Field of Invention The present invention relates an improved process for the preparation of

Escitalopram, which is the S-enantiomer of well known antidepressant drug Citalopram, /. e. (S)- 1 -[3 -(dimethylamino)propyl] - 1 -(4-flouorphenyl)- 1 ,3 -dihydro-5 - isobenzofuran carbonitrile or a pharmaceutically acceptable salt thereof. Background of Invention Citalopram is a well-known antidepressant drug that has now been in the market for some years and has the following structure shown in figure 1 :

Figure 1 It is a selective centrally acting serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly having antidepressant activities.

Citalopram was first disclosed in DE 2,657,013, corresponding to US 4,136,193. This patent publication outlines a process for preparation of Citalopram from the corresponding 5-bromo derivatives by reaction with cuprous cyanide in a suitable solvent. US' 193 describes the C-alkylation reaction of 5-cyanophthalane with 3-NjN'-dimethylaminopropyl chloride using sodium hydride as a base ϊn dimethyl sulphoxide (DMSO) medium. 13 volumes of DMSO is used in this reaction with respect to 5-cyanophthalane. After the completion of the reaction Citalopram base is isolated as oil, which is purified by high vacuum distillation (0.03mm at 175-18O ⁰ C) and then converted into acid addition salts by conventional methods. A main drawback of this process is the need to purify the oily Citalopram base using high vacuum distillation (0.03mm) at 175-18O ⁰ C. Achieving such a high vacuum at plant level is difficult and apart from these constraints, the process has another drawback in that Citalopram base having a cyano group at the 5 ^th position of the bicyclic ring system may decompose during high vacuum distillation at high temperature to form

Citalopram carboxamide as one of the impurity, resulting in poor quality product and yield.

Another drawback of US' 193 is the use of 13 volumes of DMSO as a reaction medium for generation of sodium salt of DMSO (demsil ion). DMSO being a very polar solvent may result in the formation of impurities such as l-[3- (dimethylamino)propyl] - 1 -(4-fluorophenyl)-5 -acetyl- 1 ,3 -dihydroisobenzofuran (acetyl Citalopram), 1 - [3 -(dimethylamino)ρropyl]- 1 -(4-fluorophenyl)-5 -acetyl- 1,3- dihydroisobenzofuran carboxamide (amide), l-[3-(dimethylamino)propyl]-l-(4- fluoropheny^-S-acetyl-l^-dihydroisobenzofuran-S-carboxalic acid (acid) and l-[3- (methylamino)propyl]-l-(4-fluorophenyl)-5-acetyl-l,3-dihydro isobenzofuran-5- carbonitrile (desmethyl) are formed during the workup due to the degradation and decomposition of the reaction mass, resulting in poor quality of Citalopram.

US Patent No.4,650,884 discloses diol of formula (II), 4-[4-(dimethylamino)-l- (4 ' -fluorophenyl)- 1 -hydroxy- 1 -butyl] -3 -(3 -hydroxy methyl)-benzonitrile, its preparation and use as an intermediate in the preparation of Citalopram. Further processes for the preparation of Citalopram by exchange of 5-halogen or CF ₃ -(CF ₂ ) _n - SO ₂ -O-, n being 0-8, with cyano are disclosed in WOOOl 1926 and WO0013648.

Escitalopram, the pharmaceutical activity thereof and crystalline oxalate are disclosed in US Patent no. 4,943,590. Methods for the preparation of Escitalopram along with the disclosure of Escitalopram free base existing as an oil as well as the oxalic, pamoic and L-(+)-tartaric acid addition salts of Escitalopram are disclosed in US'590.

In US'590, two routes are disclosed, both of them starting with racemic diol. In the first route (scheme 1) the diol is reacted with enantiomerically pure derivatives such as (+) or (-)-α-methoxy-α-trifluoromethylphenyl acetyl chloride to form a mixture of diastereomeric esters, which are separated by HPLC or fractional crystallization, where upon the ester with the right stereochemistry is enantioselectively converted into Escitalopram. In the second route the diol is separated into enantiomers by stereo selective crystallization with an enantiomerically pure acid such as (+)-di- _J p- toluoyltartaric acid, whereupon the S-enantiomer of the diol is enantioselectively converted to Escitalopram. Both of theses routes involve consumption of expensive, enantiomerically pure reagents, and give relatively low yields resulting in products which are economically infeasible for industrial production.

ration

Scheme-1

In WO 03/006449 process for the preparation of Escitalopram is disclosed. According to this publication the diol 4-[4-(dimethylamino)- 1 -(4 '-fluorophenyl)- 1 - hydroxy- 1 -butyl] -3 -(3 -hydroxy methyl)-benzonitrile is separated into its enantiomers by chromatography using a chiral stationary phase. The obtained enantiomerically pure isomer can be transformed into Escitalopram by treating with p-tohiene sulphonyl chloride in the presence of base such as triethylamine. This process requires additional chromatographic purification to get pure Escitalopram. The salt is subjected to crystallization in a solvent medium to get enantiomerically enriched crystalline form (scheme 2).

Diol p-toluene sulphonyl Chloride triethyl amine

(+) Escitalopram

Scheme 2

WO 03/087081 discloses the process in which the racemic diol intermediate is treated with optically active acid such as (+)-di-/?-toluoyl tartaric acid to form a diastereiomeric salt. It is subjected to enantiomeric selective cyclization to get 5- substituted Escitalopram, which is replacement of bromine by a nitrile group to get pure

Escitalopram (scheme 3).

tartaric acid

diol ester

Methane sulphonyl chloride Potassium t-butoxide

Scheme-3

There is no method, which enables one, a priori; to forecast which solvent system is effective in separating a given pair of enantiomers In highly pure form and in high yields. Therefore there is a need to develop an improved process for Escitalopram production that can be employed commercially. Especially such an improved process would be welcome considering the difficulties associated with the commercial application of the above-mentioned processes for the preparation of Escitalopram. Keeping this aspect into consideration, we aimed to develop a simple and economical process for commercial production of Escitalopram.

Objects of the invention

It is, therefore, an important object of the present invention to provide an improved and economically feasible process for the preparation of Escitalopram upon limitations in the prior art. It is another object of the present invention to provide an improved process for the preparation of Escitalopram of formula (I) in a way to improve the yield and purity and obviates the formation of byproduct.

It is another object of the present invention to provide a process for the preparation of pure crystalline Escitalopram base and its acid addition salts thereof. It is another object of the present invention to provide to provide a process for the preparation of highly pure Escitalopram or its acid addition salts thereof. Summary of the Invention

The above and other objects of the present invention are achieved by inter alia, by the separation of enantiomerically pure diol or its ester derivatives from a racemic compound by reacting it with optically pure acid in a mixture of solvent system.

Accordingly, the present invention provides a process for the preparation of highly pure Escitalopram or its acid addition salts thereof, which comprises: a) reacting racemic diol or its ester derivative (III) with an optically active acid and at least one solvent to get enantiomerically pure diastereomer (IHA); b) separating the enantiomerically pure diastereomer (IIIA) from its optically active acid salt by treating it with base and followed by stereo selective cyclization; c) separating the Escitalopram base;

Preferably, said optically active acid is selected from the group consisting of tartaric acid, diberizoyl tartaric acid, di-j9-toluoyl tartaric acid, bis-napthyl phosphoric acid, and 10-camphor sulphonic acid.

Preferably, said solvent is selected from the group consisting of lower alcohol having 1 to 4 carbon atoms such as methanol, ethanol, isopropyl alcohol and butyl alcohol; acetonitrile; acetone or any mixture thereof. Preferably, said base is selected from the group consisting of triethyl amine, alkali metal carbonates, bicarbonates and their hydroxides and liquid ammonia.

Preferably, said stereo selective cyclization is carried out by reacting with methane sulphonyl chloride or p-toluene sulphonyl chloride in presence of a base. Preferably, said base is triethyl amine.

Preferably, said enantiomerically pure diastereomer (IIIA) is optionally purified in a solvent or a mixture of solvents.

Preferably, said solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol, ethyl acetate and acetone or mixture thereof. Preferably, said Escitalopram or its acid addition salt is purified using a mixture of solvents.

Preferably, said mixture of solvents contains at least isopropyl alcohol and one or more of methanol, ethanol, ethyl acetate, acetone or mixtures thereof.

Preferably, said highly pure Escitalopram is optionally converted into its acid addition salt.

In a preferred embodiment, the Escitalopram or its acid addition salts of the present invention have a chiral purity of 99.5% or greater and HPLC purity of 99.5% or greater.

In a preferred embodiment, the Escitalopram or its acid addition salts of the present invention have a a chiral purity of 99.5% or greater and HPLC purity of 99% or greater.

In a preferred embodiment, the Escitalopram or its acid addition salts of the present invention have a a chiral purity of 99% or greater. Detailed description of the invention The disclosed embodiment of the present invention deals with a process for the preparation of highly pure Escitalopram or its acid addition salts thereof of formula (I) according to scheme 4;

acid salt

(+)

I

Pure Escitalopram Oxalate

Scheme 4

which comprises: a) reacting racemic diol or its ester derivative (III) with an optically active acid and at least one solvent to get enantiomerically pure diastereomer (IIIA); b) separating the enantiomerically pure diastereomer from its optically active acid salt by treating it with base and followed by stereo selective cyclization; c) separating the Escitalopram base; d) optionally, converting Escitalopram base into its acid addition salt.

According to process of the present invention, racemic diol compound of formula III is treated with pure optically active acid in a mixture of solvents to get an enantiomerically pure diol of formula IIIA. The optically active acid used herein is selected from the group consisting of but not limited to tartaric acid, dibenzoyl tartaric acid, di-p-toluoyl tartaric acid, bis-napthyl phosphoric acid, and 10-camphor sulphonic acid preferably di-jι?-toluoyl tartatic acid. The reaction is carried out in a solvent selected from the group consisting of lower alcohol having 1 to 4 carbon atoms such as methanol, ethanol, isopropyl alcohol and butyl alcohol; acetonitrile; acetone or mixture thereof preferably in a mixture of methanol and isopropyl alcohol. The reaction is carried out firstly at a temperature of 40-60 ⁰ C and then at a temperature of 20-25 ⁰ C for a period of 6-24 hrs. The reaction mixture is then cooled to 0-5 ⁰ C to get the solid material, which is separated by filtration to get a compound of formula IIIA with a chiral purity of greater than 99%.

The compound of formula IIIA is optionally purified using a mixture of solvents to get the chiral purity in the range of 99.5-99.8%. The solvent used herein is selected from the group consisting of but not limited to methanol, ethanol, isopropyl alcohol, ethyl acetate and acetone or mixture thereof preferably methanol and isopropyl alcohol or methanol and ethanol. The purification is carried out by dissolving the compound of formula IIIA in a mixture of solvent at a temperature of 40-60 ⁰ C and then cooled to 0- 5 ⁰ C. Solid material is filtered to get the compound of formula IIIA with a chiral purity in the range of 99.5-99.8%.

The compound of formula IIIA is treated with base to get converted into a free diol (chirally pure), which is then subjected to stereo selective cyclization to get a compound of formula 11 i.e. Escilalopram base in chirally pure form with chiral purity greater than 99%.

The enantiomerically pure optically active acid salt of diol is then converted to optically pure diol by treating with a base in presence of water or optionally in a mixture of water and water immiscible solvent. The base used herein is selected from the group consisting of organic and inorganic base. Organic base are selected from the group of triethyl amine whereas inorganic base are selected from the group of alkali metal carbonates, bicarbonates and their hydroxides and liquid ammonia. The reaction is carried out at a basic pH range of 7.0-9.0 preferably 8.0-8.5 and at a temperature range of O ⁰ C to room temperature. The resulting solution is then extracted with water immiscible organic solvents to get the optically pure diol compound. The solvent used

herein is selected from the group consisting of toluene, chloroform, dichloromethane and dichloroethane preferably dichloromethane. Optically pure diol as such i.e. without isolation, is further subjected to stereo selective cyclization by reacting with a methane sulphonyl chloride or p-toluene sulphonyl chloride in presence of triethyl amine and a solvent system i.e. dichloromethane. After completion of the reaction, liquor ammonia is added to the reaction mass and separated the layers. The organic layer is washed with water and extracted with 10-20% aqueous acid. The aqueous acid group is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid and acetic acid preferably acetic acid. The aqueous extract is then diluted with water miscible organic solvent. The solvent used herein is selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-propanol, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylacetamide, and dimethylsulfoxide preferably isopropyl alcohol. The pH of the resulting solution is adjusted to basic by employing base selected from sodium, potassium hydroxide, and ammonia solution. The preferred base employed to precipitate the Escitalopram base, is liquid ammonia. The reaction mass is cooled to 0-5 ⁰ C and the solid is separated by filtration to get crystalline Escitalopram base with a chiral purity in the range of 99.5-99.8%.

The crystalline Escitalopram base is then converted to its acid addition salts by reacting it with acid in presence of solvent. The solvent used herein is selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, acetonitrile, tetrahydrofuran or mixtures thereof preferably isopropyl alcohol. The amount of acid used herein is 1.0 equivalent to the Escitalopram base. The acid used herein is selected from the group consisting of oxalic acid, hydrochloric acid, and hydrobromic acid, preferably oxalic acid. The reaction mixture is stirred for 2-10 hours at 20-25 ⁰ C. The separated acid addition salts are filtered and washed with solvent to get pure Escitalopram acid addition salts.

The Escitalopram acid addition salt is further purified by employing simple purification in a solvent. The solvent used herein for purification is selected from the group consisting of methanol, ethanol, isopropyl alcohol, ethyl acetate, acetone or mixtures thereof preferably mixture of methanol and ethyl acetate or methanol and isopropyl alcohol.

The racemic diol of formula III is prepared according to the process already disclosed in prior art i.e. in WO2005077927.

In conclusion, this is an improved, economical and a high yielding process for the industrial production of highly pure Escitalopram base as well as Escitalopram acid addition salts using novel solvent system.

The following non-limiting examples illustrate specific embodiments of the present invention. They are, however, not intended to limit the scope of present invention in any way. Example 1:

Process for the preparation of 4-[4-(dimethylamino)-l-(4'-fluorophenyI)-l- hydroxy-l-butyl]-3-(3-hydroxy methyl)-benzonitrile (Diol) A solution of 4-fluorophenyl magnesium bromide (prepared from 153.3g 4- flouro bromobenzene, 25.3g magnesium turnings and Iodine (0.05gm) in dry 300ml tetrahydrofuran), was added to a suspension of lOOg 5-cyanophthalide in 900ml dichloromethane at -4 to -2°C. After the completion of the reaction a solution of 3- (N,N-dimethylamino)propyl magnesium chloride in toluene/THF mixture [generated in situ by reacting 175g 3-(N,N-dimethylamino)propyl chloride in 350ml toluene with 41.6gm magnesium turnings, 6.0 gin 4-bromofluorobenzene and Iodine in dry tetrahydrofuran] was added between 0 to -5 ⁰ C. The reaction mass was stirred for 3-4 hours. After completion of the reaction, the reaction mass was quenched with 20% aqueous ammonium chloride solution. The organic layer was separated and washed with water. Organic layer was then extracted with 20% acetic acid. The aqueous acid extract was cooled and pH was adjusted to 8.5 to 9.0 using liquor ammonia, and extracted with toluene 3 x 600ml. The toluene layer was washed with water, dried and then treated with carbon. Reaction mixture was filtered and subjected to salt formation to get Diol acid addition salts. Example 2:

Process for the preparation of (-)-4-[4-(dimethylamino)-l-(4'-fluorophenyl)-l- hydoxy-l-butyl]-3-(hydroxymethyl)-benzonitrile hemi (+)-di-p-toloyltartaric acid salt.

To a solution of 100 g of 4-[4-(dimethylamino)-l-(4'-fluorophenyl)-l-hydoxy- l-butyl]-3-(hydroxymethyl)-benzonitrile hydrobromide in 500 ml water 500 ml toluene was added. The pH of the solution was adjusted to 9.0 to 10.0 using 2M NaOH solution. The mixture was stirred for 30minutes and toluene layer was separated and dried. The organic layer was then removed under vacuum to get racemic diol base as oil. The oil was dissolved in a mixture of methanol (15OmL) and isopropyl alcohol

(30OmL) at 40-60 ⁰ C followed by the addition of (+)-di-p-toloyl tartaric acid hydrate (5Og) with vigorous stirring at 40-60 ⁰ C. The mixture was cooled to 20-25 ⁰ C and stirred for 6-10 hrs at the same temperature then cooled to 0-5 ⁰ C. The solid formed was filtered off and dried. Chiral purity: >99.0% Example 3:

Process for the preparation of (-)-4-[4-(dimethylamino)-l-(4'-fluorophenyl)-l- hydoxy-l-butyl]-3-(hydroxymethyl)-benzonitrile hemi (+)-di-p-toIoyItartaric acid salt. To a solution of 100 g of 4-[4-(dimethylamino)-l-(4'-fluorophenyl)-l-hydoxy- l-butyl]-3-(hydroxymethyl)-benzonitrile hydrobromide in 500 ml water 500 ml toluene was added. The pH of the solution was adjusted to 9.0 to 10.0 using 2M NaOH solution. The mixture was stirred for 30minutes and toluene layer was separated and dried. The organic layer was then removed under vacuum to get racemic diol base as oil. The oil was dissolved in a mixture of methanol (15OmL) and ethanol (20OmL) at 40-60 ⁰ C followed by the addition of (+)-di-p-toloyl tartaric acid hydrate (50g) with vigorous stirring at 40-60 ⁰ C. The mixture was cooled to 20-25 ⁰ C and stirred for 6-10 hrs at the same temperature then cooled to 0-5°C. The solid formed was filtered off and dried. Chiral purity: >99.0% Example 4:

Process for the preparation of (-)-4-[4-(dimethylamino)-l-(4'-fluorophenyl)-l- hydoxy-l-butyl]-3-(hydroxymethyl)-benzonitriIe hemi (+)-di-p-toIoyltartaric acid salt. Tυ u solution of 100 g of 4-[4-(dimethylamino)-l-(4'-fluoiophenyl)-l-hydoxy- l-butyl]-3-(hydroxymethyl)-benzonitrile hydrobromide in 500 ml water 500 ml toluene was added. The pH of the solution was adjusted to 9.0 to 10.0 using 2M NaOH solution. The mixture was stirred for 30 minutes and toluene layer was separated and dried. The organic layer was then removed under vacuum to get racemic diol base as oil. The oil was dissolved in a mixture of methanol (15OmL) and ethyl acetate (30OmL) at 40-60 ⁰ C followed by the addition of (+)-di-p-toloyl tartaric acid hydrate (50g) with vigorous stirring at 40-60 ⁰ C. The mixture was cooled to 20-25 ⁰ C and stirred for 6-10

hrs at the same temperature then cooled to 0-5 ⁰ C. The solid formed was filtered off and dried.

Chiral purity: >99.0% Example 5: Purification of (-)-4-[4-(dimethylamino)-l-(4'-fluorophenyI)-l-hydoxy-l-buty l]-3- (hydroxymethyl)-benzonitrile hemi (+)-di-p-toloyltartaric acid salt.

(-)-4-[4-(dimethylamino)- 1 -(4 ' -fluorophenyl)- 1 -hydoxy- 1 -butyl] -3 - (hydroxymethyl)-benzonitrile hemi (+)-di-p-toloyltartaric acid salt (4Og) was dissolved in a mixture of methanol (12OmL) and IPA (24OmL) at 40-60 ⁰ C. The mixture was cooled and the solid formed was filtered off and dried. Chiral purity: > 99.8% Example 6:

Purification of (-)-4-[4-(dimethylamino)-l-(4'-fluorophenyl)-l-hydoxy-l-buty I]-3- (hydroxymethyl)-benzonitrile hemi (+)-di-p-toloyltartaric acid salt.

(-)-4-[4-(dimethy lamino)- 1 -(4 ' -fluorophenyl)- 1 -hydoxy- 1 -butyl] -3 - (hydroxymethyl)-benzonitrile hemi (+)-di-p-toloyltartaric acid salt obtained as above (4Og) was dissolved in a mixture of methanol (12OmL) and ethanol (18OmL) at 40- 60 ⁰ C. The mixture was cooled and the solid formed was filtered off and dried. Chiral purity: > 99.8% Example 7:

Purification of (-)-4-[4-(dimethyIamino)-l-(4'-fluorophenyl)-l-hydoxy-l-buty I]-3- (hydroxymethyl)-benzonitrile hemi (+)-di-p-toloyltartaric acid salt. (-)-4-[4-(dimethylaminυ)- 1 -(4 ¹ -fluorophenyl)- 1 -hydoxy- 1 -butyl]-3-

(hydroxymethyl)-benzonitrile hemi (+)-di-p-toloyltartaric acid salt obtained as above (4Og) was dissolved in a mixture of methanol (12OmL) and ethylacetate (18OmL) at 40- 60 ⁰ C. The mixture was cooled to 0-5 ⁰ C and the solid formed was filtered off and dried. Chiral purity: > 99.8% Example 8:

Preparation of crystalline Escitalopram base:

To a solution of pure (-)-4-[4-(dimethylamino)-l-(4'-fluorophenyl)-l-hydoxy-l- butyl]-3-(hydroxymethyl)-benzonitrile hemi (+)-di-p-toloyltartaric acid salt (35g) in

175mL DM water 20OmL dichloromethane was added. The pH was adjusted to 8.0-8.5 using Hq. ammonia. The mixture was stirred and the dichloromethane layer separated, washed with water and dried. Triethylamine (32mL) was added to organic layer. The mixture was cooled and followed the addition of methane sulphonyl chloride (8.5mL) in 5OmL dichloromethane. The mixture was stirred for lhr at 20-25°C. After completion of reaction, a mixture of DM water and Hq. Ammonia (1:1) was added to it and stirred. Organic layer was separated, washed with water and then extracted with 10% aq. acetic acid (10OmL). The aqueous layer was diluted with 10OmL IPA and the pH was adjusted to basic using Hq. ammonia. The mixture was stirred at 20-25°C for 4 to 6 hrs, cooled to 0-5 ⁰ C and the solid formed was filtered off and dried yielding of Escitalopram base as a pale yellow crystalline solid. HPLC purity: > 99% Chiral purity: > 99.8%. Example 9: Preparation of crystalline Escitalopram base:

To a solution of pure (-)-4-[4-(dimethylamino)-l-(4'-fluorophenyl)-l-hydoxy-l- butyl]-3-(hydroxymethyl)-benzonitrile hemi (+)-di-p-toloyltartaric acid salt (35g) in 175mL DM water 20OmL dichloromethane was added. The pH was adjusted to 8.0-8.5 using Hq. ammonia. The mixture was stirred and the dichloromethane layer separated, washed with water and dried. Triethylamine (32mL) was added to organic layer. The mixture was cooled and followed the addition of methane sulphonyl chloride (8.5mL) in 5OmL dichloromethane. The mixture was stirred for lhr at 20-25 ⁰ C. After completion of reaction, a mixture of DM water and Hq. Ammonia (1:1) was added to it and stirred. Organic layer was separated, washed with water and then extracted with 10% aq. acetic acid (10OmL). The aqueous layer was diluted with 10OmL methanol and the pH was adjusted to basic using Hq. ammonia. The mixture was stirred at 20- 25°C for 4 to 6 hrs, cooled to 0-5 ⁰ C and the solid formed was filtered off and dried yielding of Escitalopram base as a pale yellow crystalline solid. HPLC purity: > 99% Chiral purity: > 99.8%. Example 10: Preparation of crystalline Escitalopram base:

To a solution of pure (-)-4-[4-(dimethylamino)-l-(4'-fluorophenyl)-l-hydoxy-l- buryl]-3-(hydroxymethyl)-benzonitrile hemi (+)-di-p-toloyltartaric acid salt (35g) in

175mL DM water 20OmL dichloromethane was added. The pH was adjusted to 8.0-8.5 using Hq. ammonia. The mixture was stirred and the dichloromethane layer separated, washed with water and dried. Triethylamine (32mL) was added to organic layer. The mixture was cooled and followed the addition of methane sulphonyl chloride (8.5mL) in 5OmL dichloromethane. The mixture was stirred for lhr at 20-25°C. After completion of reaction, a mixture of DM water and Hq. Ammonia (1:1) was added to it and stirred. Organic layer was separated, washed with water and then extracted with 10% aq. acetic acid (10OmL). The aqueous layer was diluted with 10OmL ethanol and the pH was adjusted to basic using Hq. ammonia. The mixture was stirred at 20-25 ⁰ C for 4 to 6 hrs, cooled to 0-5 ⁰ C and the solid formed was filtered off and dried yielding of Escitalopram base as a pale yellow crystalline solid. HPLC purity: > 99% Chiral purity: > 99.8%. Example 11: Preparation of crystalline Escitalopram base: _#

To a solution of pure (-)-4-[4-(dimethylamino)-l-(4'-fiuorophenyl)-l-hydoxy-l- butyl]-3-(hydroxymethyl)-benzonitrile hemi (+)-di-p-toloyltartaric acid salt (35g) in 175mL DM water 20OmL dichloromethane was added. The pH was adjusted to 8.0-8.5 using Hq. ammonia. The mixture was stirred and the dichloromethane layer separated, washed with water and dried. Triethylamine (32mL) was added to organic layer. The mixture was cooled and followed the addition of methane sulphonyl chloride (8.5mL) in 5OmL dichloromethane. The mixture was stirred for lhr at 20-25 ⁰ C. After completion of reaction, a mixture of DM water and Hq. ammonia (1:1) was added to it and stirred. Organic layer was separated, washed with water and then extracted with 10% aq. acetic acid (10OmL). The aqueous layer was diluted with 10OmL DMF and the pH was adjusted to basic using Hq. ammonia. The mixture was stirred at 20-25 ⁰ C for 4 to 6 hrs, cooled to 0-5 ⁰ C and the solid formed was filtered off and dried yielding of Escitalopram base as a pale yellow crystalline solid. HPLC purity: > 99% Chiral purity: > 99.8%. Example 12: Preparation of Escitalopram oxalate (crude):

The crystalline Escitalopram base (21 g) was dissolved in isopropyl alcohol (105mL) at 50-60 ⁰ C. Oxalic acid dihydrate (8.2 g) was added and the mixture was

stirred at 50-60 ⁰ C, cooled to 0-5°C, the solid formed was filtered and dried to get

Escitalopram oxalate (crude).

HPLC purity: > 99.5%

Chiral purity: > 99.8%. Example 13:

Preparation of Escitalopram oxalate (crude):

The crystalline Escitalopram base (21 g) was dissolved in methanol (105mL) at

50-60 ⁰ C. Oxalic acid dihydrate (8.2 g) was added and the mixture was stirred at 50-

6O ⁰ C, cooled to 0-5 ⁰ C, the solid formed was filtered and dried to get Escitalopram oxalate (crude).

HPLC purity: > 99.5%

Chiral purity: > 99.8%.

Example 14:

Preparation of Escitalopram oxalate (crude): The crystalline Escitalopram base (21 g) was dissolved in ethanol (105mL) at

50-60 ⁰ C. Oxalic acid dihydrate (8.2 g) was added and the mixture was stirred at 50-

60 ⁰ C, cooled to 0-5 ⁰ C, the solid formed was filtered and dried to get Escitalopram oxalate (crude).

HPLC purity: > 99.5% Chiral purity: > 99.8%.

Example 15:

Preparation of Escitalopram oxalate (pure):

Crude Escitalopram oxalate (23g) was dissolved in methanol (7OmL) at 5O ⁰ C.

Carbon (2.3g) was added and filtered through Celite. The clear filtrate was diluted with ethyl acetate (14OmL) and stirred for 4-6 h at room temperature., cooled to 0-5 ⁰ C and filtered to get pure Escitalopram oxalate.

HPLC purity: > 99.8%

Chiral purity: > 99.8%.

Example 16: Preparation of Escitalopram oxalate (pure):

Crude Escitalopram oxalate (23g) was dissolved in methanol (7OmL) at 5O ⁰ C.

Carbon (2.3g) was added and filtered through celite. The clear filtrate was diluted with

IPA (14OmL) and stirred for 4-6 h at room temperature, cooled to 0-5 ⁰ C and filtered to get pure Escitalopram oxalate.

HPLC purity: > 99.8%

Chiral purity: > 99.8%.

Example 17:

Preparation of Escitalopram oxalate (pure): Crude Escitalopram oxalate (23g) was dissolved in ethanol (7OmL) at 5O ⁰ C.

Carbon (2.3g) was added and filtered through celite. The clear filtrate was diluted with ethyl acetate (14OmL) and stirred for 4-6 h at room temperature, cooled to 0-5 ⁰ C and filtered to get pure Escitalopram oxalate. HPLC purity: > 99.8% Chiral purity: > 99.8%.