Title of Invention

A PROCESS FOR THE PREPARATION OF AZIDO ACIDS USEFUL AS INTERMEDIATES IN THE PREPARATION OF CLOPIODOGREL

Abstract

The present invention relates to modified release dosage form for low dose active ingredient targeted to be delivered in the proximal part of the gastrointestinal tract and preparation thereof. The dosage form of the present invention is an inlay tablet comprising of two portions, wherein the inner portion comprising active ingredient is embedded in the outer portion. The inner portion of the said dosage form comprises of pharmaceutically active ingredient, release controlling agent(a) and pharmaceutically acceptable excipients and the outer portion comprises one or more hydrophobic non¬biodegradable materials, one or more water soluble diluent(s) and other pharmaceutically acceptable excipients. The dosage form made by using the present invention is gastro retentive.

Full Text

Form 2 THE PATENTS ACT, 1970 COMPLETE SPECIFICATION (Section 10) «A PROCESS FOR THE PREPARATION OF AZIDO ACIDS USEFUL AS INTERMEDIATES IN THE PREPARATION OF CLOPIODOGREL " Cadiia Healthcare Limited, a company incorporated under the Companies Act, 1956, of Zydus Tower, Satellite Road, Ahemdabad 308 015, Gujarat India. The following specification particularly describes and ascertains the nature of the invention and manner in which it is to be performed: NIPR-005 Field of invention : The present invention describes novel approaches to prepare a-amino phenyl acetic acid derivatives described by the following general formula {1) Another aspect of this invention describes an intramolecular cyclization of 8 to give (!) by using a novel formyl equivalent dioxalane as a Ci electrophilic synthon, to give 'Clopidogrcl'. The present invention also describes a novel process for the preparation of the intermediate phcnylglycinc derivatives 6 as a racemate as well as its optical antipodes. The a-amino phenyl acetic acicl derivatives are frequently used drug intermediates. The present invention also relates to a process for the preparation of compound of formula I, wherein R represents H, lower alkyl group such as methyl, ethyl, propyl, iso-propyl and benzyl and X represents H, halogen such as fluorine, chlorine, bromine and iodine. Background of the invention: The present invention aims to provide a process to prepare a-amino phenyl acetic acid derivatives described by the above given formula. The present invention particularly provides a process to one such derivative, Clopidogrel described by formula 1(a), and its pharmaceutically acceptable salts. These a-amino phenyl acetic acid derivatives are known for their therapeutic applications, especially for their platelet anti-aggregating and anti-thrombotic properties. Such compounds have been described especially in French patent application no. 2,215,948,2,530,247 and 2,612,929. Various other strategies to prepare Clopidogrel are disclosed in WO 98/51681, WO 98/51682, WO 98/51689, WO 99/18110, US 5,036,156, US 5,132, 435, US 5,139,170, US 5,204,469 and US 6,080,875. We have recently disclosed novel processes for the manufacture of (S)-(+)- Clopidogrel bisulfate (Indian Patent Applications 335/MUM72O01 and 630/MUM/2001). We have also disclosed novel polymorphs of Clopidogrel in our application no. 1190/MUM/2001. US Patent No. 4,847,265 discloses that the dextrorotatory enantiomer of formula (I) of Clopidogrel has an excellent antiagregant platelet activity, whereas the corresponding l NIPR-005 levorotatory enantiomer of (I) is less tolerated of the two enantiomers and is less active. Subsequently filed Patent -Application WO 99/65915 titled "Polymorphic Clopidogrel hydrogensulfate form", which is herein incorporated by reference, discloses the existence of a specific polymorphic Form II of the hydrogen sulfate of (5)-(+)-Clopidogrel (m.p. = 176 ± 3 °C). It is also disclosed in this patent application that the earlier processes described in the U.S. Patent 4,847,265 gives Form I (m.p. 184 ± 3 °C). Clopidogrel and its pharmaceutically acceptable salts, is relatively a newer class of therapeutic agents useful in the treatment and prophylaxis of various cardiovascular disorders. US Patent 5,576,328 describes use of Clopidogrel for secondary prevention of ischemic events, while WO0061549 describes use for oxidative stress and endothelial dysfunction.. The methods used to prepare these compounds, involve a-halophenylacetic acid derivatives, which are known to be strongly lachrimatory and mucous membrane irritants (European patent application no. 099802, 0420706, 0466569). Use of such chemicals pose difficulties during handling and up-stream processing; further these chemicals are also unfavorable for human health and environment. Furthermore, yields of the reactions are poor to average. Therefore, it is desirable to develop a new and novel process which can be scaled up and is cost effective. Objects of the invention: The objective of the present invention is to develop a novel process for the preparation of compounds of formula (I), in particularly of S(+)-Clopidogrel. Another objective of the present invention is to prepare Clopidogrel through a novel intramolecular cyclization of the intermediate 8 using dioxalane as Ci synthon or a formyl equivalent Yet another objective of the present invention is to develop a novel process for the preparation of substituted phenylglycine intermediate of formula 6.as a racemate as well as its optical antipode. 2 NTPR-005 A further objective of the invention is to develop a cost -effective process which can be scaled up for the preparation of Clopidogrel. Another objective of the invention is to develop a process which involves relatively non-toxic chemicals A further objective of the invention is to develop a process for the preparation of Clopidogrel bisulfate with lesser impurity. Summary of the invention : The present invention provides a process to prepare racemic as well as optically pure oc-amino phenyl acetic acid derivatives of formula (I) particularly the present invention provides a regiospecific process to prepare Clopidogrel and its pharmaceutically acceptable salts. The process involves intermediates as described in Scheme 1 & 2. The most preferred method to prepare involves conversion of 2 to (Tj via the intermediates 3, 4, 5, 6, 8 and 9 i.e. 7 stage synthesis yielding optically pure (S)-(+) Clopidogrel (Scheme 1). Detailed description of the invention : The present invention describes methods to manufacture compounds of formula (I), in particular, Clopidogrel and its pharmaceutically acceptable salts following the routes described in Scheme 1 & Scheme 2: Scheme 1 1. Epoxy alcohol 2. 2. Opening of epoxide with azide to give 3-azido-3-(o-halo phenyl).-propane-l,2-diol 3 3. Oxidative cleavage of diol 3 to give azido acid 4. 4. Esterification of azido acid 4_to azido ester fv 5. Reduction of the azido ester 5 to substituted phenylglycine ester 6. 6. Optionally resolving 6 to its optical antipodes. 7. N-Alkylation of 6 or its optical antipodes with (thiophen-2-yl)-2-ethyl derivative to give corresponding compound 8. 8. Intramolecular cyclization of appropriate compound 8_to cyclized product £1} Optionally, resolution of racemic mixture of (i) to (+)-(!) & (-)-(!) NIPR-005 Scheme 2 1. Oxidation of epoxy alcohol 2 to give epoxy acid of formula 10. 2. Converting epoxy acid 10) to a-hydroxy azido acid 11_and oxidation in situ to give 4. 3. Esterification of azido acid 4_to 5. 4. Oxidation of the azido ester 5 to substituted phenylglycine ester 6. 5. Optionally, resolving 6_to its optical antipodes. 6. N-Alkylation of 6 with substituted (thiophen-2-yl)ethyl derivatives to give corresponding compound 8. 7. Intramolecular cyclization of product 8_to cyclized product 0X 8. Optionally, resolution of racemic mixture of (I) to (+) & (-)-(I). When, the chiral amino ester 6 is resolved and optically pure aminoester is used, the optically pure S-(+)-Clopidogrel is obtained, when X = CI and R = Me (via 8). The present invention describes novel process to prepare Clopidogrel, which involves a number of approaches and each of the approach leads to Clopidogrel in 6 to 8 steps. The synthetic steps involved are briefly described in Schemes 1 & 2 and the relevant literature from the prior art is cited at the end. The o-halo cinnamyl epoxy alcohol 2, the starting material required for carrying out the multi step synthetic operation involved with this invention is a known compound, which can be easily prepared from o-halo cinnamyl alcohol by those skilled in the art, starting from readily available o-halpbenzaldehyde, using known conventional methods. The process of this invention provides novel approaches to convert the compound of the formula 2 into another key intermediate, described by the formula 6. The distinct advantage of this approach is that it circumvents the use of toxic metal cyanides during the synthesis of key intermediates. Conversion of the compound of epoxy iticohoi (2} into 3-azido-3-(o-chloro phenyl)-propane-1,2-diol 3}: Substituted epoxy alcohols 2 may be converted into its corresponding azido diol 3 using metal azide salts [1,2,3]. Suitable azides can be such as sodium azide, potassium azide, tetraalkyl ammonium azide, 4 NIPR-005 trimethyl silyl azide, titanium (iso-propoxide) azide and the like. The molar ratio of azide source to epoxy alcohol is at least one equivalent. The azide reagents can be used in the ratio of 1:3 equivalents, with respect to epoxy alcohol. Further, the azide may be added as such or along with a solvent mixture consisting of either methanol: water (8:1) or methoxy ethanol : water (8:1). The process to prepare the intermediate of formula 3 can be carried out in the presence of organic solvents such as benzene or toluene in the ratio of 1:1 to 1:10 with respect to the reagent. Suitable temperature range for above processes can be from 20 °C to 150 °C, preferably from 60 °C to 125 °C. The above reaction may be effected by addition of ammonium salt. Suitable ammonium salts that can be used include ammonium chloride, ammonium bromide and the like. The reaction may be carried out in the presence of an inert atmosphere such as N2, He or Ar. The reaction time may range from 15 minutes to as long as 3 hours. The work up of reaction is carried out in a conventional manner i.e. extraction in a suitable organic solvent, aqueous washing, drying of organic solvent, concentrating organic extract under reduced pressure and finally purifying the product. Preferably, X represents CI. The ring opening of epoxide 2 with azides is known to be regiospecific and stereospecific [1]. Conversion of 3-azido-3-(o-chloro phenyl)-propane-l,2-diol (3) into azido acid (4}: Substituted azido diol 3 may be converted into azido acid 4 with one carbon less, using a suitable peroxy acid or salt and in presence of a suitable catalysts [1,4,5], Suitable peroxy acid or salt used during the reaction may be sodium metaperiodate, potassium permanganate and the like. Suitable catalysts for the above reaction, can be Ruthenium trichloride hydrate, and the like. The molar ratios of the above reagents namely azido diol: periodate: catalyst is 1:2:0.01 to 1:6:0.4 correspondingly, preferably 1:4:0.05 equivalents respectively. The solvent mixture is usually preferred and may be selected from the group consisting from aqueous, nonpolar and a cosolvent. The reaction may be carried out in suitable amount of aqueous protic /aptotic solvent such as water, DMSO and the like or in a nonpolar medium such as chloroform, carbon tetrachloride and the like or it can be mixture of solvents. Suitable amount of cosolvent / third solvent may be used to mix two immiscible solvents and may be methanol, ethanol or acetonitrile and the like. The process to prepare the novel intermediate 4 can be carried out in the presence of solvents such as benzene or toluene in the ratio of 1:1 to 1:10 with respect of the regent. Suitable temperature range for above processes can be from 0 °C to 60 °C, preferably from 20 °C to 50 °C. The reaction may be effected in the presence of NTPR-Q05 ammonium salt. Suitable ammonium salts can be selected from ammonium chloride and ammonium bromide and the like. The reaction may be carried out in the presence of an inert atmosphere such as N2, He or Ar. The reaction time may range from 1-5 hours. Esterification of Azido acid (4) to Azido ester (5): Substituted azido acid 4 may be converted into corresponding azido ester 5 using standard esterification conditions. Preferably, the esterification is carried with thionyl chloride and an alcohol, to obtain the corresponding ester. The reaction is carried out at room temperature and preferably allowed to continue for 3-4 hours to obtain optimum conversion. Preferably, methanol is used to get the methyl ester and X represents chlorine, CI. Reduction of azido ester (5} to amino ester (6): Substituted azido ester 5 may be reduced to corresponding amino ester 6. This reduction may be carried out by using the methods described in the known prior art [6,7]. Suitable catalyst used during this reaction may be palladium on carbon (5- 10 %), Raney-Nickel, and the like. The reaction is usually carried under inert atmosphere of hydrogen gas. The reagents may be used in the range of 1:0.01 to 1: 0.2 proportion w.r.t. azido diol : catalyst, preferably 2 to 10 % equivalents by weight respectively. The polar solvent used may be selected from the group consisting of methanol, water, methylene dichloride, ethylene dichloride, ethyl acetate and the like or a mixture of solvents in different ratios can be used. The ratio of solvents used may vary from 1:1 to 1:10 with respect to the reagent. Suitable temperature can be from ambient to the reflux temperature of the solvent mixture used. Preferably the temperature are in the range from 30° C to 150° C. Preferably, in compound 5, X represents Ci. N-Alkylation of (6} with 2-EthyI substituted thiophene (7): AJkylation of amines 6 to electrophiles such as mesylate, tosylate, benzene sulfate 7j etc. of thiophene ethanol or thiophene ethyl halide give 8. Usually both the compounds 6_& 7_are heated in an inert polar aprotic solvent. Some of the polar aprotic solvents are ethyl acetate, dimethyl formamide, dimethyl acetamide and acetonitrile. The temperature range varies from 50 °C to 120 °C. The reaction is accomplished preferably in the presence of a base, such as alkali metal carbonate (NaHC03, KHCO3) or organic base such as triethyl amine, pyridine etc. The work up is in usual way. When optically active or optically pure 6 is used, 6 NTPR-005 corresponding optically pure compound 8 is obtained. Intramolecular cyclization of (8) to give (I): The open compound 8 is cyclized-using 1,3-dioxalane as described in [9] to get compound of formula (I). A principally similar strategy is followed to effect the cyclization of optically active or optically pure 8_to give corresponding compound {I). Usually catalytic amount of protic acid is used for intramolecular cyclization, whereas 1,3-dioxalane is used as reagent and solvent both. Preferably X represents CI. When (+)-8 is used where X=C1 and R=OMe, (S)(+)-Clopidogrel is obtained. Conversion of epoxy alcohol (2) to give epoxy acid (10): In a yet another strategy instead of preparing 3-azido-3-(o-chloro)-propane-l,2-diol of formula 3, the epoxy alcohol is oxidized to give epoxy acid 10. In the later case, epoxide is opened by azide source mentioned earlier the conversion being carried in manner similar to conversion of 2 to 3 as described in Scheme 1. The opening of epoxy acid W can be done in a similar way as 2 to 3 [1,2,3]. Subsequent in situ oxidation [11], obtained by azidation of 10, give azido acid 4, The process for converting them is similar to those followed in the conversion of 2 to 3 to 4. NTPR-005 The intermediate 6 in the present invention may be used either as optically pure or as a racemate to synthesize optically active (I), in particular Clopidogrel where X = CI and R=Me. As dextrorotatory isomer of Clopidogrel is active, suitable chiral intermediate preferably giving the desired dextrorotatory isomer is preferred. The optically active amino ester 6 is prepared by resolution of racemate 6. A typical resolution of racemic (±) Clopidogrel, (la), is described below: The racemates of intermediate 6 or of (I) of Clopidogrel can be resolved by conventional methods [as described in references 9,10,11] such as microbial resolution, resolving the diastereomeric salts formed with chiral acids, chiral amino alcohols, amino acids into a 1:1 mixture of diastereomeric salts and the diastereomers may be separated by conventional methods of fractional crystallization, chromatography and the like followed by cleaving the derivative. Preferably, a diastereomeric salt is formed with chiral acid. The process comprises of dissolving the racemate mixture and a suitable chiral acid in suitable solvent, which optionally may contain By repeated crystallization from the solvent, the precipitate is enriched in the salt of dextrorotatory isomer of the desired diastereomer to yield a product of constant optical rotation. Then dextro-rotatory isomer is liberated from the salts by the addition of a mild base such as sodium or potassium hydrogen carbonate in aqueous media at temperatures varying between 5 °C to 25 °C. If required, another salt can be formed between the dextrorotatory isomer and a pharmaceutically acceptable acid. Determination of the enantiomeric purity of the dextro-rotatory and levorotatory enantiomers may be carried out either through proton NMR spectroscopy with the addition of a chiral rare earth metal, shift reagent or by HPLC using a chiral stationary phase. 10 NIPR-005 The solvents used during the resolution can include solvents or mixtures thereof such as (Ci-C4) alcohol, (C1-C4) ketone or dimethylformamide, ethyl acetate, methyl acetate, methyl ethyl ketone and the like; the solvent used optionally may contain water upto 5 %. Suitable temperature range for the resolution includes temperature from 5 to 80 °C. The chiral acids used to form the diastereomeric salts can be tartaric acid, mandelic acid, lactic acid, camphorsulfonic acid, amino acids and the like. The optically active acid that may be advantageous is levorotatory camphor-10-sulfonic acid or tartaric acid. The pharmaceutically acceptable mineral and organic acid salts of Clopidogrel can be further prepared using the known techniques in prior art. The preferred pharmaceutically acceptable salts are those, which can crystallize readily, are not hygroscopic and are sufficiently water-soluble to make their use as active medicinal principles advantageous. S(+)-Clopidogrel bisulfate is prepared by reacting free base with cone. H2SO4 in acetone. The process described in the present invention is demonstrated in the examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation to the scope of the invention. Example 1 Preparation of Epoxy alcohol (1} from o-chiorocinnamyl alcohol: To 1.5 litres of dichloromethane in a triple neck round bottomed flask was added 50 gm of cinnamyl alcohol at a temperature of 0-5 °C. To the reaction mixture was added 66.54 gms of meta chloro perbenzoic acid with stirring, in lots. The temperature was maintained at 5 °C. The reaction mixture was stirred at 0 to 5 °C for 3 hours and the stirring was continued slowly at room temperature overnight. The progress of the reaction was monitored by T.L.C., until all the starting material was consumend. To this reaction mixture was added saturated sodium meta bisulfite aqueous solution, followed by the addition of aqueous Na2C03 whereby two layers got separated. The organic layer was separated out, while the aqueous layer was re-extracted with 300 ml of dichloromethane. The organic layers was washed with 300 ml. of D. M. water and was dried, concentrated under reduced pressure, and purified by usual procedure yielding the desired 6.0 gm of epoxy alcohol (50% yield). NIPR-005 Example 2 Preparation of 3-azido-3-(o-chloro)-propane-l,2-diol (3) from 2,3-Epoxy o-chlorodnnamyl alcohol (2): 10 gm of epoxy alcohol (2) was taken in a one litre round bottomed flask and 17.33 gm of NaN3 and 6.27 gm of NH4C1 was added to it. To the mixture was added 416 ml methanol and 52 ml water and it was stirred for 3 hours at 65 °C under mild reflux condition. The solvent was evaporated under low pressure when the salt precipitated out of the reaction mixture. To the salt was added 75 ml of dichloromethane, filtered and the residue was rejected. To the filtrate was added 200 ml of water when two layer got separated. The lower MDC was separated, and dried with 20 gm of anhydrous Na2S04. The solvent was evaporated at 40 °C under reduced pressure to give 11.2 gm (91%) of the diol. TR (cm"1) : (CHC13) 3384 (-OH stretch); 2106 (N3) JHNMR (CDCI3): 8 1.96 (t, 1H), 2.4 (d, 1H) 3.7 (t,2H), 3.9-4.0 (q,lH) 5.2 (d,lH), 7.2-7.5 (m,4H) 13CNMR (CDCI3): 5 ppm 62.56, 63.73, 73.06 127.4, 128.7, 129.7 130.02, 133.7, 133.91 MS : m/z 288.1 (M+H)+, 245.2 (M+NH4)+ Example 3 Preparation of azido acid (4) from 3-Azido-3-(o-chloro phenyl) propane-l,2-diol (3). In a 500 ml round bottomed flask was taken the azido diol obtained above and to it added 87 ml of acetinitrile, 87 ml of CC14 and 131 ml. D. M. water, when two layer was formed. To the mixture was added 4.2 eq. periodic acid and 226 mg of R.UCI3.H2O, when the colour changed to brick red. The reaction mixture was stirred for 4 hours at room temperature and kept overnight. To the mixture was added 200 ml of ether, the organic layer was filtered out through hyflow bed, washed with water and dried over anhydrous N&2SO4 to give 6.0 gm (64.5%) of azido acid. 12 NIPR-005 IR (cm-1): (CHCh) 2928 (NH), 2110 (N3),-1725 (CO) !H NMR (CDCI3): 5.59 (s,lH), 7.3-7.36 (m, 2H) 7.42-7.48 (m, 2H), 9.5 (b, 1H) 13 C NMR (CDCI3): 5 ppm 61.99, 127.5, 128.87 130.19, 130.7, 131.5, 134.02 173.8 MS : m/z 210 (M+-H) Example 4 Preparation of azido (5) ester from corresponding azido acid (4): 0.5 gm of azido acid obtained above was taken in a round bottomed flask and 5 ml of merhanol was added to it and the solution was stirred for 10 minutes. To the reaction mixture was added 0.42 grams of thionyl chloride dropwise. The reaction mixture was siirred for 4 hours at room temperature. The excess solvent was evaporated under reduced pressure. To the residue was added 25 ml MDC, the organic layer formed was washed with a 2% solution of NaHCCb and 25 ml of D. M. water and the organic layer was dried with 10 gm anhydrous Na2S04. The excess solvent was evaporated under reduced pressure when the azido ester was obtained in 90% yield (0.48 gm). 1R (cm"1) : 2108 (N3), 1751.2 (CO) *HNMR (CDCI3): 3.79 (s, 3H), 5.5 (s, Hi) 7.31-7.46 (m,4H) 13C NMR (CDCb): 5 ppm 53.03, 62.02, 62.02, 127.3, 128.7, 130.0, 130.4 132.05, 133.09, 169.06 MS : m/z 243.2 (M+NH4)+ Example 5 Preparation of Amino Ester (6) by reduction of Azido Ester (5) using Palladium on Charcoal: 2 gm of azido ester prepared above was dissolved in 40 ml MeOH and added to the 13 NIPR-005 metallic container of Parr apparatus. To it was added Palladium charcoal(10%) and the container was shaken for 48 hours under hydrogen pressure of 3 Kg/cm . After completion of the reaction, the reaction mixture was filtered, the solvent evaporated under reduced pressure and 25 ml of MDC added to the reaction mixture. The amino ester obtained was purified by conventional techniques, when 500 gm (28.4%) of the purified product was obtained. IR (Cm"1) : 3381 (NH-stretch), 1738 (CO), 1126 (CN stretch) 'H NMR (CDC13) : 6 2.0 (bs 2H), 3.72 5 (s, 3H, OCH3) 5.05 (s, 1H), 7.24-7.28 (m, 2H) 7.33-7.40 (m, 2H) MS : m/z 200 (M+H)+ 13 C NMR : - Example 6 Preparation of 2,3-epoxy-o-chlorocinnamic acid (10): 200 ml of a mixture of acetonitrile, CCU & water in the ratio of 2:2:3 was taken in a 50 ml round bottomed flask and to it was added 0.124 gm RuCl3.H20 and NIO4. Separately, 5gm of epoxy alcohol was dissolved in 50 ml of a mixture of acetonitrile, CCU & water ( 2:2:3), and added to the reaction mixture. The mixture was stirred at room temperature for 24 hours. The aquous layer was extracted with dichloromethane and the organic layer was washed with water, concentrated under reduced pressure and dissolved in 250 ml ether. The ether layer was filtered over hyflow bed, and the filtrate was dried over sodium sulfate and evaporated under reduced pressure. The crude acid thus obtained was dissolved in a little amount of EtOAc & re-precipitated with n-hexane to give 3.98 gm (74.11%) of the pure acid. IR (cm"1) ((KBr): 1718 (CO), 'HNMR (CDCI3): 5 3.43-3.44(d, 1H), 4.48-4.49 (d, 1H), 6.0 (b, 2H), 7.2-7.4 (m, 4H) 13CMvTR(CDCl3):5ppm55.51, 125.19, 127.1, 129.4, 129.9, 132.6, 133.5, 172.55 MS : m/z 216.1 (M+NH4)+ 14 NIPR-005 Example 7 Preparation of the precursor of Ciopidogrel free base (8) by coupling 2-thiophene ethanol tosylate (7) with amino ester derivative (6): 1 gm of the amino ester (6) obtained previously was taken in a round bottomed flask & to it was added 1.2 eq. of 2-thiophene ethanol tosylate (7), 15 ml of ethyl acetate and 2 eq. of NaHC03. The mixture was refluxed for 2 hours, kept overnight and the excess solvent was evaporated under reduced pressure. The crude product was purified using conventional techniques to obtain 0.5 gm (35.4%) of 8. Alternatively The precursor can be prepared by mixing 2.5 gm of the ester with 5.76 gm of 2-thiophene ethanol tosylate, 25 ml of acetonitrile and 2.52 gm of NaHCCb. The mixture was refluxed for 8 hours and extracted with a mixture ofMDC (50 ml) and water (50 ml). The extract was dried over Na2S04 and purified using conventional techniques. It was converted subsequently to its acid salt with cone. HC1 giving 65% yield. IR (cm"1): 3018.4 (NH stretch), 1736 (CO) lR NMR (CDC13): 5 2.1 (b, 1H), 3.0 (m, 1H), 3.3 (m, 1H) 5 3.5-3.6 (m, 2H), 5.65 (s, 1H), 6.8 (d, 1H) 6.9 (dd, 1H), 7.1 (dd, 1H) 7.3-7.48 (m, 3H), 8.0 (dd, 1H) 13 C NMR: 5 ppm 30.44, 48.89, 52.33; 61.5, 123.5, 124.9, 126.7, 127.2, 128.5, 129.1, 129.7, 134.0, 136.0 and 142 172.59 MS :m/z 310.2 (M+H)+ Example 8 Cyclization of open chain Ciopidogrel free base 8 to 1: To 1.0 gm of the HC1 salt of the ester (8) obtained above was added 7 ml of 1,3-dioxolane and 0.2 ml of methanolic HC1. The mixture was stirred for 6 hours at 65 °C, the excess dioxolane was evaporated under reduced pressure. The residue was dissolved in 50 ml 15 N1PR-UU5 dichloromethane, basified with 10% NaIiC03, the organic layer was washed with 25 ml of water and the excess solvent was evaporated under reduced pressure to obtain 0.88 gm (94.63%) of Clopidogrel free base. IR Cm"1): 1740 (CO) JH NMR (CDCh): 5 2.88 (s, 4H), 3.6-3.8 (s, 3H, m, 2H) 4.9 (s, 1H), 6,6 (d, 1H) 7.0 (d, 1H), 7.2-7.7 (m,4H) 13 C NMR (CDC13): 25.545 48.3, 50.6, 52.14, 67.8, 122.7, 125.2, 127.1, 129.4, 129.7, 129.9, 133.2 133.8, 134.7 and 171.34 MS : m'z 322.1 (M+H)+ Example 9 Resolution of Amino ester (6): A mixture of 6.2 gm of amino ester 6 and 4.5 gm of (+) tartaric acid is refluxed in a mixture of methanol (25 ml. excess), acetonitrile (1 ml) and acetone (2 ml) and slowly cooled for a day to give (+) tartarate of methyl amino ester [a]ft20 = +85 ° (C=l, MeOH). The (+) methyl amino ester is liberated in usual way by removing (+) tartarate and precipitating its HC1 salt. Example 10 Preparation of the (+)Clopidogrel free base (8) by coupling 2-thiophene ethanol tosylate (7) with (+) amino ester derivative (6): 1 gm of the (+) amino ester (6) obtained previously was taken in a round bottomed flask & to it was added 1.2 eq. of 2-thiophene ethanol tosylate (7), 15 ml of ethyl acetate and 2 eq. of NaHC03. The mixture wa.s refluxed for 2 hours, kept overnight and the excess solvent was evaporated under reduced pressure. The crude (+) isomer was purified using conventional techniques to obtain 0.5 gm (35.4%) of 8. JR (cm'1): 3018.4 (NH stretch), 1736 (CO) 'HNMR (CDCI3): 5 2.1(b, 1H), 3.0 (m, 1H), 3.3 (m, 1H) 3.5-3.6 (m, 2H), 5.65 (s, 1H), 6.8 (d, 1H) 6.9(dd,lH),7.1(ddilH) 7.3-7.45 (m,-3H), 8.0 (dd,lH) 13 C NMR : 8 ppm 30.44, 48.89, 52.33; 61.5 123.5, 124.9, 126.7, 127.2, 128.5, 129.1, 129.7, 134.0, 136.0 and 142 172.59 MS :m/z3W.2(M+H) (+) Methyl a-(2-thienyl ethyl amino(2-chloro phenyl acetate) [a]D2° = + 99 ° 16 N1PR-005 Example 11 Cyclization of open chain (+) Clopidogrel free base: To 1.0 gm of the HC1 salt of the ester (8) obtained above was added 7 ml of 1,3-dioxolane and 0.2 ml of methanolic HC1. The mixture was stirred for 6 hours at 65 °C, the excess dioxolane was evaporated under reduced pressure. The residue was dissolved in 50 ml dichloromethane, basified with 10% NaHC03, the organic layer was washed with 25 ml of water and the excess solvent was evaporated under reduced pressure to obtain 0.88 gm (94.63%) of Clopidogrel free base. IR (Cm1) :1740 (CO) H NMR (CDC13): 5 2.88 (s, 4H), 3.6-3.8 (s, 3H, m, 2H) 4.9 (s, 1H), 6.6 (d, 1H) 7.0 (d, 1H), 7.2,7.7 (m, 4H) 13 C NMR(CDCl3): 25.54,48.3, 50.6, 52.14, 67.8, 122.7, 125.2, 127.1, 129.4, 129.7, 129.9, 133.2 133.8, 134.7 and 171.34 MS : m/z 322.1 (M+H)+ Example 12 (S)-(+)-Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno[3,2-c]pyrid-5-yl)acetatebisulfate(I) 10 g of (+) Methyl (2-chlorophenyl)-(6,7-dihydro-4H-thieno[3J2-c]pyrid-5-yl)acetate prepared above, was dissolved in 100 mL of ice-cold acetone and 2 mL concentrated sulfuric acid was added at 0 °C to 5 °C. The crystalline white to off white product formed was isolated by filtration and washed with 20 mL of acetone. The product obtained was dried in vacuum oven at 50 °C. The yield of titled product was 7.2 g (56 %). The melting point, IR spectrum and XRD of the product obtained resembles that of product obtained in EP 281459 and US 4847265 i.e. now referred as form I polymorph of Clopidogrel bisulfate (WO 99/65915). The product obtained was characterized by different physico-chemical characteristics, as given below; [a]D : + 55° (C = 1, CH3OH) Melting point :185°C±2°C IR spectrum : 2980, 1755, 1224, 1175 and 840 respectively with the respective % of percentage transmittance of approximately: 45; 16; 19; 15; 45. XRD of above product was found to be matching with the XRD of form I as reported in WO 99/65915. 17 NIPR-005 List of References : 1. M. Caron, P. L. Carlier, K. B. Sharpies, J. Org. Chem., 1988, 53, 5185. 2. J. March, in "Advanced Organic Chemistry: Reactions and Mechanisms", Wiley, 1999, page 428 and 828, and references therein. 3. P. H. J. Carlsen, T. Katsuki, V. S. Martin and K. B. Sharpless, J. Org. Chem., 1981,46,3936. 4. B. M. Trost, in "Comprehensive Organic Synthesis", Pergamon, 1991,vol. 7, Section 3.2 (page 389-436) and Section 5.3 (page 703-716) and references therein. 5. L. A. Paquette, in "Encyclopedia of reagents for Organic Synthesis", John Wiley & Sons, Inc, 1995, 7,4613-4616 and references therein. 6. R. C. Larrock^ in "Comprehensive Organic Transformations". John Wiley & Sons. Inc. 1999,. 2nd Ed., 815 - 818 and references therein. 7. T, W. Greene and P. G. M. Wuts "Protective groups in Organic Synthesis", John Wiley & Sons, Inc, 1999, 3rd Ed., 201-245 and 494-5^0, along with references therein. 8. K. Sumita, M. Koumori and S. Olmo, Chem. Pharm. Bull, 1994,42,1676. 9. R. A. Sheldon, in "Chirotechnology", Marcel Dekker, Inc. NY, Basel, 1993, 173-204 and references therein. 10. A. N. Collins, G. N. Sheldrack, J Crosby, in "Chirality in Industry II", John Wiley & Sons, Inc, 1997, 81-98 and references therein. 11. E. L. Eliel and S. H. Wilen; in "Stereochemistry of Organic Compound", John Wiley & Sons, Inc, 1999, 297-464 and references therein. Divn.-II of 335/MUM/2001 A Process for the preparation of substituted azido acids useful as intermediates for the preparation of Clopidogrel. Claims: 1. A process for preparing azido acid of formula 4 which comprises: i) oxidizing the epoxy acid of formula 2 using suitable oxidizing agents to obtain the epoxy acid of formula 10. ii) reacting the epoxy acid of formula 10 with a suitable azide source to obtain the p-azido-a-hydroxy acid of formula 11. iii) Converting said p-azido-cc-hydroxy acid of formula 11 to the corresponding azido acid of formula 4 with one carbon less by oxidation with peroxy acid of the kind such as herein described or salts thereof in presence of a catalyst of the kind such as herein described in an aqueous and non-polar solvent with a cosolvent at a temperature in the Divn.-II of 335/MUM/2001 2. A process as claimed in claim 1 wherein in step (i ), the said oxidizing agent is Sodium metaperiodate 3. A process as claimed in claim 1 wherein in step (ii), the said suitable azide source is selected from sodium azide, potassium azide, tetraalkyl ammonium azide, trimethyl silyl azide and titanium (isopropoxide) azide. 4. 5. A process as claimed in claim 3, wherein said azide source is sodium azide. A process as claimed in claim 4, where the molar ratio of epoxy alcohol to sodium azide is 1:3. 6. A process as claimed in claim 1, wherein in step (iii), the said oxidation is carried out in presence of peroxy acids selected from sodium metaperiodate or potassium permanganate. 7. A process as claimed in claim 6, wherein said oxidation is carried out in the presence of catalytic amount of Ruthenium trichloride hydrate. 8. A process as claimed in claim 1, wherein said aqueous non-polar solvent and cosolvent is selected from water, acetonitrile, carbon tetrachloride chloroform and methylene chloride. To The Controller of Patents The Patent Office at Mumbai

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