Title of Invention	INDUSTRIAL PROCESS FOR THE PREPARATION OF 2-[4-(4-CHOLORO-BUTYRYL) PHENYL]-2-METHYL PROPANOL'
Abstract	The present invention relates to an industrial process for the preparation of highly pure 2-[4-(4-choloro-butyryl) phenyl]-2-methyl propanol, a key intermediate in the preparation of Fexofenadine, from methyl 2-[4-(4-choloro-butyryl) phenyl]-2-methyl propanoate in presence of anhydrous alcoholic- hydrogen chloride.

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FIELD OF THE INVENTION The present invention relates to an improved process for the preparation of 2-[4-(4-choloro-butyryl) phenyl]-2-methyl propanol of Formula I, (Figure Removeed) which is an important intermediate in the preparation of Fexofenadine. The present invention particularly relates to a process that results in the production of 2-[4-(4-choloro-butyryl) phenyl]-2-methyl propanol and to the use of this compound as an intermediate for the preparation of an antihistaminic agent, Fexofenadine. BACKGROUND OF THE INVENTION Fexofenadine of formula II, is a non sedative antihistaminic compound. It is reported to be a specific Fb -receptor antagonist that is also devoid of any anticholinergic, antiserotoninergic and anti adrenergic effects. (Figure Removeed) Fexofenadine is a terfenadine carboxylic acid metabolite and is chemically known as 4-[4-[4-hydroxy diphenylmethy)-l-piperidinyl]-l- hydroxybutyl]-ct, a-dimethyl phenyl acetic acid, also known as terfenadine carboxylic acid metabolite. The antihistaminic activity of fexofenadine was first disclosed in US Patent 4,254,129. In general, the synthetic approach reported in the literature for the preparation of 2-[4-(4-choloro-butyryl) phenyl] -2-methyl propanol involves the hydrolysis of the corresponding ester, namely methyl 2-[4-(4-choloro-butyryl) phenyl]-2-methyl propanoate of formula (Figure Removeed) in presence of alcohol and concentrated hydrochloric acid.(WO 95/00480 Al, WO 2005/019175 Al). The hydrolysis can be carried out using ethanol and concentrated hydrochloric acid or methanol and concentrated hydrochloric acid. The prior art approach is not suitable from commercial point of view because we have found that a impurity of formula IV, (Figure Removeed) is formed in the ratio of 1-5% during hydrolysis reaction, which is very difficult to remove. This requires purification by tedious and cumbersome purification processes which leads to low yields. The percentage of impurity formation increases on scale up and results are not consistent. Further the distillation of alcoholic solvents at high temperature in the presence of acid leads to increased formation of impurities. The formation of impurity of Formula IV is due to presence of water in the reaction medium. To achieve a high efficiency of the reaction on industrial scale for the synthesis of 2-[4-(4-choloro-butyryl) phenyl]-2-methyl propanol, it is necessary to minimize the formation of the impurities and improve the yields. In view of the above there is an urgent need to develop a process for the preparation of pure 2-[4-(4-choloro-butyryl) phenyl]-2-methyl propanol with consistent yield and purity, where the formation of impurity of Formula IV can be avoided or controlled to less than 1%. Thus, it is the principal object of the present invention to provide an efficient process for the preparation of pure 2-[4-(4-choloro-butyryl) phenyl]-2-methyl propanol, which does not require any further purification and is convenient to operate on industrial scale with consistent results. Another object of the present invention is to provide a process that is industrially viable. Still another object of the present invention is to provide a process, which results in the production of 2-[4-(4-choloro-butyryl) phenyl]-2-methyl propanol in high purity so as to attribute improved quality to the desired end product. SUMMARY OF THE INVENTION The process includes hydrolyzing an ester compound of formula III, In one general aspect there is provided a process for the preparation of pure 2-[4-(4-choloro-butyryl) phenyl]-2-methyl propanol of formula I, (Figure Removeed) in presence of a solution of alcohol-hydrogen chloride under anhydrous conditions followed by extracting the compound in an organic solvent and isolating the pure hydroxyl compound of formula I. The alcohol used in the solution of alcohol-hydrogen chloride may be C| to C4 alcohols and preferably methanol and ethanol are used. The organic solvent may be one or more of hydrocarbons, ethers, esters, ketone, chlorinated solvent, or mixtures thereof. The ketone may include one or more of acetone, 2-butanone, and 4-methyl pentan- 2-one. The chlorinated solvent may include one or more of dichloromethane, dichloroethane, and chloroform. In another general aspect the organic layer obtained may be washed with water to remove acidic impurities. In another general aspect the organic layer may be distilled at atmospheric pressure to get better recovery of the solvent. In another general aspect the product obtained may have impurity of formula IV in less than 1% ratio. In another general aspect there is provided a process for the preparation of fexofenadine of formula II, from the 2-[4-(4-choloro-butyryl) phenyl]-2-methyl propanol which comprises oxidizing 2-[4-(4-choloro-butyryl) phenyl]-2-methyl propanol of Formula I, followed by esterification using methanolic hydrochloride and further condensing with azacyclonol, and reducing the resulting keto derivative. DETAILED DESCRIPTION OF THE INVENTION The inventors have developed an efficient process for the preparation of pure 2-[4-(4-choloro-butyryl) phenyl]-2-methyl propanol by hydrolyzing ester compound of formula III under anhydrous conditions using alcohol-hydrogen chloride. In general, a solution of alcohol -hydrogen chloride is prepared by purging dry hydrogen chloride in alcohol by following the methods reported in prior art. The percentage of hydrogen chloride in alcohol is preferably selected between 10-25%. The alcohol used in the solution of alcohol-hydrogen chloride is selected from Cl to €4 alcohols and preferably methanol or ethanol is used. Specifically the present invention involves hydrolysis of methyl 2-[4-(4-choloro-butyryl) phenyl]-2-methyl propanoate (formula III) in presence of methanol - hydrogen chloride to obtain a pure 2-[4-(4-choloro-butyryl) phenyl]-2-methyl propanol (formula I). The hydrolysis reaction is conducted at temperature 0-30°C and preferably at 5-15°C and it takes about 1-4 hours for completion of reaction. The progress of the reaction is monitored by high performance liquid chromatography (HPLC). When the starting compound is not more than (NMT) 2% by HPLC, the reaction mixture is quenched with water and the resulting compound is extracted in organic solvent. The organic solvent may be one or more of hydrocarbons, ethers, esters, ketone, chlorinated solvent, or mixtures thereof. The ketone may include one or more of acetone, 2-butanone, and 4-methyl pentan- 2-one. The chlorinated solvent may include one or more of dichloromethane, dichloroethane, and chloroform. The organic layer is washed with water to remove acidic impurities generated during reaction. After removal of the acidic impurities, organic solvent is distilled under atmospheric pressure to recover solvent and the product is isolated as an oil which is used as such for the preparation of fexofenadine hydrochloride. The formation of impurity of formula IV is reduced by using this procedure and is present in less than 1.0 %. The major advantages realized in the present invention as compared to prior art processes are: • Increased product purity. • The reaction does not involve larger reaction volumes. • There is no distillation of solvent (methanol or ethanol) at higher temperature in the presence of acid which leads to impurity formation; however the pure product is recovered by simple extraction of the reaction mass with organic solvent after dispensing in water. • Good yield with improved quality. • Consistency in obtaining the quality product. • No further processing to improve purity. The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. EXAMPLES EXAMPLE-1 Preparation of 2-[4-(4-choloro-butvrvl) phenyll-2-methyl propanol Methyl 2-[4-(4-choloro-butyryl) phenyl]-2-methyl propanoate (100 gm) was added slowly to cooled methanol-hydrogen chloride solution (400ml) at 5-10° C. The reaction mixture was further stirred for 3 hours at 5-10° C. After completion of the reaction, (staring material NMT 2.0%), the reaction mixture was diluted with methylene chloride (100 ml) and water (400 ml) and was stirred for 20 minutes. The layers were separated and aqueous layer was extracted with methylene chloride (50 ml) at room temperature. Combined organic layer was washed twice with water (800 ml each time) and distilled at 40° C to obtain the title compound as an oil (80 g, HPLC purity 95.5%; impurity of formula IV is 0.50%). EXAMPLE-2 Preparation of 2-|4-(4-choloro-butyrvl) phenyll-2-methyl propanol Methyl 2-[4-(4-choloro-butyryl) phenyl]-2-methyl propanoate (5.0 kg) was added slowly to cooled methanol-hydrogen chloride solution (20.0 1) at 5-10° C. The reaction mixture was further stirred for 3 hours at 10-15° C. After completion of the reaction, (staring material NMT 2.0%), the reaction mixture was diluted with methylene chloride (5.0 1) and water (20.0 1). The layers were separated and aqueous layer was extracted with methylene chloride (2.51). Combined organic layer was washed with water (40.01 x2) and distilled at 40° C to obtain 4.25 kg of title compound as an oil having 95.6% purity by HPLC, impurity of formula IV is 0.8%. Comparative Examples Preparation of 2-[4-(4-choloro-butyryl) phenyll-2-methyl propanol Methyl 2-[4-(4-choloro-butyryl) phenyl]-2-methyl propanoate (100 g) was taken in concentrated hydrochloric acid (200 ml) and ethanol (900 ml) and the reaction mixture was refluxed for 2.5 hours under nitrogen atmosphere. The solvent was evaporated under reduced pressure and the residue is taken in methylene chloride (350 ml). The organic layer was washed with water (150 mlx2), aqueous potassium carbonate solution (10%, 100 ml) and water (150 ml). The solvent was evaporated under reduced pressure to obtain the title compound as brown oil having 92.7% purity by HPLC, impurity of formula IV is 4.93 % Preparation of 2-[4-(4-choloro-butyryl) phenvll-2-methyl propanol Methyl 2-[4-(4-choloro-butyryl) phenyl]-2-methyl propanoate (25 g) was taken in methanol (37.5 ml) and the reaction mixture was cooled to 10-20°C. To this reaction mixture concentrated hydrochloric acid (12.5 ml) was added slowly at 10-20°C. The reaction mixture was stirred at room temperature for 24 hours. pH of the reaction mixture was adjusted to 7-8 with ammonia solution. The solvent was evaporated under reduced pressure and the residue was diluted with water (50 ml). The reaction mixture was extracted with methylene chloride (350 ml) and the organic layer was dried over anhydrous sodium sulphate. The solvent was evaporated to obtain the title compound as oil having 90.5% purity by HPLC, impurity of formula IV is 2.81 % While several particular forms of the inventions have been described, it will be apparent that various modifications and combinations of the inventions detailed in the text can be made without departing from the spirit and scope of the inventions. Further, it is contemplated that any single feature or any combination of optional features of the inventive variations described herein may be specifically excluded from the claimed inventions and be so described as a negative limitation. Accordingly, it is not intended that the inventions be limited, except as by the appended claims. WE CLAIM 1. An industrial process for the preparation of pure 2-[4-(4-choloro-butyryl) phenyl]-2-methyl propanol of formula I, (Formula Removed) which comprises hydrolyzing compound of formula III (Formula Removed) in the presence of anhydrous solution of alcoholic-hydrogen chloride at a temperature of 0-30°C, extracting the product in organic solvent, selected from the group consisting of hydrocarbons, ethers, esters, ketone, chlorinated solvent, separating the layers, isolating the pure hydroxy compound, 2-[4-(4-choloro-butyryl) phenyl]-2-methyl propanol of formula I by distillation of organic solvent, 2. The process as claimed in claim 1, wherein the alcohol in the solution of alcoholic-hydrogen chloride is selected from C1-C4 alcohols. 3. The process as claimed in claim 1, wherein the solution of alcoholic-hydrogen chloride is methanol-hydrogen chloride. 4. The process as claimed in claim 1, wherein the hydrolysis reaction is conducted at temperature 5-15° C. 5. The process as claimed in claim 1, wherein the organic solvent is selected from chlorinated solvent. 6. The process as claimed in claim 1, wherein 2-[4-(4-choloro-butyryl) phenyl]-2- methyl propanol of formula I prepared, is converted to fexofenadine of formula II or pharmaceutically acceptable salt thereof; (Formula Removed) by following steps of oxidation, esterification, condensation with azacyclonol and reduction step.

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917-del-2006-Abstract-(09-10-2012).pdf

917-del-2006-abstract.pdf

917-del-2006-Claims-(09-10-2012).pdf

917-del-2006-claims.pdf

917-del-2006-Correspondence-others (12-08-2008).pdf

917-del-2006-Correspondence-Others-(09-10-2012).pdf

917-del-2006-correspondence-others.pdf

917-del-2006-description(complete).pdf

917-del-2006-form-1.pdf

917-del-2006-Form-18 (12-08-2008).pdf

917-del-2006-form-2.pdf

917-del-2006-form-3.pdf

917-del-2006-form-5.pdf