Title of Invention

A PROCESS FOR THE PREPARATION OF ESCITALOPRAM

Abstract

The present invention relates to an improved process for the preparation of escitalopram of the formuia-(+)-I which consists of a sequential double Grignard reaction on 5-bromophthalide, isolation of di-magnesium salt, neutralization of di-magnesium salt, resolution of dihydroxy compound of the formula-IV and cyclization of resolved compound of the formula-(-)-IV, cyanation of compound of the formula-(+)-V using DMF and copper(I)cyanide. The present process utilizes the insoluble property of di-magnesium salt of formula-XII in a mixture of THF and a non-polar organic solvent and separates it from impurities by simple filtration thereby making the isolation and purification process simple.

Full Text

INTRODUCTION The present invention relates to an improved process for the preparation of escitalopram. Escitalopram is one of the enantiomers of the well-known antidepressant drug citalopram which [ 1 -((3 -dimethylamino)propyl)-1 -(4' -fluorophenyl)-1,3 -dihydro-5-isobenzofuran-carbonitrile] has the formula-I given below: This invention also relates to a process for the preparation of an intermediate useful for the preparation of escitalopram. BACKGROUND OF THE INVENTION Citalopram 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. The process for the preparation of antidepressant citalopram and its pharmaceutoical properties were first disclosed in DE Patent no. 2,657,013 (1977) corresponding to US Patent no. 4,136,193 (1979). Subsequently it was also disclosed in GB patent no.1,526,331 (1978). The basic process for the preparation of citalopram described in the above-referred patents involves two major routes illustrated in Scheme-1 and Scheme-2. Major difference in these two routes is introduction of dimethylaminopropyl side chain at an early stage (Scheme-1) or at a later stage (Scheme- 2). In the first route, 5-bromophthalide of the formula-II is reacted with p-fluorophenyl-magnesium bromide to get a benzophenone derivative of the formula-Ill. This benzophenone derivative is reacted with 3-(dimethylamino)prdpylmagnesium chloride to get the dihydroxy intermediate of the formula-FV. Cyclization of the compound of the formula-IV with an acid catalyst resulted in the formation of phthalane derivative of the formula-V. This bromophthalane derivative is reacted with copper (I) cyanide to get the citalopram base of the formula-I. In the second route, 5-bromophthalide of the formula-II is reacted with p-fluorophenyl-magnesium bromide to get the corresponding benzophenone derivative of the formula-Ill. This compound of the formula-Ill is reduced with lithium aluminum hydride to get the dihydroxy compound of the formula-VI, which is cyclized with an acid catalyst to get the phthalane derivative of the formula-VII. The bromo group is replaced with a cyano group and alkylated with the required side chain to get the citalopram base of the formula-I. Another method for the preparation of citalopram base of the formula-I and an intermediate useful for the preparation of citalopram was described in U S. Pat. No. 4,650,884, according to which 5-cyanophthalide of formula-IX is reacted successively with p-fluorophenylmagnesium bromide and 3-(dimethylamino)propylmagnesium chloride to get the compound of the formula-XI which is reacted with 70% sulfuric acid to get the citalopram base (Scheme-3). 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 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 compoimd 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. 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. We observed that a promising approach for a process for the preparation of escitalopram will 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. Accordingly the main objective of the present invention is to provide an improved process for the preparation of escitalopram, which is commercially applicable. Another objective of the present invention is to provide an improved process for the preparation of escitalopram avoiding the usage of 5-cyanophthalide thereby making the process simple and economical. Yet another objective of the present invention is to provide an improved process for the preparation of escitalopram avoiding the purification techniques for the intermediates formed in the process thereby making the process fiuther simpler and economical. Still another objective of the present invention is to provide an improved process for the preparation ofescitalopram wherein the overall yield is 25-35%. As an alternative process for the preparation of escitalopram disclosed in the above mentioned prior art patent, we looked particularly into the original process developed by Lundbeck for dl-citalopram (Scheme-I above). In this route, the bromo-analogue (compound of the formula-IV) of the intermediate compoimd of the formula-XI can be separated into its enantiomers by conventional resolution techniques (preferential crystallization of diastereomeric salts) and converted into escitalopram. However, in the original process for the preparation of compound of the formula-IV no purity has been mentioned. It only says that the intermediate compound of the formula-IV is prepared in an analogous manner. The yield given for the analogous compoimd of the formula-IV is only 55%. Therefore, such a process needs to be improved with respect to the yield of the compound of the formula-IV and its quality for its commercial usage in making escitalopram. Also, the compound of formula-IV is described as an oil. Surprisingly, we have foimd that if one does the sequential double Grignard reaction on 5-bromophthalide analogous to 5-cyanophthalide in tetrahydrofuran medium along with a non-polar co-solvent, the resulting magnesium salt (compound of the formula-XII) crystallizes from the reaction mass leaving all the related impurities in the reaction medium. The crystalline magnesium salt can be simply filtered off from the reaction mass and neutralized to get the pure compound of the formula-IV, an analogue of the compound of the formula-XI used in the known process for escitalopram. Although compound of the formula-IV is known, isolation of its magnesium salt in a pure form to get a pure product of the formula-IV is not known. We also found that di-magnesium salt derived from 5-cyanophthalide will not crystallize out from the reaction mixture under above-mentioned conditions (usage of non-polar co-solvent in Grignard reaction) for its bromo-analogue. The crystallization property to the di-magnesium salt of the formula-XII seems to be specific. The usage of a co-solvent in the double Grignard reaction on 5-bromophthalide and identification of crystalline property to the resulting di-magnesium salt and its isolation by filtration to get pure compound of the formula- XII is the novelty of the invention. Crystalline property of the resulting di-magnesium salt has not been identified earlier and also it has not been isolated. Such a crystalline property to the di-magnesium salt of the formula-XII in a mixture of tetrahydrofiiran and a non-polar solvent eliminated all the unwanted impurities after filtering off the di-magnesiimi salt of the compound of formula-XII from the reaction mass. The dihydroxy compound of the formula-IV obtained by this process was fovmd to be pure and crystalline and the yield was 70-75% of theory. Accordingly the present invention provides an improved process for the preparation of ;scitalopram of the formula-(+)-I, which comprises: (i) reacting 5-bromophthalide of the formula-II, with p-fluorophenylmagnesium bromide in THF medium with a non-polar co-solvent to get the benzophenone derivative of the formula-III, (ii) reacting the benzophenone derivative of the formula-Ill with 3-(dimethylainino)propylmagnesium chloride to get the crystalline di-magnesium salt of the formuIa-XII, (iii) Isolating the crystalline compound of the formula-XII by filtration and neutralizing the di-magnesium salt to get the dihydroxy compound of the formula-IV, (iv) Resolving the compound of the formula-IV with (+)-di-p-toluoyltartaric acid by preferential crystallization to get its (-)-enatiomer salt with (+)-di-p- toluoyltartaric acid (v) Neutralizing the diastereomeric salt and reacting the liberated chiral base with methanesulfonyl chloride in basic medium to get the cyclic compound of the formula-(+)-V, (vi) Reacting the compound of the fomiula-(+)-V with copper cynanide to get the chiral compound of the formula-(+)-I. (vii) and if desired converting the compound of the formula-(+)-I into its pharmaceuticaily acceptable salt, like oxalate, etc by conventional methods. According to another feature of the invention there is provided an improved process for the preparation of the intermediate compound of the formula-XII, in a crystalline form which comprises: (i) reacting 5-bromophthalide of the formula-II, II with p-fluorophenylmagnesium bromide in THF medium with a non-polar co-solvent to get the benzophenone derivative of the formula-III, (ii) reacting the benzophenone derivative of the formula-III with 3-(dimethylamino)propylmagnesium chloride to get the crystalline di-magnesium salt of formula-XII, (iii) and Isolating the crystalline compound of the formula-XII by filtration. The Grignard reaction in steps (i) and (ii) may 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 non-polar co-solvent used in steps (i) and (ii) may be benzene, toluene, cyclohexane, etc., preferably toluene or cycohexane. The neutralization reagent used in step (iii) may be organic or mineral acid. The organic acid can be acetic acid, propionic acid, oxalic acid, succinic acid, ammonium chloride, etc. The mineral acid can be hydrochloric acid, sulfuric acid, etc. The solvent used in resolution step may be methanol, ethanol, isopropanol, ethyl acetate, acetone, acetonitrile, or a mixture thereof. The solvent used in cyclization step may be methylene chloride, toluene, cyclohexane, tetrahydroforan, isopropyl ether, ether, acetonitrile, etc. The cyanation step may be done in N,N-dimethylformamide, N,N-dimethylacetamide, pyridine, N-methyl-2-pyrrolidone, etc. The pharmaceutically acceptable oxalate salt formation can be done in solvents like, methanol, ethanol, isopropanol, water, acetone, acetonitrile, or a mixture thereof The details of the process of the invention are provided in the Examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention Example 1 Preparation of escitalopram: (i) Preparation of di-magnesium salt of formula-XII: The Grignard solution prepared from 90gr of 4-fluorobromobenzene and 13gr magnesium turnings in 450ml of THF was added drop wise to a suspension of 5-bromophthalide (lOOgr) in THF (400ml) at -15 to -10°C under nitrogen atmosphere. After the addition was completed, the reaction mixture was stirred at same temperature for another 3hrs. The second Grignard reagent prepared from 68gr of 3-(dimethylamino)propyl chloride and 16gr of magnesum turnings in THF (300ml) and toluene (300ml) was added to the above reaction mixture at -15 to 0°C over a period of 2-3hrs and maintained for additional Ihr. TLC of the reaction mixture showed the absence of starting material. Slowly the reaction mixture was allowed to rise to 10°C and filtered the salts. The wet cake was washed with 200ml of toluene and air dried to get 210gr of free-flowing white crystalline solid di-magnesium salt of formula-XII. (ii) Preparation of dihydroxy compound of formula-IV: The solid di-magnesium compound of formula-XII obtained above was suspended in 1000ml of water and treated with l00gr of ammonium chloride. After stirring for 30min, product was extracted into toluene (1 x 500ml, 2 x 200ml) and the combined organic layer treated with l0gr of active charcoal. Toluene was distilled off from the reaction mixture below 60°C and to the residue di-isaopropyl ether was added. The crystalline compound of formula-IV was isolated by filtration to get 130gr (70% based on 5-bromophthalide). Melting point: 118-120°C. Purity by HPLC: 98.5%. 'H-NMR (CDCI3, 200MHz): 7.39-7.44 (m, 2H, ar. H), 7.25-7.34 (m, 3H, ar. H), 6.90-7.00 (m, 2H, ar. H), 4.33 (d, J = 12.0Hz, IH, -CH2OH), 4.06 (d, J = 11.7Hz, IH, -CH2OH), 2.46-2.54 (m, 4H, -CH2CH2CH2-), 2.22 (s, 6H, 2 X NCH3), and 1.51-1.75 (m, 2H, -CH2CH2CH2-). (iii) Resolution of diliydroxy compound of formula-IV: The dihydroxy compound of formula-IV (lOOgr) was dissolved in 300ml of isopropyl alcohol at 40-45°C. Solid (+)-di-p-toluoyltartaric acid monohydrate (50gr) was added to the reaction mixture and kept under stirring for overnight at 20-25°C. The crystals formed in the reaction mixture were filtered and washed with 50ml of isopropyl alcohol to get 55gr (74%) of (-)-4-bromo-a'-(4-fluorophenyl)- a'-[3-(dimethylamino)propyl]-1,2-benzenedimethanol, hemi (+)-di-p-toluoyltartaric acid salt. Melting point: 126-130°C. The above salt (50gr) was suspended in 150ml of isopropyl alcohol and heated to 70°C. The resulting suspension was maintained at 70°C for Ihr and cooled to 25-30°C. The solids were filtered off and dried to yield 45gr of above salt. Chiral purity by HPLC is 99.4%. Melting point: 128-130°C. [a]D = +7.49° (c = 1, methanol). (iv) Cyclization of resolved dihydroxy compound of formula-IV: To 72gr of (-)-4-bromo-a'-(4-fluorophenyl)- a'-[3-(dimethylamino)propyl]-l,2-benzene-dimethanol, hemi (+)-di-p-toluoyltartaric acid salt in 720ml of water was added a solution of 11.5gr of sodium hydroxide in 140ml of water. After stirring for Ihr at 25-30°C product was extracted into toluene (1 x 300ml, 2 x 100ml) and the toluene layer distilled off below 60°C to get 46.0gr (95%) of the (-)-isomer of dihydroxy compound as oil. [a]D = -50.98° (c = 1, methanol). To a solution of the above base in toluene (700ml) was added triethylamine (34.2gr) and cooled to -5°C. Methanesulfonyl chloride (17.8gr) was slowly added to the reaction mixture at -5 to 0°C over a period of 3hrs. After maintaining for Ihr at same temperature reaction was found to complete by TLC. The reaction mixture was poured into water (350ml) and separated toluene layer. Aqueous layer was extracted with toluene (2 x 50ml) and the combined toluene layer washed with 200ml of water. Toluene was distilled off fi-om the reaction mixture below 60°C to get 40gr (91%). [a]o = +2.0° (c = 1, methanol). Chiral purity by HPLC: 99.2%. A small sample (5.0gr) was converted to its oxalate salt in acetone medium. Melting point: 160-162°C. [a]D = +2.2° (c = 1, methanol). Chiral purity by HPLC: 99.5%. (v) Cyanation of bromo compound of formula-VI: To a solution of bromo compound (lOOgr) of formula-VI in DMF (1000ml) was added copper(I)cyanide (31.0gr) and the reaction mixture heated xmder nitrogen atmosphere to 145-150°C. After maintaining the reaction mixture at this temperature for 8hrs, reaction mixture was cooled to 25-30°C and poured into water (3000ml). After stirring for Ihr, ethylenediamine (100ml) was slowly added to the reaction mixture and maintained for 3hrs under stirring. Toluene (300ml) was added to the reaction mixture and stirred for 30min. Inorganic copper salts were filtered off fi-om the reaction mixture with the aid hiflow. The hiflow bed was washed with 200ml of toluene. Filtrate was taken into a separating fimnel and the toluene layer separated. The aqueous layer was extracted with toluene (200ml). The combined organic layer was washed with water. The organic layer was extracted with 10% aqueous acetic acid (200ml and 100ml). The combined acetic acid layer was treated with charcoal (l0gr) and filtered. Aqueous ammonia was added to the filtrate to get a pH of 8.5-9.0. The product was extracted into isopropyl ether (1 x 300ml, 2 X 100ml) and the solvent distilled off to get 60gr (70%) of crude escitalopram base as oil. Purity by HPLC was found to be >97%. Chiral purity by HPLC is 99.2%. Example 2 Preparation of escitalopram: (i) Preparation of di-magnesium salt of formuIa-XII: The Grignard solution prepared from 90gr of 4-fluorobromobenzene and 13gr magnesium turnings in 450ml of THF was added drop wise to a suspension of 5-bromophthalide (lOOgr) in THF (400ml) at -15 to -10°C under nitrogen atmosphere. After the addition was completed, the reaction mixture was stirred at same temperature for another 3hrs. The second Grignard reagent prepared from 68gr of 3-(dimethylamino)propyl chloride and 16gr of magnesium turnings in THF (300ml) and cyclohexane (300ml) was added to the above reaction mixture at -15 to 0°C over a period of 2-3hrs and maintained for additional Ihr. TLC of the reaction mixture showed the absence of starting material. Slowly the reaction mixture was allowed to rise to 10°C and filtered the salts. The wet cake was washed with 200ml of cyclohexane and air dried to get 165gr of free-flowing white crystalline solid di-magnesium salt of formula-XII. (ii) Preparation of dihydroxy compound of formula-IV: The solid di-magnesium compound of formula-XII obtained above was suspended in 1000ml of water and treated with lOOgr of ammonium chloride. After stirring for 30min, product was extracted into ethyl acetate (1 x 500ml, 2 x 200ml) and the combined organic layer treated with lOgr of active charcoal. Ethyl acetate was distilled off from the reaction mixture below 50°C and to the residue di-isopropyl ether and hexane were added. The crystalline compound of formula-IV was isolated by filtration to get 75gr. Melting point: 117-120°C. Purity by HPLC: 98%. (iii) Resolution of dihydroxy compound of formula-IV: The dihydroxy compound of formula-IV (70gr) was dissolved in 210ml of isopropyl alcohol at 40-45°C. Solid (+)-di-p-toluoyltartaric acid monohydrate (35gr) was added to the reaction mixture and kept under stirring for overnight at 20-25°C. The crystals formed in the reaction mixture were filtered and washed with 30ml of isopropyl alcohol to get 30gr (58%) of (-)-4-bromo-a'-(4-fluorophenyl)- a'-[3-(dimethylamino)propyl]-1,2-benzenedimethanol, hemi (+)-di-p-toluoyltartaric acid salt. Melting point: 126-130°C. The above salt (30gr) was suspended in 100ml of isopropyl alcohol and heated to 70°C. The resulting suspension was maintained at 70°C for Ihr and cooled to 25-30°C. The solids were filtered off and dried to yield 26gr of above salt. Chiral purity by HPLC is 99.5%. Melting point: 128-130°C. [ajo = +7.4° (c = 1, methanol). (iv) Cyclization of resolved dihydroxy compound of formula-IV: To 25gr of (-)-4-bromo-a'-(4-fluorophenyl)- a'-[3-(dimethylamino)propyl]-l,2-benzene-dimethanol, hemi (+)-di-p-toluoyltartaric acid salt in 250ml of water was added a solution of 4.0gr of sodium hydroxide in 50ml of water. After stirring for Ihr at 25-30°C product was extracted into toluene (1 x 100ml, 2 x 30ml) and the toluene layer distilled off below 60°C to get 16.5gr of the (-)-isomer of dihydroxy compound as oil. [a]D = -51.0° (c = 1, methanol). To a solution of the above base in toluene (200ml) was added triethylamine (11.2gr) and cooled to -5°C. Methanesulfonyl chloride (6,0gr) was slowly added to the reaction mixture at -5 to 0°C over a period of 3hrs. After maintaining for Ihr at same temperature reaction was found to complete by TLC. The reaction mixture was poured into water (100ml) and separated toluene layer. Aqueous layer was extracted with toluene (2 x 25ml) and the combined toluene layer washed with 75ml of water. Toluene was distilled off fi'om the reaction mixture below 60°C to get an oil (IS.Ogr). [ajo = +1.8° (c = 1, methanol). Chiral purity by HPLC: 99.0%. (v) Cyanation of bromo compound of formula-VI: To a solution of bromo compound (30gr) of formula-VI in pyridine (25ml) was added copper(I)cyanide (9.0gr) and the reaction mixture heated under nitrogen atmosphere to 145-150°C. After maintaining the reaction mixture at this temperature for 8hrs, reaction ethylenediamine (30ml) was slowly added to the reaction mixture and maintained for 3hrs under stirring. Toluene (100ml) was added to the reaction mixture and stirred for 30min. Inorganic copper salts were filtered off from the reaction mixture with the aid hiflow. The hiflow bed was washed with 100ml of toluene. Filtrate was taken into a separating funnel and the toluene layer separated. The aqueous layer was extracted with toluene (100ml). The combined organic layer was washed with water. The organic layer was extracted with 10% aqueous acetic acid (100ml and 50ml). The combined acetic acid layer was treated with charcoal (5gr) and filtered. Aqueous ammonia was added to the filtrate to get a pH of 8.5-9.0. The product was extracted into isopropyl ether (1 x 100ml, 2 x 50ml) and the solvent distilled off to get the crude escitalopram base (18gr). Purity by HPLC was found to be >96%. Chiral purity by HPLC is 99.0%. Example 3 Preparation of (-)-isomer of citalopram: (!) Resolution of dihydroxy compound of formula-IV: The dihydroxy compound of formula-IV (lOOgr) was dissolved in 300ml of isopropyl alcohol at 40-45°C. Solid (-)-di-p-toluoyltartaric acid monohydrate (50gr) was added to the reaction mixture and kept under stirring for overnight at 20-25°C. The crystals formed in the reaction mixture were filtered and washed with 50ml of isopropyl alcohol to get 50gr (67%) of (+)-4-bromo-a'-(4-fluorophenyl)- a'-[3-(dimethylamino)propyl]-1,2-benzenedimethanol, hemi (-)-di-p-toluoyltartaric acid salt. Melting point: 126-130°C The above salt (50gr) was suspended in 150ml of isopropyl alcohol and heated to 70°C. The resulting suspension was maintained at 70°C for Ihr and cooled to 25-30°C. The solids were filtered off and dried to yield 40gr of above salt. Chiral purity by HPLC is 99.4%. Melting point: 128-130°C. [ajo = -8.3° (c = 1, methanol). (ii) Cyclization of resolved dihydroxy compound of formula-IV: To 40gr of (+)-4-bromo-a'-(4-fluorophenyl)- a'-[3-(dimethylamino)propyl]-l,2-benzene-dimethanol, hemi (-)-di-p-toluoyltartaric acid salt in 400ml of water was added a solution of 3.5gr of sodium hydroxide in 40ml of water. After stirring for Ihr at 25-30°C product was extracted into toluene (1 x 100ml, 2 x 50ml) and the toluene layer distilled off below 60°C to get 26gr of the (+)-isomer of dihydroxy compound as oil. [a]o = +52.0° (c=l, methanol). To a solution of the above base in toluene (300ml) was added triethylamine (18gr) and cooled to -5°C. Methanesulfonyl chloride (9.1gr) was slowly added to the reaction mixture at -5 to 0°C over a period of 3hrs. After maintaining for Ihr at same temperature reaction was found to complete by TLC. The reaction mixture was poured into water (250ml) and separated toluene layer. Aqueous layer was extracted with toluene (2 x 50ml) and the combined toluene layer washed with 100ml of water. Toluene was distilled off from the reaction mixture below 60°C to get an oil (17.0gr). [ajo = -2.4° (c = 1, methanol). Chiral purity by HPLC: 99.4%. (iii) Cyanation of bromo compound of foi*muIa-VI: To a solution of bromo compoimd (lO.Ogr) of formula-VI in DMF (100ml) was added copper(I)cyanide (B.lgr) and the reaction mixture heated under nitrogen atmosphere to 145-150°C. After maintaining the reaction mixture at this temperature for 8hrs, reaction mixture was cooled to 25-30°C and poured into water (300ml). After stirring for Ihr, ethylenediamine (10ml) was slowly added to the reaction mixture and maintained for 3hrs under stirring. Toluene (50ml) was added to the reaction mixture and stirred for 30min. Inorganic copper salts were filtered off from the reaction mixture with the aid hiflow. The hiflow bed was washed with 50ml of toluene. Filtrate was taken into a separating funnel and the toluene layer separated. The aqueous layer was extracted with toluene (50ml). The combined organic layer was washed with water. The organic layer was extracted with 10% aqueous acetic acid (50ml). The acetic acid layer was treated with charcoal (2gr) and filtered. Aqueous ammonia was added to the filtrate to get a pH of 8.5-9.0. The product was extracted into isopropyl ether (2 x 50ml) and the solvent distilled off to get the crude (-)-citalopram base (5.0gr). Purity by HPLC was found to be >97%. Chiral purity by HPLC is 99.3%. Advantages of the present invention: 1. Escitalopram of formula-(+)-I can be prepared in a simple and easy to adopt manner 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-IV. 4. The present process produces pure (>99.8%) enantiomeric forms of the intermediates of the formulae-FV and V or its salts. 5. The present process produces pure (>98%) di-magnesium salt of intermediate compound of the formula-XII, which is not isolated earlier. WE CLAIM: 1. An improved process for the preparation of escitalopram of the fomiula-(+)-I, and its phannaceutically acceptable salts which comprises: (i) reacting 5-bromophthalide of formula-II, with p-fluorophenylmagnesium bromide in THF medium with a non-polar co-solvent to get the benzophenone derivative of formula-Ill, (ii) reacting the benzophenone derivative of formula-Ill with 3-(dimethylamino)-propylmagnesium chloride to get the crystalline di-magnesium salt of formula-XII, (iii) isolating the crystalline compound of the formula-XII by filtration and neutralizing the di-magnesium salt to get the dihydroxy compound of the formula-IV, (iv) resolving the compound of the fonnula-IV with (+)-di-p-toluoyltartaric acid by preferential crystallization to get its (-)-enatiomer salt with (+)-di-p-toluoyltartaric acid (v) liberating the chiral base from the diastereomeric salt by neutralization and reacting the liberated chiral base with methanesulfonyl chloride in basic medium to get the cyclic compound of the formula-(+)-V, (vi) reacting the compound of the formula-(+)-V with copper cynanide to get the chiral compound of the formula-(+)-I. (vii) and if desired converting the compound of the formula-(+)-I into its pharmaceutically acceptable oxalate salt by conventional methods. 2. An improved process as claimed in claim 1 wherein the Grignard reaction in steps (i) and (ii) is effected at a temperature in the range of -25°C to 0°C, preferably at -20°C to -10°C. 3. An improved process as claimed in claims 1 & 2 wherein the non-polar co-solvent used in steps (i) and (ii) is selected from benzene, toluene, cyclohexane, etc, preferably toluene or cyclohexane. 4. An improved process as claimed in claims 1 to 3 wherein the ratio between THF and non-polar co-solvent used in steps (i) and (ii) is in the range of 3-6:1-3, preferably 4:1. 5. An improved process as claimed in claim 1 to 4 wherein the neutralization reagent used in step (iii) is selected from acids like acetic acid, propionic acid, oxalic acid, succinic acid, ammonium chloride, etc., preferably acetic acid or ammonium chloride. 6. An improved process as claimed in claim 1 to 5 wherein the mineral acid used for neutralization in step (iii) is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, etc., preferably hydrochloric acid or hydrobromic acid. 7. An improved process as claimed in claim 1 to 6 wherein the solvent used in resolution in step (iv) is selected from methanol, ethanol, isopropanol, ethyl acetate, acetone, acetonitrile, preferably, ethanol, isopropanol or ethyl acetate. 8. An improved process as claimed in claim 1 to 7 wherein the solvent used in cyclization in step (v) is selected from methylene chloride, toluene, cyclohexane, tetrahydrofuran, isopropyl ether, ether, acetonitrile, etc., preferably, methylene chloride, toluene or cyclohexane. 9. An improved process as claimed in claim 1 to 8 wherein the base used to get the cyclic compound of formula-(+)-V in step (v) is selected from a tertiary amine like, triethylamine, tributylamine, pyridine, etc., preferably, triethylamine or pyridine. 10. An improved process as claimed in claim 1 to 9 wherein the cyanation step is done in NjN-dimethylformamide, N,N-dimethylacetamide, pyridine, N-methyl-2- pyrrolidone, etc., preferably, N,N-dimethylformamide, pyridine or N-methyl-2- pyrrolidone. 11. An improved process for the preparation of escitaslopram of formula-(+)-I and its pharmaceutically acceptable salts substantially as described herein with reference to the Examples. 12. A Process for the preparation and isolation of compoimds of the formulae-XII, (-)-IV, (+)-V which are intermediates used in the preparation of escitaslopram of the formula-(+)-I, substantially as described in example 1 and 2.

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