WO2012153348A2

WO2012153348A2 - Process for preparation of prasugrel and its intermediates

Info

Publication number: WO2012153348A2
Application number: PCT/IN2012/000327
Authority: WO
Inventors: Dattatray Shivaji SHEJUL; Sanjay S. BHISE; Srinivas Reddy Sanikommu; Tarun Kant Sharma; Milind Gharpure
Original assignee: Glenmark Generics Limited
Priority date: 2011-05-09
Filing date: 2012-05-02
Publication date: 2012-11-15
Also published as: WO2012153348A3

Abstract

The present invention relates to a process for the preparation of prasugrel, its intermediates, and pharmaceutically acceptable salts and pharmaceutical compositions thereof.

Description

PROCESS FOR PREPARATION OF PRASUGREL AND ITS INTERMEDIATES

PRIORITY

[0001] This application claims the benefit of IN1430/MUM/201 1, filed on May 9,201 1, the content of which is incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to a process for the preparation of prasugrel, its

intermediates, and pharmaceutically acceptable salts and pharmaceutical compositions thereof.

BACKGROUND OF THE INVENTION

[0003] Prasugrel and pharmacologically acceptable salts thereof are known to have a platelet aggregation-inhibiting action and are useful as an active ingredient of a medicine particularly as an antithrombotic or anti-embolic agent. Prasugrel hydrochloride is chemically described as 2- acetoxy-5-(a- cyclopropyl carbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride and is represented by the structural formula below;

[0004] United States Patent No. 5,288,726 (US^'726) describes tetrahydrothienopyridine derivatives, including prasugrel and their pharmaceutically acceptable salts. US '726 discloses a process for the preparation of prasugrel and intermediates of prasugrel. The key intermediate for preparing prasugrel is a 2-halo-l-cyclopropyl-2-fluorosubstituted phenylethanohe, for example, 2-bromo-l-cyclopropyl-2-fluorosubstituted phenylethanone, compound of Formula IVA, wherein Y is fluorine.

Formula IVA

[0005] The compound of Formula IVA is formed by brominating the compound of Formula IIA

Formula IIA

with bromine in carbon tetrachloride. Disadvantageously, bromine is highly corrosive and hazardous, which make handling difficult, requiring use of special reaction conditions.

[0006] United States Patent No 6,693,1 15 (US' 1 15) discloses a process for preparing a compound of Formula IVA, wherein Y is fluorine, by brominating a compound of Formula IIA in carbon tetrachloride using N-bromosuccinimide in the presence of benzoyl peroxide and refluxing the reaction for about 6 hours. The compound of Formula IVA is then purified by subjecting it to column chromatography. The disadvantages of the US^' l 15 process may include the use of N-bromosuccinimide, which may generate bromine, that is in turn, hazardous; and the use of carbon tetrachloride, which is a Class I known carcinogen. Additionally, the reaction conditions require refluxing conditions, whereupon the product obtained has to be subjected to column chromatography for purification. The process of US" 1 15, which discloses the formation of Formula IVA, the reaction of a compound of Formula IIA, wherein Y is fluorine, which is brominated using N-bromosuccinimide in the presence of azaisobutyronitrile in methylene dichloride, when reproduced gives the following observations , viz., the reaction required refluxing for about 24 hours; the ensuing product, the compound of Formula IVA contained the starting material, compound of Formula IIA, to the extent of at least 5-6%; and the dibromo- compound impurity, which was formed by the opening of cyclopropyl ring, was present to the extent of at least 4-7%.

[0007] The present invention, on the one hand, provides a novel process for the preparation of 2-halo-l- cyclopropyl -2- halosubstituted phenylethanone. The instant process can be used for preparing 2-bromo-l -cyclopropyl-2-fluorosubstituted phenylethanone, compound of Formula IVA, which may be used as a key intermediate for preparing prasugrel, compound of Formula I. The instant process advantageously can be carried out at room temperature, with the exclusion of liquid bromine. The environmentally benign instant process can be completed within about 2 hours, and is thus efficient, robust and of commercial significance.

[0008] The present invention provides a process for the preparation of compound of Formula IVA, which can be isolated in high yields and purity, while avoiding extraneous purification techniques, like column chromatography. SUMMARY OF THE INVENTION

[0009] The present invention provides a process for the preparation of the compound of

Formula IV

Formula IV wherein X represents chlorine or bromine and Y is halogen, the process comprising reacting compound of Formula II with a quaternary ammonium trihalide, compound of Formula III

Formula II Formula III wherein in [A-R], A is selected from the group consisting of Ci-C₆ trialkyl amino radical and pyridyl radical and R is selected from the group consisting of Ci-C₂₂ alkyl radical, alkylaryl, aryl, aralkyl and X is as defined above.

[0010] The present invention provides a process for the preparation of a compound of Formula

Formula IVA wherein Y is halogen, the process comprising reacting a compound of Formula II A with a quaternary ammonium tribromide, compound of Formula III A.

Formula IIA Formula IIIA wherein in [A-R], A is selected from the group consisting of Ci-C₆ trialkyl amino radical and pyridyl radical and R is selected from the group consisting of C1 -C22 alkyl radical, alkylaryl, aryl, aralkyl. [0011] The present invention provides a process for the preparation of a compound of Formula I or acid addition salt thereof

Formula I the process comprising a) reacting a compound of Formula IIA, wherein Y is fluorine, with a quaternary ammonium tribromide , compound of Formula IIIA.

Formula IIA Formula IIIA wherein in [A-R], A is selected from the group consisting of Ci-C₆ trialkyl amino radical and pyridyl radical and R is selected from the group consisting of Ci -C₂₂ alkyl radical, alkylaryl, aryl, aralkyl, to obtain a compound of Formula IVA;

Formula IVA b) reacting the compound of Formula IVA ,wherein Y is fluorine, with 5,6,7,7a-tetrahydro-4H- thieno[3,2-c]pyridine-2-one, compound of Formula V, or its acid addition salt ,to obtain a compound of Formula VI;

Formula V Formula VI c) optionally converting the compound of Formula VI to its acid addition salt ; and d) reacting the compound of Formula VI, or its acid addition salt, with an acetylating agent to obtain compound of Formula I.

[0012] The present invention provides process for the preparation of prasugrel hydrochloride, the process comprising reacting the compound of Formula I with hydrochloric acid in methyl ethyl ketone. [0013] The present invention provides a process for the purification of a hydrochloride salt of compound of Formula I, the process comprising slurrying a compound of Formula I hydrochloride in methyl ethyl ketone; isolating the hydrochloride of compound of formula I; and slurrying with acetone.

BRIEF DESCRIPTION OF THE ACCOMPANYING FIGURES

[0014] Fig. 1 : X-ray powder diffraction pattern of prasugrel compound of formula 1 obtained by

Example 6.

[0015] Fig. 2: X-ray powder diffraction pattern of prasugrel HC1 obtained by Example 8.

DETAILED DESCRIPTION OF THE INVENTION

[0016] The present invention provides a process for the preparation of prasugrel and of compounds that may useful as its intermediates.

[0017] Advantageously, the instant process eliminates the use of hydrogen halide or the use of any additional halogenating agents; such as bromine, which is hazardous and inconvenient to handle safely.

[0018] The present process can be carried out without the use of hydrogen halides and is advantageously efficiently carried out at ambient room temperature of about 20°C to about

35°C.

[0019] The present invention provides a process for the preparation of a compound

Formula IV

Formula IV wherein X represents chlorine or bromine and Y is halogen, the process comprising reacting a compound of Formula II with a quaternary ammonium trihalide, a compound of Formula III

[0020] The term "alkyl" as used herein includes a straight or branched chain hydrocarbon containing from 1 to 6 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert- butyl, n-pentyl, isopentyl, neopentyl, n-hexyl.

[0021] The term Ci-C trialkyl amino group represents amino group trisubstituted with alkyl moiety Representative examples of trialkyl amino include, but are not limited to, trimethylamino, triethylamino, tripropylamino and the like.

[0022] The term "aryl" as used herein, refers to aromatic ring systems, which may include fused rings. Representative examples of aryl include, but are not limited to, phenyl, and naphthyl, anthracenyl, phenanthrenyl.

[0023] The term "alkylaryl" as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylaryl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-ylethyl. [0024] The term "arylalkyl" as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety and substituted with an alkyl group, as defined herein. Representative examples of arylalkyl include, but are not limited to tolyl and phenyl ethyl. [0025] The halogens include chlorine, bromine, fluorine and iodine.

[0026] The present invention provides the preparation of compound of Formula IV, the process comprising reacting compound of Formula II with compound of Formula III, optionally in the presence of a solvent.

[0027] The solvent may be selected from the group consisting of ethers, alcohol and halogenated hydrocarbons.

[0028] The ether may be selected from the group consisting of cyclic ethers like tetrahydrofuran, tetrahydropyran and the like.

[0029] The alcohol may be selected from the group consisting of methanol, ethanol, isopropanol and the like. [0030] The halogenated hydrocarbon solvent may be selected from the group consisting of methylene dichloride, ethylene dichloride and the like.

[0031] The present invention provides the preparation of a compound of Formula IV, the process comprising reacting compound of Formula II with a compound of Formula III at a temperature in the range of about 20°C to about 35 °C. Preferably the reaction is carried out at room temperature.

[0032] In one embodiment, the present invention provides the preparation of compound of Formula IV, the process comprising reacting a compound of Formula II with a compound of Formula III, wherein A is Cj-C₆ trialkyl amino radical and R is selected from aryl and benzyl and X is bromine. [0033] The quaternary ammonium trihalide, compound of Formula III can be a quaternary ammonium trichloride or quaternary ammonium tribromide.

[0034] Representative quaternary ammonium tribromides that can be used are compounds of Formula IIIA

Formula IIIA wherein in [A-R], A is trimethyl amino radical and R is methyl; the quaternary ammonium tribromide is tetramethyl ammonium tribromide, Formula IIIA'

Formula IIIA' wherein A is triethyl amino radical and R is methyl; the quaternary ammonium tribromide is triethylmethylammoniumtribromide, Formula III A"

^C2^H5

I ^{2 5}

N— CH, Br.

C₂H₅

Formula IIIA' [0035] By varying the alkyl substituents, different quaternary ammonium tribromides, for e.g. tetraethylammoniumtribromide, tetrabutylammoniumtribromide and the like, can be used in the reaction.

[0036] Quaternary ammonium tribromides, compound of Formula IIIA, wherein A is Ci-C₆ trialkyl amino radical and R is selected from aryl and benzyl may also be used. For e.g.

phenyltrimethylammonium tribromide, compound of Formula IIIA, when A is trimethyl amino and R is phenyl can be used.

[0037] Other quaternary ammonium tribromides that can be used include benzyltrimethyl ammonium tribromide, cetyltrimethylammonium tribromide, and cetylpyridinium tribromide

[0038] In one embodiment, the present invention provides a process for the preparation of a compound of Formula IV wherein, X is Br and Y is halogen.

[0039] In one embodiment, the present invention provides a process for the preparation of a compound of Formula IV, the process comprising reacting a compound of Formula II with phenyltrimethyl ammonium tribromide, compound of Formula IIIA, wherein in [A-R], A is trimethylamino group, R is phenyl.

[0040] The reaction of compound of Formula II with phenyltrimethylammonium- tribromide may be carried out at a temperature in the range of about 20°C to about 35 °C. Preferably the reaction is carried out at room temperature.

[0041] The reaction of compound of Formula II with phenyltrimethylammonium-tribromide may be carried out for a period of about lhour to about 2 hours.

[0042] In one embodiment, the present invention provides a process for the preparation of a compound of Formula IV A

Formula IVA wherein Y is halogen, the process comprising reacting a compound of Formula IIA with a quaternary ammonium tribromide, compound of Formula III A.

Formula IIA Formula IIIA wherein in [A-R], A is selected from the group consisting of C]-C₆ trialkyl amino radical and pyridyl radical and R is selected from the group consisting of Ci-C₂₂ alkyl radical, alkylaryl, aryl, aralkyl .

[0031] The quaternary ammonium tribromide, compound of Formula III A may be selected from the group consisting of tetramethyl ammonium tribromide, triethylmethylammoniumtribromide, tetraethylammoniumtribromide, tetrabutylammoniumtribromide, phenyltrimethylammonium tribromide, benzyltrimethyl ammonium tribromide, cetyltrimethylammonium tribromide, and cetylpyridinium tribromide.

[0032] In one embodiment, the present invention provides a process for the preparation of a compound of Formula IVA, wherein Y is fluorine, the process comprising reacting a compound of Formula IIA, wherein Y is fluorine with phenyltrimethylammonium tribromide, compound of Formula IIIA, wherein A is trimethylamino group and R is phenyl.

[0033] The reaction of compound of Formula IIA with phenyltrimethylammoniumtribromide, compound of Formula IIIA, wherein A is trimethylamino group and R is phenyl may be carried out at room temperature of about 20°C to about 35 °C.

[0034] The reaction of compound of Formula IIA with phenyltrimethylammoniumtribromide, compound of Formula IIIA, wherein A is trimethylamino group and R is phenyl may be carried out for a period of about 1 hour to about 10 hours. Preferably about 6 hours to about 7 hours.

[0035] The reaction of compound of Formula IIA with phenyltrimethylammoniumtribromide, compound of Formula IIIA, wherein A is trimethylamino group and R is phenyl may be carried out, in presence of a solvent.

[0036] The solvent may be selected from the group consisting of ethers, alcohol and halogenated hydrocarbons.

[0037] The ether may be selected from the group consisting of cyclic ethers like tetrahydrofuran, tetrahydropyran and the like.

[0038] The alcohol may be selected from the group consisting of methanol, ethanol, isopropanol and the like

[0039] In one embodiment the reaction of compound of Formula IIA with phenyltrimethyl ammoniumtribromide, compound of Formula IIIA, wherein A is trimethylamino group and R is phenyl may be carried out, in presence of tetrahydrofuran.

[0040] After completion of the reaction, the reaction mixture is cooled to about 0°C to about 5 °C. The reaction mass is quenched by addition of water and is extracted with an organic solvent like halogenated hydrocarbon, for example methylene dichloride. Preferably, methylene dichloride is used and then the compound of Formula IVA is isolated by evaporation of solvent. [0041] In one embodiment, the reaction of compound of Formula II A with phenyltrimethyl ammoniumtribromide, compound of Formula IIIA, wherein A is trimethylamino group and R is phenyl may be carried out, in presence of an alcoholic solvent, preferably methanol.

[0042] After completion of the reaction, the pH of the reaction mixture is adjusted in the range of about 6-7. The pH may be 'adjusted by use of base selected from the group consisting of alkali metal or alkaline earth metal hydroxides like sodium hydroxide, potassium hydroxide and alkali or alkaline earth metal carbonates and bicarbonates like sodium carbonate, potassium carbonate, potassium bicarbonate and the like.

[0043] The compound of Formula IVA may be isolated by distilling out the solvent.

[0044] In one embodiment, the present invention provides a process for purifying compound of

Formula IVA comprising an extraction procedure using water and a hydrocarbon system.

[0045] The hydrocarbon may be selected from aliphatic hydrocarbon like hexane, heptane, pentane; cyclic hydrocarbons like cyclohexane, cyclopentane and the like or aromatic hydrocarbon like toluene, benzene and the like.

[0046] In one embodiment, the present invention provides a process for purifying the compound of Formula IVA, the process comprising extracting the compound using water and cyclohexane; then distilling cyclohexane layer to isolate the compound of Formula IVA.

[0047] The present invention provides a compound of Formula IVA, obtained as herein described, containing a compound of Formula HA, at about less than 2%.

[0048] The present invention provides a compound of Formula IVA, obtained as herein described, containing a dibromo compound, compound of Formula VII, at about no greater than

2%. The compound of Formula VII is recognized as an impurity generated by ring opening of cyclopropane ring.

Formula VII [0049] The present invention provides a compound of Formula IVA, obtained as herein described, having a dibromo compound, compound of Formula VII, at about less than 0.5%.

[0050] The compound of formula IVA, obtained by following the process of the present invention may be converted to compound of formula I or salt thereof. Preferably the hydrochloride salt of compound of formula I is obtained.

[0051] The conversion of compound of formula IVA to compound of formula I or salt thereof may be facilitated by any method known in the art or by a process as discussed below.

[0052] In one embodiment, the present invention provides a process for the preparation of a compound of Formula I or acid addition salt thereof.

Formula I the process comprising : a) reacting a compound of Formula IIA, wherein Y is fluorine with a quaternary ammonium tribromide, compound of Formula IIIA

Formula IIA Formula IIIA wherein in [A-R], A is selected from the group consisting of Ci-C₆ trialkyl amino radical and pyridyl radical and R is selected from the group consisting of C]-C₂₂ alkyl radical, alkylaryl, aryl, aralkyl, to obtain compound of Formula IVA;

Formula IVA b)reacting the compound of Formula IVA, wherein Y is fluorine with 5,6,7,7a-tetrahydro-4H- thieno[3,2-c]pyridine-2-one acid, compound of Formula V or its acid addition salt to obtain a compound of Formula VI;

Formula V Formula VI c) optionally, converting the compound of Formula VI to its acid addition salt ; and d) reacting the compound of Formula VI or its acid addition salt with an acetylating agent to obtain compound of Formula I.

[0053] In a) of the process described directly above, the quaternary ammonium tribromide may be selected from the group consisting of tetramethyl ammonium tribromide, triethylmethylammoniumtribromide, tetraethylammoniumtribromide, tetrabutylammonium- tribromide, phenyltrimethylammonium tribromide, benzyltrimethyl ammonium tribromide, cetyltrimethylammonium tribromide, and cetylpyridinium tribromide; preferably phenyltrimethylammonium tribromide, compound of formula IIIA wherein A is trimethylamino group and R is phenyl. [0054] The reaction of compound of Formula IIA with phenyltrimethylammonium-tribromide may be carried out at a temperature in the range of about 20°C to about 35 °C. Preferably the reaction is carried out at room temperature.

[0055] The reaction of compound of Formula IIA with phenyltrimethylammonium-tribromide, may be carried out, in presence of a solvent selected from the group consisting of ethers, alcohol and halogenated hydrocarbons.

[0056] The ether may be selected from the group consisting of cyclic ethers like tetrahydrofuran, tetrahydropyran and the like, preferably tetrahydrofuran.

[0057] The alcohol may be selected from the group consisting of methanol, ethanol, isopropanol and the like, preferably methanol.

[0058] After completion of the reaction, the reaction mixture is cooled to about 0°C to about 5 °C. The reaction mass is quenched by addition of water and is extracted with an organic solvent like halogenated hydrocarbon, for example methylene dichloride. Preferably, methylene dichloride is used and then the compound of Formula IV A is isolated by evaporation of solvent.

[0059] In b) of the process described directly above, the compound of Formula IVA obtained is reacted with hydrochloride salt of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridine-2-one acid, compound of Formula V to obtain a compound of Formula VI.

[0060] The reaction of compound of Formula IVA with the hydrochloride salt of 5,6,7,7a- tetrahydro-4H-thieno[3,2-c]pyridine-2-one, compound of Formula V is carried out in the presence of alkali metal carbonate like sodium carbonate, potassium carbonate and the like and nitrile solvent like acetonitrile, propionitrile and the like. Preferably, the reaction is carried out with potassium carbonate and acetonitrile. The compound of Formula VI may be isolated by standard procedures, known in the art.

[0061] In c) of the process described directly above, the compound of Formula VI is reacted with an acid to obtain the acid addition salt. The acid may be selected from the group consisting of hydrobromic acid, hydrochloric acid, sulfuric acid and acetic acid. Preferably, the acid is hydrobromic acid.

[0062] In one embodiment, the compound of Formula VI is reacted with hydrobromic acid to form a hydrobromide salt of compound of Formula VI. The reaction may be carried out in the presence of an organic solvent, preferably ketones like acetone. The hydrobromide salt of compound of Formula VI obtained may be purified by acid base purification. For example, the hydrobromide salt of compound of Formula VI may be dissolved in an organic solvent and treated with an organic base and ammonia followed by removal of organic solvent and treating the residue obtained with hydrobromic acid. If required the procedure is repeated to obtain a pure hydrobromide salt of compound of Formula VI.

[0063] The organic base may be selected from the group consisting of diisopropylethyl amine triethylamine, tributylamine, 4- dimethylaminopyridine, N-methylmorpholine and pyridine.

[0064] In one embodiment, the present invention provides a purification process of the hydrobromide salt of compound of Formula VI, the process comprising dissolving the hydrobromide salt in ethyl acetate and adding a mixture of ammonia and triethyl amine; isolating the compound of Formula VI; treating with aqueous hydrobromic acid to obtain the hydrobromide salt of compound of Formula VI.

[0065] In d) of the process described directly above, the reaction of compound of Formula VI or its acid addition salt with an acetylating agent is carried out in the presence of an organic base and a halogenated solvent to obtain the compound of Formula I.

[0066] The acetylating agent may be selected from the group consisting of acetic acid, acetyl chloride, acetic anhydride, trimethyl silyl acetate and the like, preferably acetic anhydride.

[0067] The organic base may be selected from the group consisting of diisopropylethyl amine, triethyl amine, tributylamine, 4- dimethylaminopyridine, N-methylmorpholine and pyridine. Preferably, the base is triethylamine.

[0068] The halogenated solvent may be selected from methylene dichloride, ethylene dichloride and the like. Preferably, the solvent is methylene dichloride.

[0069] In one embodiment, the compound of Formula VI is reacted with acetic anhydride in the presence of triethylamine in methylene dichloride to obtain the compound of Formula I. [0070] In one embodiment, the hydrobromide salt compound of Formula VI is reacted with acetic anhydride in the presence of triethylamine in methylene dichloride to obtain the compound of Formula I.

[0071] In one embodiment, the present invention provides a process for the preparation of a compound of Formula I or acid addition salt thereof.

Formula I the process comprising : a) reacting a compound of Formula IIA, wherein Y is fluorine with phenyltrimethylammonium tribromide, compound of Formula IIIA, wherein A is trimethylamino group and R is phenyl

Formula IIA Formula IIIA to obtain a compound of Formula IVA;

Formula IVA b) reacting the compound of Formula IVA, wherein Y is fluorine with 5,6,7,7a-tetrahydro-4H- thieno[3,2-c]pyridine-2-one acid, compound of Formula V or its acid addition salt to obtain a compound of Formula VI;

Formula V Formula VI c) converting the compound of Formula VI to its hydrobromide salt; and d) reacting the hydrobromide salt of compound of Formula VI with an acetylating agent to obtain compound of Formula I.

[0072] In one embodiment, the present invention provides a process for purifying the compound of Formula I comprising dissolving the compound of Formula 1 in ketone and precipitating the compound of Formula I, by adding an antisolvent.

[0073] The ketone may be selected from the group consisting of acetone, propanone, methyl ethyl ketone and the like. Preferably, the solvent is acetone.

[0074] The antisolvent may be a hydrocarbon. The hydrocarbon may be an aliphatic hydrocarbon like hexane, heptane and the like, cyclic hydrocarbon like cyclopentane cyclohexane and the like or aromatic hydrocarbon such as benzene, toluene, ethylbenzene and the like. Preferably, the antisolvent is cyclohexane.

[0075] In one embodiment, the compound of Formula I may be purified by dissolving in acetone and precipitating the compound of Formula I, by adding cyclohexane.

[0076] The present invention provides a compound of Formula I, containing a compound of Formula VI at least no more than about 0.1%. Preferably about less than 0.08% as determined by high performance liquid chromatography (HPLC).

[0077] The present invention provides a process for preparing compound of Formula I, containing a compound of Formula VI at least no more than about 0.1%, the process comprising dissolving the compound of Formula I in acetone and precipitating the compound of Formula I, by adding cyclohexane.

[0078] In one embodiment the present invention provides a compound of Formula I, having an X-ray diffraction pattern (XRD), substantially in accordance with Figure 1.

[0079] In one embodiment, the present invention provides a process for preparing the hydrochloride salt of compound of Formula I , the process comprising reacting the compound of Formula I with hydrochloric acid in methyl ethyl ketone.

[0080] In one embodiment, the present invention provides a process for preparing the hydrochloride salt of compound of Formula I in a non-aqueous medium.

[0081] In one embodiment, the present invention provides a process for preparing the hydrochloride salt of compound of Formula I in a non-aqueous medium, the process comprising reacting the compound of Formula I with HCl gas dissolved in an organic solvent.

[0082] The non-aqueous medium is selected from the group consisting of ethyl acetate, acetone, methyl ethyl ketone and the like.

[0083] The HCl gas is dissolved in organic solvent selected from acetone, ethyl acetate and the like.

[0084] In one embodiment, the present invention provides a process for preparing the hydrochloride salt of compound of Formula I in ethyl acetate, the process comprising reacting the compound of Formula I with ethyl acetate-HCl.

[0085] The hydrochloride salt of compound of Formula I can be further purified by slurrying it in a ketonic solvent. [0043] In one embodiment, the present invention provides a process for the purification of hydrochloride salt of compound of Formula I, the process comprising slurrying it in methyl ethyl ketone;isolating the hydrochloride of compound of formula I and slurrying with acetone. The slurrying with acetone is preferably carried out at room temperature. [0086] In one embodiment the present invention provides a hydrochloride salt of compound of Formula I having an XRD pattern, substantially in accordance with Figure 2.

[0087] The characterization of the crystalline form of compound of Formula I and hydrochloride salt thereof of the present invention by X-ray powder diffraction was performed on a Philips X'pert PRO Diffractometer using Cu Ka radiation (Cu Ka 1=1.54060 A). The X-ray source is operated at 45 kV and 40mA. Spectra are recorded in the 2Θ range of 2-50°, a step size 0.0167° with a "time-per-step" optimized to 1000 seconds.

[0088] The present invention provides compound of Formula I or hydrochloride salt of compound of Formula 1, wherein the corresponding 2-fluoro and 3-fluoro regioisomeric impurity of compound of Formula 1 and desfluoro impurity are present to the extent of about less than 0.1% as determined by high performance liquid chromatography (HPLC).

[0089] In one embodiment, the present invention provides a process for purifying prasugrel HC1 comprising washing the dried prasugrel Hcl crystals with a hydrocarbon. The hydrocarbon may be an aliphatic hydrocarbon like hexane, heptane and the like, cyclic hydrocarbon like cyclopentane cyclohexane and the like or aromatic hydrocarbon such as benzene, toluene, ethylbenzene and the like.

[0090] In one embodiment, the present invention provides a pharmaceutical composition comprising prasugrel or its pharmaceutically acceptable salt/s obtained by the processes herein described and suitable pharmaceutical carriers. The pharmaceutical compositions may be administered to a mammalian patient in any dosage form, e.g., liquid, powder, elixir, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, buccal, parenteral, ophthalmic, rectal and transdermal routes. Oral dosage forms include, but are not limited to, tablets, pills, capsules, troches, sachets, suspensions, powders, lozenges, elixirs and the like. The pharmaceutical compositions comprising prasugrel or its pharmaceutically acceptable salts, obtained by the process disclosed herein, and suitable pharmaceutical carriers also may be administered as suppositories, ophthalmic ointments and suspensions, and parenteral suspensions, where the most preferred route of administration is oral.

[0091] The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLES

COMPARATIVE EXAMPLE 1

Preparation of 2-bromo-l-cvclopropyl-2-(2-fluoropheiivD ethanone compound of Formula IVA using N-bromosuccinimide A mixture of l-cyclopropyl-2-(2-fluorophenyl) ethanone (100 grams), methylene dichloride (900 ml), N-bromosuccinimide (120 grams), azabisisobutyronitrile (10.0 grams) was stirred for about 24hours at reflux temperature. The reaction mixture was cooled to about 5-10°C and stirred for about 60-120 minutes and the precipitated solid was filtered. The filtrate was distilled off completely under reduced pressure. Hexane was added to the obtained residue and the solvent distilled off under reduced pressure to get 2-bromo-l-cyclopropyl-2-(2-fluorophenyl) ethanone compound of Formula IVA. Impurity: Dibromo compound from ring opening of cyclopropane ring: 4-7%^Unreacted starting compound: 5-6%

EXAMPLE 1

Preparation of 2-bromo-l-cyclopropyl-2-(2-fIuorophenyl) ethanone, compound of Formula IVA, using phenyltrimethylammonium tribromide.

A mixture of l-cyclopropyl-2-(2-fluorophenyl) ethanone (25 grams), tetrahydrofuran (125 ml) phenyltrimethyl ammonium tribromide (52.6grams) was stirred at about room temperature for about 30-60 minutes. The reaction mixture was cooled to about 0-5°C and stirred for about 30 minutes. 125ml of water and 125 ml of methylene dichloride was added to the reaction mass and the mass was stirred. The organic layer was separated and aqueous layer washed with methylene dichloride. The combined methylene dichloride layers were washed with sodium bisulphite, water and 10% aqueous HC1 and distilled out to get 2-bromo-l-cyclopropyl-2-(2-fluorophenyl) ethanone compound of Formula IVA.Impurity: Dibromo compound from ring opening of cyclopropane ring, compound of Formula VII: 1-2%; Unreacted starting compound: less than 2% Example 2: Preparation of 2-bromo-l-cvclopropyl-2-(2-fluorophenvD ethanone, compound of Formula IVA, using phenyltrimethylammonium tribromide, To a suspension of phenyl trimethyl ammonium tribromide (38 g) in methanol (200 ml) was added, 20 g of l-cyclopropyl-2-(2-fluorophenyl) ethanone over a period of 15-20 min at 25- 30°C and the reaction mass was stirred for 7 hours. After the completion of reaction, the pH of the reaction mass was adjusted to about 6 to about 7 using aqueous NaOH and the solvent was distilled off under vacuum below 45°C. To the oily mass, cyclohexane (80 ml) and water (80 ml) were added. The aqueous layer was separated and extracted with cyclohexane. To the combined organic layers, 100 ml water wash was added. The organic layer was separated and distilled out under vacuum below 40°C to provide 26 g of 2-bromo-l-cyclopropyl-2-(2-fluorophenyl) ethanone compound of Formula IVA.Impurity: Dibromo compound from ring opening of cyclopropane ring compound of Formula VII: less than 0.5%i.Unreacted starting compound: less than 5%

Example 3: Preparation of 5-(a-cvclopropylcarbonyl-2-fluorobenzyl)-2-oxo- 2,4,5,6, 7,7a- hexahvdrothieno[3,2-clpyridine, compound of Formula VI.

A round bottom flask (RBF) was charged with 800 ml of acetonitrile and 96.7gm of 4,5,6,7- tetrahydro(3,2-c)thienopyridine-3-one HCl. 261.0 gm of dried potassium carbonate was added and flushed with acetonitrile. The reaction mixture was stirred for about 20-30minutes at about 25°C to about 30°C. 130 gm of 2-bromo-l-cyclopropyl-2-(2-fluorophenyl) ethanone was added slowly at about 25°C to about 30°C. The reaction mixture was flushed with acetonitrile. The reaction mixture was stirred for about 3-4hours at about 25°C to about 30°C. The reaction mixture was washed with 400ml of acetonitrile. The acetonitrile was distilled under vacuum at about 45°C. 650ml of methylene dichloride was added into the reaction mixture. The methylene dichloride layer was washed with water and distilled out under vacuum to obtain a residue. To the residue obtained, methylene dichloride was added. Another fresh RBF was charged with 1 105.0 ml of diisopropylether. The methylene dichloride solution was added into diisopropylether dropwise. The reaction mixture was stirred for about 30-40minutes and filtered. The hyflo bed was filtered and washed with 130 ml of diisopropylether. The solvent was distilled under vacuum at about 40°C. The reaction mixture was degassed to obtain 1 17.0 gm of 5-(a- cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo- 2,4,5,6, 7,7a-hexahydrothieno[3,2-c]pyridine, a compound of Formula- VI as an oily mass. Alternatively to the residue obtained, ethyl acetate was added and washed with water and brine. Cyclohexane was added to the ethyl acetate layer followed by addition of charcoal. The reaction mixture was stirred for about 30-40minutes and filtered through a hyflo bed and washed with cyclohexane. The solvent was distilled under vacuum at about 40°C. The reaction mixture was degassed to obtain 1 17.0 gm of 5-(a- cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo- 2,4,5,6, 7,7a-hexahydrothieno[3,2-c]pyridine, a compound of Formula- VI as an oily mass.

Example 4: Preparation of 5-(a-cvclopropylcarbonyl-2-fluorobenzyl)-2-oxo- 2,4,5,6, 7,7a- hexahydrothieno [3,2-cl yridine hvdrobromide

1 17.0 gm of 5-(a-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo- 2,4,5,6, 7,7a- hexahydrothieno[3,2-c]pyridine, compound of Formula-VI (prepared as in Example 3) was dissolved in acetone 1300ml. The reaction mixture was cooled to about 0°C to about 10°C. 70 ml of aqueous hydrobromic acid was added slowly at about 0°C to about 10°C. The reaction mixture was maintained at a temperature of about 25°C to about 30°C for about 12-14hours. The reaction mixture was filtered and washed with 65.0 ml of acetone. The obtained residue was dried at about 50°C to about 60°C for about 8-1 Ohours in an air oven. A fresh RBF was charged with 90.0 gm dry material and 750 ml of ethyl acetate. 45.0 ml of triethylamine/aq. ammonia was added into reaction mixture. The reaction mixture was stirred to about 15-30 minutes. The organic layer was washed with 600 ml of water. The solvent was distilled under vacuum at about 40°C. The obtained dried residue was dissolved in 700 ml of acetone. The reaction mixture was cooled to about 0°C to about 10°C. 36.0 ml of aqueous hydrobromic acid was added slowly to the reaction mixture at about 0°C to about 10°C for about 30-45 minutes. The reaction mixture was maintained for about 12-14 hours at about 25 °C to about 30°C. The reaction mixture was filtered and washed with 65.0 ml of acetone. The obtained residue was dried for about 8-1 Ohours at about 50°C to about 60°C in an air oven to obtain 5-(a-cyclopropylcarbonyl-2-fiuorobenzyl)- 2-oxo- 2,4,5,6, 7,7a-hexahydrothieno[3,2-c]pyridine hydrobromide.

Example 5: Preparation of prasugrel, compound of Formula I

A RBF was charged with 400ml of methylene dichloride and 100 gm of 5-(<x- cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo- 2,4,5,6, 7,7a-hexahydrothieno[3,2-c]pyridine. The reaction mixture was flushed with 100ml of methylene dichloride. The reaction mixture was stirred at about 25°C to about 30°C. The reaction mixture was cooled at about 0°C to about 10°C. 100 ml of acetic anhydride was added into the reaction mixture. 39.6 gm of triethylamine was added dropwise in about 15-30 min at about 0°C to about 10°C. The reaction mixture was maintained at about 0°C to about 10°C for about 2-4hours. 200ml of water was added into the reaction mixture. The reaction mixture was stirred at about 25°C to about 30°C. The organic layer was separated. The organic layer was washed with 600 ml of sodium carbonate solution followed by 200 ml of water. The solvent was distilled under vacuum at about 45°C; followed by stripping with 100 ml of methanol. 150 ml of methanol was added. The reaction mixture was stirred about 30-45 minutes at about 0°C to about 10°C. The reaction mixture was filtered and washed with 50 ml of methanol. The reaction product was dried at about 50°C to about 55°C in hot air oven. Optionally, the residue was dissolved in acetone and heated to about 50°C to about 55°C and cyclohexane was added. The reaction mass was cooled to about 0°C to about 5°C and washed by adding cyclohexane. Purity 99.75%, Compound of formula VI :ND

Example-6 Preparation of prasugrel, compound of Formula I

A RBF was charged with 400ml of methylene chloride and 100 gm of 5-(a-cyclopropylcarbonyl- 2-fluorobenzyl)-2-oxo- 2,4,5,6, 7,7a-hexahydrothieno[3,2-c]pyridine hydrobromide. The reaction mixture was flushed with 100ml of methylene chloride. The reaction mixture was stirred at about 25°C to about 30°C. The reaction mixture was cooled at about 0°C to about 10°C. 100 ml acetic anhydride was added into the reaction mixture. 73.5 gm of triethylamine was added dropwise in about 15-30 min. at about 0°C to about 10°C. The reaction mixture was maintained at about 0°C to about 10°C for about 2-4hours. 200ml of water was added into the reaction mixture. The reaction mixture was stirred at about 25°C to about 30°C. The organic layer was separated. The organic layer was washed with 600 ml of sodium carbonate solution followed by 200 ml of water. The solvent was distilled under vacuum at about 45°C; followed by stripping with 100 ml of methanol. 150 ml of methanol was added. The reaction mixture was stirred for about 30- 45minutes at about 0°C to about 10°C. The reaction mixture was filtered and washed with 50 ml of methanol. The reaction product was dried at about 50°C to about 55°C in hot air oven.

Yield: 75.0 gm; Purity 99.0%.

Example-7 Preparation of prasugrel hydrochloride

A RBF was charged with 1600 ml of methyl ethyl ketone and 100 gm of prasugrel. The reaction mixture was flushed with 100 ml of methyl ethyl ketone. The reaction mixture was stirred at about 25°C to about 30°C. The reaction mixture was charged with 10 gm of NORIT charcoal and 100 ml of methyl ethyl ketone. The reaction mixture was maintained for about 15-30 minutes at about 25°C to about 30°C. The reaction mixture was filtered and washed with 100 ml of methyl ethyl ketone. The clear filtrate was charged in another flask. The reaction mixture was stirred and heated about 40°C to about 45°C. 24.0gm of concentrated hydrochloric acid was added dropwise at about 40°C to about 45°C in about 100-120 minutes. The reaction mixture was maintained at about 40°C to about 45°C for about 2-3 hours. The reaction mixture was filtered and washed with 100 ml of methyl ethyl ketone. The dry residue was sucked. The wet residual cake was heated in acetone at about 50°C to about 55°C. The reaction mixture was stirred for about 60-70 minutes. The reaction mixture was filtered and washed with acetone. The reaction product was dried in a vacuum oven to obtain prasugrel hydrochloride. Purity 99.50%,

Example-8 Preparation of prasugrel hydrochloride

A RBF was charged with 1300 ml of methyl ethyl ketone and 75 gm of prasugrel. The reaction mixture was flushed with 100 ml of methyl ethyl ketone. The reaction mixture was stirred at about 25°C to about 30°C. The reaction mixture was charged with 7.5 gm of NORIT® charcoal and 100 ml of methyl ethyl ketone. The reaction mixture was maintained for about 15-30 minutes at about 25°C to about 30°C. The reaction mixture was filtered and washed with 25 ml of methyl ethyl ketone. The clear filtrate was charged in another flask. The reaction mixture was stirred and heated about 40°C to about 45°C under nitrogen atmosphere. 20.0gm of concentrated hydrochloric acid was added dropwise at about 40°C to about 45°C in about 100-120 minutes. The reaction mixture was maintained at about 40°C to about 45°C for about 2-3 hours. The reaction mixture was filtered and washed with 75 ml of methyl ethyl ketone. The dry residue was sucked. The wet residual cake was added to 500 ml of methyl ethyl ketone and stirred at about 25°C to about 30°C for about 1-2 hours. The reaction mixture was filtered and washed with 75 ml of methyl ethyl ketone. The dry residue was sucked. The wet residual cake was heated in acetone at about 25°C to about 30°C. The reaction mixture was stirred for about 60-70 minutes. The reaction mixture was filtered and washed with acetone. The reaction product was dried in a vacuum oven to obtain prasugrel hydrochloride. The dried material was heated in cyclohexane at about 50°C to reflux temp. The reaction mixture was stirred for 60-70 minutes. The reaction mixture was filtered and washed with cyclohexane. The product was dried in vacuum oven to obtain Prasugrel Hydrochloride. Purity: 99.5%, des acetyl impurity (compound of Formula VI): 0.02%, 3-Fluoro isomer: 0.07%, Des fluoro imp: 0.10%.

ExampIe-9 Preparation of prasugrel hydrochloride

A RBF was charged with 120 ml of ethyl acetate and 10 gm of prasugrel. The reaction mixture was flushed with 10 ml of ethyl acetate. The reaction mixture was stirred at about 25°C to about 30°C. The reaction mixture was charged with 1 gm of NORIT® charcoal and was maintained for about 15-30 minutes at about 25°C to about 30°C. The reaction mixture was filtered and washed with 20 ml of ethyl acetate. The clear filtrate was charged in another flask. The reaction mixture was stirred and cooled to about 0°C to about 5°C. 33.5gm of ethyl acetate HCl was added dropwise at about 0°C to about 5°C in about 100-120 minutes. The reaction mixture was maintained at about 0°C to about 5°C for about 2-3 hours. The reaction mixture was filtered and washed with 20 ml of ethyl acetate. The dry residue was sucked. The wet residual cake was added to 80 ml of methyl ethyl ketone and stirred at about 40°C to about 45°C for about 1-2 hours. The reaction mixture was filtered and washed with 20 ml of methyl ethyl ketone. The dry residue was sucked. The wet residual cake was heated in acetone at about 25°C to about 30°C. The reaction mixture was stirred for about 60-70 minutes. The reaction mixture was filtered and washed with acetone. The reaction product was dried in a vacuum oven to obtain prasugrel hydrochloride. Purity :99.5%, des acetyl impurity (compound of Formula VI): 0.02%,3 -Fluoro isomer : 0.07% Des fluoro imp: 0.10%

Example 10 Purification of 2-(fluoro phenyl) acetic acid

Diisopropyl amine (35.7 g) was added to a solution of 2-(fluoro phenyl) acetic acid (50 g) in ethyl acetate (200 ml) at about 0°C to about -10°C over a period of about 1 hour. The reaction mass was stirred for about 2 hours at about 0 to about -10°C. The product was filtered and was washed with 25 ml chilled ethyl acetate. The wet cake was dissolved in 200 ml water at about 25-30°C. To the clear solution, cone. HCl was added and the pH adjusted to 1-2. The product was extracted in 250 ml methylene dichloride (MDC). The organic layer was washed with water, and the solvent was distilled out under vacuum. 400ml of cyclohexane was added and then distilled out. 100 ml cyclohexane was added and filtered to provide 82 g (82 %) of the title compound as a white solid.

Claims

1. A process for the preparation of a compound of Formula IV

The process as claimed in claim 1 wherein the quaternary ammonium trihalide, a compound of Formula III is selected from the group consisting of quaternary ammonium trichloride and quaternary ammonium tribromide.

The process as claimed in claim 1 wherein, X is Br and Y is a halogen.

A process for the preparation of a compound of Formula IVA

Formula IV A wherein Y is halogen, the process comprising reacting a compound of Formula IIA with a quaternary ammonium tribromide, compound of Formula IIIA.

Formula IIA Formula IIIA wherein in [A-R], A is selected from the group consisting of Ci-C₆ trialkyl amino radical and pyridyl radical and R is selected from the group consisting of C1-C22 alkyl radical, alkylaryl, aryl, aralkyl. 5. The process as claimed in claim 4 wherein the quaternary ammonium tribromide, a compound of Formula IIIA, is selected from the group consisting of tetramethyl ammonium tribromide, triethylmethyl ammoniumtribromide tetraethylammonium tribromide, tetrabutylammoniumtribromide, phenyltrimethylammonium tribromide, benzyltrimethyl ammonium tribromide, cetyltrimethylammonium tribromide,. and cetylpyridinium tribromide. 6. The process as claimed in claim 4, wherein the compound of Formula IIA, where Y is fluorine, is reacted with phenyltrimethylammonium tribromide, a compound of Formula III A, wherein A is trimethylamino group and R is phenyl, to obtain compound of formula IV A, where Y is fluorine. The process as claimed in claim 4 wherein the reaction is carried out at room temperature of about 20°C to about 35 °C.

The process as claimed in claim 6 further comprising converting the compound of formula IVA to a compound of formula I or salt thereof.

A process for the preparation of a compound of Formula I or acid addition salt thereof

Formula I the process comprising: a) reacting a compound of Formula IIA, wherein Y is fluorine with a quaternary ammonium tribromide, compound of Formula IIIA.

Formula IIA Formula IIIA wherein in [A-R], A is selected from the group consisting of C|-C₆ trialkyl amino radical and pyridyl radical and R is selected from the group consisting of Ci-C₂₂ alkyl radical, alkylaryl, aryl, aralkyl, to obtain a compound of Formula IVA;

Formula IVA b) reacting the compound of Formula IVA ,wherein Y is fluorine with 5,6,7,7a-tetrahydro thieno[3,2-c]pyridine-2-one, compound of Formula V or its acid addition salt to obtain a compound of Formula VI;

Formula V Formula VI c. ) optionally converting the compound of Formula VI to its acid addition salt; and d. ) reacting the compound of Formula VI or its acid addition salt with an acetylating agent to obtain compound of Formula I.

10. The process as claimed in claim 9, wherein the quaternary ammonium tribromide is selected from the group consisting of tetramethyl ammonium tribromide, triethylmethyl ammoniumtribromide tetraethylammonium tribromide, tetrabutylammoniumtribromide, phenyltrimethylammonium tribromide, benzyltrimethyl ammonium tribromide, cetyltrimethylammonium tribromide, and cetylpyridinium tribromide.

1 1. A process as claimed in claim 9, wherein in c), the compound of Formula VI is reacted with an acid selected from the group consisting of hydrobromic acid, hydrochloric acid, sulfuric acid and acetic acid to form the acid addition salt of compound of Formula VI.

12. A process as claimed in claim 9, further comprising purifying the compound of Formula I by dissolving the compound of Formula I in acetone and precipitating the compound of Formula I, by adding cyclohexane.

13. A process for the preparation of hydrochloride salt of compound of Formula I, the process comprising reacting the compound of Formula I with hydrochloric acid in methyl ethyl ketone.

14. A process for the purification of hydrochloride salt of compound of Formula I, the process comprising slurrying compound of Formula I hydrochloride in methyl ethyl ketone, isolating the hydrochloride of compound of formula I and slurrying with acetone.