Claims:1. A process for the preparation of compound of formula (I) and its pharmaceutically acceptable acid addition salts
………….. (I)
Comprising,
i) reduction of a compound of formula (A) in presence of chiral ligand to obtain compound of formula B;
ii) oxidation of compound of formula B to obtain compound of formula D;
iii) reaction of compound of formula D with methylamine to obtain compound of formula E;
iv) reduction of a compound of formula (E) in presence of chiral ligand to obtain compound of formula I;
v) optionally compound of formula I is converted to pharmaceutically acceptable acid addition salts.
2. The process of claim 1, wherein the reduction reaction of step (i) takes place in the presence of alcoholic solvent.
3. The process of claim 2, wherein the alcoholic solvent is selected from methanol, ethanol, n-propanol, isopropanol n-butanol, sec-butanol and ter-butanol.
4. The process of claim 1, wherein the chiral ligand of step (i) and (iv) is used for the selective reduction reaction,
5. The process of claim 4, wherein the chiral ligand used is (S)-BIQAP.
6. The process according to claim 1, wherein the pharmaceutically acceptable acid addition salt is sertraline hydrochloride.
, Description:FIELD OF THE INVENTION
The present invention relates to a process for preparing sertraline or its pharmaceutically acceptable salts which is substantially free of impurities and directly resolving the cis racemate without any purification to get pure required enantiomer of Sertraline or its pharmaceutically acceptable salts using suitable chiral BIQAP compound as novel resolving agent and a method for preparation of the same.
BACKGROUND OF THE INVENTION
Sertraline is chemically known as cis (IS, 4S)-4-(3,4- dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l-naphthalenamine hydrochloride. Sertraline is an antidepressant that has been approved for the treatment of panic disorder and obsessive compulsive disorder by FDA and EMEA and is commercially available under the trade name of Zoloft and Lustral.
………..Formula I
Sertraline has two chiral centers present at carbon 1 and 4 positions. According to the R, S-nomenclature by Cahn, Ingold and Prelog, sertraline has the (IS, 4S)-configuration.
The methods of synthesis of racemic compounds of formula (I) are very successful for large –scale industrial manufacture. However, the production of optically pure compound of formula (I) is not easy.
Several processes for the preparation of sertraline are known in the prior art. US patent no. 4,536,518 discloses a two-step synthesis of sertraline hydrochloride from sertralone. The first step comprises of condensation of sertralone with methyl amine in the presence of an acid catalyst to yield the Schiff base of sertralone, which is reduced to sertraline (amine) in the second step by using 10% Pd/C catalyst at atmospheric pressure or by sodium borohydride (NaBH4) in an alcohol preferably methanol.
US Patent No. 6,232,501 describes that the hydrogenation of sertraline- 1-imine or sertraline- 1-imine N-oxide is carried out at very high pressure (10-15 bars) and/or at high temperature (100-1500C) using copper containing catalyst, to give (±)-cis/trans ratio of 95:5.
PCT Application Publication No. WO 99/57093 describes a process of selective hydrogenation of sertraline- 1-imine with a palladium catalyst supported onto a carrier which is preferably in the form of 5-30% by wt. of Pd loaded on charcoal pretreated with an alkyl halide to obtain (±)-cis and (±)-trans sertraline diastereoisomers in the ratio of about 19:1 and wherein the total dechlorinated contaminant side products amounts to less than 0.5%. The invention suffers from a serious drawback in using alkyl halide for said process since halogenated reagents are often not environment friendly and thus render the process industrially non- viable.
US Patent No. 6,232,501 describes that the hydrogenation of sertraline- 1-imine or sertraline- 1-imine N-oxide is carried out at very high pressure (10-15 bars) and/or at high temperature (100-1500C) using copper containing catalyst, to give (±)-cis/trans ratio of 95:5.
US Patent no. 6,034,274 describes hydrogenation of sertraline- 1-imine N-oxide under 1 atmosphere hydrogen pressure in an inert solvent in the presence of Raney nickel as the catalyst at a temperature of 25°C, followed by treating the resulting mixture with an alcoholic solution of hydrogen chloride, converting the resulting cis-racemic acid addition salt to the free base by using known methods, resolving and then converting the resulting (+)-cis-sertraline base to acid addition salt.
PCT Application Publication No. WO 01/116089 describes process involving reductive amination of sertralone, wherein said process involves reacting sertralone with methyl amine in hydrogen atmosphere at a pressure of 450-500 psi and temperature of 600C in the presence of Raney nickel as the catalyst to obtain a mixture of cis- and trans- sertraline, followed by separating the cis isomers from the mixture by fractional crystallization in methanol followed by resolution of the cis isomers by known methods to yield the desired cis-(lS, 4S) isomer of sertraline
US Patent no. 6,723,878 describes a process for the preparation of cis-sertraline, comprising hydrogenating sertraline- 1-imine under a hydrogen pressure of 2-5 bar and a temperature of 20-500C in the presence of a catalyst selected from palladium or platinum, and a dehalogenation inhibitor such as an ester of phosphorous or hypophosphorous acid to drastically reduce the formation of dehalogenated by- products to less than 0.1% and to enhance the (±)-cis- and (±)-trans sertraline ratio to as high as 97:3.
US patent no. 7,276,629 relates to a process for preparing sertraline from sertraline- 1-imine comprising the step of hydrogenating sertraline- 1-imine in the presence of a catalyst in a trickle bed reactor. Hydrogenation of the imine to mine is carried out using cobalt or nickel containing catalyst which is prepared by calcining it on an aluminum-silica support and wherein the hydrogenating temperature and pressure is maintained at about 80-1500C and 5-20 bar.
PCT Application Publication No. WO 01/116089 describes process for preparing sertraline and a pharmaceutically acceptable acid addition salt thereof comprising hydrogenation of 4-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl-1- naphthalenimine in the presence of a polar solvent using palladium / alumina as a catalyst at a temperature ranging from 25°C to 35°C to obtain (±)-cis/trans- sertraline with the (±)-cis racemate of sertraline as the major product.
Though process of manufacturing of Sertraline has been described in various applications which requires either drastic reaction conditions like high pressure or tedious isolation techniques, like two to three recrystallizations to minimize impurities and resolving the cis racemate to get the final compound which affect the yield of the final product. Present process is a novel approach by the inventor towards attaining significant cost effective method by using chiral ligand to give better yield.

OBJECTS OF THE INVENTION
Thus, a basic object of the present invention is to provide an improved process for the synthesis of (±)-cis-sertraline and its pharmaceutically acceptable acid addition salt thereof involving use of enantioselective ligand 6,6'-bis(diphenylphosphino)-5,5'-biquinoline ((S)-BIQAP) for achieving good yield and purity of (±)-cis-sertraline.
Another object of the present invention is to provide an improved process for the preparation of (±)-cis sertraline that is convenient wherein the synthesis can be accomplished by hydrogenation method using palladium as the catalysts and (S)-BIQAP as chiral ligand and moderate reaction conditions and yet achieving high yields.
Another object of the present invention is to provide an improved process for the preparation of (±)-cis sertraline which includes isolation of product by simple and convenient techniques.
Still another object of the present invention is to provide an improved process for the manufacture of (±)-cis sertraline that would result in highly pure product.

SUMMARY OF THE INVENTION
Thus, according to one aspect of present invention is an improved process for preparation of an optically pure or optically enriched enantiomer of compound of formula (F) with good yield and high purity
Another aspect of the present invention is to provide an improved process for the synthesis of (±)-cis-sertraline and its pharmaceutically acceptable acid addition salt thereof involving use of enantioselective ligand (S)-6,6'-bis(diphenylphosphino)-5,5'-biquinoline (S)-(BIQAP) for achieving good yield and purity of (±)-cis-sertraline.
Another aspect of the invention is process for preparation of sertraline in easily obtainable manner.
Another aspect of the present invention provides chiral (S)-BIQAP as a novel resolving agent represented by the compound of formula 2.

In another aspect, the invention provides a process for the preparation (S)-BIQAP.

DETAILED DESCRIPTION
In one embodiment, the invention provides process for preparation of an optically pure or optically enriched enantiomer of compound of formula (I) or its pharmaceutically acceptable acid addition salt which comprising the steps of:
a) reduction of compound of formula A:

Scheme 1
The ketone compound of formula A is reduced with Palladium catalyst as reducing reagent and chiral ligand (S)-BIQAP in a suitable alcoholic solvent to give the compound of formula B. Solvent for the reduction reaction is selected from lower alcohols which includes methanol, ethanol, n-propanol, isopropanol n-butanol, sec-butanol and ter-butanol and mixtures thereof. Most specifically the solvent is ethanol.
The reduction reaction is carried out at room temperature and in hydrogen atmosphere in autoclave at 60 PSI.
b) oxidation of compound of formula B,

Scheme 2
with PCC in organic solvent to give the compound of formula D.
Hydroxy compound of formula B is oxidized with PCC as oxidizing reagent in a suitable organic solvent to give the compound of formula D. Solvent for the oxidation reaction is selected from halogenated solvent which includes methylene chloride, ethylene chloride, carbon tetrachloride, chloroform and mixtures thereof. Most specifically the solvent is methylene chloride.
c) reaction of compound D with methyl amine to give compound E:

Scheme 3
Conversion of sertralone (compound D) to imine (Compound E) was done by the methods known in the prior art.

d) reduction of compound of formula E:

Scheme 4
with Palladium catalyst and (S)-BIQAP ligand in a lower alcohol solvent under hydrogen environment to give the compound of formula I
The imine compound of formula E is reduced with Palladium catalyst as reducing reagent and chiral ligand (S)-BIQAP in a suitable alcoholic solvent. Solvent for the reduction reaction is selected from lower alcohols which includes methanol, ethanol, n-propanol, isopropanol n-butanol, sec-butanol and ter-butanol and mixtures thereof. Most specifically the solvent is ethanol.
The reduction reaction is carried out at room temperature and in hydrogen atmosphere in autoclave at 60 PSI.
e) isolating compound of formula (I) or its pharmaceutically acceptable salt.
The isolation of compound of formula I and its pharmaceutically acceptable salt could be done by conventional techniques known to a person skilled in the art such as concentration, filtration, centrifugation etc.
In an another aspect the present invention provides chiral BIQAP as a novel resolving agent represented by the compound of formula 2 ((S)-BIQAP).

In another aspect, the invention provides a process for preparation (S)-BIQAP as illustrated in scheme 5. The aforementioned process comprises reacting (S)-BIQOL with triflic anhydride in pyridine under nitrogen atmosphere at 0-50C, to yield ditriflate compound. Then, a coupling reaction between ditriflate (compound 1) and diphenylphosphine was carried out with a Ni-based catalyst and 1,4-diaza[2.2.2]bicyclooctane (DABCO) in DMF at 850C. Thus obtained (S)-BIQAP is characterized by Mass, IR and NMR.

Scheme 5

Examples:
Example 1:
Synthesis of (S)-[5,5'-biquinoline]-6,6'-diyl bis(trifluoromethanesulfonate) (Compound I)
To a stirred solution of (S)(+)-BIQOL (0.8 gm, 0.0028 moles) in dichloromethane was added pyridine (0.68 gm, 0.00864) slowly under nitrogen atmosphere. The reaction mass was cooled to 0oC and added triflic anhydride (2.30 gm, 0.0072 moles) in DCM (5 ml). The reaction mass was allowed to come at room temperature and stirred till completion. Reaction progress was monitored by TLC. After completion of the reaction, water (3.8 ml) was added. Organic layer was separated, concentrated under vacuum to give crude mass which was further purified by column chromatography to give desired product.
Dry Weight – 1.32 gm.
Example 2:
Synthesis of (S)-BIQAP (Formula 2)
To the stirred solution of 1,2-Bis(diphenylphosphino)ethane nickel(II) chloride (0.089 gm , 0.000169 mole) and DABCO (0.946 gm,0.0084 moles) in anhydrous dimethylformamide (6.5 ml) was added Compound-1 (0.938 gm,0.00169 moles). Reaction mass was allowed to stir for 5-10 min and added diphenylphosphine (0.629 gm, 0.00338 moles). Reaction mass was was heated to 85°C. Three lots of diphenyl phosphine (0.314 gm, 0.00169 moles) was added at interval of 4 hrs. to the reaction mass. The reaction mass was stirred for 72h. Cooled the reaction mass to -5°C and added n-Hexane (20 ml). Obtained solid was filtered and purified on column chromatography (100-200 mesh Silica, Eluted with methanol: chloroform) to obtained desired product. (68% yield)
Dry Weight – 0.721 gm.
Example 3:
Preparation of 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydronaphthalen-1-ol
To a solution of Compound of formula A (1.6 gm, 0.0055 moles) in methanol (16 ml) was added 160 mg of Pd/C (10% by wet) and (S)-BIQAP (514 mg, 0.000825 moles) ligand. Reaction mixture was stirred under hydrogen atmosphere for 2-3 h at room temperature and 60 PSI. After complete consumption of starting material on the TLC plate, the reaction mass was filtered on celite bed and the filtrate was concentrated under reduced pressure. The crude reaction mass was purified by column chromatography using chloroform: methanol mixture as eluent to give desired product (73%).
Dry weight – 1.17 gm.
Example 4:
Preparation of (S)-4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-1(2H)-one
To a solution of Compound of formula B (0.714 gm, 0.00244 moles) in THF (3.57 ml) was slowly added PCC (0.525 gm, 0.0024 moles) at 0-50C. Reaction mixture was stirred at ambient temperature. After complete consumption of starting material on the TLC plate, the solvent was removed under reduced pressure, the crude reaction mass was purified by column chromatography to give desired product.
Dry weight – 0.673 gm.
Example 5:
Preparation of cis-sertraline hydrochloride
Compound D (0.630 gm, 2.17 moles) was stirred in mixture of Aq. monomethyl amine(4 ml) and methanol (6.3 ml) solution and heated at 60-650C for 4 h. when reaction was completed on TLC plate reaction mass was cooled and product was isolated by filtration. Obtained crude product was dissolved in methanol (6.3 ml) and added (10% by wet) of Pd/C and S-BIQAP (27 mg, 0.434 moles) of ligand. Reaction mixture was stirred under hydrogen atmosphere for 2-3 h at room temperature and 60 PSI. After complete consumption of starting material on the TLC plate, the reaction mass was filtered on celite bed and the filtrate was concentrated under reduced pressure. The crude reaction mass was purified by column chromatography to give desired product. (63%)
Dry weight – 0.418 gm.