FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
Novel process for 2-substituted-1-cyclopropyl-2-(2-fluorophenyl) ethanone

2. APPLICANTS)
(a) NAME : CADILA PHARMACEUTICALS l-IMITED
(b) NATIONALITY: An INDIAN Company
(c) ADDRESS : "Cadila Corporate Campus", SarKhej - Dholka Road, Bhat, Ahmedabad
-382210, Gujarat, India
3. PREAMBLE TO THE DESCRITION
PROVISIONAL SPECIFICATION
The following specification describes the
invention.

COMPLETE SPECIFICATION
The following spocification particularly deserters tho invention and tho manner in which it is to bo performed

4. DESCRIPTION
(Description starts from next page)


FIELD OF THE INVENTION
The present invention relates to preparation of 2-substituted -1-cyclopropyl-2-(2-fluorophenyljethanone, which is used as an intermediate for the preparation of 5-[2-cyclopropyl-1-(2-fIuorophenyl)-2-oxoethyl]-4,5,6l7-tetrahydrothieno[3,2-c]pyridine-2-yl acetate, used for the prevention and treatment of thrombosis and thromboembolism.
BACKGROUND OF THE INVENTION
Analogues of Prasugrel i.e., 2-acetyloxy-5-alkyl-4,5,6,7-tetrahydrothieno[3,2-c]-pyridine derivatives have been initially disclosed in Japanese provisional patent publication No. 130289/1991 & 41139/1994. Prasugrel and its pharmaceutical^ acceptable salts have been disclosed in US patent 5,288,726.
Hungarian Patent No. 218785 and Hungarian Patent No. 211876 disclose Prasugrel, its derivatives and platelet inhibitor and the process for their preparation. According to the process disclosed in Hungarian Patent No. 218 785 and Hungarian Patent No. 211 876, cyclopropyl benzyl ketone compounds of formula (II) are prepared by the reaction of 2-Fluorobenzy! magnesium bromide or 2-chlorobenzyl magnesium bromide and Cyclopropanecarbonitrile. The reaction is carried out at the boiling point of diethyl ether, and the obtained complex is quenched with aqueous ammonium chloride, the product is extracted and purified by column chromatography. The yield of the process is 70 % or 69 %, respectively.
Hungarian Patent No. 211 876 also describes another process, wherein the compound of 2-fluorobenzyl magnesium halogenide is reacted, instead of Cyclopropanecarbonitrile, with an acid chloride, for example Cyclobutanecarbonyl chloride. The reaction is carried out at a very low temperature (-70°C), and the pure product is obtained by extraction and purification by column chromatography. The yield of the process is very low, 39 %.
In the above described Grignard reactions for the preparation of compounds of formula (II), it is possible that the ester, nitrite or acid chloride reagents react with two equivalents of the grignard reagent, instead of one. These reactions reduce the yield of the manufacturing process, and some by-products, containing a hydroxyl group, can be derived from the process.
In the preparation processes described in Hungarian Patents No. 218 785 and 211 876, the Grignard reagents are obtained from bromo derivatives.
According to the publication WO 2009/068923, the preparation process of Cyclopropyl benzyl ketone compounds of formula (II), the Grignard reagent is obtained from the more suitable and cheaper 2-fluorobenzyl chldride instead of 2-fluorobenzyl bromide.
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Preparation processes described in Hungarian Patent No. 211876 are not suitable for the preparation of a drug on industrial scale, because the purification is carried out by column chromatography and this purification process is not suitable for the preparation of a large quantity of the final product.
Another disadvantage of the reactions known from the literature is that the carboxylic acid derivatives, namely the acid chlorides and the anhydrides, as seen in the description of Hungarian Patent No. 211876, react with benzyimagnesium bromide at a very low temperature, at -70 to -50 °C. Therefore these processes, beyond the difficulties caused by the purification of column chromatography, are hardly applicable on an industrial scale and are energy-consuming and expensive reactions.
In United States Patent No. 5874581 a process is described for the preparation of compound of formula (III), wherein two equivalents of 2-propyl magnesium chloride are reacted with 2-Fluoroacetic acid in Tetrahydrofuran, at the boiling point of the solvent. The obtained complex is reacted at a temperature of 5°C with ethyl or methyl cyclopropanecarboxylate. The reaction mixture is stirred for three hours and hydrochloric acid is added, then the mixture is neutralized, extracted, evaporated, and finally the fractions are obtained in vacuum. The process as described in United States Patent No. 5874581 gives 56% yield which is low.
WO2009/062044 describes preparation of Prasugrel and its salts and polymorphs, processes for preparing prasugrel and its salts and polymorphs, and the use of prasugrel and its salts and polymorphs, especially in pharmaceutical compositions. Further, this publication relates to intermediates of Prasugrel, processes for preparing intermediates of Prasugrel, and the use of such intermediates for preparing Prasugrel and its salts and polymorphs.
WO2009/066326 uses the term "highly pure l-cyclopropyl-2-(2-fluorophenyl) ethanone" for l-cyclopropyl-2-(2-fluorophenyl) ethanone with is purity equal to 85.00 % or more by HPLC. This process involves a large number of steps hence the process is less suitable for industrial scale synthesis.
International publication WO2009/09068923 describes preparation of 1-cyclopropyl-2-(2-fluorophenyl)ethanone using Grignard reaction of 2-Fluorobenzyl magnesium chloride on various cyclopropyl compounds such as cyclopropyl carbonyi chloride, cyclopropyl carbonitrile or N,N-dialkyl cyclopropyl carboxamide.
WO2009/066326 A2 describes the preparation of Prasugrel as per scheme mentioned below.
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PRASUGREL HYDROCHLORIDE
Wherein PG =BenzoyI/BOC/trityI
Y= nucleophilic leaving group
US 5288726 describes as per Example-12b [as per Ex-6) ] preparation of 2-bromo-1 -cyclopropyl-2-(2-fluorophenyl)ethanone from 1 -cyclopropyl-2-(2-fluorophenyl)ethanone using bromine in carbon tetrachloride in 69 % yield.
Due to extreme toxicity and low vapor pressure of liquid bromine, its use on large scale creates health hazards , an alternative reagent is required for preparing same compound on large scale applications.
International publication WO2004/098713, and US6693115 [Reference example-lb] describe preparation of a-cyclopropylcarbonyl-2-fluorobenzyl bromide from cyclopropyl 2-fluorobenzyl ketone using N-bromosuccinimide and benzoyl peroxide in carbon tetrachloride. After the reaction was over, toluene was added, resulting solid was filtered off and the filtrate
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was concentrated under reduced pressure to give a residue which was purified by column chromatography.
As the process involves column chromatography, the process is unsuitable to large scale manufacture.
US 7064126 in example- 4 describes the preparation of describes preparation of N-methoxy-N-methyl-cyclopropanecarboxamide [as per analogous method given as per Ex-3-step (a)] , using cyclopropane carbonyl chloride , triethyl amine and N.O-dimethyl hydroxyl amine using dichloromethane as a solvent.
Cyclopropyl carbonyl chloride is susceptible to moisture which gives on hydrolysis cyclopropane carboxylic acid, it is to be made afresh which limits its commercial applications.
Thus there is a long-felt need to provide an improved method for preparing 2-substituted -1-cyclopropy!-2-(2-f!uorophenyl)ethanone more particularly 2-haio substituted -1-cyclopropyl-2-(2-fluorophenyl)ethanone , which is an intermediate to manufacture prasugrel on commercial scale. SUMMARY OF THE INVENTION
The main object of the present invention is to develop a cost effective process for the preparation of 2-substituted ~1-cyciopropyl-2-(2-fiuorophenyl)ethanone, wherein substituent at 2 position of 1-cyclopropyl-2-(2-fluorophenyl)ethanone, is a leaving group such as -CI, -Br, -l.-OMs, -OTs,-OAc,-OCOAr. which is an intermediate for preparing Prasugrel.
Yet another object of the invention is to develop a cost effective process for the prepration of 2-bromo-1-cyclopropyl-2-(2-fluorophenyl)ethanone, which is an intermediate of Prasugrel
Yet another object of the invention is to provide an alternative reagent, which can be used on commercial scale, for providing 2-bromo-1-cyclopropyl-2-(2-fluorophenyl)ethanone. Or 2-chloro-1-cyclopropyl-2-(2-fluorophenyl) ethanone.
Yet another object of the invention is to provide a process for converting 2-substituted 1-cyclopropyl-2-(2-fluorophenyl)ethanone. to Prasugrel .without involving use of column chromatographic isolation at any stage of synthesis.
Yet another object of the invention is to provide a novel / alternative process to prepare N-methoxy-N-methyl-cyclopropanecarboxamide.
Yet another object of the invention is to provide a novel / alternative process to prepare 1-cyclopropyl-2-(2-fluorophenyl) ethanone of high purity DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention a novel process for preparing N-methoxy-N-methyl-cyclopropanecarboxamide, by reaction of Cyclopropanecarboxylie acid, in
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dichloromethane, using tertiary organic amine as a base , using pivaloyl chloride to form a mixed anhydride, followed by reaction of mixed anhydride with N.O-dimethyl hydroxy! amine.
N-methoxy-N-methy!-cyclopropanecarboxamide is further treated with 2-fluorobenzyl magnesium bromide to provide 1-cyclopropyl-2-(2-fluorophenyl)ethanone.
1-cyclopropyl-2-(2-fluorophenyl)ethanone, is then treated with a suitable reagent which introduces a leaving group for the next reaction. The suitable leaving group may include, may include but not limited to , a group such as -CI, -Br, -l,-OMs, -OTs,-OAc,-OCOAr.
Such group can be introduced say for example , by substituting a benzylic proton by method such as by halogenation.
As per present invention 1~cyclopropyl-2-(2-fluorophenyl)ethanone, is treated with CuX2, wherein X is CI, Br, I to provide 2-halo -1-cyclopropyl-2-(2-fluorophenyl)ethanone.
The halo substituent can optionally be converted to other good leaving groups by proper functional group introducing reagents such as for example sodium acetate, sodium benzoate NaOMs or NaOTs.
2- substituted -1-cyclopropyl-2-(2-fluorophenyl)ethanone more particularly 2-halo substituted -1-cyclopropyl-2-(2-fluorophenyl)ethanone, prepared by this invention is further converted to prasugrel using steps of N-alkylation of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2(3H)-one followed by O-acetylation of the product formed.
The present invention is further illustrated by following non-limiting examples.
Example-1 Preparation of N-methyl,N-methoxy cyclopropane carboxamide [Weinreb
amide]
Cyclopropane carboxylic acid [5.0 gm; 0.058 mole] was taken in dichloromethane [40 ml] and cooled to 0-5°C. Triethyl amine [29.37 gm; 0.290 mole] was added dropwise upto 15°C. Pivaloyl chloride [10.47 gm;0.086 mole] was added at 15-20°C.The reaction was stirred for 30 minutes at 15-20°C.N,O-dimethyl hydroxyl amine hydrochloride [5.07 gm;0.052 mole] , was added at 15-20°C , catalytic amount of 4-dimethylamino pyridine (DMAP) was added and the reaction mass was stirred at 25-3Q°C for 20-24 hours.The reaction mass was treated with water , the layers were separated and the organic layer was washed with 1N HO, water and 5% NaHC03 solution. The solution was dried over anhydrous sodium sulfate, and distilled in vacuo to give N-methyl.N-methoxy cyclopropane carboxamide as an oil.Wt. = 7.4gm. Example-2 Preparation of 1-cyclopropyl-2-(2-fluorophenyl)ethanone
Mg metal [1.07 g, 0.0441 mole] was taken in diethyl ether [25 ml]lodine under nitrogen atmosphere. 2-fluorobenzyl bromide [6.96 gm g, 0.0368 mole] was added at 30°C under vigorous stirring. N-methyl-N-methoxy cyclopropane carboxamide [4.75 gm 0.0368
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mole] was taken up in 15 ml diethyl ether and added at 30°C. The temperature was raised to 30-35°C within 2 hours and stirred at same temperature for 2 hours.The reaction mass was dumped into saturated solution of ammonium chloride (40 ml) and ethyl acetate [ 50 ml] was added and the layers were separated, washed with water, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over anhydrous sodium sulphate, filtered and evaporated to dryness to give yellow 1-cyclopropyl-2-(2-fluorophenyl)ethanone as an oil. Yield = 5.0gm.
Example-3 Preparation of 5-[2-cyclopropyl-1 -(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-2(3H)-one
A solution of CuBr2 [ 1.78 gm] in CCI4 [15 ml] was added to a solution of 1-cyclopropyI-2-(2-fluorophenyl)ethanone [ 1.85 gm] in CCI4 [30 ml] at 25-30°C and stirred for 6-8 hours at 25-30°C.The progress of the reaction was monitored using TLC [ Mobile phase Toluene : Ethyl acetate 9:1] . Water was added and aqueous phase was extracted with chloroform, dried over anhydrous sodium sulfate and evaporated to dryness to provide oil. To it was added 4,5,617--tetrahydro-thieno[3,2-c]pyridin-2(3H)-one, anhydrous potassium carbonate[ 3.38 gm] and DMF [30 ml] at room temperature. The reaction mass was stirred for 5 hours at 25-30°C. Toluene ( 25 ml) was added and the mass was filtered. The filtrate was evaporated under reduced pressure to give 5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5t6,7-tetrahydrothieno[3,2-c]pyridin-2(3H)-one as yellow oil. Wt= 1.17 gm. Example-4 Preparation of 5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-yl acetate
5-[2-cyclopropyl-1-(2-fluorophenyl)2--oxoethylH.S.ej-tetrahydrothieno)3-2-c]pyridin-2(3H)-one [2.6 gm] was taken in DMF [10 ml] and treated with acetic anhydride [ 5 ml] and then sodium hydride [0.35 gm] at 0-5°C. The reaction mass was stirred for for 3 hours at 25-30°C. The progress of the reaction was monitored by TLC [ Mobile phase Toluene: Ethyl acetate 9:1]. The reaction mass was washed with saturated NaCI solution. The organic layer was dried over anhydrous sodium sulphate and evaporated under reduced pressure to give oil recrystallized from diisopropyl ether [100 ml].

For, Cadila Pharmaceuticals Ltd.,
Dr. Bakulesh M. Khamar Executive Director - Research
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