Title of Invention	A PROCESS FOR PREPARATION OF RAMIPRIL
Abstract	The present invention provides a process for preparation of ramipril comprising reacting an acid addition salt of bicyclic amino ester of formula (VII) with N-(l-S carboethoxy)-3-phenyl-propyl-L-alanine in presence of dicyclohexylcarbodimide and 1 -hydroxybenzotriazole in a suitable solvent medium.

Full Text

FORM 2 THE PATENT ACT 1970 (39 of 1970) & The Patents Rules, 2003 PROVISIONAL SPECIFICATION (See section 10 and rule13) 1. TITLE OF THE INVENTION: "A process for preparation of Ramipril " 2. APPLICANT (a) NAME: IPCA LABORATORIES LIMITED (b)NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS: 48, Kandivli Industrial Estate, Mumbai - 400 067, Maharashtra, India 3.PREAMBLE TO THE DESCRIPTION The following specification particularly describes the invention Technical field: The present invention relates to a process for preparation of Ramipril of formula (X) The invention also relates to optically pure intermediate benzyl (S,S,S)-2-azabicyclo [3.3.0]-octane-3-carboxylate of formula (VIII) and its salts. Formula (VIII) Background and Prior art: Ramipril also known as (2S,3aS,6aS)-l-[(S)-2-[[(S)-l-(ethoxycarbonyl)-3-phenylpropyl]-aminopropyl] octahydrocyclopenta[b]pyrrole-2-carboxylic acid is an ACE inhibitor, and is used to treat hypertension and congestive heart failure. Ramipril and process for its preparation is disclosed in US5061722. Synthesis of Ramipril is also disclosed in several other prior art such as CA1338162, EP79022, US4668796, US5977380, US6541635, US5175306, WO2005121084, WO2005/049568, WO2005/108366, WO2005068422, US2007/0232680. A thorough study of the prior art for the process of Ramipril indicates that the following route of synthesis (Scheme-I, wherein R means H, Alkyl, benzyl group; and HA means an inorganic or sulphonic acid) is widely used. Scheme-I According to our search, in all the preparative methods disclosed for Ramipril involving the usual DCC-HOBt mediated coupling of intermediate of formula VIII and compound of formula IX, obtainment of intermediate of formula (VIII) as free base from its salt (Formula VII) is common. Such process comprises reaction of said salt (Formula VII) with an alkali followed by an extractive work-up prior to its use in the process of coupling with intermediate IX. It is seen that intermediate (VIII) being an oily substance, it is advantageous to convert to an acid addition salt for better handling, isolation/purification and storage and therefore, its conversion to a salt form is almost unavoidable for stable storage/handling. But, carrying out the conversion of salt into free base of Formula VIII before peptide coupling reaction makes the process lengthy and cumbersome due to the increased number of unit operations and therefore such process is not suitable from an industrial standpoint. Yet another publication, US5055591 discloses use of alkane phosphonic acid anhydrides as coupling reagent in place of conventional dicyclohexylcarbodimide (DCC) andl-hydroxybenzotriazole (1-HOBT) for preparation of ramipril using intermediate VII and IX, and stated that DCC and 1-HOBT catalyzed reaction under similar condition results in poor yields of ramipril. However, the use of alkane phosphonic acid anhydride does not appear to be practical as it is expensive and not readily available in commercial quantities compared to DCC. Although US2007/0232680 describes direct use of azabicycloester salt formula VII in the process for ramipril, but employ acid chloride of formula (XI) as reaction partner in place of intermediate (IX) which involves an additional step of preparing the compound of formula (XI) Needless to say it is advantageous to develop a process which eliminates the necessity of converting the salt into a free ester in an additional step in the DCC mediated coupling of azabicycloester salt formula VII with IX, yet providing Ramipril in high yields and thereby making the overall process simpler and shorter. Another major insufficiency in the literature process appeared to be related to the optical purity of Ramipril as the product obtained is contaminated with its optical antipodes, which is in contrast to the required pharmacopoeial purity criteria. The crystallization methods so far reported do not effectively remove the undesired optical isomers, unless a thorough repeated crystallization from organic solvents is done, which is not only unacceptable from stability point of the compound but also for economy of the process. Purification of ramipril to increase optical purity is troublesome mainly because of it's susceptible degradation to form the hydrolyzed diacid and/or intermolecular cyclisation to diketopiperazine impurities. These impurities may form during isolation, purification, formulation or storage as has been seen and documented in US2007/0232680, WO2005/121084, US20060159742, and WO2006052968. Most of the purification processes involves either solvent purification from an organic solvent, and aqueous solvents, for example in US20070232680, WO2005/068422 or an acid/base treatment. This accelerates the possibility of hydrolysis or diketopiperazine formation and hence isolation and purification of ramipril appears to be a very delicate process and it is advantageous to avoid too many processing steps in final purification or finding a process that results in optically pure ramipril Generally speaking, the optical purity of ramipril can be controlled by the purity of intermediate (VII) and intermediate IX. Although intermediate IX can be obtained in reasonable optical purity, but obtaining the intermediate (VII) of high optical purity is doubtful, because the diastereomeric resolution of the compound of formula (V) with optical acids and subsequent purification of the resulting diastereomeric salt known so far, for example from US4668796, WO2005/049568, INI91949, US2007/0232680, US4659838, WO2005/049568 invariably result into compound of formula (VIII) contaminated with 2-4% of the undesired (R,R,R)-stereoisomer. Another alternative, for example the enantioselective synthesis of compound (VII) or derivative reported in Tetrahedron Lett, 1993, 34 (41), 6603-6603 or Heterocyclic 1989 28(2),957-965, however, result in very low yield and is not economically feasible for large scale production, which is substantiated by the disclosure of US6407262 (column 3,line 45-65). US2007/0232680 discloses preparation of (S,S,S)-azabicyclo [3.3.0]-octane-3-carboxylic acid benzyl ester hydrochloride having 100% HPLC purity, on the other hand, it is noticed by the present inventors as well as evident from several prior art processes that it is difficult to achieve high optical purity of azabicycloester either by resolution or subsequent purification of diastereomeric salt, meaning the mentioned purity might be related to chemical purity and not optical purity. Thus it is evident from the above study that exclusive obtainment of (S,S,S) isomer of 2-azabicyclo [3.3.0]-octane-3-carboxylic acid benzyl ester is not enabled by the prior art processes and using the same for obtaining optically pure Ramipril without the need for exhaustive purification measures. Thus there is still a need in the art for an improved process to prepare optically pure ramipril which reduces the processing steps involved in preparation and purification while using the inexpensive and readily available reagents like dicyclohexylcarbodimide and 1-HOBT for peptide condensation. The present invention ameliorates above problems in the prior art and also reduces a number of unit operations. Summary of the invention: The present invention thus provides a process for Ramipril directly by condensation of salt of intermediate VII. According to one aspect, the present invention provides a process for preparation of ramipril comprising reacting an acid addition salt of bicyclic amino ester of formula (VII) with N-(l-S carboethoxy)-3-phenyl-propyl-L-alanine in presence of dicyclohexylcarbodimide and 1 -hydroxybenzotriazole in a suitable solvent medium. In a preferred embodiment, the process comprises of reacting an optically pure acid addition salt of benzyl (S,S,S)-2-azabicyclo[3.3.0]octane-3-carboxylate of formula (VII) with l-[-N-(lS)-ethoxycarbonyl)-3-phenylpropyl-L-alanine (IX) in presence of a base in presence of DCC and HOBt in a suitable solvent, followed by removal of benzyl ester to obtain optically pure ramipril In a second aspect, the invention provides optically pure benzyl (S,S,S)-2-azabicyclo [3.3.0] octane-3-carboxylate of formula (VIII) or its salts, and a process for preparing the same. The present process, according to the present invention, for optically pure benzyl (S,S,S)-2-azabicyclo [3.3.0] octane-3-carboxylate of formula (VIII) and its salts substantially free from other stereoisomers, especially (R,R,R-isomer) comprises isolating the compound of formula (VII) as an inorganic/sulfonic acid salt from solvents selected from C1-C4 linear or branched chain alcohol. Detailed Description: Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. To describe the invention, certain terms are defined herein specifically as follows: The term "optically pure" in the context of the present invention means the chiral isomeric purity exceeding 99.5%. The term "substantially free" in the context of the present invention means the stated product is free from contamination of stated thing or impurities at least less than 0.5%, preferably less than 0.1% and most preferably less than 0.05%. The details of one or more embodiments in the practice of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the appended examples and claims. Accordingly, the present invention provides a process to prepare ramipril. The process involves condensation of an acid addition salt of formula (VII) with an intermediate of formula (IX) in presence of catalyst DCC and HOBt in a suitable solvent. The process of the present invention is advantageously carried out in presence of a base substance. The acid addition salt of formula (VII), which may be used in the present invention, is selected from an inorganic acid salt or sulfonic acid salts such as /7-toluene sulphonic acid, benzene sulphonic acid, methane sulphonic acid. The preferred inorganic salt is hydrochloric acid salt and sulfonic acid salt is/?-toluene sulfonic acid salt. The base used in the present invention may be selected appropriately from an organic class of compounds. The most preferred bases are alkyl amines for example triethyl amine, diisopropyl ethylamine. The base is conveniently used in an amount, although not limited to, equal or greater than molar equivalents relative to the starting intermediate of Formula VII, preferably in a range between 1.5 to 3 moles, more preferably between 2.0 to 2.8 moles. Dicyclohexylcarbodimide in the application of the present invention may be used in an amount ranges between 1.0 moles to 2.0 moles, preferably between about 1.1 to 1.5 moles with respect to intermediate (VII). The 1-hydroxybenzotriazole may be used in catalytic amounts or in molar amounts in the range between 1.0 to 2.0 with respect to the starting intermediate (VII) salt. The reaction is advantageously carried out in a solvent. The solvent may be selected from any inert organic solvent. Examples of solvents include, esters such as ethyl acetate; hydrocarbons such as dichloromethane, dichloroethane etc; polar aprotic solvent dimethylformamide. The especially preferred solvent is dichloromethane or ethyl acetate. The reaction may be carried out at suitable temperature, either under cooling or at ambient temperature. Although the reaction can be carried out under heating, but to minimize the possible decomposition of product, the reaction is carried out at room temperature. The especially preferred reaction temperature is between 25-30 ° C. On completion of the reaction, the intermediate benzyl ramipril can be recovered from the reaction in a conventional manner. The isolated benzyl ramipril may be purified from the by-products such as dicyclohexyl urea by treating in a suitable organic solvent. In the process, the benzyl ramipril is subjected to catalytic debenzylation to obtain Ramipril either by methods known in the art or the process as disclosed herein. In a typical procedure the benzyl ramipril is treated with a hydrogenation catalyst, for example Palladium charcoal, in a suitable organic solvent, and the reaction is carried under hydrogen pressure at a temperature in the range of 20-40°C. The solvents used herein can be selected from C1-C3 linear or branched chain alcohol. Preferably ethanol is used in present process. On completion of debenzylation reaction, Ramipril can be isolated by removing catalyst followed by optionally removing the solvent or precipitating and/or crystallizing from a suitable purification solvent to remove chemical impurites. The suitable purification solvent is an organic solvent, especially selected from a group consisting of aliphatic ethers, aliphatic ketones, aliphatic or aromatic hydrocarbons, alkyl esters, aliphatic nitrile or aliphatic alcohols. A single solvent or mixture of suitable solvents can be used for recovery/purification of ramipril. The optical purity of Ramipril obtained by the present invention depends on the optical purity of intermediate VII. Thus by employing an intermediate salt obtained by any one of the process according to the US4668796, WO2005/049568, INI 91949, US2007/0232680, US4659838, WO2005/049568, yielded Ramipril of about 96-98% optically pure. The inventors had recognized that purification of Ramipril to increase the optical purity from 96-98% by the known methods is not a reliable methodology to improve optical purity because changes in manufacturing parameters or presence of acid/alkali might lead to formation of impurities in the known methods. Although these methods may improve the optical purity but finally contaminate the product with those chemical impurities generated during purification. Thus in a preferred embodiment of the present invention, an optically pure benzyl (S,S,S)-2-azabicyclo [3.3.0] octane-3-carboxylate of formula (VIII) and its salts, substantially free from its other stereoisomers, especially (R,R,R)-isomer is provided in the present invention to use in the process for Ramipril. In this embodiment, the process for Ramipril comprises purifying an optically impure inorganic/sulfonic acid salt of benzyl (S,S,S)-2-azabicyclo [3.3.0] octane-3-carboxylate of formula (VIII) from selected solvents to provide corresponding optically pure benzyl (S,S,S)-2-azabicyclo [3.3.0] octane-3-carboxylate salt; treating said optically pure benzyl (S,S,S)-2-azabicyclo [3.3.0] octane-3-carboxylate salt and intermediate of Formula IX in presence of a base and a peptide coupling catalyst in a suitable solvent; and hydrogenation the resulting benzyl Ramipril to obtain optically pure Ramipril. The reagents and conditions may be used as illustrated before and further exemplified in the accompanying examples. Thus in the second aspect, the invention provides optically pure benzyl (S,S,S)-2-azabicyclo [3.3.0] octane-3-carboxylate or its salt, especially an inorganic/sulfonic salt substantially free from other stereoisomers, especially (R,R,R)-isomer for the first time. Said optically pure intermediate finds use in the synthesis of optically pure ramipril. In this aspect of the invention, the present invention provides an efficient purification process for preparing the optically pure intermediate of formula (VII) which comprises isolating an inorganic/sulfonic salt of benzyl (S,S,S)-2-azabicyclo [3.3.0] octane-3-carboxylate from solvents selected from the group of C1-C4 linear or branched chain alcohol. Especially preferred solvent is isopropanol or ethanol or their mixture. The process, according to the present invention comprises mixing benzyl (S,S,S)-2-azabicyclo [3.3.0] octane-3-carboxylate or its inorganic/sulfonic acid salt contaminated of (R,R,R)-isomer; optionally adding an inorganic acid or sulfonic acid; and recovering an optically pure benzyl (S,S,S)-2-azabicyclo [3.3.0] octane-3-carboxylate as inorganic/sulfonic acid salt from solvents selected from the group of C1-C4 linear or branched chain alcohol, especially ethanol or isopropanol; and if desired converting to benzyl (S,S,S)-2-azabicyclo [3.3.0] octane-3-carboxylate. In a preferred embodiment, the process comprises treating benzyl (S,S.S)-2-azabicyclo [3.3.0] octane-3-carboxylate or its inorganic/sulfonic acid salt contaminated of corresponding (R,R,R)-isomer in a solvent selected from the group of C1-C4 linear or branched chain alcohol, especially ethanol or isopropanol, and recovering the optically pure benzyl (S,S,S)-2-azabicyclo [3.3.0] octane-3-carboxylate or its inorganic/sulfonic acid salt. The inorganic acid/sulfonic acid may be selected from any known ones, especially preferred acid are hydrochloric acid, methane sulphonic acid, benzene sulfonic acid and p-toluene sulphonic acid. The process is carried out at a temperature in the range of 20°C to reflux temperature, preferably under heating to reflux temperature of solvent; and the purified salt is obtained by cooling the reaction mixture to a convenient temperature, for example room temperature or below. The cooled reaction mixture is then filtered to give salt of formula (VII) free of undesired isomers. The benzyl (S,S,S)-2-azabicyclo [3.3.0] octane-3-carboxylate or its inorganic/sulfonic acid salt may be prepared separately in a suitable solvent or in situ in the purification solvents disclosed before. In the process of purification, the starting benzyl (S,S,S)-2-azabicyclo [3.3.0] octane-3-carboxylate or its salt may contain a significant amount of corresponding (R,R,R)-isomer, especially in the range of above l%-5% , more preferably it may contain 2-4%. The starting benzyl (S,S,S)-2-azabicyclo [3.3.0] octane-3-carboxylate or its salt may contain a significant amount of corresponding (R,R,R)-isomer can be prepared by any one of the process known in literature, for example according to the following scheme. The racemic benzyl (S,S,S)-2-azabicyclo [3.3.0] octane-3-carboxylate or its salt may be obtained according to any one of the process in the following scheme. Scheme II X=any leaving group; R'=any protecting group; R"=alkyl or benzyl; R=any protecting group HA=inorganic/sulfonic acid The racemic benzyl (S,S,S)-2-azabicyclo [3.3.0] octane-3-carboxylate or its salt is further resolved to obtain the benzyl (S,S,S)-2-azabicyclo [3.3.0] octane-3-carboxylate or its salt of about 96-98% optical purity by treating the racemic mixture with an optically active acid, followed by diastereomeric crystallization. Suitable optically active acids for resolution are selected from mandelic acid, N-benzyloxycarbonyl-L-phenyl alanine, wherein mandelic acid is especially preferred. The solvent for resolution is selected form alkyl acetate, cyclohexane, alcohols like isopropanol, aromatic hydrocarbon like toluene or their mixtures thereof. The preferred solvent is ethyl acetate, or a mixture of ethyl acetate and cyclohexane. The optically enriched diastereomeric salt is crystallized by cooling the reaction mixture. This is then isolated, and optionally recrystallized from said solvents to increase optical purity followed by treatment with an alkali to liberate the free benzyl (S,S,S)-2-azabicyclo [3.3.0] octane-3-carboxylate with an optical purity of 96-98%. The alkali is selected from sodium hydroxide or sodium bicarbonate. The optically pure intermediate of formula (IX) can be obtained from any commercial source or prepared by any conventional known method, for example US4925969 The following experimental examples are illustrative of the invention but not limitative of the scope thereof. Example 1. Preparation of cis, endo,-2-azabicyclo-[3.3.0]-octane-3-carboxylic acid hydrochloride (R=H) 40 gm of methyl-3-chloro-2-acetyl amino propionate, 45.8gm of cyclopenetenopyrrolidine, 27 gm of triethyl amine and 120 ml of toluene were charged in a reaction flask at 0° C .The temperature of reaction mixture was increased to 25° C and it was stirred at the same till the completion of reaction. After completion the reaction mixture was concentrated under vaccum. The residue thus obtained was acidified with concentrated hydrochloric acid and the resultant mixture was extracted with ethyl acetate, after separation of layers the organic layer was concentrated under vacuum, 5N HC1 (135ml) was added to the residue and the mixture was stirred for 5 hr, distillation of water gave the residue which was taken into 400ml glacial acetic acid followed by addition of 4gm Pd/C.The reaction mixture was hydrogenated under pressure of 5kg/cm2 and at a temperature of 60°C± 2 °C. after completion of reaction the catalyst was filtered and the filterate was distilled to obtain a residue which was slurried with acetone to get the title product. Yield=14gm; 33% yield Example 2. Preparation of benzyl cis-endo-2-azabicyclo-[3.3.0]-octane-3-carboxylate hydrochloride 37.3 gm of thionyl chloride and 76.3 gm of benzyl alcohol were mixed in a reaction flask at 0° C,to this mixture 15 gm of carboxylic acid obtained as per example (1) was added. The temperature of reaction mixture was raised to 25° C and it was further stirred till the completion of reaction.The solvent was distilled off followed by addition of diisopropyl ether to precipitate the product.The precipitated product was filtered and dried. Yield=18.4gm;83% Example 3. Preparation of benzyl cis-endo-2-azabicyclo-[3.3.0]-octane-3-carboxylatep-toluene sulphonic acid salt 15 gm of carboxylic acid obtained as per example (1) and 150 ml of toluene were mixed in a reaction flask followed by addition of 16.6 gm of p-toluenesulphonic acid and 29.6 gm of benzyl alcohol. The reaction mixture was heated to reflux and water was removed by dean stark .Once the theoretical amount of water was collected ,solvent was distilled off from reaction mixture under vaccum,diisopropylether (45 ml) was added to the residue and the precipitated product was collected by filtration. Yield 23gm; 70% Example 4. Preparation of mandelic acid salt of 2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl ester Sodium hydroxide (25.5 gm) was dissolved in 150ml water and to the resultant solution 100 gms of racemic -2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl ester hydrochloride in 400 ml of ethyl acetate were added. The reaction mixture was stirred and layers were separated. To the ethyl acetate layer 29.7 gm of S-(+) -mandelic acid in 400ml of ethyl acetate was added. The reaction mixture was cooled to 0° C, the precipitated mandelic acid salt was filtered and dried. Yield 57.0gm (81% of required isomer) Examples 5. Preparation of (S,S,S)-2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl ester hydrochloride 50.0 gms of mandelic acid salt of 2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl ester and 137.5 ml water were mixed, to this mixture a solution of sodium hydroxide (5.53 gm sodium hydroxide+50ml water) and 250 ml of dichloromethane were added. The reaction mixture was stirred at 25-30° C, layers separated and organic layer was concentrated to obtain a residue, to this 250 ml isopropyl alcohol and 50 ml of isopropanolic solution of hydrochloric acid was added. The reaction mixture was cooled to about 0° C the product thus crystallized was filtered and dried. Yield 32.5gm (91%) Purity SSS isomer 98%, RRR isomer 2% (HPLC area %) 30 gm of salt obtained as above mentioned process step was dissolved in 1200ml of isopropyl alcohol the reaction mixture was heated to reflux followed by cooling to about 30° C, the reaction mixture was filtered and the product thus obtained was dried under vacuum Yield 27.5 gm; 91% Purity SSS isomer 100%. RRR isomer nil (HPLC area %) Example 6. Prepartion of benzyl ramipril 40 gms of (S,S,S)-2-azabicyclo[3.3.0]-octane-3-carboxylic acid benzyl ester hydrochloride was charged in a round bottom flask to this 40 gms of triethylamine,26gms of 1 -hydroxybenzotriazole,46 gms of N-[l-(S)-(ethoxy carbonyl)-3-phenylpropyl]-L-alanine, 33 gms of N,N dicyclohexyl carbodimide and 700ml of dichloromethane were added. The reaction mixture was stirred at 25-30° C for 16 hrs. Dicyclohexyl urea precipitated out and was removed by filteration.The filtrate was washed with 1200ml of water followed by distillation of solvent to obtain benzyl ramipril as oil. Yield=71.9gm Example 7. Preparation of ramipril 15 gms of benzyl ramipril, 100ml of ethanol, and 1.5 gm of Pd/C were taken in an autoclave. The hydrogenation was carried out at 30° C and a pressure of 5.0 kg/Cm2 till completion of reaction, after completion of reaction the catalyst was filtered out, the filtrate was distilled off to obtain residue. To the residue 75ml of acetonitrile was added, the product was crystallized, reaction mixture was filtered and the crystalline product thus obtained was dried. It was further purified using acetonitrile. Yield 6.9 gm (56%)

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