WO2012052788A1

WO2012052788A1 - Method for preparing pharmaceutically active ingredient and intermediates thereof

Info

Publication number: WO2012052788A1
Application number: PCT/HU2011/000099
Authority: WO
Inventors: Bálint NYULASI; Márta PORCS-MAKKAY; Gábor NÉMETH; Tamás GREGOR; József Barkóczy; Balázs VOLK; Kálmán NAGY; György RUZSICS; Zsófia PAPP-FÜZFAI; Enikö MOLNÁR; Angéla PANDUR; Adrienn Keszthelyi; Tibor Mezei; Dávid FRIGYES
Original assignee: Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság
Priority date: 2010-10-22
Filing date: 2011-10-21
Publication date: 2012-04-26
Also published as: HU1000565D0; HUP1000565A2

Abstract

The present invention is related to a safe and industrially applicable method for the preparation of 2-acetoxy-5-(2-fluoro-α-cyclopropyl- carbonyl-benzyl)-4,5,6,7-tetrahydro-4H-thieno[3,2-c]pyridine in a quality suitable for use as pharmaceutically active ingredient wherein the concentration of the impurities of the Formula.(XXIV) or (XXIVa) is reduced.

Description

Method for preparing pharmaceutically active ingredient and intermediates thereof

Technical field of the invention

The present invention is related to a safe and industrially applicable method for the preparation of 2-acetoxy-5-(2-fluoro-a-cyclopropyl- carbonyl-benzyl)-4,5,6,7-tetrahydro-4H-thieno[3,2-c]pyridine of the Formula (I)

in a quality suitable for use as pharmaceutically active ingredient. 2- acetoxy-5-(2-fluoro-a-cyclopropyl-carbonyl-benzyl)-4,5,6,7-tetra- hydro-4H-thieno[3,2-c]pyridine is known by the International Nonproprietary Name prasugrel, which is a pharmaceutically active ingredient used in the treatment of disorders of blood coagulation. Further subject of the present invention is a method for the preparation of 2-bromo-l-cyclopropyl-2-(2-fluorophenyl)-ethanone of the Formula (III) and

2-choro-l-cyclopropyl-2-(2-fluorophenyl)-ethanone of the Formula (Ilia)

as well as the use of the intermediates of the Formula (III) and (Ilia) produced according to the present invention in the preparation of prasugrel of the Formula (I).

Background Art

Prasugrel of the Formula (I) is an important representative of the pharmaceutically active tetrahydro-thienopyridine derivatives useful in the inhibition of trombocyte aggregation.

Prasugrel and thrombocyte aggregation inhibiting analogs thereof as well as methods for their preparation have been described for the first time in US Patent No. 5288726. Preparation of prasugrel according to Reaction Scheme 1 comprises reacting 5,6,7,7a-tetrahydro-4H- thieno[3,2-c]pyridin-2-one hydrochloride of the Formula (II), wherein HA represent HC1

with 2-bromo-l-cyclopropyl-2-(2-fluorophenyl)-ethanone of the Formula (III) in NN-dimethylformamide in the presence of excess potassium carbonate for five hours. In this way, 5-[2-cyclopropyl-l- (2-fluorophenyl)-2-oxo-ethyl]-2,4,5,6,7,7a-hexahydro-4H-thieno[3,2- c]pyridin-2-on of the Formula (IV)

is obtained in the form of a brownish oil in poor yield. The raw product is further purified by column chromatography and crystallization, subsequently acetylated with acetic anhydride in the presence of sodium hydride in NN-dimethylformamide and the acetylated crude product is subjected to column chromatographic purification for the second time. After evaporating the solvent, the oily residue is crystallized from diisopropylether. Thus, prasugrel free base of the Formula (I) is obtained in a low yield of 21% calculated for the intermediate of the Formula (II) and 65% for the intermediate of the Formula (IV).

The disadvantage of the above-mentioned method resides in that the product mixture comprising mainly the compound of the Formula (IV) and subsequently prasugrel of the Formula (I) are isolated and purified by column chromatography. It is well known in the state of the art that the solvent requirement of a column chromatographic process is extremely high, which results in high cost and complicated disposal or reprocessing of the waste solvents. Furthermore, the scale-up of a chromatographic purification method on an industrial scale is difficult. Specifically in the method described above, despite of the purification method, the overall yield is low. A second disadvantage of the method described above resides in that sodium hydride is used in the acetylation step, which requires observing strict safety measures for preventing explosions potentially resulting from hydrogen evolving from the reaction. Furthermore, since paraffin is used for suspending sodium hydride, the work-up of the reaction mixture is more complicated.

An essentially similar method to the one described above has been disclosed in US Patent No. 6693115 with the difference that in the reaction of the compounds of the Formulae (II) and (III), potassium hydrogencarbonate is used as a base and that the molar ratio of the reactants is different. In this method, the yield of the last step is 65%, while the overall yield of the two steps is 23 %.

A second closely similar method to those described above has been disclosed in Published International Patent Application WO 2007115305. Th work-up methods applied therein are similar to those of US Patent 5288726 and result in similarly low yields.

According to the method disclosed in US Patent No. US 5874581, prasugrel base of the Formula (I) is produced by silylating 5,6,7,7a- tetrahydro-4H-thieno[3,2-c]pyridin-2-one toluenesulfonate of the Formula (II) - wherein ΗΑ represents toluenesulfonate - in position 2, the protected intermediate of the Formula (VI)

VI thus obtained is coupled with the corresponding chloro-ketone. Subsequently the protecting group is removed from the compound of the Formula (VII)

and the thus obtained oxo-intermediate of the Formula (IV) is acetylated in situ. These reaction steps are demonstrated in Reaction Scheme 3. After the work-up of the reaction mixture, prasugrel base is obtained in 91% yield in the last step. The yield calculated for the tosylate salt of the Formula (II) - wherein HA represents p- toluenesulfonic acid - is 66.7 %.

The disadvantage of the method described above is that two further reaction steps have been introduced, wherein the use of the costly and water-sensitive tert-butyldimethylchlorosilane and the very toxic 4- dimethylamino-pyridine is required. In the method, the chlorine- containing intermediate of the Formula (Ilia)

is used instead of the alkyl bromide of the Formula (III)

Chinese Patent Application Nos. 101250192, CN 101245072, CN 101245073 es CN 101250193 disclose an essentially identical synthesis of prasugrel with little variations regarding the preparation of the intermediates.

According to the disclosure of Chinese Patent Application No. 101250192, prasugrel is prepared starting from the O-alkylated intermediate of the Formula (VIII)

wherein R represents an alkyl group. The protecting group is cleaved using an acid under mild reaction conditions. The synthetic method is demonstrated in Reaction Scheme 4.

In the method of Chinese Patent Application No.101245072, 4,5,6,7- tetrahydro-thieno[3,2-c]pyridine of the Formula (IX)

is benzylated, thereafter the thus obtained compound of the Formula (X)

is brominated yielding 2-bromo-N-benzyl key intermediate of the Formula (XI)

which is subsequently transformed into prasugrel of the Formula (I) in several steps. This method of preparation is demonstrated in Reaction Scheme 5.

The method described in Chinese Patent Application No. 101245073 is an improved version of the methods being the subjects of the previous two application. According to this procedure, the bromine atom in the 2-bromo derivative of the Formula (XI) produced according to the above-mentioned methods is exchanged into an alkoxy group, preferably into a methoxy group using sodium methylate. Subsequently the thus obtained 2-alkoxy intermediate of the Formula (XII)

is transformed in several steps into prasugrel of the Formula (I). This method of transformation is demonstrated in Reaction Scheme 6.

According to Chinese Patent Application No. 101250193, the 2- alkoxy-intermediate of prasugrel corresponding to Formula (VIII) is produced by coupling 2-alkoxy-4,5,6,7-tetrahydro-thieno[3,2- cjpyridine of the Formula (XIII)

and 2-bromo-l-cyclopropyl-2-(2-fluorophenyl)-ethanone of the Formula (III) in the presence of copper(I) salt and iodide salt. The reaction is demonstrated in Reaction Scheme 7.

The common disadvantage of the methods described above resides in that it is complicated to carry out the dealkylation (preferably the demethylation of the methoxy group) economically. Further disadvantage is that during the catalytic hydrogenation of the benzyl protecting group of the nitrogen atom, the tiophene structure unit inhibits the reaction by acting as a catalyst poison.

Published International Patent Application WO 2008108291 is related to a method for the preparation of prasugrel hydrochloride, wherein the concentration of 3-chloropropyl impurity resulting from the ring- opening of the cyclopropyl group is low. According to the disclosed method, l-cyclopropyl-2-(2-fluorophenyl)-ethanone of the Formula (V)

is chlorinated in position 2 at low temperature. Thereafter the intermediate of the Formula (Ilia) thus obtained is coupled with O- protected 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-on of the Formula (XIII), wherein R represents trialkylsilyl. The reactions are demonstrated in Reaction Scheme 8.

European Patent Application No. 2003136 is related to the preparation of high-purity prasugrel salts and prasugrel base, wherein the concentration of the desacetyl impurity (compound of the Formula (IV)) is low. Prasugrel is prepared according to the method of US Patent No. 5874581 for the salt formation and purification of the base. In the coupling reaction, 2-chloro-l-cyclopropyl-2-(2-fluorophenyl)- ethanone of the Formula (Ilia) is used, which is obtained by halogenating the corresponding ketone of the Formula (V) using gaseous chlorine with a yield of 80%. High purity prasugrel base is obtained by recrystallization. The disadvantage of the method is that the very toxic chlorine gas is used, which is complicated to handle and dispose of.

According to the method disclosed in Published International Patent Application WO 2009006859, the 5,6,7,7a-tetrahydro-4H-thieno[3,2- c]pyridin-2-on salt of the Formula (II) is coupled with the mesyloxy- derivative of the Formula (XIV)

instead of 2-bromo-l-cyclopropyl-2-(2-fluorophenyl)-ethanone of the Formula (III) and isolating the thus obtained intermediate of the Formula (IV) by column chromatography. The compound of the Formula (XIV) is produced starting from 2-fluorobenzaldehyde and trimethylsilylcyanide. After acylating the compound of the Formula (II), the crude final product is prepared by column chromatography in form of an oil, which is crystallized from diethylether. The method is uneconomical due to the extremely costly reagent. Further disadvantage of the method is that the final product has to be purified by column chromatography. No purity data regarding prasugrel thus prepared have been disclosed.

In the method disclosed in Published International Application WO 2009062044, as demonstrated in Reaction Scheme 9, 4,5,6,7- tetrahydro-thieno[3,2-c]pyridine hydrochloride is tritylated in the first step. 5-trityl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine of the Formula

(XV)

is thereafter transformed into 5-trityl-5,6,7,7a-tetrahydro-4H- thieno[3,2-c]pyridin-2-one of the Formula (XVI)

and said compound is acetylated yielding the compound of the Formula (XVII)

The N-protecting group is removed and the thus obtained derivative of the Formula (XVIII)

is coupled with the bromo-ketone of the Formula (III).. The total yield calculated for the starting material of the Formula (IX) is 4.1 % (when the recrystallization step is considered, 3.1%), which is even lower than that of the methods disclosed above.

The method disclosed in Published International Patent Application WO 2009066326 is related to coupling of 5,6,7,7a-tetrahydro-4H- thieno[3,2-c]pyridin-2-one salt and 2-bromo-l-cyclopropyl-2-(2- fluorophenyl)-ethanone of the Formula (III) in the presence of potassium carbonate, isolating the intermediate of the Formula (IV) from the reaction mixture in an oily state and acetylating said compound in the presence of diisopropylethylamine (DIPEA) acid binding agent. The disadvantages of the method are low yield, using two different bases in two stages of the process and that the final product could be produced only after isolating the intermediate of the Formula (IV).

Chinese Patent Application No. 101531667 discloses a method principally different from those described above. According to this method, 2-bromo-l-cyclopropyl-2-(2-fluorophenyl)-ethanone of the Formula (III) is transformed into the intermediate of the Formula

(XX)

XX with the yield of 73% using 2-thiophene-ethylamine of the Formula

Subsequently the compound of the Formula (XX) is reacted with formaldehyde and cyclized in presence of an acid with 75% yield. Thus 5-(2-fluoro-a-cyclopropyl-carbonyl-benzyl)-4,5,6,7-tetrahydro- 4H-thieno[3,2-c]pyridine of the Formula (XXI)

is obtained, which is oxidized using hydrogen peroxide in the presence of copper-sulfate into the intermediate of the Formula (IV) and acetylated, thus yielding prasugrel of the Formula (I). The disadvantage of the method is that hydrogen peroxide is used as an oxidant. The method is demonstrated in Reaction Scheme 10.

The method disclosed in Published International Patent Application No. WO 2009122440 for the preparation of prasugrel of the Formula (I) is similar to the one disclosed in the basic patent. The difference resides in that 5-[2-cyclopropyl-l-(2-fluorophenyl)-2-oxo-ethyl]- 2,4,5, 6,7,7a-hexahydro-4H-thieno[3,2-c]pyridin-2-one of the Formula

(IV) is acylated in the form of a salt, preferably the hydrobromide salt thereof rather than in the form of a free base. The yield of this reaction is 39% calculated for the free base.The second method disclosed in the same application is based on identical steps to those disclosed in Published International Patent Application No. WO 2009062044 with a yield of 32.89%, calculated for the tosylate of the compound of the Formula (XVIII).

It is well known from the state of the art that carbonyl compounds having a carbon in a-position and a hydrogen attached to said carbon atom yield a-halogenated derivatives in a reaction with halogens. The reaction can be catalysed by Bronsted acids and bases.

Furthermore, it is also known that carbons in benzyl-position having an attached hydrogen can be halogenated by photochemical methods or in the presence of chemical initiators capable of inducing radicals. Since the methylene group present in the compound of the Formula

(V) satisfies both criteria, both methods can be used for the halogenation thereof.

The basic patent is silent about the method of preparation, physical- chemical constants or purity of the starting material of the Formula (III). In the basic patent, reference is made to an analogous reaction described for a derivative having similar formula. According to this method, the halogen-compound of the Formula (III) is produced by W 201

17

reacting l-cyclopropyl-2-(2-fluorophenyl)-ethanone of the Formula (V) with equimolar amount of the very agressive and dangerous elementar bromine by stirring in carbon tetrachloride solution for five hours. The method is demonstrated in Reaction Scheme 2. The isolated crude product is used without any further purification in the next reaction step.

According to the method of Published European Patent Application EP2003136, 2-chloro-l-cyclopropyl-2-(2-fluorophenyl)-ethanone is produced analogously by halogenating the compound of the Formula (V) with chlorine gas.

It is well known from the state of the art that besides halogens, other halogenating agents can also be used in the reactions discussed above. Such reagents include N-halogensuccinimides, most notably N-bromosuccinimide and N-chlorosuccinimide, which are usually applied in the presence of small amount of a radical initiator, such as an elemental halogen, an organic peroxide or azobisisobutyronitrile. In the method of Published European Patent Application EP 1298132 and Published International Patent Application WO2007115305, the bromo-ketone of the Formula (III) is prepared by brominating 1- cyclopropyl-2-(2-fluorophenyl)-ethanone of the Formula (V) in carbon tetrachloride using approximately equimolar amount of N- bromosuccinimide in the presence of dibenzoylperoxide radical initiator for 6 hours at boiling temperature. The product is subsequently purified by column chromatography, yielding 83% product of undisclosed purity after chromatographic purification. Published International Patent Application WO 2009066326 discloses an improved version of the method according to the basic patent amenable to scale-up. In the application, the preparation of 1- cyclopropyl-2-(2-fluorophenyl)-ethanone of the Formula (V) starting from cyclopropylcyanide has been described, which yields a product of 85% purity according to gas chromatographic analysis. The intermediate thus obtained is brominated using N-bromosuccinimide in the presence of dibenzoylperoxide. The bromo-ketone of the Formula (III) thus obtained is isolated in the yield of 77.8 % without disclosing any data regarding its quality. ¹

According to the examples of Published International Patent Application WO 2009062044, bromination of the ketone of the Formula (V) is carried out using N-bromosuccinimide and carbon tetrachloride as solvent in the presence of azobisisobutyronitrile by stirring for 3 hours at 75 °C. The reaction mixture is washed with bisulfite solution, the solvents are evaporated in vacuo and the residue is triturated in hexane, thereafter decanted and distilled at the temperature of 36 °C. Thus a product of Formula (III) having 73.6% purity (as determined by high-performance liquid chromatography) is obtained in a yield of 76%.

Published International Patent Application WO 2009122440 discloses several methods for the bromination of l-cyclopropyl-2-(2- fluorophenyl)-ethanone. Thus the bromination reaction is performed using l,3-dibromo-5,5-dimethylhidantoin (DBDMH) or N- bromosuccinimide in the presence of an initiator using an organic solvent selected from an ether, ketone, ester, alcohol, nitrile, amide, an aromatic and/or halogenated hydrocarbon or a mixture thereof.

According to the methods disclosed above, 2-bromo-l-cyclopropyl-2- (2-fluorophenyl)-ethanone of the Formula (III) is produced by brominating l-cyclopropyl-2-(2-fluorophenyl)-ethanone of the Formula (V). Generally this is carried out using N-bromosuccinimide or elementar bromine in carbon tetrachloride or cyclohexane in the presence of a radical initiator (e.g. dibenzoylperoxide, azobisisobutyronitrile). The drawback of these methods is that the reactions are performed in carbon tetrachloride which should be avoided in the pharmaceutical industry. Furthermore, these methods involve the use of explosive peroxides or other initiators.

There is little information in the state of the art about the quality of the intermediates of the Formulae (III) or (Ilia) produced according to method known from the state of the art. Since the yield of the subsequent reaction steps is low, it can be expected that the content of the compounds of the Formulae (III) or (Ilia) is low or said intermediates are contaminated by impurities.

Published International Patent Application 2009068924 discloses a new method for the preparation of 2-bromo-l-cyclopropyl-2-(2- fluorophenyl)-ethanone of the Formula (III). l-cyclopropyl-2-(2- fluorophenyl)-ethanone of the Formula (V) is brominated in an aqueous hydrogenperoxide-hydrogenbromide system containing dioxane. Hydrogen bromide is produced „in situ" from potassium bromide and sulfuric acid.. However, even in this case, impurities are formed by the opening, halogenation or oxidation of the cyclopropane ring in a total amount of 5 to 8 % by weight. These impurities and the dibrominated byproducts can be removed by distillation only partially.

2-chloro-l-cyclopropyl-2-(2-fluorophenyl)-ethanone of the Formula (Ilia) is manufactured according to the method disclosed in US Patent No. US 5874581. In this method, l-cyclopropyl-2-(2-fluorophenyl)- ethanone of the Formula (V) is chlorinated. According to the first version of the method, the reaction with sulfuryl chloride is carried out in dichloromethane by keeping the temperature during the addition of the chlorinating reagent below 5 °C, thereafter stirring the reaction mixture for 1.5 hours at 20 °C. According to the second version of the method, which has not been disclosed in details, chlorine gas is used as a halogenating reagent. In both cases, the compound of the Formula (Ilia) is obtained as an oil having 80% content.

During these brominating (halogenating) reactions, several byproducts are formed by the multiple bromination of l-cyclopropyl-2-(2- fluorophenyl)-ethanone of the Formula (V), which can not be removed entirely from the intermediate and which react analogously to 2- bromo-l-cyclopropyl-2-(2-fluorophenyl)-ethanone of the Formula (III) with 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]pyridin-2-one of the Formula (II) or a salt thereof during the coupling reaction. Such reactions can result in potentially genotoxic alkylbromide analogons of prasugrel. There are no methods available in the state of the art which could provide for prasugrel or key intermediates thereof wherein said impurities are absent or their concentration is reduced significantly. Furthermore, the prior art is silent about the conditions upon which said impurities are formed, nor a specific method for their removal is available in the state of the art. Presently known methods of purification applied in an industrial scale are suitable only for partial removal of said impurities or result in great losses of the target compound.

The subjects of Published European Patent Applications EP2003136 and EP2123656 are methods for the preparation of prasugrel hydrochloride which contains the 3-chloropropyl impurity resulting from the ring-opening of the cyclopropyl group of prasugrel in low concentration only. According to the method disclosed, chlorine absorbed in the reaction mixture comprising dichloromethane as solvent and added to the ketone at low ((0-5 °C) temperature. Post- reaction is performed at the same temperature. Thus, the intermediate of the Formula (Ilia) is obtained in 81 % yield and 65.0-74.5 % purity.

The disadvantage of the methods disclosed for the preparation of the compound of the Formula (Ilia) resides in that in most methods, the toxic, difficult to handle, gaseous reactant, chlorine is used and that the quality of the intermediate of the Formula (Ilia) is poor (content determined by gas chromatography is lower than 80 %).

During our research-development work we observed that the halogenation reaction of l-cyclopropyl-2-(2-fluorophenyl)-ethanone of the Formula (V) strongly influences the quality of the end product. We have found that performing the halogenation reaction according to methods known from the prior art, byproducts overhalogenated in the side chain or in the ring system as well as byproducts formed by the opening of the cyclopropyl ring are formed, some of which are of the potentially genotoxic alkyl halogenide type. By reacting with 5,6,7,7a- tetrahydro-4H-thieno[3,2-c]pyridin-2-one of the Formula (II), such byproducts indirectly increase the impurity level or they may appear directly in the final product. Removing the overhalogenated byproducts and those formed by the opening of the cyclopropyl ring is an especially demanding task which can be solved by extreme expenditure and work efforts in multiple purification steps.

Potentially genotoxic impurities are evaluated by the health authorities according to particularly strict regulations (European Medicines Agency, Guideline on the limits of genotoxic impurities). The limit concentration of a genotoxic impurity usually falls within the ppm range. The actual limit concentration is determined by the number of impurities falling into this category and the daily dose of the active ingredient. It is known for a person skilled in the state of the art related to the manufacturing of pharmaceutically active ingredients that production of an active ingredient in such a high purity and development of analytical methodology suitable for quality assurance of such products is an especially demanding problem.

Summary of the invention The objective of the present invention is providing a new method suitable for transformation of l-cyclopropyl-2-(2-fluorophenyl)- ethanone of the Formula (V) into 2-bromo-l-cyclopropyl-2-(2- fluorophenyl)-ethanone of the Formula (III) by bromination or alternatively, providing a method for converting the compound of the Formula (V) into 2-chloro-l-cyclopropyl-2-(2-fluorophenyl)-ethanone of the Formula (Ilia) by chlorination, wherein the products of the Formulae (III) and (Ilia), respectively, contain byproducts only which do not form genotoxic impurities in the final product or the concentration of such byproducts is so low that the concentration of the genotoxic impurities in the final product is lower than the limit concentration prescribed by the authorities. Further objective of the present invention is to provide an economic, simple method free from the disadvantages of the known methods for the transformation of 4,5,6,7-tetrahydro-thieno[3,2-c]pyridin hydrochloride into prasugrel of the Formula (I), which is industrially amenable, provides good yield and devoid of column chromatographic purification steps using 2- bromo-l-cyclopropyl-2-(2-fluorophenyl)-ethanone of the Formula (III) or 2-chloro-l-cyclopropyl-2-(2-fluorophenyl)-ethanone of the Formula (Ilia) produced according to the present invention as an intermediate.

During our research-development work, our aim was to react the intermediate of the Formula (V) with N-halogen-succinimide under such conditions, by which the use of toxic and accumulating carbon tetrachloride and the explosive chemical radical initiators can be avoided and by which the production rate of the overhalogenated byproducts is reduced or diminished. Overhalogenated impurities of the compounds of Formulae (III) and (Ilia) respectively, may yield halogenated, thus potentially genotoxic impurities in the end product prasugrel of the Formula (I).

Surprisingly we have found that bromination of l-cyclopropyl-2-(2- fluorophenyl)-ethanone of the Formula (V) can be carried out with N- bromosuccinimide in an aromatic or chlorinated aromatic hydrocarbon solvent or without any solvent in the absence of a chemical radical initiator using photochemical initiation or acidic catalysis. The advantage of this method resides in the fact that in this way, high purity prasugrel of the Formula (I) can be produced wherein the concentration of the genotoxic impurities is lower than 25 ppm.

Analogously, by using N-chlorosuccinimide, 2-chloro-l-cyclopropyl- 2-(2-fluorophenyl)-ethanone of the Formula (Ilia) can be produced by chlorinating l-cyclopropyl-2-(2-fluorophenyl)-ethanone of the Formula (V).. Using 2-chloro-l-cyclopropyl-2-(2-fluorophenyl)- ethanone of the Formula (Ilia), prasugrel of the Formula (I) obtained as a final product wherein the concentration of genotoxic impurities is lower than 25 ppm.

Bromination or analogously, chlorination of l-cyclopropyl-2-(2- fluorophenyl)-ethanone of the Formula (V) can be carried out in the absence of a chemical radical initiator in an aromatic or chlorinated aromatic hydrocarbon solvent or without any solvent. Compounds of the Formula (III) and (Ilia) thus produced can be advantageously used for the preparation of high-purity prasugrel.

We have found that by applying the method according to the present invention, the dibromo-byproduct of the Formula (XXII)

is formed in a concentration less than 0.1 %. Similarly, during the preparation of the compound of (Ilia), the dichloro analog of the compound of the Formula (XXIII)

is formed in a concentration lower than 0.1 %. Furthermore, it has been observed that in the reaction of the compound of the Formula (III) produced according to the present invention and the tetrahydro- thienopyridine of the Formula (II), the alkyl-bromide compound of the Formula (XXIV)

and the analogous alkyl-chloride compound of the Formula (XXI Va)

is formed in an especially low concentration. The advantage of the method resides in that it provides high purity prasugrel wherein the concentration of the impurities of Formulae (XXIV) or (XXIVa), respectively, is lower than 100 ppm, preferably lower than 25 ppm.

Compounds of the Formulae (XXIV) and (XXIVa) can be used as analytical impurity reference materials during the analytical testing of prasugrel of the Formula (I). Such analytical testing can be carried out using any methods known from the state of the art having suitable selectivity and limit of detection, e.g. by high-performance liquid chromatography. Developing such analytical methods belongs to the knowledge of the person skilled in the art.

Detailed description of the invention

According to the first aspect of the present invention, there is provided a method for preparing the compound of the Formula (III) or the compound of the Formula (Ilia), which comprises reacting 1- cyclopropyl-2-(2-fluorophenyl)-ethanone of the Formula (V) in an organic solvent, preferably in a halogenated aromatic hydrocarbon in the absence of a chemical radical initiator, optionally in the presence of an acidic catalyst with 1 to 2 molar equivalents, preferably 1.0 to 1.4 molar equivalents of N-halogensuccinimide, wherein the meaning of„halogen" is chloro or bromo at a temperature between 20 to 120 °C, prefeably between 40 to 90 °C. It has been found that if the acidic catalyst is absent, it is necessary to expose the reaction mixture to natural or artificial light. On the laboratory scale, a low-power incandescent bulb (40 W) is suitable for this purpose.

According to the second aspect of the present invention, there is provided a method for preparing the compound of the Formula (III) or the compound of the Formula (Ilia), which comprises reacting the compound of the Formula (V) with an N-halogensuccinimide, where halogen represents chloro or bromo under identical conditions as disclosed above with the only difference that no solvent is used. According to a further aspect of the present invention, there is provided a one-pot synthesis for the preparation of prasugrel of the Formula (I) wherein 5-[2-cyclopropyl-l-(2-fiuorophenyl)-2- oxoethyl]-2,4,5,6,7,7a-hexahydro-4H-thieno[3,2-c]pyridin-2-one intermediate of the Formula (IV) in a salt form, preferably as the p- toluenesulfonate of the Formula (II) is used as starting material, which comprises transforming l-cyclopropyl-2-(2-fluorophenyl)- ethanone of the Formula (V) into 2-bromo-l-cyclopropyl-2-(2- fluorophenyl)-ethanone of the Formula (III) or into 2-chloro-l- cyclopropyl-2-(2-fluorophenyl)-ethanone of the Formula (Ilia) according to the halogenating method of the present invention and reacting the compound of the Formula (III) or (Ilia) with 5,6,7,7a- tetrahydro-4H-thieno[3,2-c]pyridin-2-one of the Formula (II) or a salt, preferably the p-toluenesulfonate thereof.

According to the method, 2,4,5,6,7,7a-hexahydrothieno[3,2- c]pyridin-2-one /?-toluolenesulfonate (HA=PTSA) of the Formula (II) and the bromo-ketone of the Formula (III) or alternatively the chloro- ketone of the Formula (Ilia) produced according to the method disclosed above are reacted in an organic solvent selected preferably from Ν,Ν-dimethylformamide, tetrahydrofurane, toluene or acetonitrile in the presence of 1 to 6 molar equivalents, preferably 3 molar equivalents of an amine-type acid binding reagent at a temperature between 10 to 50 °C, preferably between 20 to 30 °C by stirring for 0.5 to 3 hours, preferably for 1 to 2 hours, thereafter adding 0.5 to 4 molar equivalents, preferably 1 to 2 molar equivalents of acetic anhydride into the reaction mixture and reacting at a temperature between 10 to 50 °C, preferably between 20 to 30 °C for a period of 0.5 to 3 hours, preferably for 1 to 2 hours. Subsequently, the reaction mixture is partitioned between water and ethylacetate, the organic layer is dried and evaporated and the residue is recrystallized from a suitable organic solvent (e.g. acetonitrile, diisopropyl ether, ethanol) or from a mixture of water and two suitable organic solvents (e.g. toluene-ethylacetate, hexane-ethylacetate).

The method according to the present invention, which is demonstrated in Reaction Scheme 11, is suitable for preparing prasugrel or a pharmaceutically acceptable salt thereof in a purity exceeding 99.80 % (as determined by high-performance liquid chromatography) and exhibits significantly improved yield over the methods known from the prior art. Starting from the compound of the Formula (IX), the total yield of the method is 45.7 %, while calculating the total yield for the compound of the Formula (II), it is 55%. The method can be carried out and scaled up conveniently to plant scale and does not require special conditions or apparatus. Reaction stages according to the present invention are regarded as optimal on plant scale as well. No extreme reaction conditions are required. Emphasis was made during development to avoid carrying out reactions at an extremely low (-78 ^°C) temperature and avoiding the use of a very toxic, environmentally harmful and corrosive reagents as well as applying operations requiring huge volumes of solvents and difficult scale-up (.e.g. column chromatography). Further details of the invention are demonstrated by the following examples without limiting the invention to the examples in any way.

Example 1

2-bromo-l-cyclopropyI-2-(2-fluorophenyl)-ethanone (compound of the Formula III)

50.0 g of (0.273 mol) l-cyclopropyl-2-(2-fluorophenyl)-ethanone having the purity of 97.4% as determined by gas chromatography, 400 cm³ of chlorobenzene and 53.5 g (0.30 mol) N-bromosuccinimide are weighed out and mixed. This suspension is heated to 95-100 °C while stirring and the stirring and heating is continued for 8 hours. Subsequently, while the stirring is maintained, the mixture is allowed to cool. After cooling to room temperature, the reaction mixture is washed with 250 ml of 0.5 % by weight sodium-thiosulfate solution and 250 ml of water, dried over 20 g of magnesium sulfate, filtered and evaporated. The residue is purified by vacuum distillation.

Yield, 51.4 g (49.09 g purity 70 %) pale yellow liquid.

GC assay: 95.5 %

IR (KBr, cm⁴): 3012, 1712, 1587, 1491, 1458, 1380, 1235, 1068.

1H-NMR (CDCI₃, 500 MHz): 7,49 (1H, td, J=7,5; 1,8 Hz); 7,33 (1H, m); 7,17 (1H, td, J=7,5; 1,1 Hz); 7,07 (1H, td, J=8,2; 1,1 Hz); 5,95 (1H, s); 2,14 (1H, m); 1,16 (1H, m); 1,10 (1H, m); 1,01 (1H, m); 0,93 (1H, m). C-NMR (CDCI₃, 125 MHz): 200,5; 159,7 (d, J=249,0 Hz); 131,1 (d, J-2,4 Hz); 130,8 (d, J=8,3 Hz); 124,7 (d, J=3,9 Hz); 124,0 (d, J=13,2 Hz); 115,6 (d, J=22,0 Hz); 48,2 (d, J=2,9 Hz); 18,7; 12,6; 12,6.

Elemental analysis calculated for the Formula C_uH₁₀BrFO (M: 257,10)

Calculated: C 51.39; H 3.92; Br 31.08 %.

Measured: C 51.72; H 3.89; Br 30.51 %.

Example 2

2-bromo-l-cyclopropyI-2-(2-fluorophenyl)-ethanone (compound of the Formula III )

4.0 g of l-cyclopropyl-2-(2-fluorophenyl)-ethanone (98.0% purity according to gas chromatographic assay), 0.4 g ^-toluenesulfonic acid monohydrate and 12 ml of acetonitrile are mixed. The mixture is heated to 40 °C and at the same temperature, the solution of 4.0 g N- bromosuccinimide in 32 ml of acetonitrile are added dropwise. The reaction mixture is stirred for 24 hours at 40 °C. Subsequently, the mixture is cooled to 20-25 °C and 18 g 5 % by weight sodium hydroxide solution and 30 ml of tert-butylmethylether are added, stirred for 10 minutes and the layers are separated. The organic layer is washed twice with 20 ml of water each and evaporated.

Yield: 5.5 g (5.0 g main component,; 87 %) pale yellow liquid. GC assay: 91.0 % Example 3

2-bromo-l-cycIopropyI-2-(2-fluorophenyI)-ethanone (compound of the Formula (III) )

4.0 g of l-cyclopropyl-2-(2-fluorophenyl)-ethanone having 98.0% content according to gas chromatographic analysis is introduced into a 100-ml round-bottom flask and 0.4 g of p-toluenesulfonic acid monohydrate are added. The mixture is heated to 80 °C and at the same temperature, 3.8 g of N-bromosuccinimide are added. After the reaction is complete, the mixture is cooled to a temperature between 20 and 25 °C. 18 g of 5 % by weight sodium hydroxide solution and 30 ml of methyl-t-butylether are added. The mixture is stirred for 10 minutes and subsequently the layers are separated. The organic layer is washed twice with 20 ml of water each and the organic layer is evaporated.

Yield of the raw product: 5.7 g (pure: 4.5 g, 78%), pale yellow liquid. Assay (measured by gas chromatography) 79.3%

Example 4

2-chloro-l-cycIopropyI-2-(2-fluorophenyl)-ethanone (compound of the Formula (Ilia)

7.3 g of l-cyclopropyl-2-(2-fluorophenyl)-ethanone and 0.73 g of p- toluenesulfonic acid monohydrate are weighed into a 100-ml round- bottom flask. The mixture is heated to 40 °C while stirring and 5.34 g (0.04 mol) of N-chlorosuccinimide are added in portions. The mixture is stirred for four hours with heating, thereafter cooled to a temperature between 20 and 25 °C. 53 ml of dichloromethane and 31 g of 5 % by weight sodium hydroxide solution are added to the mixture and the stirring is resumed for 10 minutes. The layers are separated and the organic layer is washed twice with 20 ml of water each. The organic layer is evaporated.

Yield, 8.0 g (6.0 g main fraction; 71%), pale yellow liquid.

Assay (gas chromatography): 75.5 %

Example 5

5-TrityI-4,5,6,7-tetrahydro-thieno[3,2-c] pyridine (compound of the Formula (XV))

52.7 g (0.30 mol) of 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine hydrochloride (compound of the Formula (IX)), 530 ml of acetonitrile and 108.0 cm³ (81.8 g; 0.63 mol) of NN-diisopropylethylamine are combined. While stirring, 87.0 g (0.312 mol) of tritylchloride are added to the mixture. Stirring is continued for three hours and the separated crystals are filtered off.

Yield, 108.0 g (94 %) colourless crystals.

1H-NMR (DMSO-< 500 MHz): 7,46 (6H, m); 7,31 (6H, m); 7,21 (1H, d, J=5,0 Hz); 7,18 (3H, m); 6,72 (1H, d, J=5,0 Hz); 3,28 (2H, s), 2,94 (2H, m); 2,45 (2H, m).

¹³C-NMR (DMS0-< 125 MHz): 142,3; 134,6; 132,9; 128,9; 127,8; 126,3; 125,8; 123,0; 76,8; 47,5; 46,7; 25,9.

Elemental analysis calculated for the Formula C₂₆H₂₃NS (M: 381,54): Calculated: C 81,85; H 6,08; N 3,67; S 8,40 %

Measured: C 81,64; H 6,19; N 3,65; S 8,31 %

Example 6

5-Trityl-5,6,7,7a-tetrahydro-4H-thieno [3,2-c] py ridin-2-one

(compound of the Formula (XVI))

95.3 g (0.25 mol) of 5-trityl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine of the Formula (XV) and 750 ml tetrahydrofurane are combined. The solution is cooled to the temperature of -40 °C. At this temperature, 150 ml (0.375 mol) of 2.5 M butyl-lithium solution in hexane are added dropwise under argon atmosphere. The solution thus obtained is allowed to warm to +10 °C and stirred at the same temperature for 30 minutes. Subsequently the solution is cooled again to -40 °C and 86.2 ml (0.375 mol) triisopropyl-borate solution prepared in 200 ml of tetrahydrofurane are added dropwise. Thereafter the reaction mixture is allowed to warm to +10 °C for the second time and stirred at the same temperature for one hour. After this period, the reaction mixture is cooled to -40 °C once more and at the same temperature, 53.75 ml of 35 % by weight hydrogen peroxide solution are added. The mixture is allowed to warm up slowly to room temperature and stirred at this temperature for 1 hour. Subsequently, while stirring and cooling, 300 cm of water are added to the mixture. The layers are separated, the organic layer is dried over magnesium sulfate and evaporated in vacuo. The residue is stirred with heptane. The precipitated crystals are filtered and washed with heptane.

Yield, 91.4 g (92 %) colourless crystalline product.

Melting point, 194-200 °C

IR (KBr, cm^"1): 3442, 3054, 2823, 1681, 1488, 1447, 1096.

1H-NMR (DMSO-< 500 MHz): 7,46 (6H, m); 7,30 (6H, m); 7, 19 (3H, m); 6,07 (IH, s); 4,13 (IH, dd, J=12,l; 2,8 Hz); 3,98 (IH, dd, J=12,l; 6,3 Hz);), 3,34 (IH, dd, J=12,2; 3,2 Hz); 2,40 (IH, m); 2,18 (IH, d, J=12,l Hz); 2,10 (IH, dd, J=12,2; 3,8 Hz); 1,68 (IH, dt, J=12,l; 1,8 Hz).

¹³C-NMR (DMSO- ₅, 125 MHz): 199,1; 169,8; 129,0; 127,8; 126,5; 125,7; 77,5; 51,6; 50,7; 47,6; 35,2.

Elemental analysis calculated for the Formula C₂₆H₂₃NOS (M: 397.54):

Calculated: C 78.55; H 5.83; N 3.52; S 8.07.

Measured: C 78.15; H 5.50; N 3.31; S 7.70. Example 7

5,6,7,7a-Tetrahydro-4H-thieno[3,2-c]-pyridin-2-one toluene-4- sulfonate (compound of the FormuIa(II), wherein HA=PTSA)

86.7 g (0.218 mol) 5-trityl-5,6,7,7a-tetrahydro-4H-thieno[3,2- c]pyridin-2-one of the Formula (XVI) and 1300 ml tetrahydrofurane are combined and while stirring intensively, 41.5 g (0.218 mol) toluene-4-sulfonic acid monohydrate are added. The reaction mixture is stirred for two hours at room temperature. The reaction mixture is subsequently cooled with an ice/water bath to 0-5 °C and stirred for three to four hours at the same temperature. The product is filtered and washed with tetrahydrofurane.

Yield, 68.2 g (96 %), colourless crystalline solid.

Melting point, 198-200 °C

IR (KBr, cm^'1): 3441, 3015, 2827, 1697, 1591, 1446, 1203, 1 164, 1123, 1032, 1008.

1H-NMR DMSO-d₆, 500 MHz): 9,30 (1H, bs); 8,98 (1H, bs); 7,53 (2H, d, J-8,1 Hz); 7,14 (2H, d, J=8,l Hz); 6,45 (1H, t, J=l,5 Hz); 4,74 (1H, dd, J=12,l ; 5.3 Hz); 4,40 (1H, d, J=13.9 Hz); 4,01 (1H, d, J=13.7 Hz); 3,46 (1H, d, J=l l,5 Hz);), 3,28 (1H, t, J=13,0 Hz); 2,59 (1H, m); 2,39 (3H, s); 1,88 (1H, m).

¹³C-NMR (DMSO-< 125 MHz): 197,4; 163,9; 144,9; 138,5; 129,3; 128,5; 125,6; 47,7; 44,0; 42,6; 30,8, 21,0. Elementar analysis calculated for the Formula C₁₄H_]7N0₄S₂ 327,42)

Calculated: C 51,36; H 5,23; N 4,28; S 19,59 %.

Measured: C 51,17; H 5,25; N 4,13; S 19,63 %.

Example 8

2-Acetoxy-5-(2-fluoro-a-cyclopropyl-carbonyI-benzyl)-4,5,6,7- tetrahydro-4H-thieno[3,2-c] pyridine (prasugrel, compound of the

Formula (I))

65.5 g (0.2 mol) of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridine-2- one joara-toluenesulfonate (compound of the Formul (II), HA=PTSA) and 160 ml of N,N-dimethylformamide are combined. To this mixture are added 75.3 cm (56.9 g; 0.44 mol) NN-diisopropylethylamine (DIPEA). Subsequently while cooling the reaction mixture on an ice/water bath, 53.8 g of 2-bromo-l-cyclopropyl-2-(2-fmorophenyl)- ethanone of the Formula (III) having 95.5% content according to gas chromatographic assay, dissolved in 94 ml (88.7 g) of Ν,Ν- dimethylformamide are added dropwise in 30 minutes and the thus obtained mixture is stirred for one hour at room temperature. Thereafter 37.65 cm³ (28.43 g; 0.22 mol) of DIPEA are added to the reaction mixture and while stirring intensively and maintaining the temperature between 15 and 20 °C, 28.4 ml (30.6 g; 0.30 mol) of acetic anhydride are added dropwise. Addition of acetic anhydride is followed by stirring for one hour at room temperature. The reaction mixture is poured into a mixture of ice, water and ethylacetate. The layers are separated, the aqueous layer is washed with ethylacetate.

The organic layer and the washings are combined and dried over magnesium sulfate. The solution is evaporated in vacuo, and ethanol is added to the residue. The mixture is cooled to a temperature between 0 and 5 °C, the crystals are filtered and washed with ethanol.

Thus 44.7 g (60.0 %) of raw prasugrel are obtained, which are recrystallized from ethanol.

Yield, 41.1 g (55.0 %) colourless, crystalline solid.

Assay (measured by high-performance liquid chromatography), better than 99.80 %.

The individual concentration of the impurities of the Formulae

(XXIV) and (XXIVa) is less than 25 ppm each.

Total yield (calculated for 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine hydrochloride of the Formula (IX)), 45.7 %.

Melting point, 120-121 °C

IR (KBr, cm^-1): 3388, 2920, 2767, 1758, 1704, 1586, 1488, 1369, 1217, 1194, 1127, 1011.

1H-NMR (CDC1₃, 500 MHz): 7,47 (1H, td, J=7,5; 1,8 Hz); 7,30 (1H, m); 7,16 (1H, td, J=7,5; 1,1 Hz); 7,10 (1H, td, J=8,2; 1,1 Hz); 6,26 (1H, s); 4,82 (1H, s); 3,56 (1H, d, J=14,3 Hz); 3,48 (1H, d, J-14,3 Hz); 2,90 (1H, m); 2,78 (3H, m); 2,28 (1H, m); 2,23 (3H, s); 1,05 (1H, m); 1,00 (1H, m); 0,84 (2H, m).

¹³C-NMR (CDCI₃, 125 MHz): 207,4; 167,5; 161,1; 149,4; 130,4; 129,7; 129,3; 125,6; 124,2; 122,0; 115,6; 112,8; 71,5; 50,3; 48,3, 24,9; 20,4; 18,1, 11,8, 1 1,3. Elemental analysis calculated for the Formula C₂₀H₂₀FNO₃S (M: 373,45)

Calculated: C 64.33; H 5.40; N 3.75; S 8.59 %.

Measured: C 64.18; H 5.50; N 3.69; S 8.75 %.

Example 9

5-bromo-l-(2-fluorophenyl)-pentan-2-one (compound of the

Formula (XXV))

10.0 g of l-cyclopropyl-2-(2-fluorophenyl)-ethanone and 50 ml of hydrogen bromide are transferred into a 100-ml round-bottom flask. The mixture is boiled for three hours, allowed to cool to room temperature, diluted with 100 ml of water. The solution is extracted with 100 ml of dichloromethane, the extract is washed with 100 ml of 5 % by weight sodium hydrogen carbonate solution, dried and evaporated. .

Yield, 1 1.32 g of yellow oil

Assay (by gas chromatography), 96.5 %

1H-NMR (CDC1₃, 500 MHz): 7,25 (1H, m); 7,17 (1H, m); 7,10 (2H, m); 3,74 (2H, s); 3,41 (2H, t, J=6,4 Hz); 2,68 (2H, t, J=6,8 Hz); 2,12 (2H, quint, J=6,6 Hz).

Example 10

5-chloro-l-(2-fluorophenyl)-pentan-2-one (compound of the

Formula (XXVa))

10.0 g of l-cyclopropyl-2-(2-fluorophenyl)-ethanone and 50 ml of concentrated hydrochloric acid are transferred into a 100-ml round- bottom flask. The mixture is boiled for three hours, allowed to cool to room temperature and diluted with 100 ml of water. The thus obtained mixture is extracted with 100 ml of dichloromethane. The organic layer is extracted with 100 ml of 5 % by weight sodium hydrogen carbonate solution, dried and evaporated.

Yield, 11.06 g of yellow oil

Assay (by gas chromatography), 98.0 %

1H-NMR (CDC1₃, 500 MHz): 7,25 (1H, m); 7,18 (1H, m); 7,10 (2H, m); 3,74 (2H, s); 3,55 (2H, t, J=6,4 Hz); 2,68 (2H, t, J=6,8 Hz); 2,105 (2H, quint, =6,6 Hz).

Example 11

l,5-Dibromo-l-(2-fluorophenyl)-pentan-2-one (Compound of the

Formula (XXII))

5.0 g (0.019 mol) of 5-bromo-l-(2-fluorophenyl)-pentan-2-one of the Formula (XXV) and 0.4 g p-toluenesulfonic acid monohydrate are transferred into a 50-ml round bottom flask. The mixture is heated with stirring until 40 °C, and 3.43 g (0.019 mol) of N- bromosuccinimide are added in portions. The reaction mixture is stirred for 30 minutes and cooled to a temperature between 20 and 25 °C. At this temperature, 25 ml of dichloromethane and 15 g of 5 % by weight sodium hydroxide solution are added. . The mixture is stirred for 10 minutes and the layers are separated. The organic layer is washed twice with 20 ml of water each time and evaporated.

Yield, 6.0 g of light brownish oil

Assay (gas chromatography), 66.0 %

The product is used without further purification is the subsequent synthesis.

Example 12

l-Bromo-5-chloro-l-(2-fluorophenyI)-pentan-2-one (Compound of the Formula (XXIII))

A 100 ml round-bottom flask is charged with 1 1.0 g (0.051 mol) 5- chloro-l-(2-fluorophenyl)-pentan-2-one (compound of the Formula (XXVa)) and 0.98 g ?-toluenesulfonic acid monohydrate. While stirring, the mixture is heated to 40 °C and 9.15 g (0.051 mol) N- bromosuccinimide are added in portions. The mixture is stirred for 30 minutes at the same temperature, thereafter allowed to cool to a temperature between 20 and 25 °C. 25 ml of dichloromethane and 15 g of 5 % by weight sodium hydroxide solution are added, stirred for 10 minutes and the layers are separated. The organic layer is washed twice with 20 ml of water each time and evaporated.

Yield, 14.2 g of light brownish oil

Assay (gas chromatography), 68.0 % W

42

The product is used without further purification in the subsequent synthesis steps.

Example 13

2-Acetoxy-5-[5-bromo-l-(2-fluorophenyl)pentyl]-4,5,6,7- tetrahydro-4#-thieno[3,2-c] pyridine (compound of the

Formula(XXIV)) maleate

4.6 g (0.014 mol) of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2- one /rara-toluenesulfonate (Compound of the Formula (II), HA=PTSA) and 11.5 ml of Ν,Ν-dimethylformamide are combined. To this mixture, 5.3 cm (0.031 mol) of NN-diisopropylethylamine (DIPEA) are added, and while cooling the mixture on a water/ice bath, the solution of 7.2 g (0.014 mol) of l,5-dibromo-l-(2-fluorophenyl)- pentan-2-one of the Formula (XXII) having 66.0% content as assayed by gas chromatography dissolved in 9.5 ml of Ν,Ν- dimethylformamide are added dropwise. The mixture is stirred for one hour at room temperature. Subsequently, 2.65 ml (0.015 mol) of DIPEA are added to the reaction mixture, and at a temperature between 15 to 20 °C and while stirring the mixture intensively, 2.0 ml (0.021 mol) of acetic anhydride are added thereto dropwise. After stirring for further one hour, the reaction mixture is poured into the mixture of water, ice and ethylacetate. The layers are separated, the aqueous layer is extracted with ethylacetate. The combined organic layers are dried over magnesium sulfate. The solvent is evaporated and the residue is purified by column chromatography (silica gel, hexane/ethylacetate). The brownish, viscous oil (1.2g) is dissolved in

10 ml of acetone and while stirring, 0.31 g (0.0026 mol) of maleic acid are added. The crystals thus obtained are filtered off.

Yield,: 0.84 g (10.5 %) of colourless crystalline solid.

IR (KBr, cm^-1): 3442, 2357, 1779, 1730, 1620, 1493, 1345, 1174,

1126.

1H-NMR (CDC1₃, 500 MHz): 11,50 (2H, s); 7,55 (IH, m); 7,45 (IH, m); 7,33 (IH, d, J=7,6 Hz); 7,28 (IH, t, J=9,0 Hz); 6,33 (IH, s); 6,30 (2H, s); 5,49 (IH, s); 4,09 (2H, s); 3,62 (IH, m); 3,37 (2H, m); 3,15 (IH, m); 3,07 (IH, m); 3,00 (IH, m); 2,59 (2H, m); 2,28 (3H, s); 2,11 (2H, m).

¹³C-NMR (CDCI₃, 125 MHz): 201,7; 169,1 ; 167,3; 161,4; 151,1 ; 133,2; 132,0; 125,8; 124,2; 123,8; 117,0; 115,8; 111,0; 68,3; 49,4; 48,2; 37,9; 32,5; 26,1; 22,3; 20,6.

Elemental analysis for the Formula C₂₄H₂₅BrFNO₇S (M: 570,44) Calculated: C 50,53; H 4,42; Br 14,01; N 2,46; S 5,62 %.

Measured: C 50,79; H 4,49; Br 14,06; N 2,44; S 5,80 %.

Example 14

2-Acetoxy-5-[5-chIoro-l-(2~fluorophenyl)pentyl]-4,5,6,7- tetrahydro-4H-thieno[3,2-c] pyridine (compound of the Formula

(XXIVa)) maleate

3.7 g (0.011 mol) of 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2- one

(compound of the Formula (II), HAHPTSA) and 9.5 cm of Ν,Ν-dimethylfonriamide are combined. To this mixture, 4.3 cm³ (0.025 mol) of N,N-diisopropylethylamine (DIPEA) are added and while cooling the mixture in a water-ice bath, the solution of 5.0 g (0.01 1 mol) of l-bromo-5-chloro-l-(2- fluorophenyl)-pentan-2-one of the Formula (XXIII) having 68.0% content as assayed by gas chromatography in 6.7 ml of Ν,Ν- dimethylformamide are added dropwise in approx. 30 minutes. Subsequently the mixture is stirred for one hour. Thereafter 2.65 ml (0.015 mol) of DIPEA are added to the reaction mixture and at a temperature between 15 and 20 °C while stirring the reaction intensively, 1.6 ml (0.017 mol) of acetic anhydride are added dropwise. Stirring is continued for a further hour at room temperature. The reaction mixture is poured onto the mixture of ice/water and ethylacetate. The layers are separated and the aqueous layer is extracted with ethylacetate. The combined organic layers are dried over magnesium sulfate. The solvent is evaporated in vacuo and the residue is purified by column chromatography (hexane/ethylacetate). The brown, viscous oil (1.53 g) thus obtained are dissolved in 20 ml of acetone aiid 0.44 g (0.0038 mol) of maleic acid are added while stirring. The crystals thus obtained are filtered and dried.

Yield, 0.90 g (15.5 %) of colourless crystalline solid.

IR (KBr, cm^"1): 3096; 2911; 2378; 1777; 1728; 1623; 1533; 1456; 1342; 1175; 1127.

1H- MR (CDC1₃, 500 MHz): 14,04 (2H, s); 7,55 (IH, dd, J=8,7; 5,7 Hz); 7,46 (IH, t, J=7,3 Hz); 7,33 (IH, t, J=8,2 Hz); 7,27 (IH, dd, J=9,7; 8,7 Hz); 6,33 (IH, s); 6,30 (2H, s); 5,50 (IH, s); 4, 10 (2H, s); 3,62 (IH, m); 3,50 (2H, m); 3,16 (IH, m); 3,08 (IH, m); 3,03 (IH, m); 2,59 (2H, m); 2,28 (3H, s); 2,04 (2H, m).

¹³C-NMR (CDCI₃, 125 MHz): 169,1 ; 167,3; 161,4; 151,0, 135,2; 133,2; 132,0; 125,8; 124,2; 123,8, 117,0; 1 15,8; 111,0; 68,3; 49,4; 48,2; 43,7; 36,7; 26,0; 22,2; 20,6.

Elemental analysis for the Formula C₂₄H₂₅ClFNO₇S (M: 525,98) Calculated: C 54,81; H 4,79; CI 6,74; N 2,66; S 6,10 %.

Measured: C 54,73; H 4,90; CI 6,82; N 2,60; S 6,23 %.

Claims

claim is:

Method for the preparation of 2-bromo-l-cyclopropyl-2-(2- fluorophenyl)-ethanone of the Formula (III) starting from 1- cyclopropyl-2-(2-fluorophenyl)-ethanone of the Formula (V),

which comprises reacting the compound of the Formula (V)

with N-bromosuccinimide in the absence of a chemical radical initiator.

2. Method for the preparation of 2-chloro-l-cyclopropyl-2-(2- fluorophenyl)-ethanone of the Formula (Ilia)

starting from l-cyclopropyl-2-(2-fluorophenyl)-ethanone of the Formula (V)

which comprises reacting the compound of the Formula (V) with N-chlorosuccinimide in the absence of a chemical radical initiator.

3. Use of 2-bromo-l-cyclopropyl-2-(2-fluorophenyl)-ethanone of the Formula (III) produced according to claim 1 or 2-chloro-l- cyclopropyl-2-(2-fluorophenyl)-ethanone of the Formula (Ilia) produced according to claim 2 for the preparation of 2-acetoxy-5- (2-fluoro-a-cyclopropyl-carbonyl-benzyl)-4,5,6,7-tetrahydro-4H- thieno[3,2-c]-pyridine (prasugrel) of the Formula (I)

or a pharmaceutically acceptable salt thereof.

4. Method for the preparation of 2-acetoxy-5-(2-fluoro-a- cyclopropyl-carbonyl-benzyl)-4,5,6,7-tetrahydro-4H-thieno[3,2-c]- pyridine (prasugrel) of the Formula (I), which comprises reacting 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2-one of the Formula

(Π)

with 2-bromo-l-cyclopropyl-2-(2-fluorophenyl)-ethanone of the Formula (III) produced according to the method of claim 1 or with 2-chloro-l-cyclopropyl-2-(2-fluorophenyl)-ethanone of the Formula (Ilia) prepared according to claim 2, transforming the thus obtained compound of the Formula (IV)

without isolation by reacting with an acylating reagent in the presence of an organic base into the compound of the Formula (I) and optionally purifying the product.

5. Method for the preparation of 2-acetoxy-5-(2-fluoro-a- cyclopropyl-carbonyl-benzyl)-4,5,6,7-tetrahydro-4H-thieno[3,2-c]- pyridine (prasugrel) of the Formula (I), which comprises a) transforming l-cyclopropyl-2-(2-fluorophenyl)-ethanone of the Formula (V) into 2-bromo-2-cyclopropyl-2-(2-fluorophenyl)- ethanone of the Formula (III) or 2-chloro-2-cyclopropyl-2-(2- fluorophenyl)-ethanone of the Formula (Ilia), preferably into the compound of the Formula (III) by reacting the compound of Formula (V) with an N-halo-succinimide, wherein halo is chloro or bromo;

b) reacting the compound of the Formula (III) or (Ilia) obtained in step a) with 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2-one of the Formula (II) or an acid addition salt thereof, preferably with 5,6,7,7a-tetrahydro-4H-thieno[3,2-c]-pyridin-2-one /?-toluene- sulfonate and optionally isolating the product; O 2012/052788

50

c) converting the compound of the Formula (IV) obtained in step b) directly in situ or after isolation into the compound of the Formula (I) (prasugrel) by reacting the compound of the Formula (IV) with an acetylating agent optionally in the presence of an organic base and if desired, purifying or transforming the compound of the Formula (I) into a pharmaceutically acceptable salt, characterized in that step a) is carried out in the absence of a chemical radical initiator.

6. Method according to any of claims 1, 2 or 4 or the method according to step a) of claim 5, characterized in that the reaction is carried out in a halogenated aromatic hydrocarbon solvent, preferably in chlorobenzene.

7. Method according to any of claims 1, 2 or 4 or the method according to step a) of claim 5, characterized in that the reaction is carried out in the absence of any solvents.

8. Method according to any of claims 1., 2. or 4 or step a) of claim 5, characterized in that the reaction is carried out with illumination.

9. Method according to any of claims 1, 2, 4 or step a) of claim 5, characterized in that the halogenating reaction is carried out in the presence of an acidic catalyst, preferably p-toluenesulfonic acid.

10. 2-acetoxy-5-(2-fluoro-a-cyclopropyl-carbonyl-benzyl)-4,5,6,7- tetrahydro-4H-thieno[3,2-c]-pyridine (prasugrel) of the Formula (I) or a pharmaceutically acceptable salt thereof, wherein the concentration of 2-acetoxy-5-[5-bromo-l-(2-fluorophenyl)pentyl]- 4,5,6,7-tetrahydro-4H-thieno[3,2-c] pyridine of the Formula (XXIV)

or an acid addition salt thereof is less than 100 ppm, preferably less than 25 ppm. 1.2-acetoxy-5-(2-fluoro-a-cyclopropyl-carbonyl-benzyl)-4,5,6,7- tetrahydro-4H-thieno [3, 2-c] -pyridine (prasugrel) of the Formula (I) or a pharmaceutically acceptable salt thereof, wherein the concentration of 2-acetoxy-5-[5-chloro- 1 -(2-fluorophenyl)pentyl]- 4,5,6,7-tetrahydro-4H-thieno[3,2-c] pyridine of the Formula (XXIVa)

or an acid addition salt thereof is less than 100 ppm, preferably less than 25 ppm.

12. 2-acetoxy-5-[5-bromo-l-(2-fluorophenyl)pentyl]-4,5,6,7- tetrahydro-4H-thieno[3,2-c] pyridine of the Formula (XXIV) or an acid addition salt thereof.

13. Use of 2-acetoxy-5-[5-bromo-l-(2-fluorophenyl)pentyl]-4,5,6,7- tetrahydro-4H-thieno[3,2-c] pyridine of the Formula (XXIV) or an acid addition salt thereof as an analytical reference material.

14.2-acetoxy-5-[5-chloro-l-(2-fluorophenyl)pentyl]-4,5,6,7- tetrahydro-4H-thieno[3,2-c] pyridine of the Formula (XXIVa) or an acid addition salt thereof.

15. Use of 2-acetoxy-5-[5-chloro-l-(2-fluorophenyl)pentyl]-4,5,6,7- tetrahydro-4H-thieno[3,2-c] pyridine of the Formula (XXIVa) or an acid addition salt thereof as an analytical reference material.

16. Use of 2-acetoxy-5-(2-fluoro-a-cyclopropyl-carbonyl-benzyl)- 4,5,6,7-tetrahydro-4H-thieno[3,2-c]-pyridine (prasugrel) of the Formula (I) produced according to any of claims 4 to 1 1 or a pharmaceutically acceptable salt thereof for the manufacture of pharmaceutical finished dosage forms.

17. Pharmaceutical finished dosage forms comprising 2-acetoxy-5-(2- fluoro-a-cyclopropyl-carbonyl-benzyl)-4,5,6,7-tetrahydro-4H- thieno[3,2-c]-pyridine (prasugrel) of the Formula (I) produced by the method according to any of claims 4 to 11 or a pharmaceutically acceptable salt thereof.