Title of Invention

A PROCESS FOR THE PREPARATION OF ESCITALOPRAM FROM 5-IODOPHTHALIDE

Abstract

The present invention relates to an improved process for the preparation of escitalopram of the formula-I which consists of a sequential double Grignard reaction on 5-iodophthalide to get the dihydroxy compound of formula-XVI, its resolution using a chiral acid, cyclization of resolved compound of the formula-XVII, and cyanation of compoimd of the formula-XVIII using DMF and copper (I) cyanide. The present process utilizes the facile displacement of iodo group with cyano group in the final step of escitalopram. Escitalopram is a widely used anti-depressant.

Full Text

FIELD OF INVENTION The present invention relates to an improved process for the preparation of escitalopram oxalate. Escitalopram ((S)-l-[3(dimethylamino)propyl]-l-(4-fluorophenyl)-l,3-dihydro-5-isobenzofurancarbonitrile) is the S-enantiomer ((+)-isomer) of the well-known antidepressant drug citalopram having the formula-I given below. Escitalopram was found to be more active than the dl-citalopram or the R-citalopram. BACKGROUND OF THE INVENTION Citalopram, which has been disclosed in DE Patent no. 2,657,013 (1977) corresponding to US Patent no. 4,136,193 (1979) is a well-known antidepressant drug available in the market for some years. It is a selective, centrally acting serotonin (5-HT) reuptake inhibitor, is accordingly having the antidepressant activity. The antidepressant activity of citalopram has been reported in several publications, e.g. J. Hyttel, Prog. Neuro-Psychophannacol. & Biol. Psychiat, 1982, 6, 277-295 and A. Gravem, Acta Psychiatr. Scand., 1987, 75, 478-486. Recently, Escitalopram is found to be more active than the dl-citalopram Process for the preparation of escitalopram is disclosed in U. S. Pat. No. 4,943,590. According to this patent, attempts to crystallize the diastereomeric salts of citalopram enantiomers have failed. In this patent a process for the preparation of escitalopram was described by resolving the intermediate (compound of the formula-XI) of citalopram and ring closure of the resolved intermediate in a stereo specific manner to get the escitalopram (Scheme-I). Scheme-I The main drawback in this process is the purity of the intermediate compound of the formula-XI obtained in the Grignard reaction, which is of 80-90% only. The crude compound of formula-XI needs extensive purification before proceeding for resolution. The purification technique given in the above patent process involves repeated charcoal and silica gel treatment to the compound of the formula-XI or its HBr salt. Also, during the HBr salt formation of compound of the formula-XI, the amount of HBr used in the process should be less than the molar quantity to avoid additional impurities formation. As the impurities present in the intermediate compound of the formula-XI have closely related properties such a purification technique is not viable on a commercial scale to make this intermediate and also the escitalopram. Also, the overall yield of escitalopram given in this patent is only 8.8% starting from 5-cyanophthalide of the formula-IX. Therefore such a low yielding process needs to be improved for commercial production of escitalopram. Recently a process for the preparation of escialopram is disclosed in WO 03/0006449. According to the method given in this patent intermediates of dl-citalopram were separated into the individual enantiomers by chromatographic method and converted to escitalopram. The main drawback in this process is the availability of chiral stationary phase on bulk scale and its implementation on a commercialization. Output from such a process will also be low. Keeping in view of the difficulties in commercialization of the above-mentioned process for the preparation of escitalopram, we aimed to develop a simple and economical process for commercial production of escitalopram. DESCRIPTION OF PRESENT INVENTION We observed that a promising approach for a process for the preparation of escitalopram would be to (a) avoid the usage of 5-cyanophthalide as starting material (b) avoid the purification of intermediates involved in making escitalopram thereby making the process commercially viable and economical (c) develop an efficient method for the conversion of intermediates into escitalopram. Focusing on these points we developed an improved process for the preparation of escitalopram and filed our patent application earlier (Indian application number: 052 / MAS /2003). According to the process (Scheme-II) disclosed in the said patent application, 5-bromophthalide is subjected to double Grignard reaction and the resulting dimagnesium salt of formula-XIV is isolated by filtration. By doing so we could remove all the related impurities present in the reaction mass and get the required compound of formula-IV in more than 98% purity after neutralization of salt. The dihydroxy intermediate thus obtained was resolved into its isomers by treating with a resolving agent. The resolved intermediate of fomiula-XVI was cyclized to the bromo derivative of formula-XVII and finally this bromo intermediate was converted to escitalopram base by treating it with copper cyanide. The quality of escitalopram obtained by this procedure is more than 97%. The main draw back in this process is the conversion of bromo group present in compound of formula-XIII into cyano group present in escitalopram. Conversion is a slow process (more than 8hr at 145-150°C) and removal of starting bromo compound present in escitalopram is difficult to due to liquid nature of escitalopram and also similar solubility properties of salts derived from both the bromo impurity and escitalopram. During our sustained research to overcome this problem we found that introduction of copper (I) iodide increased the yield and the rate of cyanation. Introduction of copper (I) iodide converts the bromo group present in compound of formula-XIII into iodo group, which is more reactive than the bromo group during cyanation with copper (I) Cyanide. Keeping this in mind we aimed to prepare iodo analogue of compound of formula-XIII and use the same in synthesizing escitalopram of formuIa-L Accordingly, iodo analogue of compound of formula-XIII can be prepared from 5-iodopthalide by following the same process as that of bromo compound (Scheme-Ill). A process for the preparation of iodo compound of formula-XVIII is disclosed in W000/13648. 5-Iodophthalide of formuia-XIV is sequentially reacted with p-fluorophenylmagnesium bromide and 3-dimethylaminopropylmagnesium chloride to get the dihydroxy compound of formula-XVI. This dihydroxy compound is subjected to acid catalyzed cyclization to get the iodo phthalane derivative of formula-XVIII as dl-mixture. The dihydroxy compound of formula-XVI is not isolated and characterized in the above patent process. Also, the process for isolation of compound of formula-XVIII (dl-mixture) requires column chromatography and the overall yield is only 8%. Maintaining high purity for the compound of formula-XVI is very essential to get optimum yield and chiral purity of compound of formu!a-XVII in the resolution process. As the procedures for preparation of high purity compound of formula-XVI are not available in the literature there is a need to develop such process for commercialization of the process for escitalopram. During the process development of citalopram hydrobromide we observed that the Grignard reaction on 5-bromophthalide is very much temperature dependant and the best yields are possible only if the reaction is done below -10°C. Similar temperature condition is anticipated for a Grignard reaction on 5-iodophthalide to get maximum yield and purity of the compound of formula-XVI. Accordingly, the main objective of the present invention is to provide an improved process for the preparation of escitalopram from the iodo compound of formula-XVI, which is commercially applicable. Yet another objective of the present invention is to provide an improved process for the preparation of escitalopram by improving the yield and quality of the dihydroxy compound of formula-XVI. Still another objective of the present invention is to provide an improved process for the preparation of escitalopram which involves the resolution of the dihydroxy compound of formula-XVI into its enantiomers by making a diasteromeric salt using a chiral acid. Another objective of the present invention is to provide an improved process for the preparation of escitalopram, which involves the cyclizeation of the chiral dihydroxy compound of formula-XVII in a stereopscefic manner via nucleophilic displacement technique. Accordingly the present invention provides an improved process for the preparation of (ii) reacting the benzophenone derivative of the formula-XV with 3-(dimethylamino)propylmagnesium chloride to get the dihydroxy compound of the formula-XVI, (iii) resolving the compound of the formula-XVI with (+)-di-p-toluoyltartaric acid by preferential crystallization in a solvent medium to get its (-)-enatiomer salt with (+)-di-p-toluoyltartaric acid (iv) neutralizing the diastereomeric salt and isolating the liberated chiral dihydroxy compound of formula-XVII, (v) cyclizing the dihydroxy compound of formula-XVII using methanesulfonyl chloride in basic medium to get the cyclic compound of the formula-XVIII, (vi) reacting the compound of the formula-XVIII with copper cynanide in dipolar aprotic solvent medium at elevated temperature to get escitalopram base of formula-I, (vii) Converting the compound of the formula-I into hs pharmaceutically acceptable salt, like oxalate, etc by conventional methods. The Grignard reaction in steps (i) and (ii) can be effected at a temperature in the range of -25°C to 0°C preferably at a temperature in the range of -20°C to -10°C. The solvent used in resolution step can be methanol, ethanol, isopropanol, ethyl acetate, acetone, acetonitrile, or a mixture thereof The solvent used in cyclization step can be methylene chloride, toluene, cyclohexane, tetrahydrofuran, isopropyl ether, ether, acetonitrile, etc. The cyanation step may be done in N, N-dimethylformamide, N, N-dimethylacetamide, pyridine, N-methyl-2-pyrrolidone, etc. Temperature of reaction during cyanation is between 80-180°C, preferably between 100-150°C, more preferably between 120-140°C. The amount of copper (I) cyanide used in the reaction can be in the range of 1.0-2.5 moles per mole of iodo compound, preferably 1.5-2.0 moles per mole of iodo compound. The pharmaceutically acceptable oxalate salt formation can be done in solvents like, methanol, ethanol, isopropanol, water, acetone, acetonitrile or a mixture thereof Escitalopram prepared according to the process disclosed in this application has high yield (>75%) and high purity (>99%) with no bromo impurity. Doing cyanation on the iodo compound of formula-XVII is novel and applied for the first time in making escitalopram. Cyanation on the iodo compound of formula-XVII has improved the quality of escitalopram and the yields are high. Advantages of the present invention: " 1. Escitalopram of formula-I can be prepared in a simple and easy to adopt maimer without involving any tedious purification steps. 2. Escitalopram of formula-I can be prepared in >25% yield, which is better than the earlier known process. 3. An improved process for the preparation of the intermediate compound of the formula-XVI. 4. The present process produces pure (>99.8%) enantiomeric forms of the intermediates of the formulae-XVII and XVIII or its salts. 5. The present utilizes mild cyanation conditions on the iodo compound of formula-XVIII thereby making the process simpler, efficient and impurity fi-ee.

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