This application claims priority to Indian patent application No. 2557/CHE/2009 filed on
23rd Oct, 2009

FIELD OF INVENTION

The present invention relates to an improved process for the preparation of S-(+)-l[3-(dimethyl-amino)propyl]-1 -(p-fluorophenyl)-5-phthalancarbonitrile oxalate

BACKGROUND OF THE INVENTION

Escitalopram and its pharmaceutical activity are first disclosed in United States reissue patent no. RE 34712 E. Escitalopram in its oxalate form, i.e. S-(+)-l-[3-(dimethylamino)propyl]-l-(p-fluorophenyl)-5-phthalancarbonitrile oxalate salt having Formula I is more suitable for developing formulations and has been recommended as a drug.

Escitalopram oxalate is marketed under the trade name LEXAPRO in the form of tablets, which contains 5, 10, or 20 mg Escitalopram, by Forest pharmaceuticals, which is licensed from H. Lundbeck A/S.

Escitalopram, (S-(+)-1 -[3-(dimethylamino)propyl]-1 -(p-fluorophenyl)-5-phthalancarbo nitrile), marketed in the form of its oxalate salt is used in the treatment of major depressive disorders

The compound 4-[4-(Dimehtyl amino)-l-(4'-fluoro phenyl)-l-hydroxy-1-butyl]-3-(hydroxy methyl) benzonitrile having Formula-II here and after referred as "cyanodiol" is one of the key Intermediate for the preparation of Escitalopram.

US 4,943,590, discloses two processes for the resolution of enantiomers of Escitalopram using racemic diol of Formula-II as starting material. According to first method enantiomeric diol of Formula-II is resoluted by reacting with enantiomerically pure acid (+) or (-)-a-methoxy- a-trifluoromethyl phenylacetyl chloride to form mixture of diastereomeric salts which are separated by HPLC followed by ring closing converted in to Escitalopram.

According to second method separation of cyano diol enantiomers is performed by using (+)-di-p-toluoyl tartaric acid and ring closure of enantiomers is performed by liable ester as methane sulfonyl chloride in presence of a base to convert into Escitalopram.

In the resolution of enantiomers of cyano diol, the yields are less thereby reducing the overall yields and more cost of Escitalopram. Hence there is a continuing need to prepare cost effective and commercially viable process processes for the preparation of Escitalopram.

Now we surprisingly found that cyano diol can be recovered from its mother liquor and further used for the preparation of Escitalopram with high yields.

OBJECT OF THE INVENTION

The principle objective of the present invention is to provide improved process for the preparation of S-(+)-l[3-(dimethyl-amino)propyl]-l-(p-fluorophenyl)-5-phthalan carbonitrile oxalate in the course of recovery of cyanodiol intermediate.

SUMMARY OF THE INVENTION

Main aspect of the present invention is to provide a process for the preparation of Escitalopram oxalate with high yield. The process of recovering cyanodiol from its mother liquor comprising: a) resoluting cyanodiol free base from a solution by using resoluting agent, b) separating the precipitated cyanodiol free base or acid addition salt thereof from mother liquor c) distilling off solvent from mother liquor; d) adding water and organic solvent; e) adjusting pH to basic; f) optionally raising the temperature; and g) recovering cyanodiol. The recovered cyanodiol is again used for the preparation of Escitalopram free base or acid addition salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the resolution of Cyanodiol intermediate into one of its enantiomeric form by using (+)-di-p-toluoyl tartaric acid and Toluene, including recovery of cyano diol salt from its mother liquor to increase the yield of the desired compound. The recovered Cyanodiol is further converted in to Escitalopram oxalate. The schematic representation of the present invention is given in the scheme-I

In one aspect, the present invention provides process for recovering cyanodiol from its mother liquor comprising the steps of:

a) resoluting cyanodiol free base from a solution by using resoluting agent,
b) separating the precipitated cyanodiol free base or acid addition salt thereof from mother liquor
c) distilling off solvent from mother liquor;
d) adding water and organic solvent;
e) adjusting pH to basic;
f) optionally raising the temperature; and
g) recovering cyano diol.

According to the present invention, the obtained cyanodiol is resoluted with (+)-di-p-toluoyl tartaric acid and further converted into Escitalopram oxalate by conventional methods.

The process of resolution of Cyano diol comprises extracting cyano diol and to this Di-para-toluoyl tartaric acid monohydrate is added and isolated (-) 4-[4- (Dimethylamino)-l-(4'-fluorophenyl)-l-hydroxy-l-butyl]-3-(hydroxymethyl)benzonitrile. Hemi (+)-Di-p-toluoyl tartaric acid.

In one embodiment of the present invention, cyano diol is resoluted by using (+)-Di-P-toluoyl tartaric acid (as described in RE 34,712). The mother liquor thus obtained from filtering the compound (-)4-(4-dimethylamino)-l-(4'fluorophenyl)-l-(hydroxybutyl)-3(hydroxymethyl)benzonitrile, hemi(+)di-p-toloyltartaricacid salt from the reaction mixture, is taken and distilled off.

According to the present invention, cyanodiol free base is resoluted with a resoluting agent selected from dibenzoyltartaric acid, Di-p-toluoyltartaric acid, 10-camphorsulfonic acid; preferably Di-p-toluoyltartaric acid monohydrate. The precipitated cyanodiol is separated from mother liquor, wherein the precipitated cyanodiol comprises S-cyanodiol salt free base or acid addition salt thereof.

In one embodiment of the present invention, the organic solvent used in the step-d is selected from water immisible solvents such as toluene, benzene, xylene, n-hexane, n-heptane, cyclohexane and chloroform.

In one more embodiment of the present invention, pH adjusted in the step-e is in the range between 8-11, preferably 8.5-10 and more preferably 9.0-9.5.

In another embodiment of the present invention, the base used for adjusting the pH in step-e is selected from alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide; carbonates such as calcium carbonate, potassium carbonate, sodium carbonate; and bicarbonates such as sodium bicarbonate, calcium bicarbonate, potassium bicarbonate or ammonium bicarbonate, preferably sodium hydroxide.

In one more embodiment of the present invention, the temperature optionally raised in the step-f is in the range between 45-65 °C, preferably 50-60 °C and more preferably 52-57 °C.

In one more aspect of the present invention, the recovered cyano diol is used for the preparation of Escitalopram or its pharmaceutically acceptable salts by conventional methods as disclosed in US 4,943,590

As per the present invention, Mother liquor of 4-[4-(Dimethyl amino)-l-(4'-fluorophenyl)-1 -hydroxy-1 -butyl]-3 -(hydroxyl methyl) benzonitrile.Hemi (+)-Di-P-toluoyl tartaric acid is taken and distilled off from an alcohol such as Isopropyl alcohol and added demineralised water and organic solvent such as toluene. Reaction mixture is basified by adjusting pH 9.0-9.5 with alkali metal hydroxides such as NaOH solution. The aqueous layer is extracted with organic solvent such as toluene and recovering cyanodiol intermediate.

The following non-limiting examples illustrates specific embodiments of the present invention. The example, not intended to be limiting the scope of present invention in any way.

Example I : Preparation of (-) 4-[4-(Dimethyl amino)-l-(4'-fluorophenyl)-l-hydroxy-l-butyl]-3-(hydroxyl methyl) benzonitrile.Hemi (+)-Di-P-toluoyl tartaric acid
To the 4-[4-(Dimehtylamino)-1 -(4'-fluorophenyl)-1 -Hydroxy-1 -Butyl] -3 -(Hydroxy methyl) Benzonitrile phosphate ( 400 g) was added 2000 ml demineralised water and 1600 ml Toluene at 25-35 °C. The reaction mixture was neutralized with sodium hydroxide solution to get pH 9.0-9.2. Reaction mixture was heated to 40-44 °C and the pH was readjusted if needed. Toluene layer was separated. Aqueous layer was extracted with toluene. Organic layer was distilled off completely under vacuum at below 60 °C and was added 2000 ml of isopropyl alcohol. The reaction mixture was heated to 40-44 °C. Resulting clear solution was treated with Di-para-Toluoyl -D-Tartaric acid and stirred for 15-20 min, above clear solution was seeded with (-) 4-[4-(Dimethyl amino)-l-(4'-fluorophenyl)-l-hydroxy-l-butyl]-3-(hydroxylmethyl) benzonitrile.Hemi (+)-Di-P-toluoyl tartaric acid and the same maintained for 10 hrs at 40-44 °C. Reaction mixture was slowly cooled to 6 to 10 °C. The reaction mixture was filtered off and washed with isopropyl alcohol, and recrystallized from isopropyl alcohol. Yield of the compound was 140-165 g.

Example-II: Recovery of cyano diol
Mother liquor (1200 mL, filtrate of the Example I) of (-) 4-[4-(Dimethyl amino)-l-(4'-fluorophenyl)-l -hydroxy-1 -butyl]-3-(hydroxy 1 methyl) benzonitrile.Hemi (+)-Di-P-toluoyl tartaric acid has taken and distilled off isopropyl alcohol completely under vacuum at below 60 °C. Reaction mixture was cooled to 25-35 °C and was added 1000 ml demineralised water and 800 ml toluene. Reaction mixture was basified by adjusting pH 9.0-9.5 with 10% NaOH solution and heated to 50-55 °C, reaction mixture was stirred and pH was readjusted if needed. Layers were separated. Aqueous layer was extracted with toluene. Toluene layer was concentrated and 120 ml toluene was added and stirred at 25-30 °C and cooled to 0-5 °C, The obtained solid was filtered and washed with toluene. Yield of the compound was 25-50 g.

Example-III: Preparation of (-) 4-[4-(Dimethyl amino)-l-(4'-fluorophenyl)-l-hydroxy-l-butyl]-3-(hydroxyl methyl) benzonitrile.Hemi (+)-Di-P-toluoyl tartaric acid
Racemic Cyanodiol (50 g, obtained in Example II) and 250 ml isopropyl alcohol was taken at 25-35 °C and heated to 40-44 °C. To the obtained clear solution added Di-para-toluoyl-D-Tartaric acid monohydrate at 40-44 °C, stirred for 10-20 mins. The resulting clear solution was seeded with (-) 4-[4-(Dimethylamino)-l-(4'-fluorophenyl)-l-hydroxy-l-butyl]-3-(hydroxylmethyl) benzonitrile.Hemi (+)-Di-P-toluoyl tartaric acid and was maintained for 10 hrs at 40-44 °C. After completion of the reaction, reaction mixture was cooled to 6-10 °C .
The reaction mass was filtered off and washed with isopropyl alcohol and recrystallized from isopropyl alcohol. Yield of the compound was 20-25 g.

Example IV: Preparation of (-) l-(3-Dimethyl amino)-propyl)-l(4-fluoro phenyl)-l,3-dihydro-5-isobenzofuran carbonitrile oxalate.
To the (-) 4-[4-(Dimethyl amino)-l-(4'-fluorophenyl)-l-hydroxy-l-butyl]-3-(hydroxyl methyl) benzonitrile.Hemi (+)-Di-P-toluoyl tartaric acid (150 g) was added 750 ml DM water and 750 ml toluene at RT. The reaction mixture pH was adjusted to 9.0-9.2 with aqueous Ammonia. Reaction mixture was heated to 40 °C and was stirred for 20 mins at 40-45 °C, layers were separated. Aqueous layer was extracted with toluene; both the toluene layers were combined and washed with 150 ml demineralised water. Toluene was distilled off completely under vacuum at below 60 °C. 450 ml of Tetrahydrofuran was added to the reaction mixture at room temperature under nitrogen atmosphere. Reaction mixture was cooled to 0-5 °C and was added 110 ml triethyl amine. To the reaction mixture added mixture of 26 g of methylsulphonyl chloride and 195 ml of tetrahydro furan was added at 0-5 °C under nitrogen and was added 15 ml of triethyl amine. Again added 5.4 g of methylsulphonyl chloride and 40.5 ml of tetrahydrofuran mixture at 0-5 °C under nitrogen. After completion of the reaction, Reaction mixture was filtered and washed with toluene. Filtrate was washed with water and was distilled off completely under vacuum at below 60 °C. Yield of the crude was about 84-90 g. To the crude was added acetone and oxalic acid solution at room temperature. The temperature was raised to 40 °C and stirred for 30 min. Reaction mixture was cooled to 0-5 °C and solid was filtered, washed with acetone. Yield of the compound was 81-94.5 g.

We Claim:

1. A process for recovering cyanodiol from its mother liquor comprising the steps of:

a) resoluting cyanodiol free base from a solution by using resoluting agent,

b) separating the precipitated cyanodiol free base or acid addition salt thereof from mother liquor

c) distilling off solvent from mother liquor;

d) adding water and organic solvent;

e) adjusting pH to basic;

f) optionally raising the temperature; and

g) recovering cyano diol.

2. The process according to claim 1, wherein resoluting agent is selected from dibenzoyltartaric acid, Di-p-toluoyltartaric acid or 10-camphorsulfonic acid.

3. The process according to claim 1, wherein organic solvent is selected from water immiscible solvents such as toluene, benzene, xylene, n-hexane, n-heptane, cyclohexane and chloroform.

4. The process according to claim 1, the base used for pH adjustment is selected from alkali metal hydroxides, carbonates or bicarbonates.

5. The process according to the claim 4, alkali metal hydroxides selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide; carbonates selected from calcium carbonate, potassium carbonate, sodium carbonate; or bicarbonates selected from sodium bicarbonate, calcium bicarbonate, potassium bicarbonate or ammonium bicarbonate.

6. The process according to claim 1, wherein in step-f the temperature is raised to 45-65 °C, preferably 50-60 °C and more preferably 52-57 °C.

7. The process according to the claim 1, wherein recovered cyanodiol is further subjected to resolution followed by cyclization to get Escitalopram.

8. The process according to claim 7, wherein Escitalopram is further converted into its acid addition salt.

9. The process according to the claim 8, wherein the acid addition salt is oxalate.

10. Escitalopram obtained by any of the preceeding claims 1-9.