Title of Invention

PROCESS FOR THE PREPARATION OF ESCITALOPRAM

Abstract

The present invention discloses a process for the preparation of the antidepressant drug, Escitalopram, chemically designated as S-(+)-1-(3-dimethylaminopropyl)-l-(4-fluoro-phenyl)-I,3-dihydroisobenzofuran-5-carbonitrile (Formula-I), or it"s pharmaceutically acceptable salts. The invention further discloses improvements in the process for preparation of intermediate compound of Formula-11; novel compounds of Formula-III, Formula-IV and Formula-V; and Escitalopram or its pharmaceutical salts substantially free of said novel compounds.

Full Text

FORM 2 THE PATENTS ACT 1970 (39 of 1970) AND The Patents Rules, 2003 PROVISIONAL SPECIFICATION (See section 10 and rule 13) 1. TITLE OF THE INVENTION: "Process for the preparation of Escitalopram" 2. APPLICANT: (a) NAME: IPCA LABORATORIES LTD. (b) NATIONALITY: Indian Company incorporated under the Indian Companies ACT, 1956 (c) ADDRESS: 48, Kandivli Industrial Estate, Charkop, Kandivli (West), Mumbai-400067, Maharashtra, India. 3. PREAMBLE TO THE DESCRIPTION The following specification describes the invention. Field of the invention: The present invention relates to a process for the preparation of the antidepressant drug, Escitalopram, chemically designated as S-(+)-l-(3-dimethylaminopropyl)-l-(4-fluoro-phenyl)-l,3-dihydroisobenzofuran-5-carbomtrile (Formula-I), or it's pharmaceutically acceptable salts. The invention further relates to an improved process for preparation of intermediate compound of Formula-II; novel compounds of Formula-Ill, Formula-IV and Formula-V; and Escitalopram or its pharmaceutical salts substantially free of said novel compounds. Formula -I Formula -II Background of Invention: Escitalopram is the S-(+)-isomer of Citalopram which is an active agent used for the treatment of depression. Racemic citalopram and its use were disclosed in US4136193 patent. Preparation of enantiomers of citalopram, & its pharmaceutical salts like oxalate, and their use were disclosed in US 4943590 (herein after referred as '590 patent) that corresponds to European Patent 0347066 Bl. The process disclosed in these patents is outlined in the following general scheme. Scheme -1 Sulfonyl halide '"^\/N 2 According to'590 patent, Escitalopram was prepared from (-)-(S)-4-(4-dimethylamino)-l- (4'-fluorophenyl)-l-(hydroxybutyI)-3-(hydroxymethyl)-benzonitrile (Formula-II, hereinafter also referred as S-diol) by a stereoselective ring closure via formation of a labile ester. The process comprised of reaction of S-diol intermediate with methanesulfonyl chloride in a dry organic solvent like dry toluene in presence of an organic base like triethylamine. The resulting diastereomers were isolated by chromatography or fractional crystallization. However, this procedure resulted in lower optical purity of Escitalopram isomer, which was purified by fractional crystallization or chromatography to increase purity. Although the ring closure of S-diol proceeds with mainly retention of configuration, however, inversion of configuration also taking place to a small extent leading to the opposite enantiomer, and ultimately lowers the optical purity and yields of Escitalopram obtained by such process. Lower optical purity of target enantiomer necessitates purification from the mixture mainly with chromatography, as exemplified in '590 patent. A second method described in '590 patent is via the derivatization of racemic diol with optically active acid derivatives forming diastereomeric esters, and subjecting diastermeric isomer separation by column elution or fractional crystallization, followed by ring closure of the selected isomer to obtain Escitalopram. This method also mainly relies on column purification to separate the isomers, as exemplified for getting optically pure Escitalopram. '590 patent describes a method to prepare the enantiomers of 4-(4-dimethylamino)-l-4'-dimethylamino)-4'-fluorophenyl)-l(hydroxybutyl)-3-hydroxymethyl)-benzonitriIe for use in preparing Escitalopram comprising resolution of racemic 4-(4-dimethylamino)-l-4'-dimethyIamino)-4'-fluorophenyI)-l(hydroxybutyl)-3-hydroxymethyI)-benzonitriIe with optically pure acids like (+) di p-toluoyl tartaric acid. A purified hydrobromide salt form of racemic diol (Formula-VII, where X is cyano) was used in the process which was requiring neutralization with NaOH before proceeding for resolution. But, carrying out the conversion of acid salt into free base form of Formula -VII through extractive work¬up process before resolution step makes the process lengthy and cumbersome due to the increased number of unit operations and therefore such process may not be economically 3 desirable from an industrial standpoint, in addition, to the lower optical purity of Escitalopram in the ring closure reaction. In subsequent publications - WO 2003/006449 and WO2006136521- similar processes were used i.e., the Escitalopram was prepared by treating S- diol with a sulphonyl chloride in an organic solvent in the presence of a base. These applications also revealed less yield and less optical purity of Escitalopram due to the aforementioned issues. US2004/0259940 describes a method to invert the configuration of opposite isomer of diol (i.e., R-diol) to form a mixture of citalopram isomers enriched with Escitalopram by treating the R-diol with acids such as dilute H2SO4 in an organic solvent. For retention of configuration this patent had suggested to use the conditions of US 4943590, i.e., via labile ester formation. Although this inversion process is useful for utilizing the unwanted isomer of diol, but is not applicable for making use of S-diol due to inversion of configuration resulting into racemic mixtures. Further, the ring closure of diol results in a mixture of citalopram isomers, which needs to be separated to obtain optically pure Escitalopram. The preparation of racemic diol (Formula - VII) by two successive Grignard reactions was disclosed in US 4650884. The diol compound was converted to hydrobromide salt in order to get purified diol compound. WO2006106531 disclosed racemic diol preparation by two successive Grignard reactions, yet the diol is purified by making the HBr salt. This diol salt was neutralized with base before resolution using optically pure acid such as di-p-toluoyl tartaric acid. Another publication, WO2007012954, describes use of oxalic acid to replace Hydrobromic acid for purifying the racemic diol, which was then neutralized with a base following an extractive work-up before proceeding for resolution with an optically active acid such as (+) di-p-toluoyl tartaric acid in order to prepare high purity Escitalopram. Thus it is evident from the above study that the ring closure of S-diol with retention of configuration was typically performed in dry organic solvents. However, Escitalopram 4 yield reaches only 76-85% percent, depending upon the solvents or character of sulfonyl chloride used and may need additional purifications mainly through column chromatography for obtainment of high purity Escitalopram. Consequently, there is a need for improved process to prepare optically pure Escitalopram ensuring better optical purity in the stereo selective ring closure of S-diol with retention of configuration and increasing the product yield, and also reduces the processing steps involved in preparation and purification of intermediate diol of Formula-VII. The present invention addresses this need. Summary of the invention: Accordingly, in a first aspect of the invention, there is provided a process for the preparation of Escitalopram of Formula-I or its salts thereof; Formula -I comprising reacting a compound of Formula -VIII wherein X - is cyano or a group which may be convertable to cyano, with an agent capable of forming a labile O-carboxyl/sulfonyl ester in a solvent medium comprised of a mixture of aqueous and organic solvent(s). The aqueous-organic solvent system 5 preferably forms a biphasic medium, wherein at least one organic solvent is selected from water immiscible solvents. The labile ester forming agent is selected from sulfonyl halides/anhydrides, acid halides or anhydrides. The ring closure reaction is effected preferably in presence of an organic or inorganic base substance. When the group X is other than cyano, the cyclized product is converted to escitalopram or its salts by transforming X- into cyano in a conventional manner. In a preferred embodiment, present invention provides a process for the preparation of Escitalopram having Formula -I and salts thereof comprising reacting S-diol having Formula - VIII with the labile ester forming agent in biphasic solvent system in the presence a catalyst, and optionally converting group X to CN, wherever applicable. According to another aspect of invention, the present invention also provides a process for preparation of S-diol or its salts of Formula-VIII comprising a) preparing Racemic diol of Formula -VII by successive Grignard reaction of Formula-IX with p-Fluoro phenyl magnesium halide, followed by 3-dimethylaminopropyl magnesium halide, respectively ; b) isolating racemic diol in free base form from the reaction mixture obtained in step (a); c) subjecting the diol obtained in step (b) to direct resolution with an optically active acid to separate diastereomeric salt of S-diol; and optionally d) neutralizing the diastereomer salt to obtain S-diol. In yet another aspect, the invention relates to novel compounds of Formula -III, Formula -IV and Formula -V. Forrmula - Forrmula -IV Formula -V 6 The present invention further provides Escitalopram substantially free of compounds of Formula-Ill, Formula-IV and Formula-V. The present invention also provides pharmaceutical compositions comprising the Escitalopram free of compounds of Formula-Ill, Formula-IV and/or Formula-V or Escitalopram obtainable according to the process of the present invention. Detailed description of the invention: While the invention will now be described in detail in connection with certain preferred and optional embodiments so that various aspects thereof may be more fully understood and appreciated, it is not intended to limit the invention to these particular embodiments. The inventors have now found an improved process for obtaining Escitalopram and salt thereof in high yield and optical purity by stereoselective ring closure of S-diol with an agent capable of forming a labile O-carbonyl/sulfonyloxy ester in a solvent medium comprised of aqueous-organic solvent(s), wherein the new method ameliorates problems associated with the methods mentioned in the prior art. The ring closure reaction is preferably carried out in presence of a base substance, customarily used for this reaction. The aqueous-organic solvent system preferably forms a biphasic medium containing an aqueous phase and an organic phase, wherein at least one organic solvent is selected from water immiscible solvents. The aqueous phase comprises preferably water. Aqueous phase may also contain non-protic water miscible solvents in small proportions. The suitable water immiscible solvents includes, but not limited to, aliphatic or aromatic hydrocarbons, chlorinated hydrocarbons, esters, ethers etc. Chlorinated hydrocarbons preferably include methylenedichloride, ethylenedichloride, chloroform, carbontetrachloride, and aromatic hydrocarbons preferably selected from toluene, xylene, and aliphatic hydrocarbons include hexane, cyclohexane, heptane etc. Esters include ethyl acetate or butyl acetate. Ether includes diisopropyl ether or diethyl ether. Most preferably the water immiscible solvent is methylenedichloride (MDC) or toluene. The proportion of the aqueous-organic solvents can be worked out by a skilled artisan on a trail and error basis. However, a proportion of 20:80 to 80:20 (Organic solvent: water) 7 may be preferred for good mixing and better reaction. The volume of solvent, although not critical, but may be selected based on the maintenance of appropriate concentration of reactants in the medium. The labile sulfonyloxy/carboxy ester forming agent is selected from sulfonyl halides/anhydrides, acid halide or anhydrides. The preferred sulfonylating agents are selected from readily available sulfonyi halides such as, but not limited, alkyl sulfonyi halide like methane sulfonyi chloride, and aromatic sulfonyi halide like benzene sulfonyi chloride, toluene sulfonyi chlorides etc. Aromatic sulfonyi halides are preferred for better optical purity and yield, and p-toluene sulfonyi chloride is especially preferred. In place of sulfonyi halide, a sulfonyi anhydride may also be used. Alkyl ester forming agents are preferably selected from organic acid halide/anhydride, and pivaloyl chloride is especially preferred. During the reaction, sulfonyi halides/acylating agent may be used in molar equivalent amount or in excess with respect to the S-diol (Formula-VIII), but preferably in the range of 1.1 -2.5 moles, most preferably 1.3-1.8 moles, relative to mole of S-diol. The base substance used in the ring closure reaction may be selected appropriately from an organic or inorganic class of compounds. The most preferred organic bases are alkyl amines for example triethyl amine, diisopropyl ethylamine or ammonia, or pyridine or dimethylaminopyridine or tetrabutylammonium hydroxide or the like. Inorganic bases are preferably selected from metal alkoxide, or carbonates, exemplary bases include, but not limited to sodium/potassium hydroxide, sodium/potassium carbonates or bicarbonate or the like. The base is conveniently used in an amount, although not limited to, equal or greater than molar equivalents relative to the starting intermediate S-diol of Formula-VIII, preferably in a range between 1.5 to 5.0 moles, more preferably between 2.5 to 3.5 moles. When inorganic base is used in the process, it is preferably dissolved in water and used as aqueous solution. According to a preferred embodiment of the invention, the ring closure of S-diol of Formula-VIII with labile ester forming agent is carried out in a biphasic solvent system, optionally in the presence of a catalyst. The catalyst may be selected from among the phase-transfer catalyst or metal iodide. The selection or presence of said catalysts accelerate the reaction and reduces the time cycle. However, the similar results may be obtained in its absence; however, owing to the economy of the process it is preferred to 8 be used. Sodium or potassium iodide is especially preferred among the metal iodides. As the phase transfer catalyst, mention can be made of, for example, quaternary ammonium salts, phosphonium salts and crown ethers. Among these phase transfer catalysts, quaternary ammonium salts substituted with a straight or branched chain alkyl group having 1-18 carbon atoms such as tetrabutylammonium bromide are particularly preferred. Tetrabutyl phosphonium chloride may be preferred among phosphonium salts. It is recommended to use the phase transfer catalyst usually in an amount of 0.01-1.0 mol and preferably 0.1-0.25 mol per mol of starting S-diol (Formula-VIII), and to use the metal iodide in an amount of 0.1 to 1.0 mole and preferably in 0.05 to 0.3 mole per mol of the S-diol (Formula-VIII), respectively. The reaction is recommended to be carried out with appropriate cooling or at room temperature, preferably at a temperature range between -15 to 35°C. Especially preferred temperature for reaction is about -5 to 5°C. The reaction time is usually from about 2 hours to about 5 hours. Once the reaction is completed the product may be isolated by conventional methods such as filtration, centrifugation, extraction or similar unit operations as exemplified in the accompanying illustrative examples. The Escitalopram obtained according to the process of the present invention is then transformed into pharmaceutically acceptable salts, especially oxalate salt by any conventional method known in the art. In case, the substitutuent X in the Formula-VIII, is a group other than cyano, it is converted to cyano group after the ring closure. X may be a group readily convertible to cyano-function, such as bromo or iodo-group or a carboxyl radical. The starting S-diol can be prepared by resolution of racemic diol compound, which may be obtained by successive Grignard reactions of a substituted phthalide of Forumula-IX, preferably cyanophthalide, with p-Fluoro phenyl magnesium halide, followed by 3-dimethylaminopropyl magnesium halide, respectively. In case the starting phtahlaide is substituted with a group other than cyano, such functional group may be converted to cyano group in diol stage or after the ring closure, wherever appropriate. The obtained 9 diol may be purified by formation of acid salts such as HBr or HC1 as customarily known, prior to the optical resolution process. The S-diol is obtained by optical resolution of the racemic diol with optically active tartaric acids, such as di-p-toluoyltartaric acid or di-benzoyltartaric acid. The inventors have found an improved process for preparation of S-diol, which obviates the need for purification of the racemic diol by acid salt formation after its preparation through aforementioned successive Grignard reaction. Thus according to this aspect, the invention provides a process for preparation of S-Diol or its salts of Formula-VIII comprising a) preparing Racemic diol of Formula-VII by successive Grignard reaction of formula-DC with p-Fluoro phenyl magnesium halide, followed by 3-dimethylaminopropyl magnesium halide, respectively ; b) isolating racemic diol in free base form from the reaction mixture obtained in step (a); c) subjecting the diol obtained in step (b) to direct resolution process with an optically active acid to separate diastereomeric salt of S-diol; and optionally d) neutralizing said diastereomeric salt to obtain the S-diol. The process for the preparation of S-diol is shown in reaction scheme-2. SCHEME -2 F b + Wherein X as defined before & Y is a halide. 10 1 .Optical acid/Solvent 2. Aq.NH3/MDC Formula -VII Formula-VIII Especially preferred p-Fluoro phenyl magnesium halide is p-Fluoro phenyl magnesium bromide and 3-dimethylaminopropyl magnesium halide is 3-dimethylaminopropyl magnesium chloride. Both the Grignard reagents may be freshly prepared and used in the reaction as exemplified. Formula -X Accordingly, in a preferred embodiment, 5- Cyanophthalide is reacted with p-fluorophenylmagnesium bromide (Grignard reagent -01) solution in an organic solvent by slow addition, over a period of 2-20 hours, preferably 12-15 hours, under cooling to obtain the intermediate of Formula-VI, followed by slow addition of 3-dimethylaminopropyl magnesium chloride (Grignard reagent -02) over a period of 2-5 hours, preferably 2-3 hours, under cooling to get racemic diol of formula-VII. The addition as well as the molar ratio of the Grignard reaction is adjusted to minimize the formation of dimer of Formula-X in the first Grignard stage. Typically this is formed to an extent of 27-30% in known processes, wherein the present improvement reduces impurity to about 5-10% levels. The organic solvent may be chosen from those customarily used for Grignard reaction such as tetrahydrofuran, 2-methyltetrahydrofuran or toluene or mixture thereof. According to the present invention, the especially preferred mole ratio of Grignard reagent-1 is between 1.05 and 3.0 moles, more preferred range is 1.6 to 2.0 moles, and Grignard reagent-2 is used in an amount range from 1.05 to 3.5 moles, more preferred range is 2.0 to 2.2 moles to limit the formation of impurities. The said crude racemic diol obtained after Grignard reaction is isolated in the free base form by pH based solvent extraction and directly used for resolution without having a salt forming purification step. The resolution is carried out by forming a diastereomer salt of an optically active acid in a suitable organic solvent such as isopropyl alcohol solvent followed by fractional crystallization to precipitate the diastereomer salt of S-diol of desired optical purity. Preferred optically active acids are di-p-toluoyltartaric acid, di-benzoyltartaric acid, bisnaphthylphosphoric acid and / or 10-camphorsulphnic acid. Most preferred acid is (+)di-p-toluoyI tartaric acid. The diastereomeric salt is isolated by filtration accompanied by neutralization to provide the optically pure S-diol. This improved process of subjecting crude diol without a salt forming purification step, the yield of S-diol as well as Escitalopram were increased significantly, yet both higher chemical and optical purity was achieved in the present invention. In the process for Escitalopram, the inventors have identified formation of three compounds having the structure as shown in Formula - III, Formula-IV and Formula-V. These three impurities are not disclosed or characterized in prior literature and thus forms part of the present invention. During the citalopram process, these compounds are found to be in a level of about 0.1% or more. The present invention, therefore, provides Escitalopram substantially free of the said impurities (either Formula- III, Formula - IV or Formula-V or both) in which III & IV are suspected genotoxic agents. Escitalopram prepared according to the present invention is converted to a pharmaceutically acceptable salt, for example oxalate salt by reacting Escitaloproam base with oxalic acid dihydrate in a suitable solvent. The Escitalopram oxalate obtained by the process of the present invention, may be formulated into a suitable dosage form such as tablets, capsules, etc., by combining with 12 one or more pharmaceuticaUy acceptable excipients using known techniques. The dosage form may include a suitable amount of the active ingredient and other pharmaceutical agents. The dosage forms prepared by the process of the present invention may be administered to a mammal in need, for treatment of depression. The following examples, which include preferred embodiments, is intended to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention. Example-1 Preparation of Escitalopram: In a 250 ml flask, 10 gm (0.029m) of S-diol (Formula VIII, wherein X=cyano) was dissolved in a mixture of 100 mL of dichloromethane (MDC), 40 mL of water and 0.1 g of Aliquat was added. The mixture was cooled to 0°C and 8.25 g triethyl amine was added. Then, 6.13 g (0.032m) of p-toluenesulfonylchloride was added drop-wise by maintaining at 0-5°C and further maintained the mixture for 2 hours to complete the reaction. 50 mL 10% NaCl aqueous solution was added and layers were separated. The MDC layer was washed with 2 x 25 mL of water. MDC layer was distilled under vacuum at 35°C to get 9.3 gm (98.9 % yield) Escitalopram as oil. (Chiral purity : 99.4 % S- isomer: 0.6% R-isomer as per Chiral HPLC analysis) Example -2 Preparation of Escitalopram: In a 250 mL flask, 10 gm (0.029m) of S-diol (Formula VIII, wherein X=cyano) was mixed with 100 mL of dichloromethane, 20 mL of water and 0.1 g of Aliquat was added. The mixture was cooled to -5°C and 8.0 g Na2CO3 dissolved in water (20 ml) was added. Then 6.13 g (0.032 moles) of p-toluenesulfonylchloride was added drop-wise at 0-5°C and further maintained for 2 hours to complete the reaction. Then escitalopram was isolated as per the example-1 and 8.9 g (94.6 % yield) Escitalopram as oil was obtained. (Chiral purity: S-isomer =99.2 % : R-isomer= 0.8 % by chiral HPLC). 13 Example 3. Preparation of S-Diol (Formula VIII, wherein X=cyano) A) Preparation of (+)-di-p-toluoyltartaric acid salt of S-diol. To a dry 2 liter reaction flask, 50 gm (0.314 moles) of 5-cyanophthalide and 200 mL of tetrahydrofuran (THF) were added under N2 atmosphere. The mixture was cooled to -6°C, p-Fluorophenylmagnesiumbromide solution in THF (prepared by reaction of 13.5 gm Magnesium and 15 ml of p-bromofluorobenzene in 15 THF) was added drop-wise over a period of 12-15 hours at 2-8°C. After agitating for half an hour, the mass was cooled to 0°C and 3-dimethylaminopropyl magnesiumbromide solution (prepared from 175 gm 3-dimethylaminopropyl chloride in mixture of 40 ml toluene and 200 ml tetrahydrofuran) was added drop-wise over a period of 3 hours at -2 to 2°C and further maintained till completion of reaction. The reaction mass was added into 600 mL of ice cold water and aqueous acetic acid solution (prepared by mixing 125 mL of AcOH with 200 mL of water) was added. THF was distilled under vacuum from the mixture, cooled to 20°C and 300 mL of toluene was added. Then pH was adjusted between 9-10 with aq.ammonia and layers were separated. The toluene layer washed with aqueous acetic acid (60 mL acetic AcOH mixed with 200 mL water) and separated aqueous layer. The aqueous layer mixed with toluene and neutralized with ammonia and then separated layers. The toluene layer is concentrated under vacuum to get crude racemic diol. The residue (racemic diol) was dissolved in 640 mL of isopropyl alcohol (IPA), heated to 40-5°C and 45 g (0.5m) of (+)-di-p-toluoyltartaric acid was added and further maintained the mass for another 30 minutes at 40°C to precipitate the diastereomer. The mixture then, cooled slowly to 30°C and further maintained for 3-5 hours at 30°C for complete crystallization. The precipitate was filtered, washed with 80 mL of IPA, and dried to get (+)-di-p-toluoyltartaric acid salt of S-diol (36 gm). B) Neutralisation of (+)-di-p-toluoyltartaric acid salt of S-diol: 23 gms (+)-di-p-toluoyltartaric acid salt of S-diol was suspended in 92mL MDC, cooled to 10°C and 20% NH3 solution was added . After agitating for 1 hour at 10°C, layers were separated and MDC layer is dried over sodium sulfate. Distilled out MDC from organic layer under vacuum to obtain 16 gm S-diol as oil (Chiral purity : S-isomer= 99.8 %,R-isomer = 0.2%). 14 Example 4. Preparation of Escitalopram oxalate 32 g of Escitalopram base was dissolved in 160 mL acetone and 13.66 g of oxalic acid dihydrate was added. The mixture was stirred at room trmperature for one hour to obtain precipitate and filtered. Washed the cake with chilled acetone and dried to obtain 33 g Escitalopram Oxalate (Chiral purity of S-isomer: 99.5% and R-isomer: 0.5%) It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative examples and that the present invention may be embodied in other specific forms without departing from the essential attributes thereof, and it is therefore desired that the present embodiments and examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Dated this 11th Day of September 2008 15 We claim, 1) A process for the preparation of Escitalopram of Formula-I or its salts thereof; comprising reacting a compound of Formula -VIII, X. F Formula -VIII wherein X is cyano or a group which may be convertable to cyano, with an agent capable of forming a labile O-carboxyl or sulfonyl ester in a biphasic solvent medium. 2) The process according to claim 1, wherein the agent capable of forming a labile O-carboxyl or sulfonyl ester is selected from sulfonyl halide such as alkyl sulfonyl halide and aryl sulfonyl halide; sulfonyl anhydride, acid halide and anhydride. 3) The process according to claim 1, wherein the biphasic medium comprises an aqueous phase and an organic phase comprises water immiscible solvents.. 4) The process according to claim 1, wherein the reaction is performed in the presence of an organic base or inorganic base. 5) The process according to claim 1, wherein the reaction is in the presence of a catalyst such as phase transfer catalyst or metal halide. 6) A process for the preparation of S-diol of Formula-VIII or its salts, wherein X is cyano or a group which may be convertable to cyano, comprising; 16 r Formula -VIII a) preparing racemic diol of Formula -VII by successive Grignard reaction of Formula-IX with p-fluoro phenyl magnesium halide, followed by 3-dimethylaminopropyl magnesium halide, respectively ; b) isolating racemic diol in free base form from the reaction mixture obtained in step (a); c) subjecting the diol obtained in step (b) to direct resolution with an optically active acid to separate diastereomeric salt of S-diol; and optionally d) neutralizing the diastereomeric salt to obtain S-diol. 7) A compound of Formula -III NC 8) A compound of Formula -IV F Forrmula -IV 17 9) A compound of Formula -V 10) Escitalopram or it's oxalate salt substantially free of Formula-Ill, IV and/or Formula-V. Dr. P. Aruna Sree Agent for the Applicant

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