Field of invention:

The present invention relates to a cost effective and eco-friendly continuous process for the preparation of Escitalopram, (S enantiomer of Citalopram) and its acid addition salts thereof from racemic diol intermediate with high yield and purity. Further, present invention provides process for recovering racemic diol intermediate from mother liquor containing salts of unwanted enantiomer.

Background of the invention:

Escitalopram is the S- enantiomer of Citalopram. It is a selective centrally acting serotonin reuptake inhibitor, accordingly having anti-depressant activity. Pharmaceutical dosage forms containing the oxalate salt of Escitalopram are widely used for oral administration.

Escitalopram chemically known as (5)-l-[3-(dimethylamino) propyl]-l-(4-fluorophenyl)-l,3-dihydroisobenzofuran-5-carbonitrile and is represented by the Formula I.

The citalopram diol is chemically known as 4- [4-(dimethyl amino) -l-(4'-fluoro phenyl) -1-hydroxy-1-butyl] -3-(hydroxyl methyl)-benzonitrile and represented by structural Formula -II as follows,


Formula-II

S-enantiomer of citalopram diol is referred as 'S-diol intermediate' chemically known as (-)- 4- [4-(dimethyl amino) -l-(4'-fluoro phenyl) -1-hydroxy-1-butyl] -3-(hydroxyl methyl)-benzonitrile.

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 5-Bromo Pthalide by exchange of 5-halogen with cyano group.

US 4,943,590 discloses two routes for preparation of Escitalopram. In first route the citalopram diol of (Formula II) is reacted with an enantiomerically pure acid derivative, such as (+) or (-) 2-methoxy-2-trifluoro methyl phenyl acetyl chloride to form mixture of diastereomeric esters, which are separated by HPLC or fractional crystallization where upon the ester with right stereochemistry is enantioselectively converted into Escitalopram.

In the second route, the diol (Formula II) is separated into the enantiomers by stereo selective crystallization with an enantiomerically pure acid such as (+)di-para toluoyl tartaric acid, where upon the S-enantiomer of the diol (Formula II) is enantioselectively converted to Escitalopram. Both the routes involve consumption of expensive, enantiomerically pure reagents and give relatively low yields resulting in the loss of the R enantiomer with consequent high cost. The above routes are economically and environmentally infeasible for industrial production.

US 7,112, 686 discloses the preparation of racemic citalopram from non-racemic citalopram comprising precipitation of citalopram as the free base or an acid addition salt thereof from a solution of non-racemic citalopram by treatment with different acids such as sulphuric acid, hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid in suitable organic solvent.

US patent no. 7,390,913 and GCC patent no. GC 0001036 also discloses process for the preparation of racemic diol free base and/or acid addition salt and/or R- or S- diol free base and/or acid addition salt comprising a separation of an initial non-racemic mixture of R- and S- diol free base and or acid addition salt with more than 50 % of one of the enantiomers into a fraction being enriched with S-diol or R-diol free base and/or acid addition salt and a fraction comprising RS-diol free base and or acid addition salt wherein the ratio of R-diol:S-diol is equal to 1:1 or closer to 1:1 than in the initial mixture of R and S diol.

The process for the preparation of Escitalopram and its acid salts from optically active acid salt of racemic citalopram diol including reaction with base followed by stereoselective cyclization have been described in WO/2006/10653, US application no. US 2011/0092719 (corresponding Indian Patent Application No.l450/CHE/2008 and 17/CHE/2009), US patent no.7,939,680 (corresponding Indian Patent Application No.l014/CHE/2005). However said process does not teach feasible process for the preparation of Escitalopram from recovered racemic diol intermediate.

The aforesaid processes though discloses the preparation of Escitalopram and its pharmaceutically acceptable salts from racemic diol intermediate of Formula II, however the consumption of the racemic diol intermediate of Formula II is high leading to high cost of the process, also yields are low, develops waste byproducts and is not environmentally feasible.

In view of the above drawbacks, the present invention provides an eco-friendly and economical continuous process for preparation of Escitalopram (Formula I) and its pharmaceutically acceptable salts in high yield and purity by recycling the recovered racemic diol intermediate (Formula II). The process of the present invention can also be conducted as batch process.

Objective of the invention:

The primary objective of the present invention is to provide an improved and economically feasible continuous process for the preparation of Escitalopram (Formula-I) and its salts with high yield and purity by recycling the recovered racemic diol intermediate (Formula II) and with optimum utilization of the recovered racemic diol intermediate (Formula-II).

The other objective of the invention is to resolve recovered racemic diol intermediate (Formula-II) to obtain S-diol of citalopram for the preparation of Escitalopram (Formula-I) and its salts with high yield and purity.

Another objective of the invention is to provide a process for the recovery of racemic diol intermediate (II) from mother liquor containing acid salts of R and S citalopram diol.

Summary of the invention:

The present invention provides a cost-effective and feasible, continuous process for the preparation of Escitalopram and its pharmaceutically acceptable salts from the racemic diol intermediate (Formula II). The process of the present invention can also be conducted as batch process.

In a preferred aspect, the present invention provides a process for the preparation of Escitalopram (Formula-I) and its salts with high yield and purity comprising:

i) resolving 'racemic diol intermediate' of Formula II with (+) DPTTA in presence of suitable solvent to obtain acid salt of enriched S-diol;

ii) converting enantiomerically pure salt of enriched S-diol from (step-i) into optically pure S-diol by treating with ammonia in presence of water and water immiscible solvent;

iii) recovering the racemic diol intermediate from mother liquor enriched with R and small amounts of S-diol acid salts by treating with a base in presence of water and water immiscible solvent;

iv) resolving the racemic diol intermediate from (step iii) in presence of(+)DPTTA and suitable solvent to obtain optically pure S-diol; and

v) adding optically pure S-diol obtained in step (iv) to the batch of optically pure S-diol obtained in step (ii) to convert into Escitalopram and its acid addition salts with high yield and purity.

In one aspect, the process for the preparation of Escitlaopram and its acid addition salts comprises resolution of optically pure S-diol acid salt from racemic diol intermediate and further conversion into Escitalopram.

In another aspect, the process for recovery of racemic diol intermediate from mother liquor enriched with R and small amounts of S-diol acid salts comprises racemization of mother liquor in presence of base and suitable solvent followed by resolving the racemic diol intermediate so obtained in presence of (+)DPTTA and suitable solvent to obtain optically pure S-diol.

In an another aspect, the present process comprises, addition of optically pure S-diol obtained in step (iv) to the batch of optically pure S-diol obtained in step (ii) to convert the same into Escitalopram and its acid addition salts with high yield and purity.

In the final aspect, present invention provides process for the preparation Escitalopram from racemic diol intermediate of Formula II in to its acid addition salts.

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. The embodiments as described are not limiting or restricting the scope of the invention.

Detail description of the invention:

The present invention provides an eco-friendly and economical feasible continuous process for the preparation of Escitalopram (Formula I) and its pharmaceutically acceptable salts in high yield and purity by recycling the recovered racemic diol intermediate (Formula II).

In a preferred aspect, the present invention provides a continuous process for the preparation of Escitalopram (Formula-I) and its salts with high yield and purity comprising:

i. resolving 'racemic diol intermediate' of Formula II with (+)DPTTA in presence of suitable solvent to obtain acid salt of enriched S-diol;

ii. converting enantiomerically pure salt of enriched S-diol from (step-i) into optically pure S-diol by treating with ammonia in presence of water and water immiscible solvent;

iii. recovering the racemic diol intermediate from mother liquor enriched with R and small amounts of S-diol acid salts by treating with a base;

iv. resolving the racemic diol intermediate from (step iii) in presence of (+) DPTTA and suitable solvent to obtain optically pure S-diol,

v. adding optically pure S-diol obtained in (step iv) to the batch of optically pure S-diol salt obtained in (step i) to convert into Escitalopram and its acid addition salts with high yield and purity.

The present invention provides eco-friendly and economically feasible continuous process for the preparation of Escitalopram and its acid addition salts from recovered racemic citalopram diol hereinafter referred to as racemic 'diol intermediate' or racemic diol.

'Mother liquor' in the present invention indicates solution that remains after resolution of enantiomerically active (S)-diol acid salt, containing enriched with R-diol acid salt and small amount of S-diol acid salt

'Di-para toluoyl tartaric acid' hereinafter referred as DPTTA, optically active di-para toluoyl D (+) tartaric acid hereinafter referred as (+) DPTTA.

The term 'racemic diol intermediate' or 'racemic diol' means a 1:1 mixture of R-and S-diols.

S-enantiomer of Escitalopram diol hereinafter referred as 'S-diol' and its (+) DPTTA salt is referred as S-diol acid salt.

In one of the embodiment, the process for resolution of racemic diol intermediate
comprises following steps;

i. resolving the racemic 'diol intermediate' of Formula II in a solvent with (+)DPTTA; filtered, dried to obtain an acid salt of enriched S-diol; ii. treating the said salt with a base in presence of a solvent and water to attain a pH in the range of 8-9, extracting with water immiscible solvent to obtain optically
pure S-diol.

Accordingly, the racemic diol intermediate (Formula II) is treated with pure optically active acid in solvent to get enanatiomericaily pure S-diol. The optically active acid used is D(+) Di-p-toluyl tartaric acid (+)DPTTA in sub molar quantity ranging from 0.20 to 0.35. The reaction is carried out in a solvent selected from group consisting of C1-C4 alcohols such as methanol, ethanol, isopropyl alcohol and butyl alcohol; acetonitrile; acetone or mixture with water thereof, preferably aqueous isopropanol with 0.5-2.5% of water. The reaction is firstly carried out at a temperature ranging from 40°C to 60°C and then at a temperature of 20-30°C for period of 2-8 hrs. The reaction mixture is cooled to 10-15°C.After cooling, the precipitated salt is filtered to get compound with a chiral purity of greater than 99%.

The enantiomerically pure active acid salt of S-diol is treated with base in presence of water and water immiscible solvent to obtain free diol (chirally pure), which is then subjected to stereo selective cyclization to get a compound of Escitalopram base as oil in chirally pure form. The base used herein is selected from the group consisting of organic and inorganic base; the organic bases are selected from triethylamine, diisopropyl ethyl amine, pyridine, piperidine, while the inorganic bases are selected from the group consisting of alkali metal carbonates, bicarbonates, and their hydroxides or liquor ammonia. The reaction is carried out at a basic pH range of 8.0-9.0 and at temperature of 20-25°C. The resulting solution is extracted with water immiscible organic solvents to get optically pure diol intermediate (Formula II). The water immiscible organic solvents used herein are selected from the group consisting of toluene, chloroform, dichloromethane and more preferably toluene.

In another embodiment, the present invention provides a process for recovering the S-diol from the mother liquor enriched with R-diol salt, which leads to more yield of Escitalopram ( Formula I) by utmost utilization of racemic diol ( Formula II), comprising steps of;

i) collecting the mother liquor enriched with tartaric acid salt of R- diol and small
amount of tartaric salt of S- diol;

ii) concentrating the liquid phase of step-i and reacting the concentrated product
with base inorganic base such as sodium hydroxide, potassium hydroxide,
sodium carbonate, ammonia and organic base like triethylamine to obtain free
racemic diol;

iii) extracting the racemic diol of step (ii) in suitable organic solvents;

iv) concentrating the extracted phase and isolating/recovering the crystalline racemic
diol intermediate (containing 1;1 mixture of R and S diol) in presence of suitable
solvent;

v) resolving recovered racemic diol (step iv) with (+)DPTTA ,in suitable solvent to
obtain acid salt of enriched S-diol in optically pure form, followed by converting
into optically pure S-diol in free base form.

According to the process, the mother liquor obtained after isolating the resolved S-diol salts is collected and further subjected to distillation under reduced pressure. The above obtained residual mass is converted into racemic diol by treating with base in a presence of water and water immiscible solvent. The base used herein is selected from the group consisting of organic and inorganic bases; organic bases are selected from triethyl amine, diisopropyl ethyl amine, pyridine, piperidine; preferably tri ethyl amine and inorganic bases are selected from the group of alkali metal carbonates like sodium carbonate, potassium carbonate, and their hydroxides like sodium hydroxide, potassium hydroxide and liquid ammonia; preferably sodium hydroxide or potassium hydroxide. The reaction is carried out at a basic pH range of 9-13, and at temperature of 20-25°C, the resulting solution is further extracted with water immiscible organic solvents to get the racemic diol compound. The water immiscible organic solvents used here are selected from the group consisting of toluene, xylene, ethyl acetate, chloroform, dichloroethane and dichloromethane; preferably dichloromethane, toluene, and ethyl acetate. The extracted phase is subjected to distillation to obtain an oily residue, which may be dissolved in another suitable solvent. Solvent may be removed by distillation with or without vacuum at elevated temperatures such as 25-60°C.

Optionally, the solvent used herein for isolation of racemic diol is selected the group consisting of Isopropyl alcohol, acetone, acetonitrile, toluene, xylene, ethyl acetate, chloroform, dichloroethane and dichloromethane, acetone preferably acetone, toluene and ethyl acetate.

Recovered racemic diol from the above process is having purity more than 99% w/w as determined by HPLC as well as chiral purity shows 1:1 ratio of R & S isomers which is further converted into optically active Escitalopram and its acid addition salts in high yield.

In yet another embodiment, the present invention provides feasible recovery process which comprises; collecting the liquid phase from mother liquor containing unwanted acid salt of R-enantiomer of diol intermediate, concentrating the liquid phase and treatment with base to obtain Racemic diol. Racemic diol thus obtained is extracted with suitable organic solvent to obtain crystalline racemic diol intermediate. In final embodiment, the process for preparation of Escitalopram and its acid addition salts with high yield and purity by utmost utilization of racemic diol comprising;

i) subjecting the pure S-diol (from above embodiments) insitu to stereo selective cyclization in presence of triethylamine, tosyl chloride and solvent to get Escitalopram free base; and

ii) converting Escitalopram free base into its acid addition salts.

Optically pure S-diol as such (without isolation)in situ is further subjected to stereo selective cyclization by reacting with a tosyl chloride in presence of triethyl amine and solvent system preferably toluene media. It is advantageous to use tosyl chloride for cyclization as the reaction proceeds under mild conditions resulting in formation of pure compound. After completion of the reaction, mixture may be quenched with water, the organic layer containing product is collected and washed with surplus amount of water. Further obtained organic layer is subjected to distillation and escitalopram free base (Formula-I) thus obtained can be converted into its desired pharmaceutically acceptable acid addition salt using conventional techniques by reacting with a pharmaceutically acceptable acid.

Pharmaceutically acceptable acids that can be used for preparing the salt of Escitalopram is preferably oxalic acid. The crystalline escitalopram acid addition salt can be prepared in suitable solvent selected from the group consisting of methanol, ethanol, isopropanol, ethyl acetate, acetonitrile, tetrahydrofuran, acetone, or mixtures thereof, preferably acetone. The amount of acid used herein is 1.0 to 1.1 equivalents to the escitalopram base. The reaction mixture is stirred for 5-8hrs, at 20-25°c and further cooled to 0-5°c. The separated acid addition salts are filtered and washed with solvent to get pure form Escitalopram acid addition salt.

Thus, the recovered racemic diol intermediate is further converted to Escitalopram and its acid salts with high yield and purity which makes the present invention cost-effective and environmentally feasible by recycling and reusing the racemic diol intermediate obtained in the process.

Having thus described the present invention with reference to particular embodiments, those skilled in the art will appreciate modifications that do not depart from the spirit and scope of the disclosure. The following examples are set forth to further describe certain specific aspects and embodiments but are not intended to, and should not be construed to, be limiting in any way. The examples do not include detailed descriptions of conventional methods; as such methods are well known to those of ordinary skill in the art and are described in numerous publications.

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown by way of example, for purpose of illustrative discussion of preferred embodiments of the invention, and are not limiting the scope of the invention.

Examples:

Example 1:

Process for the preparation of (-) - 4- r4-(dimethvlamino) -l-(4'-fluoro phenyl) -1-hydroxy-1-butyl] - 3-(hydroxyl methyl)-benzonitrile hemi (+) di -p- toluyl tartaric acid salt

100 gm of the 4- [4-(dimethylamino) -1 -(4'-fluoro phenyl) -1 -hydroxy-1 -butyl] - 3-(hydroxyl methyl)-benzonitrile was placed in a round bottom flask and dissolved in 500 ml of isopropyl alcohol at 40-45°c followed by the addition of (+)di-p- toluyl tartaric acid (28gm) with vigorous stirring at 40-45°C. 10 ml of water was added to the reaction mass. The reaction mass was maintained for 2-3 hrs at 40-45°c. The mixture further cooled to 25-30°C and maintained for 4-5hrs at the same temperature. Then cooled to 10-15°C. Filtered the solid and washed the compound and dried to attain 45-50gm of the title compound having above 99.3% of chiral purity.

Example 2:

Process for the preparation of (-) - 4- 4-(dimethylamino) -l-(4,-fluoro phenyl) -1-hydroxy-1-butyl] - 3-(hvdroxyl methyD-benzonitrile hemi (+) di -p- toluyl tartaric acid salt

100 gm of the 4- [4-(dimethylamino) -l-(4'-fluoro phenyl) -1-hydroxy-1-butyl] - 3-(hydroxyl methyl)-benzonitrile was placed in a round bottom flask and dissolved in 500 ml of isopropyl alcohol at 40-45°C followed by the addition of (+)di-p- toluyl tartaric acid (28gm) with vigorous stirring at 40-45°C. 5 ml of water was added to the reaction mass. The reaction mass was maintained for 2-3 hrs at 40-45°C. The mixture further cooled to 25-30°C and maintained for 4-5hrs at the same temperature then cooled to 10-15°C. Filtered the solid and washed the compound and dried to attain 45-50gm of the title compound with having above 99.15% of chiral purity.

Example 3:

Preparation of Escitalopram oxalate
A salt of (+) di-p-toluoyl tartaric acid with (-) - 4- [4-(dimethylamino) -l-(4'-fluoro phenyl) -1-hydroxy-1-butyl] -3-(hydroxyl methyl)-benzonitrile (50gm) was mixed with toluene (350ml) and water (350ml) in a round bottom flask. Ammonia was added to attain pH 8.5-8.8. The mixture was heated to 40-45°C for 30 minutes. The layers were separated. The separated aqueous layer was extracted with toluene. The organic layers were washed with water (200ml). The organic layer was dried with sodium sulphate. Triethylamine (25gm) was charged to the organic layer and heated to 35-40°C. Tosyl chloride (19gm) was added to the reaction mass lot wise for 1-2 hours at 40-45° C and maintained for 2-3 hours at the same temperature to complete the reaction. After completion of the reaction, it was quenched by the addition of water (300ml). The layers were separated and the organic layer subjected to wash with sodium chloride solution. After separation of organic layer from sodium chloride solution, the solvent was evaporated under reduced pressure to obtain oil which was dissolved in acetone (200ml). Further treated with charcoal (5gm) at 25-30° C and filtered through hyflow. Collected the filtrate and charged oxalic acid solution [12gm in acetone (60ml)]. The mixture was stirred for 5-8 hours at 20-25° C. The mixture was cooled to 0-5°C and stirred for 1-2 hours. The formed solid was filtered off, washed with acetone (25ml) to attain 35gm of title compound with chiral purity 99.34% and purity by HPLC is 99.88%.

Example 4:

Preparation of recovery of racemic diol intermediate from mother liquors of (-) - 4-[4-(dimethylamino) -l-(4'-fluoro phenyl) -1-hydroxy-1-butyl] - 3-(hydroxyl methyl)-benzonitrile hemi (+) di -p- toluyl tartaric acid salt

Collected mother liquor of (-) - 4- [4-(dimethylamino) -l-(4'-fluoro phenyl) -1-hydroxy-1 -butyl] - 3-(hydroxyl methyl)-benzonitrile hemi (+) di-p-toluyl tartaric acid salt. Distilled off the solvent under reduced pressure at 55-60°C to obtain syrupy mass. The syrupy mass was diluted with water (250ml) and adjusted pH 11.5-12.5 with sodium hydroxide solution. The reaction mass was stirred for 30-60 min at room temperature. Further extracted with dichloromethane (250ml) twice. Combined the all organic layers and washed with water (250ml). The layers were separated. The solvent was evaporated under reduced pressure to obtain oil which was dissolved in acetone (100ml) and stripped off. To residual mass was charged acetone (50ml) and stirred for 30-60minuites at 25-30°C. The reaction mass was cooled to 5-10°C and stirred for 1-2 hrs at the same temperature. The solid was filtered off and washed the compound with acetone (10ml). Dried the solid at 40-50°C to attain 35-40 gm of the racemic 4- [4-(dimethylamino) -l-(4'-fluoro phenyl) -1-hydroxy-1-butyl] - 3-(hydroxyl methyl)-benzonitrile. Purity by HPLC- 99.94% and chiral purity was; R isomer -50.24%,S-isomer -49.76%.

Example 5:

Preparation of recovery of racemic diol intermediate from mother liquor of (-) - 4-[4-(dimethylamino) -l-(4'-fluoro phenyl) -1-hydroxy-1-butyl] - 3-(hydroxyl methyl)-benzonitrile hemi (+) di -p- toluvl tartaric acid salt
Collected mother liquors of (-) -4- [4-(dimethylamino) -l-(4'-fluoro phenyl) -1-hydroxy-1-butyl] - 3-(hydroxyl methyl)-benzonitrile hemi (+) di -p- toluyl tartaric acid salt. Distilled off the solvent under reduced pressure at 55-60°C to obtain syrupy mass. The syrupy mass was diluted with water (250ml) and adjusted pH 11.5-12.5 with potassium hydroxide solution. The reaction mass was stirred for 30-60 min at room temperature. Further extracted with ethyl acetate (250ml) twice. Combined the all organic layers and washed with water (250ml). The layers were separated. The solvent was evaporated under reduced pressure to obtain oil. To residual mass charged toluene (50ml) and stirred for 30-60minuites at 25-30°C. The reaction mass was cooled to 5-10°C and stirred for 1-2 hrs at the same temperature. The solid was filtered off and washed the compound with toluene (10ml). Dried the solid at 40-50°C to attain 35-40 gm of the racemic 4- [4-(dimethylamino) -l-(4'-fluoro phenyl) -1-hydroxy-l-butyl]-3-(hydroxyl methyl)-benzonitrile with above 99% purity by HPLC and chiral purity was R isomer -50.14%, S-isomer -49.86%.

Example 6:

Preparation of recovery of crystalline racemic diol intermediate from mother liquor of (-) - 4- [4-(dimethylamino) -l-(4-fluoro phenyl) -1-hydroxy-1-butyl] - 3-(hydroxyl methyl)-benzonitrile hemi (+) di -p- toluvl tartaric acid salt Collected mother liquors of (-) - 4- [4-(dimethylamino) -l-(4'-fluoro phenyl) -1-
hydroxy-1-butyl] - 3-(hydroxyl methyl)-benzonitrile hemi (+) di-p- toluyl tartaric acid salt. Distilled off the solvent under reduced pressure at 55-60°C to obtain syrupy mass. The syrupy mass was diluted with water (250ml) and adjusted pH 11.5-12.5 with sodium carbonate solution. The reaction mass was stirred for 60-90 min at room temperature. Further extracted with dichloromethane (250ml) twice. Combined the all organic layers and washed with water (250ml). The layers were separated. The solvent was evaporated under reduced pressure to obtain oil. To residual mass charged ethyl acetate (50ml) and stirred for 30-60 mints at 25-30° C. The reaction mass was cooled to 5-10°C and stirred for 1-2 hrs at the same temperature. The solid was filtered off and washed with chilled ethyl acetate (10ml) .Dried the compound at 40-50°c to attain 35-40 gm of the racemic 4- [4-(dimethylamino) -l-(4'-fluoro phenyl) -1-hydroxy-1-butyl] - 3-(hydroxyl methyl)-benzonitrile with above 99% purity by HPLC and chiral purity was R isomer -50.16%, S-isomer -49.84 %.

Example 7:

Preparation of recovery of racemic diol intermediate from mother liquors of (-) - 4-[4-(dimethvlamino) -l-(4'-fluoro phenyl) -1 -hydroxy-1-butyl] - 3-(hvdroxyl methyl)-benzonitrile hemi (+) di -p- toluyl tartaric acid salt Collected mother liquors of (-) -4-[4-(dimethylamino) -l-(4'-fluoro phenyl) -1-hydroxy-l-butyl]-3-(hydroxyl methyl)-benzonitrile hemi (+) di-p-toluyl tartaric acid salt. Distilled off the solvent under reduced pressure at 55-60°C to obtain syrupy mass. The syrupy mass was diluted with water (250ml) and adjusted pH 8.5-9.5 with ammonium hydroxide solution. The reaction mass was stirred for 30-60 min at room temperature. Further extracted with toluene (250ml) twice. Combined the all organic layers and washed with water (250ml). The layers were separated. The solvent was evaporated under reduced pressure to obtain oil. To residual mass charged acetonitrile (50ml) and stirred for 30-60minuites at 25-30°C. The reaction mass was cooled to 5-10°C and stirred for 1-2 hrs at the same temperature. The solid was filtered off and washed the compound with acetonitrile (10ml). Dried the solid at 40-50°C to attain 35-40 gm of the racemic 4- [4-(dimethylamino) -l-(4'-fluoro phenyl) -1-hydroxy-1-butyl] - 3-(hydroxyl methyl)-benzonitrile with above 99% purity by HPLC and chiral purity was R isomer -50.24%, S-isomer - 49.76%.

Example 8:

Preparation of recovery of racemic diol intermediate from mother liquors of of (-) -4- [4-(dimethylamino) -1-(4'-fluoro phenyl) -1-hydroxy-1-butyl] - 3-(hydroxyl methyl)-benzonitrile hemi (+) di -p- toluvl tartaric acid salt Collected mother liquors of (-) -4-[4-(dimethylamino) -l-(4'-fluoro phenyl) -1-hydroxy-1-butyl] -- 3-(hydroxyl methyl)-benzonitrile hemi (+) di -p- toluyl tartaric acid salt. Distilled off the solvent under reduced pressure at 55-60°C to obtain syrupy mass. The syrupy mass was diluted with water (250ml) and adjusted pH 11.5-12.5 with triethylamine. The reaction mass was stirred for 30-60 min at room temperature. Further extracted with ethyl acetate (250ml) twice. Combined the all organic layers and washed with water (250ml). The layers were separated. The solvent was evaporated under reduced pressure to obtain oil. To residual mass charged toluene (50ml) and stirred for 30-60minuites at 25-30°C. The reaction mass was cooled to 5-10°C and stirred for 1-2 hrs at the same temperature. The solid was filtered off and washed the compound wivh toluene (10ml). Dried the solid at 40-50°C to attain 35-40 gm of the racemic 4- [4-(dimethylaminc) -l-(4'-fluoro phenyl) -1-hydroxy-1-butyl] -3-(hydroxyl methyl)-benzonitrile with above 99% purity by HPLC and chiral purity was R isomer -50.24%, S-isomer- 49.76%.

Example 9;

Process for the preparation of (-) - 4- [4-(dimethylamino) -l-(4'-tluoro phenyl) -1-hydroxy-1-butyl] - 3-(hydroxyl methyl)-benzonitrile hemi (+) di -p- toluyl tartaric acid salt by using recovered 4- [4-(dimethylamino) -l-(4'-fluoro phenyl) -1-hydroxy-1-butyl] - 3-(hydroxvl methyl)-benzonitrile 40 gm of the recovered 4- [4-(dimethylamino) -l-(4'-fluoro phenyl) -1-hydroxy-l-butyl] - 3-(hydroxyl methyl)-benzonitrile was placed in a round bottom flask and dissolved in 200 ml of isopropyl alcohol at 40-45°C followed by the addition of (+)di-p- toluyl tartaric acid (11.5gm) with vigorous stirring at 40-45°C. 5 ml of water added to the reaction mass. The reaction mass was maintained for 2-3 hrs at 40-45°C. The mixture was further cooled to 25-30°C and maintained for 4-5hrs at the same temperature then cooled to 10-15°C. Filtered the solid and washed the compound and dried to attain 18-20gm of the title compound with having above 99% of chiral purity.

Example 10:

Preparation of Escitalopram oxalate from (-) - 4- f4-(dimethvlamino) -l-(4'-fluoro phenyl) -1-hydroxy-1-butyl] - 3-(hydroxyl methyl)-benzonitrile hemi (+) di -p- toluyl tartaric acid salt which is obtained from recovered racemic diol intermediate.

A salt of (+) di-p-toluoyl tartaric acid with (-) - 4- [4-(dimethylamino) -l-(4'-fluoro phenyl) -1-hydroxy-1-butyl]- 3-(hydroxyl methyl)-benzonitrile (20gm) was mixed with toluene (150ml) and water (150ml) in a round bottom flask. Ammonia is added to attain pH 8.5-8.8. The mixture was heated to 40-45°C for 30 minutes. The layers were separated. The separated aqueous layer was extracted with toluene. The organic layers were washed with water (100ml). The organic layer was dried with sodium sulphate. Triethylamine (l0gm) was charged to the organic layer and heated to 35-40°C. Tosyl chloride (8 gm) was added to the reaction mass lot wise for 1-2 hours at 40-45° C and maintained for 2-3 hours at the same temperature to complete the reaction. After completion of the reaction, it was quenched by the addition of water (120ml). The layers were separated and the organic layer subjected to wash with sodium chloride solution. After separation of organic layer from sodium chloride solution, the solvent was evaporated under reduced pressure to obtain oil which was dissolved in acetone (100ml). Further treated with charcoal (5gm) at 25-30°C and filtered through hyflow. Collected the filtrate and charged oxalic acid solution [5gm in acetone (25ml)]. The mixture was stirred for 5-8 hours at 20-25° C. The mixture was cooled to 0-5°C and stirred for 1-2 hours. The formed solid was filtered off, washed with acetone (10ml) to attain 12gm of title compound with chiral purity 99.37%.and purity by HPLC- 99.78%.

We Claim:

1) A continuous process for preparation of Escitalopram and its pharmaceutically
acceptable acid addition salts in high yield and purity comprising;

i) resolving racemic diol intermediate' of Formula II with (+)DPTTA in presence of suitable solvent to obtain acid salt of enriched S-diol;

ii) converting enantiomerically pure salt of enriched S-diol from (step-i) into optically pure S-diol by treating with ammonia in presence of water and water immiscible solvent;

iii) recovering the racemic diol intermediate from-mother liquor enriched with R and small amounts of S-diol acid salts by treatment with a base;

iv) resolving the racemic diol intermediate from (step ii) in presence of (+)DPTTA and suitable solvent to obtain optically pure S-diol; and

v) adding optically pure S-diol obtained in (step iv) to the batch of optically pure
S-diol obtained in (step ii) to convert into Escitalopram and its acid addition salts with high yield and purity.

2) The process according to claim (1), where optically active acid is Di-Para toluoyl D(+) tartaric acid (+)DPTTA used in sub molar quantities 0.25- 0.30.

3) The process according to claim 1, the solvent used in step (i) and step (iv) is aqueous isopropyl alcohol.

4) The process according to claim 1, wherein the water immiscible solvent used in step (ii) is selected from lower aromatic hydrocarbons, chlorinated hydrocarbons, lower esters, acetone, and acetonitrile.

5) The process according to claim 1, wherein the base used in step (ii), is ammonia.

6) The process according to claim 1, wherein the base used in step (iii) is selected from organic or inorganic base.

7) The process according to claim (6), wherein the organic base is triethylamine.

8) The process according to Claim (6), wherein the inorganic base is selected from sodium hydroxide, potassium hydroxide, or liquor ammonia.

9) A process for recovering the racemic diol intermediate from mother liquor according to claim 1 comprising steps of;

i) collecting the mother liquor enriched with tartaric acid salt of R- diol and small amount of tartaric acid salt of S- diol and

ii) concentrating the liquid phase of (step-i) followed by treatment with base to obtain free racemic diol.

10) The process according to claim 9, wherein the base is selected from inorganic
base comprises sodium hydroxide, potassium hydroxide, sodium carbonate; ammonia and organic base comprise triethylamine.

11) A process for recovering the S-diol from the mother liquor enriched with acid salt
of R-diol comprising steps of;

i. collecting the mother liquor enriched with tartaric acid salt of R- diol and
small amount of tartaric salt of S- diol;

ii. concentrating the liquid phase of (step-i) followed by treatment with base to
obtain free racemic diol;

iii. extracting the racemic diol of step (ii) in suitable organic solvents;

iv. concentrating the extracted phase and isolating/recovering the crystalline racemic diol intermediate (containing 1;1 mixture of R and S diol) in presence of suitable solvent; and

v. Resolving recovered racemic diol (step iv) with (+)DPTTA in suitable solvent to obtain acid salt of enriched S-diol in optically pure form followed by converting into optically pure S-diol in free base form.

12) The process according to claim 11, wherein the base is selected from inorganic
base such as sodium hydroxide, potassium hydroxide, sodium carbonate, ammonia and organic base comprise triethylamine.

13) The process according to claim 11 wherein the solvent used in steps (iii and iv) is selected from lower aromatic hydrocarbons, chlorinated hydrocarbons, lower esters, acetone, and acetonitrile.

14) The process according to claim 11, wherein the solvent used in step (v) is aqueous isopropyl alcohol.