1. A process of preparing cis- (1S, 4S)-N-methyl-4- (3,4-dichlorophenyl)-1,2,3,4-tetrahydro- 1-naphthaleamine hydrochloride (Sertraline hydrochloride) form-I from Sertraline mandelate using water as solvent comprising steps of, a. Addition of Sertraline mandelate to hot aqueous hydrochloric acid solution and heating to get a clear solution, b. Or in another variation, heating a mixture of Sertraline mandelate and water followed by the addition of hydrochloric acid to get a clear solution, c. Cooling the reaction and isolating the solid.

2. The process according to claim 1 wherein the mixture of Sertraline mandelate and aqueous hydrochloric acid is heated at 80-85 °C.

3. The process according to claim 1 wherein the seeding crystals of Sertraline hydrochloride form-I may be optionally added during cooling the reaction.

4. A process of preparing cis- (IS, 4S)-N-methyl-4- (3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleamine hydrochloride (Sertraline hydrochloride) form-II from Sertraline mandelate using water as solvent comprising steps of, a. Addition of Sertraline mandelate to hot aqueous hydrochloric acid solution and heating to get a clear solution, b. Or in another variation, heating a mixture of Sertraline mandelate and water followed by the addition of hydrochloric acid to get a clear solution, c. Cooling the reaction with addition of seeding crystals of Sertraline hydrochloride form-II and isolating the solid.

5. The process according to claim 4 wherein the mixture of Sertraline mandelate and aqueous hydrochloric acid is heated at 80-85 °C.

6. The process according to claim 4 wherein the seeding crystals of Sertraline hydrochloride form-II is added during cooling the reaction. Dated this Day of 2005. SANTOSH KUMAR NAIR (GENERAL MANAGER - LEGAL & COMPANY SECRETARY) UNICHEM LABORATORIES LIMITED

FORM 2
THE PATENT ACT 70
(ACT 39 of 70)
COMPLETE SPECIFICATION
(SECTION 10)

Improved processes for the preparation of
Forms I & II of Sertraline Hydrochloride •
and sertraline mandelate;

UNICHEM LABORATORIES LIMITED, A COMPANY
REGISTERED UNDER THE INDIAN COMPANIES ACT, 1956, HAVING ITS
REGISTERED OFFICE LOCATED AT MAHALAXMI CHAMBERS, 2ND
FLOOR; 22, BHULABHAI DESAI ROAD, MUMBAI- 400 026. MAHARASHTRA,
INDIA
The following specification particularly describes the nature of the invention and the manner in which it is to be performed


Background of the invention :-
The invention relates to an improved process for the preparation of Form-I and Form-II of Sertraline Hydrochloride . The Form-I and Form-II of Sertraline Hydrochloride, which is cis-(l S,4S)-N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-1-naphthalenamine hydrochloride, prepared by the process of the present invention is useful for the treatment of mental depression, obsessive-compulsive disorder and panic disorder. The Cis-(lS,4S)-N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l- naphthalenamine hydrochloride has the formula-I given below.

. HCI

I
The invention also relates to an improved process for the preparation of Sertraline mandelate useful for the preparation of Forms I & II of Sertraline hydrochloride
State of the art
U.S. Patent no 4,536,518 ( Welch et al)., issued on August 20, 1985 describes the synthesis and basic activities of the family of compounds including Sertraline.
In the synthesis of Sertraline hydrochloride according to the said patent 3,4-dichlorobenzoyl chloride is reacted with benzene in the presence of anhydrous aluminum chloride to give 3,4-Dichlorobenzophenone, which is reacted with

diethyl succinate in the presence of potassium t-butoxide and t-butanol to give 3-ethoxycarbonyl-4-(3,4-dichlorophenyl)-4-phenyl-but-3-enoic acid. This compound was hydrolyzed and decarboxylated in 48% aqueous HBr:glacial acetic acid to give 4-(3,4-dichlorophenyl)-4-phenyl-but-3-enoic acid. The resultant compound was hydrogenated with 5% Pd/C at room temperature and at atmospheric pressure to give 4-(3,4-dichlorophenyl)-4-phenyl-butanoic acid. Further this was treated with thionyl chloride in toluene followed by reaction with carbon disulfide and aluminum chloride to get 4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalenone. The naphthalenone so obtained was reacted with methylamine in the presence of titanium tetrachloride and tetrahydrofurane to get the schiff base. This schiff base was reduced with 10% Pd/C catalyst at atmospheric pressure and at room temperature, passing hydrogen chloride gas in anhydrous ether as solvent to isolate the cis racemate.
The combined HC1 salt which contained about 70% cis-racemate and 30% trans
racemate of N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-
naphthalenamine hydrochloride, was dissolved in hot methanol. Upon addition of ether and cooling overnight the cis-(lS)(lR)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-l- naphthalenamine hydrochloride precipitated out.
The above-prepared compound was resolved with the help of D-(-)-mandelic acid as follows.
The cis-(lS)(lR) compound was portioned between 20% aqueous NaOH and ethyl acetate to yield a solution of the cis-racemate free base in ethyl acetate. This was dissolved in absolute alcohol and D-(-)-mandelic acid (1:1 mole) added, the mandelate was isolated by filtration.

The combined crops of the mandelates salt were suspended in ethyl acetate and treated with 10% NaOH solution thereby the converting the hydrochloride to the free base, the resulting ethyl acetate solution was then dried, diluted with ether and then treated with excess gaseous hydrogen chloride to give a gelatinous suspension. The hydrochloride salt was isolated by filtration washed with ether and dried to give the title compound sertraline hydrochloride.
J.Med.chem..l984, vol 27 no. 11 1508-1515 titled "Nontricyclic Antidepressant agents derived from cis-and trans-l-aminoaryltetralins" describes the synthesis of sertraline hydrochloride where the reduction of the schiffs base (imine) is done with sodium borohydride and the resolution is done with D-(-)-mandelic acid. Finally the hydrochloride is prepared in ethyl acetate by passing hydrogen chloride gas to get a gelatinous precipitate of sertraline hydrochloride.
U.S. Patent no 5,248,699 of Sysko et al., issued on September 28 , 1993 discloses novel crystalline forms of Sertraline hydrochloride, and reports five novel polymorphic forms, which have been designated as, Form-I, Form-II, Form-Ill, Form-IV, and Form-V, differing from one another in respect of their physical properties, stability, spectral data and method of preparation.
Form-I was prepared by stirring Sertraline hydrochloride with Isopropanol for 112 hours at 25 °C.
Sertraline mandelate was suspended in methylene chloride and water 10% sodium hydroxide is added and the resulting two clear layers are separated. The aqueous layer is extracted with methylene chloride, the combined methylene chloride layers is washed with water. The methylene chloride is atmospherically distilled out and replaced with isopropanol and water. The solution is cooled to 50 °C and seeded

with sertraline hydrochloride form-I. Hydrogen chloride in aqueous isopropanol was added to the clear solution to give a thick slurry. Additional isopropanol was also used, reaction mixture stirred for 3 hrs at 50 °C cooled to room temperature over night, the solution is distilled at atmospheric pressure to remove isopropanol, again isopropanol is added to lower the water content. The reaction mixture was then cooled and filtered to yield the crystalline polymorph, form-I.
Similarly form-I was also prepared by using ethyl acetate and cone, hydrochloric acid, stirring the reaction mixture over night.
Following the procedures disclosed in U.S. Patent no 4,536,518 it has been reported to yield sertraline hydrochloride form-II where the sertraline hydrochloride madelate is suspended in ethyl acetate and treated with 10% aqueous NaOH solution there by converting the amine to the free base. The resulting ethyl acetate solution was dried, diluted with ether and then treated with excess gaseous hydrogen chloride to give a gelatinous suspension, which crystallized over night. The crystalline hydrochloride salt was separated by filtration, wash with ether and air dried to give Sertaline hydrochloride form-II.
However the sertraline hydrochloride form-I is reported to have the greatest and most stable form. It is characterized, inter aha, by exhibiting an X-ray powder diffraction pattern with characteristic peaks expressed in degrees 2 9 at approximately 7.1, 12.7, 14.1, 15.3, 15.7,21.2,23.4 and 26.3.
U.S. Patent No 6,034,274 issued on March 7, 2000 describes the process for the preparation of Sertraline Hydrochloride i.e. cis-(lS,4S)-N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-naphthalenamine hydrochloride by reacting tetralone with N-methyl hydroxylamine hydrochloride to give the N-oxide

derivative which is reduced with Raney nickel to give the cis sertraline hydrochloride which is then resolved with the help of D-(-)-mandelic acid to give the title compound Sertraline Hydrochloride i.e. cis-(lS,4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1 -naphthalenamine hydrochloride.
U.S. Patent No 6,262,308 issued on July 17, 2001 describes the process for the preparation of the title compound "Sertraline Hydrochloride" i.e. cis-(lS,4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1 -naphthalenamine hydrochloride by reacting tetralone with N-methylformamide in the presence of formic acid followed by a treatment with base, the racemic sertraline hydrochloride was isolated as a salt.
W.O Patent no.01/68566 describes a process for the preparation of sertraline hydrochloride from tetralone. During the formation of the schiff base TiC14 is used as a catalyst. The schiff base was hydrogenated over Pd/C (10% loading) at 40 °C and at 1 arm H2 pressure for 5 hrs in t-butyl-methyl ether (MTBE) to get the racemate sertraline which is converted to the mandelate with D-(-)-mandelic acid, the isolated mandelate is purified with the help of ethanol. The purified sertraline mandelate first converted to the free base in toluene and the hydrochloride is prepared in ethanol by bubbling hydrogen chloride gas to get title compound Sertraline Hydrochloride i.e. cis-(lS,4S)-N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-1-naphthalenamine hydrochloride.
W.O Patent no.01/16089 describes the process for the preparation of Sertraline Hydrochloride i.e. cis-(lS,4S)-N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-1-naphthalenamine hydrochloride by the reduction of the schiff base with Raney nickel at about 450-500 psi hydrogen pressure.

W.O Patent no.99/57093 describes a process for the preparation of Sertraline Hydrochloride i.e. cis-(lS,4S)-N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-1-naphthalenamine hydrochloride by the reduction of the schiff base with palladium as catalyst, which is then treated with alkali halide.
WO Patent no 0032551 is directed to the preparation of forms -II, V, VII, VIII, IX and X of sertraline hydrochloride and novel methods for their preparation. In the said patent polymorph form-II is prepared form form-VI in acetone, or form-V in absolute ethanol, or sertraline freebase in acetone and HC1 or form-V in DMF to from-II.
U.S. Patent no 6495721 is directed to form II of Sertaline hydrochloride and novel methods for its preparations. According to the invention Sertaline hydrochloride form II is produced directly from Sertaline base of Sertaline mandelate. It is also produced from Sertaline hydrochloride solvate and hydrate forms, and crystalhzed from new like acetone, n-butanol, DMF, absolute ethanol, t-butyl methyl ether. Pharmaceutical compositions containing Sertaline hydrochloride form II and methods for treatment using such pharmaceutical composition are also disclosed. The Examples given in the said patent, for the preparation of form-II, described processes employing different conditions.
Sertraline base is taken in acetone and then isopropanol containing hydrogen chloride is added to the reaction mixture until pH is approx 2, the stirring is continued over night at room temperature, the resulting sohd is filtered, washed with acetone and dried to yield sertraline hydrochloride form-II.
Also form-II was prepared by bubbling HC1 through a solution of sertraline base in n-butanol.

Form-II was prepared also from form-V by suspending it in dimethylformamide heated to 70°C.
Form-II was also prepared by granulation of form-V in absolute ethanol at room temperature for 2 days.
Form-II was prepared from form-VI by slurring it in t-butyl methyl ether and heating it to reflux for 1 hrs, cooled to room temperature and filtration of the solid followed by dying under vacuum.
Sertaline hydrochloride form-VI was stirred with acetone at room temperature for 2 hrs to get sertraline hydrochloride form-II.
Sertaline hydrochloride form-VI was dried at 105 °C under vacuum over 24 hrs. The resulting dried material was sertraline hydrochloride form-II mixed with sertraline hydrochloride form-V.
Sertaline mandelate and n-butanol were stirred at room temperature. The mixture was acidified with hydrogen chloride until pH 0 was reached. After natural cooling to room temperature the reaction mixture was stirred for 2 hrs. The solid was filtered washed with n-butanol and dried at 80 °C to afford sertraline hydrochloride form-II.
Sertraline hydrochloride form-VIII was heated in acetone at reflux for 1 hrs then cooled to room temperature and filtered, after drying sertraline hydrochloride form-II was obtained.

U.S. Patent no 6,452,054 is mainly directed to novel polymorph form-XI, XII , XIII, XIV, XV, and XVI. This patent describes the process for the preparation of form II also and other forms using different solvent and different conditions
Sertraline hydrochloride form-XVI was suspended in ethyl acetate and the suspension was refluxed for 2 hrs. The suspension was cooled to 40 °C and filtered to get sertraline hydrochloride form-II.
Sertraline hydrochloride form-XVI was suspended in acetone and the suspension was refluxed for 2 hrs. The suspension was cooled to 40 °C and filtered to get sertraline hydrochloride form-II.
Sertraline hydrochloride form-XIV was suspended in ethyl acetate and the suspension was refluxed for 2 hrs. The suspension was cooled to 40 °C and filtered to get sertraline hydrochloride form-II.
Sertraline hydrochloride form-XIV was suspended in acetone and the suspension was refluxed for 2 hrs. The suspension was cooled to 40 °C and filtered to get sertraline hydrochloride form-II.
Sertraline hydrochloride form-XIV was suspended in t-butyl methyl ether and the suspension was refluxed for 3 hrs. The suspension was cooled and filtered to get sertraline hydrochloride form-II.
Sertraline hydrochloride form-XV with LOD 30% was suspended in ethyl acetate preheated at 40 °C and the suspension was refluxed for 2 hrs. The suspension was cooled and filtered to get sertraline hydrochloride form-II.

Sertraline hydrochloride form-XV was suspended in acetone and the suspension was refluxed for 3 hrs. The suspension was cooled and filtered to get sertraline hydrochloride form-II.
Sertraline hydrochloride form-XV with LOD 54% was suspended in t-butyl methyl ether preheated at 40 °C and the suspension was refluxed for 3 hrs. The suspension was cooled and filtered to get sertraline hydrochloride form-II.
U.S. Patent no 6,500987 is directed to forms II, III, V, VI,VII, VIII, IX & X of Sertraline hydrochloride and novel methods for their preparation. According to this invention sertraline hydrochloride form-II is produced by slurring sertraline hydrochloride form VI in aprotic organic solvent. Sertraline hydrochloride form III is produced by heating sertraline hydrochloride forms V & VI. Sertraline hydrochloride forms V & VI are produced from either sertraline hydrochloride or sertraline base by crystallization. Sertraline hydrochloride form VII is produced by suspending sertraline hydrochloride polymorph VI in water, followed by filtration. Sertraline hydrochloride forms Villi & IX are produced by suspending sertraline base in water followed by acidification and filtration. Sertraline hydrochloride form X is produced by suspending sertraline hydrochloride in benzyl alcohol with heating, followed by filtration. Following are the different conditions described in the patent for the preparation of form-II.
Sertraline hydrochloride form-VI was slurred in t-butyl methyl ether, heated to reflux for one hour then allowed to cool to room temperature and filtered. The solid was washed with t-butyl methyl ether and dried under 30 mm Hg vacuum with stirring. The dried solid so obtained is sertraline hydrochloride form II.

Sertraline hydrochloride form VI was stirred in acetone at room temperature for two hours the solid material was filtered and washed twice with acetone. The wet solid was dried in a vacuum agitated drier to give sertraline hydrochloride form II.
Sertraline hydrochloride for V and absolute ethanol were stirred in rotavapour at room temperature for 2 days. At the end of 2 days the material contained sertraline hydrochloride form II.
Sertraline hydrochloride ethanolate - form VI was dried at 105° C under 10 mm vacuum for 24 hours. The resulting dried material was sertraline hydrochloride form II mixed with sertraline hydrochloride form V.
Sertraline base was dissolved in acetone and then isopropanol containing hydrogen chloride was added to the solution until the pH ~ 2. The stirring was continued overnight at room temperature. The resulting solid was filtered, washed with acetone and dried to yield sertraline hydrochloride form II.
Sertraline hydrochloride for V was suspended in dimethyl formamide. The heating was started and at about 70° C a clear solution is obtained. The solution was cooled to room temperature and the solid was filtered. After drying at 80°C for 24 hours sertraline hydrochloride form II was obtained.
U.S. Patent no 2002183555 is directed to form-II of sertraline hydrochloride and novel methods for its preparation. According to this invention sertraline hydrochloride form II is produced directly from sertraline base or sertraline mandelate. It is also be produced from sertraline hydrochloride solvate and hydrochloride solvate and hydrate forms, and crystallized from new solvent

systems. Following are the different conditions described in the patent for the preparation of form-II.
Sertraline base was dissolved in acetone and then isopropanol containing hydrogen chloride was added to the solution until the pH ~ 2. The stirring was continued overnight at room temperature. The resulting solid was filtered, washed with acetone and dried to yield sertraline hydrochloride form II.
HC1 gas was bubbled through a solution of sertraline base in n-butanol, a gel like solid was formed, and the addition of HC1 gas was continued until pH 0.5 was reached. The stirring was continued for 2.5 hrs at room temperature. During the stirring the solid became a fine crystalline solid. The solid was filtered, washed with n-butanol and dried at 80 °C for 24 hrs to get sertraline hydrochloride form II
Sertraline hydrochloride form-V was suspended in dimethylformamide, and heated to 70 °C to get a clear solution. The solution was cooled to room temperature and filtered. After drying at 80 °C for 24 hrs sertraline hydrochloride form-II was obtained.
Sertraline hydrochloride for V and absolute ethanol were stirred in rotavapour at room temperature for 2 days. At the end of 2 days the material contained sertraline hydrochloride form II.
A slurry of sertraline hydrochloride form-VI and t-butyl methyl ether were heated to reflux for 1 hrs. The slurry was cooled to room temperature and filtered, washed with t-butyl methyl ether, and dried in a reactor under vacuum of 30 Hg with stirring. The dried solid so obtained is sertraline hydrochloride form-II.

Sertraline hydrochloride form VI was stirred in acetone at room temperature for two hours the solid material was filtered and washed twice with acetone. The wet solid was dried in a vacuum agitated drier to give sertraline hydrochloride form II.
Sertraline hydrochloride ethanolate - form VI was dried at 105° C under 10 mm vacuum for 24 hours. The resulting dried material was sertraline hydrochloride form II mixed with sertraline hydrochloride form V.
Sertaline mandelate and n-butanol were stirred at room temperature. The mixture was acidified with hydrogen chloride until pH 0 was reached. After natural cooling to room temperature the reaction mixture was stirred for 2 hrs. The solid was filtered washed with n-butanol and dried at 80 °C to afford sertraline hydrochloride form-II.
Sertraline hydrochloride form-VIII was heated in acetone at reflux for 1 hrs then cooled to room temperature and filtered, after drying sertraline hydrochloride form-II was obtained.
W.O. Patent no 02/096859 describes the process for the preparation of form II by extracting or dissolving the sertraline base into ethyl acetate, adding isopropanol as solvent, adding hydrogen chloride dissolved in ethyl acetate or in gaseous form, and finally isolating and drying sertraline hydrochloride form-II. Following are the different conditions described in the patent for the preparation of form-II
Sertraline mandelate is slurried in ethyl acetate and water, 50% NaOH solution is added at about 65 °C. The water phase is separated off. The ethyl acetate solution is washed with water. Ethyl acetate is distilled off and replaced with isopropanol. The solution is charcoaled and filtered. Hydrogen chloride 14% in ethyl acetate is

added smoothly at 40 °C in 30 minuets. Seed crystals of polymorphic form-II are added during the addition of HC1. The solution is cooled to 0 °C The crystalline compound is filtered and washed with ethyl acetate. The product is dried under vacuum at 80-90 °C to get sertraline hydrochloride form-II.
U.S. Patent no 2002/0019570 describes the preparation of sertraline- 1-imine followed by reduction with the help of Pd/C, the reduced compound is taken for the preparation of mandelate, and finally the hydrochloride is prepared in ethanol. To get sertraline hydrochloride form-V.
W.O. Patent no 01/32601 describes the process for the preparation of form I, II & V are disclosed. Following are the different conditions described in the patent for the preparation of form-I or form-II.
Heating sertraline hydrochloride isopropanol solvate at 70° C in high vacuum (0.1 m bar) for 20 hrs. results in the formation of sertraline hydrochloride polymorphic form I.
Sertraline hydrochloride free amine dissolved in acetone to this solution sertraline hydrochloride form II seed is added. To this reaction mixture is added a solution of HC1 in acetone at room temperature. The resulting white suspension is stirred for 2 hrs., filtered washed with acetone and dried under vacuum (0.1 m bar) for 16 hrs. to give sertraline hydrochloride form II.
Sertraline free amine is dissolved in acetone and is heated to reflux. At this temperature sertraline hydrochloride form II is added followed by the addition of aqueous hydrogen chloride solution till pH is <5. The reaction mixture is cooled to -5°C , filtered and dried in vacuum. To obtain sertraline hydrochloride form II.

Sertraline freebase amine is dissolved in methyl ethyl ketone and heated to 60°C to this form II seed is added followed by the addition of aqueous hydrogen chloride solution until pH<5. The reaction mixture is cooled to -5°C , filtered and dried in vacuum. To obtain sertraline hydrochloride form II.
Sertraline freebase amine is dissolved in methyl isobutyl ketone and heated to 60°C to this form II seed is added followed by the addition of aqueous hydrogen chloride solution until pH<5. The reaction mixture is cooled to -5°C , filtered and dried in vacuum. To obtain sertraline hydrochloride form II.
W.O. Patent no 9936394 describes the process for the preparation of sertraline hydrochloride by a one pot reaction of tetralone with methylamine and reduction with palladium on calcium carbonate further the racemic compound is resolved by the D-(-)-mandelic acid.
We have prepared sertraline hydrochloride Form-I & II in our laboratory directly from sertraline mandelate without the isolation of the sertraline free base using water as a solvent, in a single step , which is unique, which is not hitherto reported in any literature and constitute the novelty of the present invention.
We have prepared sertraline hydrochloride directly from sertraline mandelate and have obtained form-I in water and form-II in IPA as well as in water. Such a process is not hitherto known The Sertraline hydrochloride Form-I prepared by the process of the present invention is found to be thermodynamically stable as reported in the US patent no. 5248699.

According to all the above-described processes of the prior art, the compound of the formula-I is prepared by reduction of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l(2H)-naphtalenylidene]-methylamine of the formulae-II.

II
The compound of the formula-I contains two asymmetric centers and may be present in the form of four stereoisomers. These correspond to the formulae la - Id

According to J.Med. Chem 1984,27,1508-1515 the reduction of the compound of the formula - II can be performed in methanol as medium with sodium borohydride. This gives 1:1 diastereomeric mixture of the cis 1S,1R [la and lb] and the trans 1S,1R [lc and Id] diastereomers which can be separated by the formation of the hydrochloride.

Objectives of the present invention
The main objective of the present invention is , therefore , to provide an improved
process for the preparation of sertraline hydrochloride polymorph form-I & form-II
i.e. cis-(lS,4S)-N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-
naphthaleneamine hydrochloride polymorph form-I and form-II.
Another objective of the present invention is to provide an improved process for the preparation of sertraline hydrochloride polymorph form-I & form-II i.e. cis-(1S,4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-l-naphthaleneamine hydrochloride polymorph form-I and form-II from sertraline mandelate, using water as solvent. )
Yet another objective of the present invention is to provide an improved process for
the preparation of sertraline mandelate which is useful for the production of
Sertraline hydrochloride polymorph form-I and form-II by using water immiscible
organic solvent preferably toluene.
The present invention directly converts sertraline mandelate to the desired required sertraline hydrochloride polymorph form-I and polymorph form-II depending upon the conditions employed the required polymorph was achieved.
Accordingly , the present provides an improved process for the preparation of cis-(1S, 1 S)-N-methyl-4-(3,4-dichlorophenyl) 1,2,3,4-tetrahydro-1 -naphthalene-1 -amine as hydrochloride salt of the formula I having polymorph Form I which comprises.
(i) 4-(3,4-Dichlorophenyl)-3,4-dihydro-l(2H)-naphthaenone commonly known as tetralone is reacted with methanolic monomethyl amine at a temperature in the

range of 0 °C to 100 °C in a closed system to get N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l(2H)-naphthalenylidene]-methylamine of the formula II.
(ii) Reducing N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l(2H)-naphthalenyli dene]-methylamine of the formula II in the presence of sodium borohydride in a alcoholic solvent and preparing its hydrochloride by the addition of cone, hydrochloric acid to get the racemic cis Sertraline hydrochloride (mixture of two isomers of sertraline i.e. the R and the S isomers).
(iii) Converting the racemic cis sertraline hydrochloride to sertraline mandelate by suspending the racemic cis sertraline hydrochloride in a water immiscible organic solvent (preferably toluene) and heating to a temperature in the range of 50-100 °C in the presence of aqueous alkali, cooling the reaction mixture to ambient temperature. Separating the aromatic organic layer, washing the organic layer with excess water to remove alkali. Reacting the organic layer containing the sertraline base in the organic solvent (preferable toluene) with D-(-)-mandelic acid to get sertraline mandalate salt, filtering the mandelate salt , washing the filtered salt with the organic solvent drying the product sertraline mandelate.
(iv) Converting the mandelate salt obtained in step (iii) by suspending it in water containing hydrochloric acid at elevated temperature preferably above 80-85°C followed by cooling to room temperature and stirring the reaction mixture at room temperature for 24 hrs to directly get sertraline hydrochloride polymorph Form-I.

Accordingly , the present also provides an improved process for the preparation of cis-( 1S, 1 S)-N-methyl-4-(3,4-dichlorophenyl) 1,2,3,4-tetrahy dro-1 -naphthalene-1 -amine as hydrochloride salt of the formula I having polymorph Form-II which comprises.
(iv) 4-(3,4-Dichlorophenyl)-3,4-dihydro-l(2H)-naphthaenone commonly known as tetralone is reacted with methanolic monomethyl amine at a temperature in the range of 0 °C to 100 °C in a closed system to get N-[4-(3,4-dichlorophenyl)-3,4-dmydro-l(2H)-naphthalenylidene]-methylamine of the formula II.
(v) Reducing N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l(2H)-naphthalenyli dene]-methylamine of the formula II in the presence of sodium borohydride in a alcoholic solvent and preparing its hydrochloride by the addition of cone, hydrochloric acid to get the racemic cis Sertraline hydrochloride (mixture of two isomers of sertraline i.e. the R and the S isomers).
(vi) Converting the racemic cis sertraline hydrochloride to sertraline mandelate by suspending the racemic cis sertraline hydrochloride in a water immiscible organic solvent (preferably toluene) and heating to a temperature in the range of 50-100 °C in the presence of aqueous alkali, cooling the reaction mixture to ambient temperature. Separating the aromatic organic layer, washing the organic layer with excess water to remove alkali. Reacting the organic layer containing the sertraline base in the organic solvent (preferable toluene) with D-(-)-mandelic acid to get sertraline mandalate salt, filtering the mandelate salt , washing the filtered salt with the organic solvent drying the product sertraline mandelate.

(vii) Converting the mandelate salt obtained in step (iii) to hydrochloride salt by suspending it in Isopropanol containing hydrogen chloride at elevated temperature preferably above 80-85°C followed by filtration over celite bed to get a clear solution, cooled to room temperature to directly get sertraline hydrochloride polymorph form-II.
According to another embodiment of the invention there is provided an improved process for the preparation of Sertraline hydrochloride polymorph form-I by using the polymorph Form 1 obtained above as a seed
For this the Sertraline mandelate is suspended in acidic water at elevated temperature preferably at about 80-85 °C followed by cooling to room temperature with seeding of the polymorph form I obtained in the step (iv)
According to yet another embodiment of the invention there is provided an
improved process for the preparation of Sertraline hydrochloride polymorph form-
II by using the polymorph Form 11 obtained above as a seed
For this the Sertraline mandelate is suspended in acidic water at elevated temperature preferably at about 80-85 °C followed by cooling to room temperature with seeding of the polymorph form II obtained in the step (iv)
In the process described above, only 0.55 moles of D-(-)-mandelic acid is required as the cis R isomer is left as a free base and only the cis S isomer forms the mandelate as compared to 1.0 moles of D-(-)-mandelic acid used in the prior art J.Med. Chem, 1984, vol 27 no. 11 1508-1515.
The starting material 4-(3,4-dichlorophenyl)-3,4-dihydro-l-naphthalenone commonly known as tetralone used in the process of the present invention can be

prepared by reacting 1-naphthol with 1,2-dichlorobenzene in the presence of aluminum chloride as catalyst in 80% yield. Rupinskaya and co-workers previously reported the above reaction of naphthol in their article Zn.Org.Khim. 18(4) 870-8 (1982).
According to another feature of the invention there is provided an improved process for the preparation of sertraline mandelate, useful for the preparation of forms I & II of Sertraline hydrochloride of the formula I which comprises.
(i) reacting 4- (3,4-dichlorophenyl) - 3,4 - dihydro -1(2H) - naphthaenone commonly known as tetralone with monomethyl amine at room temperature to give the imine.
(ii) Reducing the resulting imine with sodium borohydride in alcoholic solvent to get the cis racemic sertraline hydrochloride.
(iii)Resolving the cis racemic sertraline-hydrochloride, using D-(-)-mandelic acid in the presence of anorganic water immiscible solvent to get sertraline mandelate,
(iv)Converting sertraline mandelate to sertraline hydrochloride polymorph form-I or form-II under different reaction condition to get sertraline hydrochloride.
The details of the invention are given in the Examples provided below which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention

Example 1
Preparation of sertraline hydrochloride polymorph form-I without seeding .
Step (i) Preparation of N-[4-(3,4-dichlorophenyl)-3,4-dihydrol(2H)-naphthalenylidene]methylamine (Schiff base)
In a 20 lits RB flask 4-(3,4-dichlorophenyl)-3,4-dihydro-l(2H)-naphthalenone (2.0 kg) was suspended in methanol (8.0 lits) and 35% methylamine solution in methanol (2.5 lits) was added to the reaction mixture. The reaction mixture is stirred for 24 hrs. After stirring the reaction mixture for 24 hrs the color of reaction mixture changes from light brown to yellow colored. The reaction mixture was cooled to 10 °C and the product was filtered, the filtered product was washed with chilled methanol (2.0 lits) and dried at 75 °C for 16 hrs to give 2.0 - 2.1 kg of N-[4-(3,4-dichlorophenyl)-3,4-dihydro 1 (2H)-naphthalenylidene] methylamine (Schiff base).
Step (ii) Reduction of N-[4-(3,4-dichlorophenyl)-3,4-dihydrol(2H)-naphthalenylidene] methylamine to racemic Sertraline hydrochloride
In a 20 lits RB flask N-[4-(3,4-dichlorophenyl)-3,4-dihydrol(2H)-naphthalenylidene]methyl amine (2.0 kg) prepared as described in step(i) was stirred in methanol (12.0 lit). The reaction mixture was cooled to 5 °C. Sodium borohydride (107 gms) was added in small lots of 5 gms each to the reaction mixture at 5-10 °C over a period of 2-2.5 hr. The reaction mixture was stirred for additional 1 hour and checked for the absence of schiff base by TLC. Cone, hydrochloric acid (2.0 lits) was added to the reaction mixture at 5-10 °C in 1 hr. The reaction was further stirred for 1 hr. The product was filter, washed with

chilled methanol (2.0 Uts) and dried at 75 °C for 16 hrs to give 1.1- 1.15 kg of racemic sertraline hydrochloride.
Step (iii) Preparation of Sertraline mandelate
In a 20 lits RB flask sodium hydroxide (235 gms) was added to water (3.6 lits) and stirred to get a clear solution, then toluene (3.6 lits) and racemic sertraline hydrochloride (1.0 kg) prepared by the process described in step (ii) was added The reaction mixture was heated to reflux temperature (85-90°C) to get a solid free reaction mixture. Maintained at reflux temperature for 60 mins. Cooled the reaction mixture to 30-35 °C and separated the layers. The toluene layer was washed with three times water (3 x 3.6 lits) to get the toluene layer free of any alkalinity due to sodium hydroxide. The Toluene layer was dried over anhydrous sodium sulphate and was taken in a 10 lits RB-flask. Added D-(-)-Mandelic acid (245 gms) to the reaction mixture, stirred the reaction for 30 mins, solid was thrown out of the reaction mixture (If the product was filtered at this stage then the filtration rate was very slow). The reaction mixture was heated to reflux temperature (above 100 °C) to get a clear solution. The reaction mixture was cooled to 30-35 °C. Stirred at 30-35 °C for 30 mins. The product was filtered, washed with toluene (2.0 lits) and dried at 75°C for 16 hrs to give 500-550 gms of Sertraline mandelate.
Step (iv ) Preparation of sertraline hydrochloride polymorph form-I.
In a 1 Uts R.B.flask, 500 ml water was added, to this 25 ml cone hydrochloric acid was added. Heated the reaction mixture to 80 °C and add 50 gms product of step (iii) of example 1 i.e. sertraline mandelate to the reaction mixture in one lot. The reaction mixture becomes a clear solution, naturally cooled the reaction mixture to room temperature. The reaction mixture was stirred for 24 hrs at room temperature.

Filtered the product, washed with 2 x 50 ml water, suck dry the filtered product and dry the product at 75 °C for 6 hrs to get sertraline hydrochloride polymorph form-I.
Example 2 Preparation of sertraline hydrochloride polymorph form-II without seeding . Step (i) Preparation of N-[4-(3,4-dichlorophenyI)-3,4-dihydrol(2H)-naphthalenylidene]methylamine (Schiff base)
In a 20 lits RB flask 4-(3,4-dichlorophenyl)-3,4-dihydro-l(2H)-naphthalenone (2.0 kg) was suspended in methanol (8.0 lits) and 35% methylamine solution in methanol (2.5 lits) was added to the reaction mixture. The reaction mixture is stirred for 24 hrs. After stirring the reaction mixture for 24 hrs the color of reaction mixture changes from light brown to yellow colored. The reaction mixture was cooled to 10 °C and the product was filtered, the filtered product was washed with chilled methanol (2.0 lits) and dried at 75 °C for 16 hrs to give 2.0 - 2.1 kg of N-[4-(3,4-dichlorophenyl)-3,4-dihydro 1 (2H)-naphthalenylidene] methylamine (Schiff base).
Step (ii) Reduction of N-[4-(3,4-dichlorophenyl)-3,4-dihydrol(2H)-naphthalenylidene] methylamine to racemic Sertraline hydrochloride
In a 20 lits RB flask N-[4-(3,4-dichlorophenyl)-3,4-dihydrol(2H)-naphthalenylidene]methyl amine (2.0 kg) prepared as described in step(i) was stirred in methanol (12.0 lit). The reaction mixture was cooled to 5 °C. Sodium borohydride (107 gms) was added in small lots of 5 gms each to the reaction mixture at 5-10 °C over a period of 2-2.5 hr. The reaction mixture was stirred for additional 1 hour and checked for the absence of schiff base by TLC. Cone, hydrochloric acid (2.0 lits) was added to the reaction mixture at 5-10 °C in 1 hr.

The reaction was further stirred for 1 hr. The product was filter, washed with chilled methanol (2.0 lits) and dried at 75 °C for 16 hrs to give 1.1- 1.15 kg of racemic sertraline hydrochloride.
Step (iii) Preparation of Sertraline mandelate
In a 20 lits RB flask sodium hydroxide (235 gms) was added to water (3.6 lits) and stirred to get a clear solution, then toluene (3.6 lits) and racemic sertraline hydrochloride (1.0 kg) prepared by the process described in step (ii) was added The reaction mixture was heated to reflux temperature (85-90°C) to get a solid free reaction mixture. Maintained at reflux temperature for 60 mins. Cooled the reaction mixture to 30-35 °C and separated the layers. Wash the toluene layer with three times water (3 x 3.6 lits) to get the toluene layer free of any alkalinity due to sodium hydroxide. The Toluene layer was dried over anhydrous sodium sulphate and was taken in a 10 lits RB-flask. Added D-(-)-Mandelic acid (245 gms) to the reaction mixture, stirred the reaction for 30 mins, solid was thrown out of the reaction mixture (If the product was filtered at this stage then the filtration rate was very slow). The reaction mixture was heated to reflux temperature (above 100 °C) to get a clear solution. The reaction mixture was cooled to 30-35 °C. Stirred at 30-35 °C for 30 mins. The product was filtered, washed with toluene (2.0 lits) and dried at 75°C for 16 hrs to give 500-550 gms of Sertraline mandelate.
Step (iv) Preparation of sertraline hydrochloride polymorph form-II.
In a 2 lits R.B.flask, add 1 lit isopropanol and add 100 gm the product of step (iii) i.e. sertraline mandelate to the reaction mixture in one lot. The reaction mixture is heated to 80 °C, add 100 ml of 25% hydrogen chloride gas absorbed in isopropanol to the reaction mixture in one lot. The reaction mixture will become solid free

solution. At 80 °C the reaction mixture was filtered over celite bed to get clear solution. Cool the reaction mixture to 30 °C, further cool the reaction mixture to 5 °C and filter the separated product. Washed the product with 100 gm chilled isopropanol and suck dry the product, dry the product in vacuum oven at 50-55 °C for about 8 hrs to get sertraline hydrochloride polymorph form-II
Example 3 Preparation of sertraline hydrochloride polymorph form-I by seeding
In a 10 lits RB flask water (5.0 lits) and cone, hydrochloric acid (250 is added ml) is added. The diluted acid was heated to 80 °C and then sertraline mandelate (500 gms) prepared by the process described in step (Hi) of Example 1 was added to the hot reaction mixture in one lot. The reaction will become a clear solution in 5 mins. Cooling the reaction mixture was started and a seed of form-I (prepared in step (iv) of Example 1) was added. Further cooled the reaction mixture to 75 °C and added the seed of form-I again, cooled the reaction to 72.5 °C and add again added the seed of form-I, cooled the reaction to 70 °C and added further the seed of from-I, cooled the reaction mixture to 30-35 °C and filtered the product. Washed the product with water (2 x 500 ml). Dry the product at 75 °C for 16 hrs to get 350-370 gms of sertraline hydrochloride polymorph form-I.
Example 4 Preparation of sertraline hydrochloride polymorph form-II by seeding.
In a 1 lit RB flask was added water (500 ml) and cone, hydrochloric acid (25 ml). It was heated to 80 °C and added sertraline mandelate (50 gms) prepared by the process as described in step (iii) of Example 2 to the reaction mixture in one lot. The reaction will become a clear solution in 5 mins. Cooling the reaction mixture

was started and added the seed of form-II prepared in step (iv) of Example 2 Cooled the reaction mixture to 75 °C and added the seed of form-II, cooled the reaction mixture to 73°C and added the seed of form-II, cooled the reaction mixture to 71°C and added the seed of from-II, cooled the reaction mixture to 30-35 °C and filtered the product. Washed the product with water (2 x 50 ml) dried at 75 °C for 16 hrs to get 35-37 gms of sertraline hydrochloride Form-II.
♦ The advantage of the present invention :.
1. Only a single solvent i.e./toluene is used in preparing sertraline mandelate, making it very simple and convenient for the commercial production The reported literature uses two or more different solvents and making it complicated and lengthy manufacturing process on commercial production.
2. The sertraline mandelate is converted to the hydrochloride with the help of hot aqueous hydrochloric acid in water the required polymorph is obtained by seeding the reaction mixture with the desired form-I or form-II continuously during cooling.
3. The process for the preparation of sertraline hydrochloride polymorph form-I is simple and avoids use of organic solvents and is economical as only water is used as the solvent in the formation of hydrochloride.
4. The process for the preparation of sertraline hydrochloride polymorph form-II is simple and is economical as either water or isopropanol is used as a solvent in the formation of hydrochloride.
5. During the formation of hydrochloride in the final step there is no need to isolate the free base i.e. the sertraline mandelate, which is directly converted to the hydrochloride in a single step without the isolation of the free base as an oil or in the form of a solution, which makes the process still more economical.

6. As the formation of the hydrochloride is a single step therefore is a simplified manufacturing process and it has been successfully scaled up thereby making it commercially feasible
7. During the formation of the schiff base the toxic chemical Titanium tetrachloride is not used hence making the process safe and environmentally friendly.

We claim: -
1. A process of preparing cis- (1S, 4S)-N-methyl-4- (3,4-dichlorophenyl)-1,2,3,4-tetrahydro-
1-naphthaleamine hydrochloride (Sertraline hydrochloride) form-I from Sertraline
mandelate using water as solvent comprising steps of,
a. Addition of Sertraline mandelate to hot aqueous hydrochloric acid solution and
heating to get a clear solution,
b. Or in another variation, heating a mixture of Sertraline mandelate and water followed
by the addition of hydrochloric acid to get a clear solution,
c. Cooling the reaction and isolating the solid.
2. The process according to claim 1 wherein the mixture of Sertraline mandelate and aqueous hydrochloric acid is heated at 80-85 °C.
3. The process according to claim 1 wherein the seeding crystals of Sertraline hydrochloride form-I may be optionally added during cooling the reaction.
4. A process of preparing cis- (IS, 4S)-N-methyl-4- (3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleamine hydrochloride (Sertraline hydrochloride) form-II from Sertraline mandelate using water as solvent comprising steps of,
a. Addition of Sertraline mandelate to hot aqueous hydrochloric acid solution and
heating to get a clear solution,
b. Or in another variation, heating a mixture of Sertraline mandelate and water followed
by the addition of hydrochloric acid to get a clear solution,
c. Cooling the reaction with addition of seeding crystals of Sertraline hydrochloride
form-II and isolating the solid.
5. The process according to claim 4 wherein the mixture of Sertraline mandelate and aqueous hydrochloric acid is heated at 80-85 °C.
6. The process according to claim 4 wherein the seeding crystals of Sertraline hydrochloride form-II is added during cooling the reaction.
Dated this Day of 2005.

SANTOSH KUMAR NAIR
(GENERAL MANAGER - LEGAL & COMPANY SECRETARY)
UNICHEM LABORATORIES LIMITED