Title of Invention

A SIMPLE AND EFFICIENT PROCESS FOR THE SYNTHESIS OF TRANDOLAPRIL

Abstract

A process for preparing of trandolapril comprising the steps of reacting sub-molar proportion of N- [1-(S)-ethoxy carbonyl-3- phenyl propyl ]-L-alanine N- carboxyanhydride with trans-octahyrdro-1H-indole-2-carboxylic acid and optionally with (2S,3aR,7aS) octahydro-1H-indole-2-carboxylic acid, in the presence of organic base in non - polar organic solvent is disclosed. The present invention also discloses a process for resolution of racemic trans octahydro-1H-indole-2-carboxylic acid.

Full Text

FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 COMPLETE SPECIFICATION (See section 10 and rule!3) 1. TITLE OF THE INVENTION: “A Simple and Efficient Process for the Synthesis of an ACE inhibitor" 2. APPLICANT (a) NAME: CIPLA LTD. (b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS: 289, Bellasis Road, Mumbai Central, Mumbai - 400 008, Maharashtra, India. 3. PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention and the manner in which it is to be performed. 793 - 5 JUL 2815 Technical field of the Invention The present invention relates to an improved, simple and efficient process for the synthesis and isolation of (2S,3aR,7aS)-l-[(2S)-2-[[(lS)-l-Ethoxycarbonyl-3-phenylpropyl]amino]-l-oxopropyl] octahydro-lH-indole-2-carboxylic acid. i.e. Trandolapril (I). (I) Background of the Invention Trandolapril a compound of formula (I) is chemically described as (2S,3aR,7aS)-l-[(2S)-2-[[( 1S)-1 -Ethoxycarbonyl-3-phenylpropyl] amino] -1 -oxopropyljoctahydro-1 H-indole-2-carboxylic acid. Trandolapril is the ethyl ester prodrug of a nonsulfhydryl angiotensin converting enzyme (ACE) inhibitor, trandolaprilat. Trandolapril is a drug that is used to lower blood pressure. Blood pressure is dependent on the degree of constriction (narrowing) of the arteries and veins. The narrower the arteries and veins, the higher the blood pressure. Angiotensin II is a chemical substance made in the body that causes the muscles in the walls of arteries and veins to contract, narrowing the arteries and veins and thereby elevating blood pressure. Angiotensin II is formed by an enzyme called angiotensin converting enzyme (ACE). Trandolapril is an inhibitor of ACE and blocks the formation of angiotensin II thereby lowering blood pressure. The drop in blood pressure also means that the heart doesn't have to work as hard because the pressure it must pump blood against is less. The efficiency of a failing 2 heart improves, and the output of blood from the heart increases. Thus, ACE inhibitors such as trandolapril are useful in treating heart failure. Trandolapril’s ACE-inhibiting activity is primarily due to its diacid metabolite, trandolaprilat, which is approximately eight times more active as an inhibitor of ACE activity. Trandolapril along with other related compounds was first disclosed in US4933361. The process for the synthesis of Trandolapril was described m^S4933i61 & W09633984. US4933361 describes a process for the synthesis of trandolapril wherein racemic benzyl ester of octahydro indole-2-carboxylic acid is reacted with N-[l-(S)-ethoxy carbonyl-3 -phenyl propyl]-L-alanine(ECPPA), to get racemic benzyl trandolapril which is purified using column chromatography to get the 2S isomer of benzyl trandolapril, which is further debenzylated with Pd on carbon to get trandolapril as a foamy solid. This process has certain disadvantages; the product is obtained in very low yield. Purification is done using column chromatography, which is not suitable for industrial scale up. W09633984 discloses a process in which N-[l-(S)-ethoxy carbonyl-3- phenyl propyl]-L-alanine is activated with N-chlorosulfinyl imidazole, to get (N-[1-(S) N-[l-(S)-ethoxy carbonyl-3- phenyl propyl]-L-alanyl-N-Sulfonyl anhydride and which further reacted with silyl protected 2S,3aR,7aS octahydro indole 2-carboxylic acid to obtain Trandolapril. The main disadvantage of this process is that, the silyl-protected intermediates are very sensitive to moisture and it requires anhydrous conditions to be maintained and solvent used has to be completely dried. It is very difficult to maintain such conditions on industrial scale, failing to do so leads to low yield of product. The processes for preparing N-[l-(S)-ethoxy carbonyl-3- phenyl propyl]-L-alanine N-carboxyanhydride which is used in the process of the present invention are well known 3 and are disclosed in JP57175152A, US4496541, EP215335, US5359086 and EP1197490B1. Octahydro-lH-indole-2-carboxylic acid and its esters are the key intermediates in the synthesis of trandolapril. It exist in four isomeric forms as shown in Fig-1 From the process known in the prior art, octahydro-lH-indole-2-carboxylic acid is converted to its ester and the ester is then either reacted directly with N-[l-(S)-ethoxy carbonyl-3- phenyl propyl]-L-alanine (ECPPA) and then the isomers are separated by column chromatography, or alternatively the ester is reacted with ECPPA followed by deprotection. Octahydro-lH-indole-2-carboxylic acid is always used in its protected form. No attempts have been made to resolve free octahydro-lH-indole-2-carboxylic acid to covert it to the desired isomer (A). EP0088341, US4490386 describe a method for the resolution of N-benzoyl (2RS,3aR,7aS) octahydro-1 H-indole-2-carboxylic acid using a-phenyl ethyl amine. US6559318, EP1140826 describes a process for the synthesis of (2S,3aR,7aS) octahydro-1 H-indole-2-carboxylic acid by using enzymatic resolution of its intermediate. Enzymatic resolution involves many steps and also requires column chromatography for purification making the process uneconomical industrially. WO8601803 describes the preparation of (2S,3aR,7aS) octahydro-lH-indole-2-carboxylic acid ethyl ester and benzyl ester using 10-D-camphor sulphonic acid. 4 WO2004065368 describes the synthesis of (2S,3aR,7aS) octahydro-lH-indole-2-carboxylic acid benzyl ester by resolution using 10-D-camphor sulphonic acid to prepare trandolapril. This process gives poor yields because the product has to be first resolved and then the ester is deprotected leading to further loss in yield, making the process low yielding and expensive. The processes for preparing N-[l-(S)-ethoxy carbonyl-3- phenyl propyl]-L-alanine N-carboxyanhydride starting from N-[l-(S)-ethoxy carbonyl-3- phenyl propyl]-L-alanine (ECPPA) are well known and are disclosed in JP57175152A, US4496541, EP215335, US5359086 and EP1197490B1. The processes for the synthesis of Trandolapril, described in the prior art have numerous disadvantages as described above. Hence there is a need for a simple and efficient process for the synthesis of Trandolapril. The present invention describes a process, which solves this problem. The present process is neither obvious nor anticipated from any of the processes described in the prior art. Object of the Invention The object of the present invention is to provide an improved process for the synthesis of (2S,3aR,7aS)-1 -[(2S)-2-[[( 1S)-1 -Ethoxycarbonyl-3-phenylpropyl]amino]-1 -oxopropyl] -octahydro-lH-indole-2-carboxylic acid from (2S,3aR,7aS) octahydro-lH-indole-2-carboxylic acid. Another object is to provide a stereo selective process of preparing Trandolapril from Racemic trans octahydro-lH-indole-2-carboxylic acid (fig-1). Further object is to provide a process for the resolution of (2RS,3aR,7aS) octahydro-lH-indole-2-carboxylic acid. 5 Summary of the invention A process for preparation of trandolapril comprising the steps of reacting sub-molar proportion of N-[l-(S)-ethoxy carbonyl-3- phenyl propyl]-L-alanine N-carboxyanhydride with trans- octahydro-lH-indole-2-carboxylic acid and optionally reacting with (2S,3aR,7aS) octahydro-1 H-indole-2-carboxylic acid in the presence of organic base in non-polar organic solvent is disclosed. The present invention also discloses a process for resolution of racemic trans octahydro-lH-indole-2-carboxylic acid. Detailed description of the invention The present invention relates to an improved, simple and efficient process for the synthesis of Trandolapril, which is ideally suitable for industrial scale-up. The process of the present invention is described in Scheme below 6 One aspect of the present invention provides a process for the synthesis of trandolapril wherein Trans octahydro-lH-indole-2-carboxylic acid (III) is reacted with N-[1-(S)-ethoxy carbonyl-3- phenyl propyl]-L-alanine N-carboxyanhydride (II) (referred herein as NCA) in a suitable organic solvent preferably a non polar organic solvent more preferably in dichloromethane, in the presence of a base preferably triethylamine at a temperature ranging from 5°C to ambient temperature, preferably at ambient temperature. The reaction mass is quenched with water and the pH is adjusted to 4-7 preferably to pH 4.2 with an acid. The reaction mass is then extracted with dichloromethane and concentrated to residue. The residue is dissolved and refluxed in a suitable solvent preferably in ethyl acetate, isopropyl acetate, acetone, acetonitrile, isopropyl alcohol more preferably acetonitrile. The product is isolated by cooling the reaction mass to room temperature and filtering the resulting solid. Other aspect of the present invention provides a process for resolution of racemic trans octahydro-lH-indole-2-carboxylic acid to obtain (2S,3aR,7aS) octahydro-lH-indole-2-carboxylic acid compound of formula (IV) using R(+) phenyl ethyl amine as a resolving agent using ethanol as a solvent. All the processes in the prior art describes resolving the esters of racemic trans octahydro-lH-indole-2-carboxylic acid, none of the prior art teaches a process for resolving trans octahydro-lH-indole-2-carboxylic acid. During the process of optimizing the reaction conditions for the present invention, surprising results were obtained, which led to another object of the present invention. It was found that Trandolapril can be synthesized by reacting NCA directly with racemic trans octahydro-lH-indole-2-carboxylic acid. There is no need to resolve the compound of formula (III), this leads to an efficient process. Also we have found that NCA reacts selectively with the desired isomer of octahydro-lH-indole-2-carboxylic acid (A) in Fig-1, thus making the process of the present invention a stereo selective process. It was observed that if NCA (II) was used in an equimolar proportion to the racemic trans acid, a significant amount of NCA remains unreacted and is recovered back as ECPPA. 7 This led us to lower the amount of NCA (II) used in the reaction, which gave very encouraging results. Therefore in most preferred embodiment of the present invention a process for synthesis of trandolapril comprising reaction of racemic trans octahydro-1H-indole-2-carboxylic acid with a sub-molar proportion of NCA (II) preferably about 0.9-0.4 moles more preferably 0.6 to 0.8 moles most preferably 0.7 is provided. NCA required for the reaction was synthesized using known processes starting from N-[l-(S)-ethoxy carbonyl-3- phenyl propyl]-L-alanine. The following specific examples are presented to illustrate the best mode of carrying out the process of the present invention. The examples are not limited to the particular embodiments illustrated herein but include the permutations, which are obviously set forth in the description. Examples Example 1 Step A: Preparation of N-[l-(S)-ethoxy carbonyl-3- phenyl propyl]-L-alanine N-carboxy anhydride (NCA) Disodium dihydrogen phosphate dihydrate (177 gms;0.994 moles) was dissolved in water (300 ml) at 35°C and cooled to ambient temperature. Dichloromethane (250 ml) was charged and stirred for 15 mins. N-[l-(S)-ethoxy carbonyl-3- phenyl propyl]-L-alanine (106 gms;0.381 moles) was added to the above solution and the reaction mass was cooled to 15°C. Solution of triphosgene (52.8 gms;0.177 moles) dissolved dichloromethane (40 ml) was added dropwise to the reaction mass in 40 mins at 15-20°C. The reaction mass was further stirred for 30 min. Pyridine (0.5 ml; 0.006 moles ) was added and the reaction mass was stirred for 1 hr at 15-20°C. The reaction mass was settled and layers were separated. Organic layer was washed with 2N HC1 till the neutral pH obtained. The organic layer was further washed with water and dried over sodium sulphate. The solvent was evaporated to residue (110 gms). 8 Step B: Preparation of (2S,3aR,7aS)-l-[(2S)-2-[[(lS)-l-Ethoxycarbonyl-3-phenylpropyl] amino] -1-oxopropyl] octahydro-lH-indole-2-carboxylic acid (2S,3aR,7aS) octahydro-lH-indole-2-carboxylic acid (65 gms 0.384 moles) was stirred in dichloromethane (200 ml), triethyl amine (30 ml) was added under stirring at ambient temperature for 30 mins. N-[l-(S)-ethoxy carbonyl-3- phenyl propyl]-L-alanine N-carboxy anhydride ( 110 gms; 0.378 moles) (residue from Step A) dissolved in dichloromethane (50 ml) was added dropwise to the reaction mass at ambient temperature and further stirred for 3 hrs. Water (500 ml) was added and the reaction mass was cooled to 15°C, pH of the reaction mass was adjusted to 4.2 using 2N HC1. The organic layer was separated and aqueous layer reextracted with dichloromethane. The combined organic layer was dried with sodium sulphate and concentrated to residue. The residue was dissolved in ethylacetate at reflux temperature. The reaction mass was cooled to ambient temperature. The resulting solid was filtered and dried under vacuum to get 50 gms of Trandolapril (HPLC purity 99.5%) Example 2 Racemic Trans octahydro-lH-indole-2-carboxylic acid (65 gms; 0.384 moles) was stirred in dichloromethane ( 200 ml), triethyl amine (30 ml) was added under stirring at ambient temperature for 30 mins. N-[l-(S)-ethoxy carbonyl-3- phenyl propyl]-L-alanine N-carboxyanhydride ( 88 gms; 0.302 moles) (prepared using procedure of Step A of Example 1 ) dissolved in dichloromethane 300ml was added dropwise to the reaction mass at ambient temperature and further stirred for 3 hrs. Water (500 ml) was added and the reaction mass was cooled to 15°C, pH of the reaction mass was adjusted to 4.2 using 2N HC1. The organic layer was separated. The organic layer was dried with sodium sulphate and concentrated to residue. The residue was dissolved in ethylacetate at reflux temperature. The reaction mass was cooled to ambient temperature. The resulting solid was filtered and dried under vacuum at 30-35°C to get 40 gms of Trandolapril (HPLC purity 99.3%). 9 Example 3 Racemic Trans octahydro-lH-indole-2-carboxylic acid ( 100 gms; 0.592 moles) was stirred in dichloromethane (300 ml), triethyl amine (46 ml) was added under stirring at ambient temperature for 30 mins. N-[l-(S)-ethoxy carbonyl-3- phenyl propyl]-L-alanine N-carboxyanhydride (119 gms; 0.42 moles) (prepared using procedure of Step A of Example 1 ) dissolved in dichloromethane (300 ml) was added dropwise to the reaction mass at ambient temperature and further stirred for 3 hrs. Water (700 ml) was added and the reaction mass was cooled to 15°C, pH of the reaction mass was adjusted to 4.2 using 2N HC1. The organic layer was separated. The organic layer was dried with sodium sulphate and concentrated to residue. The residue was dissolved in ethylacetate at reflux temperature. The reaction mass was cooled to ambient temperature. The resulting solid was filtered and dried under vacuum at 30-35°C to get 55 gms of Trandolapril (HPLC purity 99.5%). Example 4 Racemic Trans octahydro-lH-indole-2-carboxylic acid ( 50 gms; 0.295 moles) was stirred in dichloromethane (150 ml), triethyl amine (23 ml) was added under stirring at ambient temperature for 30 mins. N-[l-(S)-ethoxy carbonyl-3- phenyl propyl]-L-alanine N-carboxyanhydride (41 gms; 0.148 moles) (prepared using procedure of Step A of Example 1 ) dissolved in dichloromethane (150 ml) was added dropwise to the reaction mass at ambient temperature and further stirred for 3 hrs. Water (350 ml) was added and the reaction mass was cooled to 15°C, pH of the reaction mass was adjusted to 4.2 using 2N HC1. The organic layer was separated. The organic layer was dried with sodium sulphate and concentrated to residue. The residue was dissolved in ethylacetate at reflux temperature. The reaction mass was cooled to ambient temperature. The resulting solid was filtered and dried under vacuum at 30-35°C to get 25 gms of Trandolapril (HPLC purity 99.3%). Example 5 RacemicTrans octahydro-lH-indole-2-carboxylic acid ( 410 gms 2.42 moles) was refluxed in ethyl alcohol (3.81trs). Heating of the reaction mass was discontinued, R(+) 10 phenyl ethyl amine (500 gms;4.13 moles) was charged to the reaction mass and stirred at ambient temp for 16-18 hrs. The reaction mass was then chilled to 10°C and resulting solid was filtered. This solid was stirred in a mixture of water (3.6 ltrs.) and 10% NaOH (100 ml) for 15 mins. The clear aqueous layer was washed with ethyl acetate (1 ltr). The pH of the aqueous layer was adjusted to 6.5 using 10% HCI. The aqueous layer was concentrated under vacuum below 60°C to residue. Acetonitrile (100 ml) was charged and the resulting suspension was stirred at ambient temperature for 1 hr. and filtered. The solid was filtered and washed with acetonitrile and dried under vacuum at 60°C to give 200 gms of (2S,3aR,7aS) octahydro-1 H-indole-2-carboxylic acid . 11 We Claim 1. A process for the synthesis of Trandolapril of Formula (I) which comprises condensing sub-molar proportion of N-[l-(S)-ethoxy carbonyl-3- phenyl propyl]-L-alanine N-carboxyanhydride compound of formula(II) H5C2OOC CH with trans octahydro-1 H-indole-2-carboxylic acid of formula (III); in non-polar organic solvent in the presence of a base and isolating compound of formula(I) from a suitable organic solvent. 2. A process according to claim-1 wherein said solvent used in the condensation of compound of the formula (II) with compound of the formula (III) is a non polar organic solvent preferably dichloromethane. 12 3. A process for the synthesis of Trandolapril of Formula (I) which comprises condensing compound of formula(II). with (2S,3aR,7aS) 0ctahydro-lH-indole-2-carboxylic acid of formula (IV) (IV) in non-polar organic solvent in presence of a base and isolating compound of formula(I) from a suitable organic solvent. 4. A process for the synthesis of Trandolapril as in claim3 wherein (2S,3aR,7aS) octahydro-lH-indole-2-carboxylic acid of formula (IV) is prepared by resolution of compound of formula (III) using R (+) phenyl ethyl amine in a suitable organic solvent. 5. A process according to claims 1 and 3, wherein said base used for the condensation is an organic base. 6. The process as claimed in claims 1 and 3, wherein said suitable organic solvent is selected from ethyl acetate, isopropyl acetate, acetone, acetonitrile, isopropyl alcohol and more preferably acetonitrile. 7. An improved process for the synthesis and isolation of Trandolapril as substantially described herein with reference to the foregoing examples 1 to 5. Dated this 5tn day of July, 2005 13 ABSTRACT: A process for preparation of trandolapril comprising the steps of reacting sub-molar proportion of N-[l-(S)-ethoxy carbonyl-3- phenyl propyl]-L-alanine N-carboxyanhydride with trans- octahydro-lH-indole-2-carboxylic acid and optionally with (2S,3aR,7aS) octahydro-lH-indole-2-carboxylic acid, in the presence of organic base in non-polar organic solvent is disclosed. The present invention also discloses a process for resolution of racemic trans octahydro-lH-indole-2-carboxylic acid. 14

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