of formula (I), its enantiomers thereof and esters and salts thereof, and resolution of compound of formula (I), after conversion to its N-acetyl derivative of formula (VII) 34 using 1-cinchonidine in organic solvent to give compound of formula (I1). 2. A process as claimed in claim 1, wherein the transition metal catalyst containing rhodium is selected from rhodium on alumina or rhodium on carbon. A process as claimed in anyone of claims 1 and 2, wherein the transition metal catalyst containing rhodium is employed in the range of between 10% to 100% w/w of compound of formula (III). A process as claimed in anyone of claims 1, 2 and 3, wherein the transition metal catalyst containing rhodium is employed in the range of between 20% to 50% w/w of compound of formula (III). A process as claimed in claim 1, wherein the water-soluble organic solvent is selected from aC1-4aliphatic alcohol, tetrahydrofuran, 1,4-dioxane. acetonitrile and N,N-dimethylformamide. A process as claimed in claim 1, wherein the conversion of compound of formula (I) to its N-acetyl derivative (VII) is achieved by reaction of compound of formula (I) with acetic anhydride or acetyl chloride and a base in aqueous medium. A process as claimed in claim 1, wherein resolution of compound of formula (I), after conversion to its N-acetyl derivative of formula (VII) 35 comprises the steps of : a) reacting compound of formula (VII) with an equimolar or slight excess of equimolar proportion of 1-cinchonidine in an organic solvent to give the 1-cinchonidine salt of formula (VIII), b) reacting the cinchonidine salt of formula (VIII) with an acid in an organic solvent to give compound of formula (IX), and c) N-deacylation of compound of formula (IX) by treatment with an acid to give compound of formula (I1). 36 A process as claimed in claim 6, wherein the base is selected from sodium hydroxide or potassium hydroxide. 9. A process as claimed in claim 8, wherein the catalytic hydrogenation is carried out at a temperature preferably between 30°C to 35°C. 10. A process as claimed in claim 1 wherein the catalytic hydrogenation is carried out at a pressure preferably between 50-60 psi of hydrogen gas. Dated this 3ru day of October 2003 Dr. Sanchita oanguli Of S. Majumdar & Co. Applicant's Agent

Full Text

FORM -2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION
(See section 10; rule 13)
I. TITLE
PROCESS FOR PREPARATION OF (TRANS)-OCTAHYDRO-IH-INDOLE-2-CARBOXYLIC ACID; ITS ESTERS AND SALTS THEREOF.
2. (a) LUPIN LTD. (b) 159, CST Road, Kalina, Santacruz (East), Mumbai - 400 098, State of Maharashtra, India, (c) An Indian Company.
The following specification particularly describes the nature of this invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to process for manufacture of octahydroindole -2-carboxylic acid of formula (I), wherein the A/B ring junction is trans, its enantiomers thereof its esters and salts thereof,

and more specifically [2p, 3ap, 7aa] or [2S, 3aR, 7aS]-octahydro-lH-indole-2-carboxylic acid, its esters and salts thereof of formula (I ) of high optical purity and substantially free of other isomers and impurities.

d1)

2
The compounds of formula (I) and (I1) are valuable as intermediates in the synthesis of the therapeutically valuable Angiotensin Converting Enzyme (ACE) Inhibitor, viz. Trandolapril of formula (II).

BACKGROUND OF THE INVENTION

(2S,3aR,7aS)-l-[(2S)-2-[[(lS)-l-(ethoxycarbonyl)-3-phenylpropyl] amino]-l-oxopropyl] octahydro-lH-indole-2-carboxyilc acid, gcncrically known as Trandolapril of formula (II) is a therapeutically valuable ACE inhibitor.
(

A key intermediate in preparation of trandolapril is the trans isomer of the octahydro-lH-indoIe-2-carboxylic acid of formula (I) or (I1), referred to hereinbefore.

Taking the case of trans configuration of the hydrogen atoms on C3a and C7a of the octahydro-lH-indole-2-carboxylic acid moiety, there are two possible configurations for me Vicyc'le, namely the (3acc, *?a]V) configuration, as represented by "rormu'ia (Ti ) ana tpa'p), 7aa) configuration, represented by formula (I ), shown below.

H

H
Taking the carboxyl group on C2 into consideration, this group can be oriented in the exo position or p position or the carboxyl group can be oriented in the endo position or the a position, which gives rise to four isomeric compounds of formula (I ), (I ), (I ), and (I ) shown below.
3

Several methods are known for preparation of the abovementioned trans octahydro-lH-indoIe-2-carboxylic acid derivatives, namely as disclosed in
1) US Patent No. 4,933,361-(Urbach et. al.), wherein four methods are disclosed for synthesis of octahydro-lH-indole-2-carboxylic acid.
The first method (Method-I) comprises acylation of a compound of formula (1), followed by anodic oxidation in the presence of an aliphatic alcohol and in the presence of a conducting salt to give compound of formula (2). Reaction of compound (2) with Irimethylsilyl cyanide in the presence of a Lewis acid gives the corresponding cyano derivative (3). Hydrolysis of the cyano derivative gives compound of formula (1), along with the corresponding cis isomers (cis configuration of hydrogen atoms on C3a and C7a of the bicycle), all in the form of racemates.
The second method (Method-II) comprises Beckmann rearrangement of compound (4) to give compound (5). Halogenation gives compound (6), which on catalytic reduction gives compound (7). Compound (7) is then converted to compound (I) through a Favorskii reaction. Compound (I) thus obtained is accompanied by the corresponding cis isomers (cis configuration of hydrogen atoms on C3a and C7a of the bicycle), all in the form of racemates.
In the third method (Method-Ill) compound of formula (I), in which the hydrogen atoms on the bridgehead carbon have the trans configuration is prepared by first reduction of compound of formula (8) with sodium formate/formic acid to give compound (9) and reacting compound (9) as in Method-II to give compound (I).
4

The last method (Method-IV) comprises catalytic hydrogenation or reduction using complex borohydrides or boranc-aminc complexes, of enamincs of formula (10 or 11), wherein the carboxylic acid group is optionally protected as alkyl or aralkyl esters.
The four methods disclosed in US Patent No. 4,933,361 are schematically represented in Scheme-I.
Methods I and II as mentioned hereinearlier give compound (I) in admixture with the corresponding cis isomers. In addition, they involve the steps of anodic oxidation and cyanation reactions using expensive and hazardous compounds such as tetramethylammonium tetrafluoborate and trimethylsilyl cyanide respectively. Further, the halogenation and dehalogenation reactions utilize corrosive phosphorous pentachloride and hazardous Raney Nickel, which in general render the methods not attractive on a
commercial scale. Moreover, Methods-I and II result in formation of cis octahydro1H-indole-2-carboxylic acid, rather than the trans analogue as can be seen from the description residing in Examples 1 and 4 of the US Patent No. 4,933,361.
Method IV is described in Examples 48 and 89 of the US Patent No. 4,933,361.
In Example 48, the imino compound (11), namely (3,3a,4,5,6,7)-2H-hexahydroindole-2-carboxylic acid hydrochloride is hydrogenated using platinum on carbon in glacial acetic acid as solvent. After the reduction the residue obtained after filtration of the catalyst and evaporation of acetic acid is caused to precipitate out from ethanol cooled to -20° C and isolated after concentration of ethanol followed by addition of isopropanol to give (2p,3a[3.7aa)-octahydroindole-2-carboxylic acid of formula (1 ).
However, the description does neither provide any information on the amount ot the trans product obtained, nor it gives any details on the proportions of other isomers formed in the reaction.
Further, in our hands reproduction of the conditions described in Example 48 invariably was found to give cis isomers in major amounts. In particular, the ratio of the cis : trans isomers obtained was found to be 53 : 36.
In the description provided in Example-89, the imino compound (11), namely (3,3a,4,5,6,7)-2H-hexahydroindole-2-carboxylic acid hydrochloride is reduced with sodium borohydride in isopropanol as solvent at 40-50 C. Fractional crystallization of the residue obtained from a mixture of chloroform-diisopropyl ether gives the cis and trans octahydro-lH-indole-2-carboxylic acids.
Furthermore, both the Examples 48 and 89 of the US Patent No. 4,933,361 do not mention the optical purity of the trans isomer obtained.
5

2) F. Brion et. al. in Tetrahedron Letters, 1992, 33(34), 4889-4892 in addition to
providing a detailed account of the difficulties faced in preparation of the trans isomer (I) and (I!) have described a enantioselective synthesis of comppund (I ), starting from a meso diester, as summarized in Scheme-II.
Even though, this method is reported to give the desired 2/3 isomer (I ) in a ratio of 95 over the corresponding 2a isomer, however, this method is not only lengthy but also utilizes expensive and corrosive chemicals and enzymes like
6

diethyldihydroaluminate, sodium hydride and Pig Liver Esterase, thereby rendering the method not cost-effective as well as having little commercial application.
L. Belvisi et. al in Tetrahedron, 2001, 57, 6463-6473 have reported a stereo selective synthesis of both cis and trans octahydroindoIc-2-carboxyIic acid as summarized in Scheme-Ill.
The method comprises conversion of N-Boc protected dimethyl glutamate (A) to the 4-allyl pyroglutamic ester (C), via (B). The imide (C) was selectively reduced to the hemiaminal (D) using lithium triethylborohydride at -78° C, which was converted to the corresponding acetoxy derivative (E). Allylation of compound (E) with a twofold excess of allyltributyltin and tert-butyldimethylsilyl trifluoromethanesuifonate gave the diallylated proline derivative as a mixture of trans and cis isomers (F and G) in a ratio of 3:1. The ring closure metathesis of the separate stereoisomers (trans and cis) using Grubbs catalyst gave the corresponding ring-closed trans and cis derivatives (H and J respectively), which on hydrogenation with 5% Pd on charcoal afforded the respective trans and cis fused octahydro-indole-2-carboxylic acid (K and L respectively).
This method is also not viable on a commercial scale since it utilizes expensive, corrosive and hazardous chemicals like allyl bromide, tri fluoroacetic acid, lithium triethylborohydride, butyl lithium, allyltributyltin, tcrt-butyldimethylsilyl trifluoromethanesuifonate etc., as well as cryogenic temperatures of-780 C.
PCT Application No. WOJ30/40555. {Ebel et. al.) discloses a method for producing (2S,4R,9S)-octahydro-lH-indole-2-carboxylic acid comprising reaction of a 3,3-dialkoxypropane of formula" (M) with water in the presence of an acid catalyst to give the 3,3-diaIkoxypropionaldchyde of formula (N). which on Henry reaction with nitromethane gives the 4,4-dia!koxy-l-nitro-2-butanol of( formula (0). Dehydration of compound (O) gives the nitroolefin (P), which on Diels-Alder reaction gives the corresponding irans-4-(2,2-dialkoxyethyl)-5-nitro-l-cyclohexene, which is further hydrogenated to give the corresponding cyclohexane derivative (Q) as a racemic mixture. Compound (Q) thus obtained is resolved to give (lS,2R)-l-amino-2-(2,2-dialkoxyethyl)-cyclohexane in the enantiomerically pure form (S), which is hydrolysed to the corresponding aldehyde (T). The aldehyde (T) is converted to the corresponding nitrile (U), which on hydrolysis gives the object compound. The chemistry utilized is summarized in Scheme-IV.
Even though, the trans isomer is a major product of this process with the ratio of the trans to the cis isomers produced being 3:1, however, it is only lengthy, but also utilizes highly toxic sodium cyanide, which render the process of little industrial applicability.
7

From the foregoing, it is apparent that the methods available in the prior art for the synthesis of trans octahydroindole-1H-2 carboxylic acid (I) and/or (I ) suffer from the following limitations in that most of the methods :
i) give the cis isomer, rather than the trans isomer in major amounts,
ii) are not only lengthy but also utilize expensive, hazardous, toxic and corrosive chemicals and enzymes like dicthyldihydroaluminale, sodium hydride, allyl bromide, trifluoro acetic acid, lithium triethylborohydride, butyl lithium allyltributyltin, tert-butyldimethylsilyl trifluoromethanesulfonate, sodium cyanide. Pig Liver Esterase etc and
iii) utilize cryogenic temperatures in some of the synthetic steps,
which overall render the methods less cost-effective and commercially unattractive.
There exists a need, therefore, for a practical method for preparation of trans isomer of octahydroindole-1H-2- carboxylic acid, (I) and/or (I1), which overcomes the shortcomings of the prior art methods mentioned hereinabove.
For the foregoing reasons, the synthesis of /raws-fused octahydroindole-1-H-2 carboxylic acid was of significant interest for the present inventors, both because of the
10

inherent challenge associated with stereo selective formation of the trans isomer of octahydro-lH-indoIe-2-carboxylic acid as well as its use in synthesis of trandolapril.
OBJECTS OF THE INVENTION
It is, therefore, an object of the present invention to provide a method for preparation of octahydroindole-lH -2-carboxylic acid, its esters and salts thereof, predominantly as the trans isomer of the formula (I), and more specifically, [2p,3aB,7act] or [2S,3aR,7aS]-octahydro-lH-indole-2-carboxylic acid, its esters and salts thereof of formula (I1), which is convenient; simple; cost-effective; avoids use of toxic, corrosive and hazardous chemicals and which, moreover, gives the desired trans isomers (I1) in high chemical yield and optical purity.
Yet another object of the present invention is to provide a convenient; simple; cost-effective and efficient method for synthesis of the therapeutically valuable ACE inhibitor, Trandolapril using trans octahydroindole-lH-2-carboxylic acid, its esters and salts thereof of formula (I), and more specifically, [2p,3ap,7acc] or [2S,3aR,7aS]-octahydro-lH-indole-2-carboxylic acid, its esters and salts thereof of formula (I1).
SUMMARY OF THE INVENTION
It was found with surprising effect that the hydrogenation or reduction of the mixture containing enamine (10) and imine (11) of Scheme-I in turn corresponding to compound (II) of the present invention predominantly gives the trans isomer of formula (I) and/or (I!)by
i) proper selection of the pH conditions at which the reduction is carried out,
ii) proper selection of the transition metal catalyst for the reductive step, and
iii) proper selection of the medium in which the reduction is carried out.
In particular, it was found that a ratio of trans : cis isomers greater than or equal to 1 : 1 could be achieved by carrying out the reduction of the imine compound alkaline conditions in the presence of a transition metal catalyst containing rhodium and in the presence of water or mixture of water and a water-miscible organic solvent as a medium of reaction. Such a selection of the right and proper pH conditions, catalyst and medium of reaction in giving the trans octahydro-1H-indole-2-carboxylic acids of formula (I), its enantiomers thereof and (I1) forms the basis for one aspect of the present invention.
The trans isomer of formula (I), thus obtained can be separated from the corresponding cis isomers formed in the reaction, by a selective fractional crystallization method from a water-miscible organic, wherein the object compound (I) is obtained in high purity,
11

substantially free of the corresponding cis isomer and other impurities. This forms the basis for another aspect of the present invention.
Finally, the trans isomer (I), and its enantiomers thereof thus obtained as a mixture of racemates can be used as such or can be resolved to give the specific isomer (I1), which collectively can be used for synthesis of trandolapril of formula (II). Thus in one aspect of the present invention, there is provided a process for preparation of
[2B, 3aB 7aa] or [2S,3aR,7aS]- 2,3,3a,4,5,6,7,7a-octahydro-lH-indole-2-
carboxylic acid, its esters and salts thereof of formula (I1),

comprising catalytic hydrogenation of [3,3a,4,5,6,7]- hexahydro-2H-indole-2-carboxylic acid of formula (111)

under alkaline conditions in the presence of a transition metal catalyst containing rhodium and in the presence of water or a mixture of water and a water-miscible orgamc""so]vent andlractibnaT crystallization of the mixture of trans and cis octahydro lH-indole-2-carboxy!ic acid thus obtained from a water-miscible organic solvent at a temperature of between 60°JZ to 80 C to give trans octahydro lH-indole-2-carboxylic acid of formula (I), its enantiomers thereof and esters and salts thereof, and

resolution of compound of formula (I), after conversion to its N-acetyl derivative of formula (VII)
12
using 1-cinchonidine in organic solvent to give compound of formula (I!).
In a preferred aspect of the present invention there is provided a stereoselective, simple, convenient and cost-effective method for preparation of trans octahydroindoIe-lH -2-carboxylic acid of formula (I) and its enantiomers thereof and its esters and salts thereof, and/or

(I)

[2B,3aB,7so] or [2S,3aR,7aS]-octahydro-lH-indole-2-carboxylic acid, its esters and salts thereof of formula (I1), in predominant amounts,

comprising catalytic hydrogenation of [3,3a,4,5,6,7]-2H- hexahydroindole-2-carboxylic acid of formula III,
13

under alkaline conditions in the presence of a transition metal catalyst containing rhodium and in the presence of water or a mixture of water and a water-miscible organic solvent at a temperature of between 30° C to 35° C and at a pressure of 50-60 psi of
hydrogen gas .
In another aspect of the present invention there is provided a stereoselective, simple, convenient and cost-effective method for preparation of compound of formula (I) and its enantiomers thereof and its esters and salts thereof, and/or

[2B,3ap,7aa] or [2S,3aR,7aS]-octahydro-lH-indole-2-carboxylic acid, its esters and salts thereof of formula (I1),

in high purity, and substantially free of the corresponding cis isomers and other impurities comprising catalytic hydrogenation of [3,3a,4,5,6,7]-2H- hexahydroindole-2-carboxylic acid of formula III

under alkaline conditions in the presence of a transition metal catalyst containing rhodium and in the presence of water and a mixture of water and a water-miscible organic solvent at a temperature of between 30° C to 35° C and at a pressure of 50-60 psi of hydrogen gas, followed by repeated fractional crystallization of the product thus obtained from a water-miscible organic solvent at a temperature of 60-80 C to give
14

compound of formula (I) and its enantiomers thereof and its esters and salts thereof, in high optical purity and free of the corresponding cis isomer.
In yet another aspect of the present invention, there is provided a process for preparation of [2p,3ap,7aa] or [2S,3aR,7aS]-octahydro-lH-indole-2-carboxylic acid; its esters and salts thereof of formula (I1),

in high purity, and substantially free of the corresponding cis isomers and other impurities comprising resolution of the N-acetyl derivative of compound of formula (I) i. e. a racemic compound of formula (VII)

with 1- cinchonidine to give compound of formula (I ), comprising the steps of;
a) reacting compound of formula (VII) with an equimolar or slight excess of
cquimolar proportion of 1-cinchonidine in an organic solvent to give the 1-cinchonidine salt of formula (VIII),

15

b) reacting the cinchonidinc salt of formula (VIII) with an acid in an organic acid to
give compound of formula (IX), and

c) N-deacylation of compound of formula (IX) by treatment with an acid to give
compound of formula (I1).

In a further aspect of the present invention there is provided a stereoselective, simple, convenient, and cost-effective method for preparation of trandolapril of formula (II).

i) utilizing compound of formula (I), free of the corresponding cis isomers and other
impurities obtained by the selective method enumerated hereinabove, followed by separation of the desired diastereomer of trandolapril from a mixture obtained thereon, or
ii) utilizing compound of formula (I1) obtained by the selective method enumerated
hereinabove.
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DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a method for preparation of trans octahydroindole-lH-2-carboxylic acid derivatives via catalytic hydrogenation of the precursor imincs. This is a methodology generally practiced for synthesis of amines. However, the stereochemical outcome of such a reductive method is largely dependent on the overall effect of number of variables acting simultaneously, which makes the method highly sensitive.
Of particular significance is the extent of diastereoselectivity achieved when an angular imine compound of formula (III) is subjected to reduction, wherein the C-2 and C-3a positions of the bicycle are racemic i. e. in (R/S) configuration. Compound of formula (III) can be prepared by the methods known in the art, specially by the method disclosed in US Patent No. 4,933,361.
The diastereoselectivity of the reaction in giving either the cis or trans octahydroindole-lH-2-carboxylic acid, in principle is determined by the transition metal catalyst employed, the amount of catalyst used, the medium of reaction, the substrate concentration, pH of the reaction, the hydrogen gas pressure etc.
As mentioned hereinearlier, the known methods for reduction of the imine compound of formula (III) have invariably been carried out under acidic pH conditions, for example as described in Examples 48 and 89 of US Patent No. 4,933,361, which is diastereoselective
in leading to formation of cis octahydroindole-lH-2-carboxylic acid in predominant amounts. Further, the known methods while acknowledging the importance of the transition metal catalyst in dictating the diastereoselectivity, however, arc vague in recommending specific catalyst(s) as well as other variables, which could bring about a reversal in the diastereoselectivity in providing trans octahydroindole-lH-2-carboxylic acid in predominant amounts.
The present inventors, have found with surprising effect that such a reversal in the diastereoselectivity from production of cis octahydroindole-1 H-2-carboxylie acid to trans octahydroindole-1 H-2-carboxylic acid could be effected by selection of proper pH conditions, catalyst and medium of reaction, which is a step forward towards a practical method for manufacture of trandolapril.
The effect of the abovementioned variables, either taken individually or collectively in favouring production of octahydroindole -2-carboxylic acid, its esters and salts thereof, predominantly as the trans isomer of the formula (I) and more specifically the [2p,3a(3,7aa] or [2S, 3aR, 7aS]-octahydro-lH-indole-2-carboxylic acid, its esters and salts thereof of formula (I1) are described in detail hereinbelow.
1. Effect ofpH
It was found that production of compounds of formula (I) and (I1) are achieved when the imine compound of formula (III) is subjected to catalytic hydrogenation, when the pH of the reaction mixture is in a range of between 6.0 to 14.0. The most optimum results are
17

obtained when the pH is in the range of between 10.0'to 13.0, which happens to be the preferred range. The best results are obtained when the pll is specifically between 12 to 13.0, which is the most preferred pH for obtaining the trans derivatives (I) and (I1).
The observed effect of pH in giving either the cis or trans octahydro-III-indolc-2-carboxylic acid is graphically represented in Fig-1 given hereinbelow.
pH dependance of the invention

Effect and amount of catalyst
The selectivity of the method in giving either the cis or trans octahydro-lH-indole-2-carboxylic acid is also largely dependent on the type and amount of transition metal catalyst used for the reduction of the imine compound (III). After, carrying out several experiments, it was found that, while use of catalysts containing Platinum or Palladium such as PUC,Pdc. which are widely utilized in prior art favour formation of the cis octahydrr1H-indole-carboxylic acid in major amounts, even under alkaline pH conditions, the object trans isomer i. e. trans octahydro-lH-indole-2-carboxylic is formed and could only be obtained in predominant amounts when a transition metal catalyst containing Rhodium, specially those selected from Rhodium on Aluminium oxide (Rh/AI2O3) or Rhodium on carbon (Rh/C) is employed as catalyst for the reduction. Of these Rhodium on carbon (Rh/C) is the most preferred catalyst.

Fig. 2
The ratio of the catalyst to the substrate i. e. the iminc compound of formula (III) also plays a significant role in dictating the amount of the cis or trans octahydro-IH-indoIe-2-carboxylic acid formed in the reaction. The amount of catalyst was varied from 10% to 100% by weight of the imine compound (III) and optimum results were obtained when the amount ofthe catalyst is between 20% to 50% by weight of the imine compound (III).
The observed role of various catalysts at a pH of 12.70 in giving the cis or trans octahydro-III-indole-2-carboxylic acid is graphically represented in Fig-2, while the observed role of the amount of Rhodium on carbon (Rh/C) in dictating the proportion of the trans octahydro-lH-indole-2-carboxylic acid formed is graphically represented in Fig-3, given hereinbelow.

Effect of catalyst loading

Fig. 3
3. Effect of Solvent
The diastereoselectivity of the reaction in giving either the cis or trans octahydro-lH-indole-2-carboxylic acid is also largely dependent on medium or solvents used for the reduction of the imine compound (III). Only when either water or a mixture of water and a water-miscible organic solvent is employed as the reaction medium, the trans octahydro-lH-indoie-2-carboxylic acid was found to be formed in major amounts. On the contrary, when a water-miscible organic solvent is employed without admixture with water as the reaction medium, it was found to give the cis octahydro-IH-indole-2-carboxylic acid in major amounts.
The water-miscible organic solvents that can be utilised include those solvents that do not participate in the reaction and are selected from lower aliphatic alcohols, both straight and branched of 1-4 carbon atoms and tetrahydrofuran.
Furthermore, the diastereoselectivity in giving the maximum amounts of trans octahydro-lH-indole-2-carboxylic acid is achieved when the lower aliphatic alcohol is 2-propanol. The best results are achieved when 100% water is used or a mixture of water and 2-propanol in a ratio of 1 1 is employed.
The observed effect of the pH, nature and amount of the transition metal catalyst and medium of reaction in the reduction of the imino compound of formula (III) in giving either the cis or trans octahydro-lH-indole-2-carboxylic acid is further summarized in Table-I.
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Table-I : The effect of pH, nature and amount of the transition metal catalyst, and the medium of reaction in dictating the diastereoselectivity of the reduction of the inline compound of formula (111) under identical gas pressure (50-60 psi of hydrogen) and at ambient temperature (30-35° C)

* Carried out hydrogen pressure of 25-35 psi
Any organic or inorganic base can be used for maintaining alkaline pH during the reaction. Of these, inorganic bases are preferred because of their low cost. The inorganic bases that can be employed are selected from alkali metal carbonates, such as sodium, potassium, lithium and cesium carbonates; alkali metal hydroxides, such as sodium, potassium, lithium and cesium hydroxides etc. The preferred base is an alkali metal hydroxide and the most preferred alkali metal hydroxide is sodium hydroxide.
The reaction is ideally carried out at ambient temperature, at a temperature between 30 C to35°C.
The reaction can be carried out in a Parr hydrogenator as well as in industrial scale autoclaves, both giving reproducible results. However, in the later case the type of
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agitator, agitation speed, substrate concentration etc. would need to be set to obtain the most optimum amounts of trans octahydro-lH-indole-2-carboxyIic acid. All such variations should be construed as falling within the scope of the present invention.
The catalytic hydrogenation of the imino compound (III) under alkaline conditions, in presence of a transition metal catalyst containing rhodium and in aqueous medium or in a mixture of water and a water-miscible organic solvent leads to formation of a mixture of four diastereomers of trans octahydro-lH-indole-2-carboxylic acids of formula (I1), (I4), (I ), and (I ) shown below, which collectively correspond to compound of formula (I).
H

At the end of the reaction, the product i. e. a mixture of cis and trans octahydro-lH-indoIe-2-carboxylic acids is obtained. The product could be isolated by filtration of the catalyst, followed by acidification of the filtrate to a pH of about 6,0 to 6.5 by addition of mineral acid. The aqueous solution is concentrated under reduced pressure to dryness and traces of water and other solvents removed by azeotropic distillation with toluene. Methanol is added to the solution and the precipiated alkali metal chloride filtered off. Evaporation of the solution gives the trans octahydro-lH-indoIc-2-carboxyIic acid of formula (1) in admixture with the corresponding cis isomers and other unidentified compounds.
The ratio of the trans to cis isomer can be determined by formation of the benzyl ester of each of the isomers.
The trans octahydro-lH-indole-2-carboxylic acid of formula (I) can be separated from the corresponding cis isomers by classical column chromatography to get a pure compound. However, they can be separated by repeated fractional crystallization comprising heating of the mixture of isomers in a water-miscible organic solvent or mixtures thereof at 60-80 °C and filtering off the insoluble trans isomer. The pure trans
22

isomer can finally be obtained in a purity of greater than or equal to 96%, having a specification rotation of --0.56".
The water-miscible organic solvent can be selected from nitriles such as acetonitrile; lower aliphatic alcohols of 1-4 carbon atoms such as methanol, elhanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol and tertiary-butanol; ethers such as tetrahydrofuran and 1,4-dioxane; ketonic solvents such as acetone; and amides such as N,N-dimethylformamide.
Among these, the most preferred water-miscible solvents are acetonitrile and a lower alcohol of 1-4 carbon atoms. Methanol is the most preferred lower aliphatic alcohol.
Typically, the separation to give the pure trans isomer in a purity of greater than or equal to 96% is achieved in three or four fractional crystallizations from the water-miscible organic solvent employed.
The trans ring junction of compound (I) thus obtained was confirmed by comparing its 2D COSY-45 and ROSEY NMR spectra with those of the corresponding cis analogues as well as by converting it to trandolapril of formula (II).
The highly selective separation of trans octahydro-lH-indole-2-carboxylic acid of formula (I) from the corresponding cis isomers in optically pure form forms another novel aspect of the present invention.
The starting imino compound of formula (III) can be prepared by methods known in the art. For instance it can be prepared by the method as described in US Patent No. 4.933.361, comprising reacting an enaminc prepared from cyclohexanone. such as. for example, 1-pyrrolidinyl-cyclohcxene (IV-) with a N-protectcd 3-haIo-aIanine alkyl ester (V), where X is a halo radical selected from chloro, bromo or iodo, and PG is a nitrogen protective group selected from acetyl (COCH3), trifluoroacetyl (COCF3) or phenylacetyl (COC6H5) in presence of solvents, such as acetonitrile, dichloromethane, methanol, dimethyformamide. The N-protecting group can be acetyl, benzoyl, trifluoro acetyl or the like. Such N-protected 3-haloalanines can, in turn be prepared from L- or DL-serine as per the method described in US Patent No. 4,933,361.
The alkylation is carried out by reacting 1.0-1.5 equivalent of the enamine (IV) with 1.0 equivalent of the halo alanine ester (V) at temperatures ranging from 20 C to 80 C, preferably at room temperature, over a period of 18-24 hours to give the alpha alkylated cyclohexanones VI in near quantitative yields. Carbon NMR spectrum of VI (where PG= COCH3) shows the presence of two diastereomers indicating that both the chiral centers have been racemized.
The shift values in CDC13 are 212.92, 212.87 (both keto), 172.83, 172.64 (both ester CO), 170.31, 170.10 (both amide CO), 52.26, 52.20 (both OCH3), 50.96, 50.87 (both CH), 47.81, 47.42(both CH), 41.98, 41.85 (both CH2), 34.54, 34.39 (both CH2), 31.96, 31.63 (both CH2), 27.92, 27.81 (both CH2), 25.04, 25.16 (both CH2), 22.87 (CH3).
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Hydrolysis of VI by an acid, such as, for example, hydrochloric acid, at temperature ranging from 30-100 °C, preferably at 80-85° C. affords the imino compound (III) as the hydrochloride salt.
The chemistry for preparation of the imino compound (III) is summarized in Scheme-V.

(HI) Scheme-V : Preparation of the Starting Imino Compound (III)
As mentioned hereinbefore, the irons octahydro-III-indole-2-carboxylic acid obtained by the best mode of this invention is produced as a racemic mixture of four diastereomers of formula (I1), (I4), (I5), and (I6), which collectively correspond to compound of formula (I). The racemic acid (I) can be
a) used as such as an intermediate for further elaboration to a diastereomcric mixture of trandolapril, from which the desired diastereomer of formula (11), can be separated out by methods known in the art, or
b) it can be resolved into the optically pure (2S,4R,9S) octahydrolH-indole-2-carboxylic acid of formula (I1), through the intermediacy of a chiral resolving agent and converted to trandolapril of formula (II).
The separation of the racemate compound (I) into the pure enantiomer (I ), can be achieved by customary methods, known in the art via salt formation with optically active acids and bases.
24

In particular, the racemate compound (I) could be resolved first converting the mixture into the corresponding benzyl ester by reaction with thionyl chloride and benzyl alcohol: the benzyl ester could be reacted with 0,0'-dibenzoyl-L-tartaric acid to give the corresponding O.O'-dibenzoyl-L-tartaric acid salt and removal of the salt would give the desired compound (I ) as per the method disclosed by M. Vincent et. al. in Drug Design and Discovery, 1992, 9, 11-28.
Alternatively, the racemate compound (I) could be converted into the corresponding N-acetyl derivative of formula (VII)
H

and resolving the N-acetyl derivative (VII) using L-cinchonidine to give the desired compound (I ) in high optical purity. This is the preferred method of resolution and is summarized in Scheme-VI.
Typically, compound (I) and its enanliomer obtained is converted to the corresponding N-acetyl derivative of formula (VII) by reaction with acetic anhydride in the presence of a base. Typically, the base is employed as an aqueous solution. Suitable bases include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. The N-acetyl derivative (VII) is found to possess the following physical and spectral characteristics.
[4r]i,=+0.97(C- 0.10. methanol)
Mass Spectrum : m/z at 212.2 anm (M M )
'H NMR (CDC13, &) : 1.60-2.10 (m. 9H); 2.12 (s, 3H); 2.20-2.40 (nv 1H); 2.40-2.50 (dd.
J- 11.90 & 4.80 Hz, 1H); 2.85-3.00 (dt. J= 10.50 and 3.40 Hz. 1H); 4.53 (d, J-7.80 Hz.
1H).
The N-acetyl derivative (VII) is reacted with an equimolar or slight excess of 1-cinchonidine in a suitable organic solvent to give the corresponding l-cinchonidine salt of the [2p, 3aP, 7aa] or [2S, 3aR, 7aS]-N-acetyl isomer. (VIII) in greater than 98% optical purity and possessing the following physical and spectral characteristics.
[a]D = -85.5° (C - 0.10, methanol)
Mass Spectrum : m/z at 295.3 amu (M+l)
Melting point: 156-158° C
IR (KBr, v, cm"1): 3325, 2927.7,1720.4,1631.7 and 1593.1
25

The free [2p, 3ap, 7aa] or [2S, 3aR, 7aS]-N-acetyl isomer (IX) is then obtained by treatment of the N-acetyl cinchonidine salt (VIII) with an acid in an organic solvent and is found to possess the following spectral characteristics.
[a]D - +18.85° (C - 0.10, methanol)
Mass Spectrum : m/zat 212.1amu (M+l)
IR (KBr, v, cm"1): 3398.3, 2935.5, 1708.8 and 1593.1
Finally, the [2p, 3a(3, 7aa] or [2S, 3aR, 7aS]-octahydro-lH-indole~2-carboxylic acid, of formula (I1) can be obtained by treatment of the N-acetyl derivative (IX) with an acid. Compound (I!) thus obtained was found to possess the following physical and spectral characteristics.
[a]D=-75.70(C= 1.0, water)
26

Mass Spectrum : m/z at 170.2amu (M+1)
Melting point : 272-274° C1
IR(KBr, v. cm"1) : 3460.1, 2935.5. 1612.4, 1596.9 and 1454.2
lH NMR (CDCh. 8) : 0.90-1.30 (m. 3H); 1.30-1.70 (m. 3H); 1.70-2.00 (m. 31!): 2.00-
2.20 (m, 2H); 2.77 (dt, J= 3.6 and 11.60 Hz, 1H); 4.15 (dd, J=2.20 and 10.50 Hz, 1H)
Both the methods for synthesis of Irandolapril are within the scope of the present invention.
For instance, the racemic acid (I) can be reacted with N-carboxy anhydride (NCA) of N-(lS)-2-ethoxycarbonyl-3-phenyIpropyl)-S-alanine (NEPA) as per the method disclosed in US Patent No. 4,716,235 or giving trandolapril as a mixture of diastereomers, from which the pure optical antipode (II) can be separated out.
Alternatively, the pure optical antipode (I1), can be reacted with N-carboxy anhydride (NCA) of N- (lS)-2-ethoxycarbonyl-3-phenylpropyl)-S-alanine (NEPA) as per the method disclosed in US Patent No. 4,716,235 to give directly trandolapril (II) in pure optical form.
The following examples serve to illustrate the invention, but however, should not be construed as limiting the scope of the invention.
Example -1
To obtain the disatereomeric mixture of trans and cis octahydro 1H-indole -2-carboxylic acid.
In a 500 ml Parr hydrogenation bottle was placed 0.5 g (2.4 m moles) of imino acid hydrochloride (III) dissolved in 10 ml of deionized water and the pH of the solution was adjusted to 12.70 by addition of 2.5 ml of 10% aqueous sodium hydroxide solution. To this was added 250 mg of rhodium (5%) on activated carbon and the mixture was shaken under a hydrogen atmosphere at 50-60 psi for 14-15 hours till TLC analysis showed completion of reaction. The reaction mixture was filtered through a Whatman #1 filter paper and the catalyst bed was washed with 5 m of demineralised water. The filtrate was cooled to 10° C and the pH was adjusted to 2.3-2.6 by addition 6N HC1. Again the solution was neutralized to pH 6.0-6.2 by addition of 10% NaOH. The solution was concentrated to dryness under vacuum, swapped twice with 2X5 ml toluene and toluene distilled off. Finally 20 ml of methanol was added to the residue and the precipitated NaCl was filtered off. The methanol filtrate was concentrated under reduced pressure to give 400 mg (2.4 m moles) of the diastereomeric mixture of trans and cis octahydroindole -2-carboxylic acid as a white solid.
In a three-necked dry round-bottomed flask, equipped with a magnetic stirrer, thermowell and a Dean - Stark apparatus the diastereomeric mixture of trans and cis octahydro indole -2-carboxylic acid as obtained above was mixed with 20 ml of cyclohexane, 410 mg (2.4 m moles) of p-toluene sulfonic acid and I.04g (9.7 m moles) of benzyl alcohol. The resulting heterogeneous mixture was vigorously stirred for 8-10 hours at 80° C, with
27

concurrent removal of water azeotropically. The mixture was cooled to 25° C and cyclohexane was decanted out. The residual mixture was triturated with cyclohexane till excess benzyl alcohol was removed. The residual mixture was concentrated under vacuum to give 1,04g of the benzyl ester of diastereomeric mixture of octahydroindole -2-carboxylic acid (I). HPLC analysis of the benzyl ester revealed it contained 50.40% of the racemic trans octahydroindole -2-carboxylic acid (I).
Example-2
To obtain the disatereomeric mixture of trans and cis octahydro W-indole -2-carboxylic acid,
In a 500mL Parr hydrogenation bottle was placed 5 g (24.57 moles) of imino acid hydrochloride (III), 50 ml of demineralised water, 50 ml of isopropanol and the pH of the reaction mixture was adjusted to 12.60 by addition of 30 ml of 10% aqueous sodium hydroxide solution. To this was added 1 g of rhodium (5%) on activated carbon. The mixture was shaken under hydrogen atmosphere at 50-60 psi for twenty-four hours till TLC indicated completion of reaction. The reaction was mixture was workuped the same way as described in Example-1, to give the title compound, containing 49.9% of the racemic trans octahydroindole -2-carboxylic acid (I).
Example-3
To obtain the disatereomeric mixture of trans and cis octahydro IH-indole -2-carboxylic acid,
Into a 500 mL Parr hydrogenation bottle was placed 10.0 g (49.1 mmoles) of imino acid hydrochloride (III), 200 ml of demineralised water, 50 ml of 10% aqueous sodium hydroxide solution to adjust the pll to 12.5± 0.1 and 2.0 g of rhodium (5%) on activated carbon. The mixture was shaken under a hydrogen gas atmosphere of 50-60 psi pressure for 23 hours till completion of reaction as indicated by TLC. The mixture was filtered through a Whatman filter paper No. 1, the residue was washed with 10 ml of water and the filtrate was cooled to 10°C. The plI of the solution was adjusted to 6.5 by addition of 6N I1C1 and then concentrated to dryness under vacuum. Residual water was removed b\ azeotropic distillation with 2X30 ml of toluene. Thereafter 100 ml of methanol was added and the sodium chloride precipitated out and was filtered off. The filtrate was concentrated to dryness and the resulting solids were slurried with 40 ml of 2-propanol , the solid fdtered and dried to afford 5.4 g the title compound, containing 39.9% of the racemic trans octahydroindole -2-carboxylic acid (I).
28

To obtain the racemic mixture of trans octahydro 1 H-indole-2-carboxylic acid (I1 + 16) from the disater corner ic mixture of tran
s and cis octahydroindole ~2-carboxylic acid, 5.4 g of the disatereomeric mixture of trans and cis octahydroindole -2-carboxyIic acid, as obtained from Example 3 was suspended in 15 ml of methanol and agitated for 0.5 hours at 60-65 C. The mixture was cooled to 30 C and the solid filtered off. The solid were washed with 2X5 ml of methanol and dried to give 4.2 g of solid.
The solid thus obtained hereinabove was suspended in 12.5 ml of methanol and the slurry was agitated at 60-65 C for 0.5 hours. The solid was filtered and washed with 2X3.0 ml of methanol, dried under vacuum to give 3.0g of g of trans octahydro lH-indole-2-carboxylic acid (I), having a purity of 95-96% as shown by HPLC (as benzyl ester).
Specific rotation : +0.2 (C= 1, H20)
IR (KBr, v, cm"1): 3431, 3068, 2954, 1597
'H NMR (200 MHz. D20, 5): 3.96(d, 111, J=10.4 Hz), 2.70 (dt, 1H. .1=11.6.3.3 Hz), 2.15-1.90 (m. 211). 1.90-1.65 (m, 3H). 1.65-1.50 (m, 1H), 1.50-1.25 (m. 211). 1.25-0.80 (m, 311):
13
C NMR (200, MHz, D20, 5): 175.01 (COOH), 64.17 (CH), 59.37 (CH), 41.56(CII), 34.03(CH2), 28.49(CH2), 28.17(CH2), 24.08 (CH2), 23.82(CH2).
Mass(m/z)= 170.5 (M+l) m.p = 270-271 °C
Example-5
[2B 3aB 7aa] or [2S, 3aR, 7aS]-(23l3a,4,5,6,7,7a)octahydro-lH-indole-2-carboxylic acid, (I1) can be prepared using the following steps
Step-1 : Preparation of (±)-N-acetyl- octahydro-indole-2-carboxylic acid as a mixture of [2S, 3aR, 7aS]-and [2R, 3aS, 7aR] isomers
29

To a solution of 6.9 g (40.80 mmoles) of racemic trans octahydro -lH-indole-2-carboxylic acid (I, as obtained from Example-3 and Example-4) in 51.3 ml of aqueous sodium hydroxide (128.3 mmoles), cooled to 2° C was added acetic anhydride 911.9 g, 116.7 mmoles), dropwise over a period of 15 mns, maintaining a temperature between 2 to 13 C. During the addition, the pH of the reaction mixture was maintained between 9.0 to 10.0 by addition of a 10% aqueous solution of sodium hydroxide. After the addition, the reaction mixture was cooled to 0-5° C and agitated at this temperature for 5 hrs. The pH of the reaction mixture was adjusted to 2.0 by addition of Cone. HC1 (25 ml) and extracted with dichloromethane (200 ml). The layers were separated and the organic layer was concentrated under reduced pressure to give an oily residue.
The residue was stirred with n-hexane (80 ml) for 3 hrs and the solid separated out was filtered, washed with n-hexane (3x10 ml) and dried under vacuum at 45-50 C to give 8.14 g (95%) of the title compound as a white solid.

[a]97(C Mass .Spectrum "HNMR(CDC J= 11.90 &4.8(
1H).
IR(KBr, cm"1):-2925.8, 1728. 1708.8 and 1616.2
m.p144.1450C
0.10, methanol)
m/z at 212.2 amu(M+l)
, 5) : 1.60-2.10 (m, 911); 2.12 (s. 3H; 2.20-2.40 (m. 1H); 2.40-2.50 (dd.
Hz, 1H); 2.85-3.00 (dt, J= 10.50 and 3.40 Hz, 1H); 4.53 (d, J- 7.80 Hz.

30
Step-2 : Preparation of (-)-N-acetyl-[2S, 3aR, /aSJ- octahydro-indole-2-carboxylic acid, l-cinchomdine salt

A mixture of 9.0 g (42.6 mmoles) of (±)-N-acetyl- octahydro-indole-2-carboxylic acid as a mixture of [2S; 3aR, 7aS]-and [2R, 3aS, 7aR] isomers (as obtained in Step-1), ethyl acetate (100 ml) and 1-cinchonidine (12.54 g, 42.6 mmolcs) was heated to reflux to obtain a clear solution. The solution was cooled to 20-25° C and stirred at this temperature for 5 hrs. The solid separated out was filtered, washed with ethyl acetate (3x5 ml) and dried at 40-45° C under vacuum.
The above solid was resuspended in ethyl acetate and the above procedure was repeated twice to give (-)-N-acetyI-[2S, 3aR, 7aS]- octahydro-lH-indole-2-carboxyIic acid, L-cinchonidine salt having optical purity >98%.
[CC]D = -85.5° (C = 0.10, methanol)
Mass Spectrum : m/z at 295.3 and 212.2 amu (M+lof cinchonidine and N-acetyl acid
derivative respectively)
Melting point: 156-158° C
IR (KBr, v, cm"1): 3325, 2927.7,1720.4,1631.7 and 1593.1
Step-3 : Preparation of {+)-N-acetyl-[2S, 3aR, 7aS]~ octahydro-indole-2-carboxylic acid,

4.9 g (9.7 mmolcs) (-)-N-acetyl-[2S, 3aR, 7aS]- octahydro-III-ole-2-carboxylic acid. 1-cinchonidinc salt (as obtained in Stc-20 was dissolved in dichloromcthane (49 ml). The solution was washed thrice with 15 ml portions of 2N hydrochloric acid. The organic layer was separated and concentrated under vacuum to give an oily residue.
The residue was stirred with n-hexane (5 ml) for 2 hrs at 25° C. The solid separated out was filtered, washed with n-hexane and dried at 40-45° C under vacuum to give the title compound having 99.7% optical purity.
[a]D = +18.85° (C = 0.10, methanol)
Mass Spectrum : m/z at 212.1 amu (M+1)
IR (KBr, v, cm"1) : 3398.3, 2935.5, 1708.8 and 1593.1
mp. - 170-172 6C
PMR: 0.1-1.6 (m, 5H); 1.6-2.1 (m, 4H); 2.2 (s, 3H); 2.25-2.4 (m, 1H), 2.4-2.6 (m, 1H);
3.0 (m, 1H) and 4.61 (d, J=8.3 Hz, 1H)
31

Step-4 : Preparation of [2/3, 3a/3, 7a a] or [2S, 3aR, 7aS]-octahydro-lH~indole-2-corboxylic acid, (I)

A mixture of 0.35 g (1.79 mmoles) of (+)-N-acetyl-[2S, 3aR, 7aS]- octahydro-indole-2-carboxylic acid (as obtained in Step-3) and 3.8 ml of 5N hydrochloric acid was stirred at 90-95° C for 30 hrs. The mixture was cooled to 25 C and extracted with dichloromethane (4x5 ml). The layers were separated and the aqueous layer was concentrated under vacuum to give a residue.
The residue was dissolved in water (5 ml) to which was added 1.42 ml (1.69 mmoles) of 10% aqueous sodium carbonate solution to adjust the pH to 5.60 and the mixture again concentrated under vacuum to give a residue.
The residue was dissolved in methanol (40 ml) and heated to reflux. The solution was filtered hot through a 0.20 u membrane and the filtrate concentrated under reduced pressure to give 0.216 g (72%) of [2/3, 3a/3, 7aa] or [2S, 3aR, 7aS]-octahydro-lH-indoie-2-carboxylic acid, (l') as a white crystalline solid.
[a]D --75.7° (C= 1.0, water)
Mass Spectrum : m/z at 170.2amu (M+l)
Melting point : 272-274° C
1R (KBi\ v. cm"1) : 3460.1, 2935.5. 1612.4, 1596.9 and 1454.2
!H NMR (CDC13, 5) : 0.90-1.30 (m. 3H); 1.30-1.70 (m. 311); 1.70-2.00 (m. 3H: 2.00-
2.20 (m, 2H); 2.77 (dt, J= 3.6 and 11.60 Hz, 1H); 4.15 (dd, J-2.20 and 10.50 Hz, 111)
ExampIe-6
To obtain irandolapril as a mixture of diastereomers utilizing racemic trans octahydro
1 H-indole-2-carboxyhc acid (1),

32

To a solution of 0.5 g (2.96 mmoles) of racemic trans octahydro III-indoIc-2-carboxyIic acid (I.(as obtained in example IV) in 15 ml of water was added 1.3 ml (3.25 mmoles) of 10% aqueous sodium hydroxide, followed by 0.344 g (3.25 mmoles) of sodium carbonate. The reaction mixture was stirred to get a clear solution and then cooled to -5° C. A solution of 0.86 g (2.81 mmoles) of in 20 ml of acetone was added N-Carboxy anhydride of N-[l-(S)-ethoxycarbonyl-3-phenylpropyl]-(S)-alanine (NEPA-NCA) rapidly in one lot and the reaction mixture was stirred at -5 to 0 ° C for one hour, The reaction mixture was acidified to pH 4.5 withn 1.2 ml of 6Nhydrochloric acid. To the aqueous solution was added 20 mL of ethyl acetate and the solvent was concentrated under vacuum. The resulting aqueous solution was then extracted with 3X10 ml of ethyl acetate and the combined organic extract was dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. The thick syrup obtained slowly solidified at 25 ° C. HPLC analysis showed two peaks, in which the peak eluting out first had the same retention time as that of authentic trandolapril (II), thereby meaning it is the (S,R?S,S,S) diastereomer and the one eluting second is the (R,S,R,S,S) diastereomer.
ExampIe-7
To obtain trandolapril (II) utilizing [2B 3afi 7aa] or [2S, SaR, 7aS]-octahydro-1H-
indole-2-carboxylic acid, (I)

To a solution of 0.1 g (0.5917 mmoles) of [2B 3aB 7aa] or ['2S, 3aR, 7aS]-oclahydro-lH-indolc-2-carboxylic acid, (I1, as obtained in Step-4 of Example-5) in water (5 ml), cooled to 0° C was added 5% aqueous sodium carbonate solution (2.8 ml) and the mixture stirred at 0° C for 10 mns. To this was added a solution of 0.162 g (0.532 mmoles) of N-Carboxy anhydride of N-[l-(S)-ethoxycarbonyl-3-phenyIpropyl]-(S)-alanine (NEPA-NCA) in acetone (2 ml) in one lot and the reaction mixture was stirred at 0° C for 2 hrs. The pH of the mixture was adjusted to 4.0 with 2N hydrochloric acid and the solution concentrated under vacuum. The residue was dissolved in a mixture of water (5 ml) and ethyl acetate (10 ml). The organic layer was separated out and the aqueous layer was extracted twice with ethyl acetate (2x10 ml). The combined organic layer was washed with saturated solution of aqueous sodium chloride (5 ml) and concentrated under vacuum to give an gummy residue.
The residue was stirred with diisoproplyl ether (30 ml) to obtain a solution. Dry hydrogen chloride gas was bubbled into the solution for 15 mns at 25 C and the reaction mixture was evaporated under vacuum. To the residue obtained was added n-hexane (5 ml) and the mixture stirred at 25° C for 1 hr. The precipitated solid was filtered, washed with n-hexane (3 ml) and dried at 40-45° C under vacuum to give 0.084 g trandolapril (II).
33

We Claim:
A process for preparation of [2B, 3aB, 7aa] or [2S,3aR,7aSl- 2,3,3a,4,5,6,7,7a-octahydro-lH-indole-2-carboxylic acid for formula (I1);

comprising catalytic hydrogenation of [3,3a,4,5,6,7]- hexahydro-2H-indole-2-carboxyiic acid of formula (III)

under alkaline conditions in the presence of a transition metal catalyst containing rhodium and in the presence of water or a mixture of water and a water-miscible organic solvent and fractional crystallization of the mixture of trans and cis octahydro lH-indole-2-carboxylic acid thus obtained from a water-miscible organic solvent at a temperature of between 60 C to 80 C to give trans octahydro lH-indole-2-carboxylic acid of formula (I), its enantiomers thereof and esters and salts thereof, and

resolution of compound of formula (I), after conversion to its N-acetyl derivative of formula (VII)
34

using 1-cinchonidine in organic solvent to give compound of formula (I1).
2. A process as claimed in claim 1, wherein the transition metal catalyst
containing rhodium is selected from rhodium on alumina or rhodium on carbon.
A process as claimed in anyone of claims 1 and 2, wherein the transition metal catalyst containing rhodium is employed in the range of between 10% to 100% w/w of compound of formula (III).
A process as claimed in anyone of claims 1, 2 and 3, wherein the transition metal catalyst containing rhodium is employed in the range of between 20% to 50% w/w of compound of formula (III).
A process as claimed in claim 1, wherein the water-soluble organic solvent is selected from aC1-4aliphatic alcohol, tetrahydrofuran, 1,4-dioxane. acetonitrile and N,N-dimethylformamide.
A process as claimed in claim 1, wherein the conversion of compound of formula (I) to its N-acetyl derivative (VII) is achieved by reaction of compound of formula (I) with acetic anhydride or acetyl chloride and a base in aqueous medium.
A process as claimed in claim 1, wherein resolution of compound of formula (I), after conversion to its N-acetyl derivative of formula (VII)
35

comprises the steps of :

a) reacting compound of formula (VII) with an equimolar or slight excess of equimolar proportion of 1-cinchonidine in an organic solvent to give the 1-cinchonidine salt of formula (VIII),
b) reacting the cinchonidine salt of formula (VIII) with an acid in an organic solvent to give compound of formula (IX), and

c) N-deacylation of compound of formula (IX) by treatment with an acid to give compound of formula (I1).
36

A process as claimed in claim 6, wherein the base is selected from sodium hydroxide or potassium hydroxide.
9. A process as claimed in claim 8, wherein the catalytic hydrogenation is carried out at a temperature preferably between 30°C to 35°C.
10. A process as claimed in claim 1 wherein the catalytic hydrogenation is carried out at a pressure preferably between 50-60 psi of hydrogen gas.

Dated this 3ru day of October 2003

Dr. Sanchita oanguli Of S. Majumdar & Co.
Applicant's Agent

Documents:

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1033-mum-2003-description(granted).doc

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Patent Number

206246

Indian Patent Application Number

1033/MUM/2003

PG Journal Number

31/2008

Publication Date

01-Aug-2008

Grant Date

19-Apr-2007

Date of Filing

03-Oct-2003

Name of Patentee

LUPIN LTD.

Applicant Address

159, CST ROAD, KALINA, SAMTACURUZ (EAST), MUMBAI - 400 098.

Inventors:

#	Inventor's Name	Inventor's Address
1	DATTA, DEBASHISH	LUPIN LTD. (RESEARCH PARK), 46A/47A, NANDE VILLAGE, TALUKA MULSHI, PUNE - 411 042.
2	WANI, Mukesh Jagannath	Lupin Ltd. (Research Park), 46A/47A, Nandc Village, Taluka Mulshi, Pune - 411 042,

PCT International Classification Number

C 07 D 209/12

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA