WO2005121074A2

WO2005121074A2 - Processes for the preparation of sertraline hydrochloride

Info

Publication number: WO2005121074A2
Application number: PCT/IB2005/051911
Authority: WO
Inventors: Kintali Venkata Ramana; Kaptan Singh; Mohan Prasad; Keshav Deo; Yatendra Kumar
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2004-06-09
Filing date: 2005-06-09
Publication date: 2005-12-22
Also published as: WO2005121074A3

Abstract

The invention relates to processes for the preparation of Schiff's base, and to the use of Schiff's base as intermediate in the preparation of naphthalenamine derivatives which are active compounds for treating the anxiety related disorders. The invention also relates to processes for the preparation of sertraline or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions that include the sertraline.

Description

Description PROCESSES FOR THE PREPARATION OF SERTRALINE HY- DROCHLORIDE Technical Field

[1] The field of the invention relates to processes for the preparation of Schiff s base, and to the use of Schiff s base as intermediate in the preparation of naphthalenamine derivatives which are active compounds for treating the anxiety related disorders. The invention also relates to processes for the preparation of sertraline or a pharmaceutically acceptable salt thereof, and pharmaceutical compositions that include the sertraline. Background Art

[2] Chemically, sertraline hydrochloride is ( 1 S-cis)-4-(3,4-dichlorophenyl)- 1 ,2,3 ,4-tetrahydro-N-methyl- 1 -naphthalenamine hydrochloride having the structural Formula I. It is useful in the treatment of anxiety- related disorders (U.S. Patent No. 4,962,128), symptoms associated with premenstrual disorders (U.S. Patent No. 5,789,449) and late luteal phase dysphoric disorder (U.S. Patent No. 5,744,501).

[4] FORMULA I [5] Schiff s base of Formula II which is chemically [4-(3,4-dichlorophenyl)-3,4-dihydro-l(2H)-naphthalenylidene]methanamine is a useful intermediate in the synthesis of sertraline hydrochloride of Formula I.

[6]

[7] FORMULA II [8] U.S. Patent No. 4,536,518 discloses a process for the hydrogenation of Schiff s base using palladium on carbon catalyst in presence of hydrogen gas to get a mixture of cis- racemate sertraline. The use of palladium catalyst during the hydrogenation, results in dehalogenation of aromatic halogen atom and formation of a dehalo-sertraline impurity of Formula III.

[10] FORMULA III [11] In order to minimize the formation of dehalo-impurity, several processes have been reported.

[12] U.S. Patent No. 5,082,970 discloses a process for treating trans-sertraline with potassium tert-butoxide to get cis-sertraline. An additional step however, needs to be performed.

[13] PCT Patent Application WO 99/47486 discloses use of copper containing catalyst for achieving a 98.5% cis-sertraline formation. [14] PCT Patent Application WO 99/57093 describes use of palladium catalyst pretreated with alkyl halides to minimize the formation of dehalo-impurity. A ratio of cis: trans:: 95:5 with dehalo-impurity below 0.5% is reported.

[15] PCT Patent Application WO 02/102761 discloses a process for the hydrogenation of Schiff s base using noble metal catalyst in presence of dehalogenation inhibitor compound such as triphenyl phosphite to get a ratio of cis : trans :: 97:3 and dehalo- impurity less than 0.1%.

[16] PCT Patent Application WO 01/16089 describes a one-pot process for formation and simultaneous reduction of Schiff s base using methylamine gas in presence of Raney nickel catalyst under hydrogen pressure of about 200 to 1000 pound per square inch (PSI) and the temperature of about 50 to 100°C.

[17] The prior art approach for the preparation of sertraline or a pharmaceutically acceptable salt thereof is not suitable from commercial point of view because the product is not obtained in high purity and is not cost effective, thus making the approach commercially difficult to implement.

[18] To achieve a high efficiency of reaction for industrial scale synthesis of sertraline or a pharmaceutically acceptable salt thereof, it is necessary to minimize the formation of the impunities.

[19] The present inventors have found that these problems associated with prior-art could be attributed to non-effective removal of trapped methylamine which is used during the formation of Schiff s base from tetralone intermediate. The entrapped methylamine imparts alkalinity to the reaction mass during the hydrogenation step and leads to the formation of the dehalo impurity.

[20] Thus, the present invention provides a process which does not result in impure sertraline or a pharmaceutically acceptable salt thereof; rather pure sertraline having a higher isomeric ratio of cis to trans-sertraline in excess of 99:1 and dehalo impurity less than 0.1% is obtained. Disclosure

[21] Summary of the Invention

[22] In one general aspect there is provided a process for the preparation of Schiff s base of Formula II.

[24] FORMULA II

[25] The process includes:

[26] a) obtaining a solution of tetralone of Formula IV in one or more solvents;

[28] FORMULA IV [29] b) purging methylamine gas through the solution obtained in step a); [30] c) passing the solution obtained in step b) through a column packed with anhydrous molecular sieves; and

[31] d) isolating the Schiff s base of Formula II by the removal of the solvent. [32] In another general aspect there is provided a process for the preparation of cis-(-) sertraline or a pharmaceutically acceptable salt thereof. The process includes:

[33] (a) treating a solution of tetralone of Formula IV

[35] FORMULA IV [36] in one or more solvents, with methylamine gas in the presence of activated molecular sieves to get a solution of Schiff base of formula II,

[38] FORMULA II [39] (b) concentrating the solution of step (a) until pH of the solution is from about 7.0 to about 8.0;

[40] (b) reducing the product of step (b) with a reducing agent to get cis-racemate of sertraline or a pharmaceutically acceptable salt thereof; and

[41] (c) resolving the product of step c) with a chiral reagent to get cis-(-) sertraline or a pharmaceutically acceptable salt thereof.

[42] The process may produce the cis-(-) sertraline or a pharmaceutically acceptable salt thereof having dehalo-impurity of Formula III less than 0.2% by HPLC. In particular, it may produce the cis-(-) sertraline or a pharmaceutically acceptable salt thereof having dehalo-impurity less than 0.1% by HPLC for example, less than 0.05% by HPLC.

[43] The process may further include converting the product obtained into stable Form II of sertraline hydrochloride.

[44] In another general aspect there is provided cis-(-) sertraline hydrochloride having a purity of more than 99% of cis-(-) sertraline hydrochloride and dehalo-impurity less than 0.1% by HPLC.

[45] In another general aspect there is provided pure stable Form II of sertraline hydrochloride having a purity of more than 99.5% of cis-(-) sertraline hydrochloride and dehalo-impurity less than 0.05% by HPLC.

[46] In another general aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of pure stable Form II of sertraline hydrochloride having a purity more than 99.5% of cis-(-) sertraline hydrochloride and the dehalo-impurity of Formula III less than 0.05% by HPLC; and one or more pharmaceutically acceptable carriers, excipients or diluents.

[47] In another general aspect there is provided a method method of treating anxiety- related disorders, symptoms associated with premenstrual disorders and late luteal phase dysphoric disorder in a warm-blooded animal, the method comprising administering a pharmaceutical composition that includes pure stable Form II of sertraline hydrochloride having a purity more than 99.5% of cis-(-) sertraline hydrochloride and dehalo-impurity of Formula III less than 0.05% by HPLC.

[48] The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims. Description Of Drawings

[49] Figure 1 is an X-ray powder diffraction pattern of stable Form II of sertraline hydrochloride. Detailed Description of the Invention [50] The inventors have developed a process for the preparation of Schiff s base of Formula II by obtaining a solution of tetralone of Formula IV in one or more solvents; purging methylamine gas through the solution; passing the solution so obtained through a column packed with anhydrous molecular sieves; and isolating the Schiff s base by the removal of the solvent.

[51] In general, the solution of tetralone of Formula IV may be obtained by dissolving tetralone in a suitable solvent. The solvent containing tetralone may be heated to obtain a solution. It can be heated from about 30 °C to about reflux temperature of the solvent used, for example from about 30 °C to about 120 °C.

[52] The term 'obtaining' includes dissolving, slurrying, stirring or a combination thereof.

[53] The term 'suitable solvent' includes any solvent or solvent mixture in which tetralone is soluble, including, for example, aromatic hydrocarbons, primary alcohols, polar aprotic solvents and mixtures thereof.

[54] A suitable aromatic hydrocarbon includes one or more of toluene, xylene and benzene. Examples of primary alcohols include methanol, ethanol, n-propanol and isopropanol. Examples of polar aprotic solvents include one or more of tetrahydrofuran, acetonitrile and 1,4-dioxane. Mixtures of all of these solvents are also contemplated.

[55] In general, the resulting solution may be cooled before purging the methylamine gas. The solution may be cooled from about 20 °C to about -20°C. The resulting reaction mass may be circulated through a column packed with anhydrous molecular sieves. The solution may be passed through the column at a temperature of from about 30°C to about 120°C for about 10 to 48 hours. After completion of reaction, the reaction mass may be cooled and solvent may be recovered under vacuum to get a residue of the Schiff s base.

[56] The Schiff s base may be recovered from the solution by a technique which includes, for example, distillation, distillation under vacuum and evaporation.

[57] The inventors also have developed a process for the preparation of cis-(-) sertraline or a pharmaceutically aceeptable salt thereof by treating a solution of tetralone of Formula IV in one or more solvents, with methylamine gas in the presence of activated molecular sieves to get a solution of Schiff s base of Formula II; concentrating the solution so obtained until pH of the solution is from about 7.0 to about 8.0; reducing the product obtained with a reducing agent to get cis-racemate of sertraline or a pharmaceutically acceptable salt thereof; and resolving the product so obtained with a chiral reagent to get cis-(-) sertraline or a pharmaceutically acceptable salt thereof.

[58] The tetralone of Formula IV may be dissolved in a solvent, including, for example aromatic hydrocarbons, primary alcohols, polar aprotic solvents and mixtures thereof and activated molecular sieves may be added to the solution. The methylamine gas may be purged through the solution. The solution may be heated from about 30°C to about 120°C for about 0.5 hours to about 24 hours.

[59] The solution of Schiff s base of Formula II may be obtained after cooling the resultant mass and filtering the molecular sieves. The molecular sieves may be washed with a solvent and washings may be combined with the filtrate obtained after filtration.

[60] The solution containing the Schiff s base may be concentrated. It may be concentrated by a technique which includes, for example, distillation, distillation under vacuum and evaporation. It may be concentrated under vacuum at a temperature from about 30°C to about 100°C. Fresh solvent may be charged and concentration continued till no detectable methylamine is found in the distillate. The pH of the resultant mass may be maintained from about 7.0 to about 8.0.

[61] The Schiff base residue may be dissolved in a solvent for the reduction step. It may be dissolved in any solvent commonly known to a person of ordinary skills in the art for carrying out the reduction reactions. These solvents include, for example lower alkanols, ethers, tetrahydrofuran, esters and aromatic hydrocarbons. The solution may be hydrogenated with a reducing agent for about 1 to 50 hours at 2 to 15 psi hydrogen pressure.

[62] Examples of reducing agents include noble metals such as palladium on carbon, palladium acetate, palladium chloride, platinum oxide, platinum chloride, ruthenium and rhodium. Raney nickel can also be used as a reducing agent. After the hydrogenation reaction, the reaction mixture may be filtered to remove the reducing agent and the filtrate may be concentrated under vacuum to get a residue. The residue so obtained may be optionally converted to its salt form by treating it with a suitable acid. The cis-racemate of sertraline or a pharmaceutically acceptable salt thereof so obtained may be dried under vacuum.

[63] The hydrogenation may also be carried out in the presence of Raney nickel catalyst in an organic solvent under hydrogen pressure of about 35 to 150 psi at 30 to 60°C. The hydrogenation reaction does not require presence of any dehalogenation inhibitors such as triphenyl phosphite, trimethyl phosphite or tritoyl phosphite. After complete reduction of the Schiff s base, catalyst may be removed by filtration and the reaction mass may be treated with concentrated hydrochloride acid to get cis-sertraline hydrochloride having more than 99% cis-sertraline hydrochloride and less than 0.1% of dehalo-impurity.

[64] The cis-racemate of sertraline or a pharmaceutically acceptable salt thereof may be subjected to resolution using a chiral auxiliary such as mandelic acid, tartaric acid or derivatives thereof. The salt of chiral auxiliary with sertraline may be further purified to remove the unwanted cis-(+)-sertraline isomer and then the pure cis-(-)- sertraline salt of chiral auxiliary may be converted to sertraline or a pharmaceutically acceptable salt thereof by neutralization with a base followed by conversion to a pharmaceutically acceptable salt. Cis-(-)-sertraline or a pharmaceutically acceptable salt thereof so obtained can be further purified to get sertraline or a pharmaceutically acceptable salt thereof having the de-halo impurity less than 0.2%.

[65] The process may produce the cis-(-) sertraline or a pharmaceutically acceptable salt thereof having dehalo-impurity of Formula III less than 0.2% by HPLC. In particular, it may produce the cis-(-) sertraline or a pharmaceutically acceptable salt thereof having dehalo-impurity less than 0.1% by HPLC for example, less than 0.05% by HPLC.

[66] The inventors also have developed a process for the preparation of stable Form II of sertraline hydrochloride by treating a a solution of tetralone of Formula IV in one or more solvents with methylamine gas in the presence of activated molecular sieves to get a solution of Schiff s base of Formula II; concentrating the solution so obtained until pH of the solution is from about 7.0 to about 8.0; hydrogenating the Schiff s base of Formula II with Raney nickel catalyst in the presence of hydrogen pressure; isolating cis-racemate of sertraline hydrochloride from the reaction mass; converting cis-racemate of sertraline hydrochloride to cis-racemate sertraline free base and treating the free base with D-(-)-mandelic acid to get mandelate salt of cis-sertraline; converting the mandelate salt of cis-sertraline to cis-sertraline free base and then treating the free base with a source of hydrogen chloride to get sertraline hydrochloride; suspending the sertraline hydrochloride in an organic solvent comprising one or both of methyl isobutyl ketone and N,N-dimethylacetamide; and isolating Form II of sertraline hydrochloride.

[67] The cis-racemate may be partitioned between an aqueous solution of a base and an organic solvent for example, toluene to convert the hydrochloride salt to a free base. The free base in toluene may be treated with a D-(-)-mandelic acid to get mandelate salt of cis-sertraline which may optionally be recrystallized from a suitable alkanol for example, methanol, ethanol, isopropanol or n-propanol. The pure sertraline mandelate so obtained may be re-partitioned between aqueous solution of base and an organic solvent such as ethyl acetate and cis-sertraline free base may be extracted in the ethyl acetate layer. The ethyl acetate layer may be treated with a source of hydrogen chloride and sertraline hydrochloride obtained may be suspended in a solvent for example, methyl isobutyl ketone, N,N-dimefhylacetamide or mixtures thereof. The resultant mixture may be heated and cooled, to get a precipitate of stable form II of sertraline hydrochloride. It may also be seeded with a seed crystal of Form II setraline hydrochloride to enhance precipitation of Form II. The Form II sertraline hydrochloride so obtained may be filtered and dried. It may be further dried under vacuum. [68] The process may produce the pure stable Form II sertraline hydrochloride having a purity of more than 99.0% of cis-(-) sertraline hydrochloride and the dehalo-impurity less than 0.1%. In particular, it may also produce the pure Form II sertraline hydrochloride having a purity more than 99.5% of cis-(-) sertraline hydrochloride and dehalo-impurity less than 0.05%. It may also produce the pure Form II sertraline hydrochloride wherein the dehalo-impurity is not present in any detectable quantity as measured by HPLC.

[69] The resulting stable Form II of sertraline hydrochloride may be formulated into ordinary dosage forms such as, for example, tablets, capsules, pills, solutions, etc. In these cases, the medicaments can be prepared by conventional methods with conventional pharmaceutical excipients.

[70] The compositions include dosage forms suitable for oral, buccal, rectal, and parenteral (including subcutaneous, intramuscular, and ophthalmic) administration. The oral dosage forms may include solid dosage forms, like powder, tablets, capsules, suppositories, sachets, troches and lozenges as well as liquid suspensions, emulsions, pastes and elixirs. Parenteral dosage forms may include intravenous infusions, sterile solutions for intramuscular, subcutaneous or intravenous administration, dry powders to be reconstituted with sterile water for parenteral administration, and the like.

[71] The stable Form II of sertraline hydrochloride can be administered for the treatment of anxiety-related disorders, symptoms associated with premenstrual disorders and late luteal phase dysphoric disorders, in a warm-blooded animal.

[72] For the purpose of this disclosure, a warm-blooded animal is a member of the animal kingdom possessed of a homeostatic mechanism and includes mammals and birds.

[73] The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

[74] Example 1: Preparation of pure cis-racemate sertraline hydrochloride

[75] A: Preparation of Schiff s base

[76] A solution of 4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)naphthalenone (100 g) in toluene (1.12 lit) was cooled to 0 to -10°C and methylamine gas (90 g) was purged. The resulting reaction mixture was circulated through a column of anhydrous molecular sieves (200 g) at 70 - 75°C for about 24 hours. After cooling the reaction mixture to room temperature, toluene was completely recovered from the reaction mass under vacuum to yield a solid residue of Schiff s base.

[77] B: Reduction of Schiff s base

[78] The residue obtained in step A) was dispersed in ethanol (500 ml) and Raney nickel catalyst (wet, 60 g, pre-washed with ethanol) was added. The resultant mass was subjected to hydrogenation for about 3 to 4 hours at 4 to 5 Kg pressure and at 40 to 50°C. After removal of the catalyst by filtration, the reaction mixture was treated with concentrated hydrochloric acid (50 ml) and heated to 70 - 75 °C for about 2 hours. The reaction mixture was cooled to 10 - 15°C and an off-white precipitate was filtered, dried at 40 - 50°C to get the pure cis-racemate sertraline hydrochloride.

[79] Yield: 80 g

[80] Cis-sertraline hydrochloride content: 99.3% w/w (by HPLC)

[81] Dehalo-impurity: less than 0.1 % w/w (by HPLC).

[82] Example 2; Preparation of Schiff base

[83] To a mixture of tetralone (25 g) and toluene (350 ml), activated molecular sieves (100 g) were added. A solution of methylamine gas (16 g) in toluene (50 ml) was charged to the above mixture. The reaction mixture was heated to 90 - 95°C gradually in 3-4 hrs and cooled to 25-30°C. The molecular sieves were filtered, washed with toluene (50 ml x 2) and the filtrate was combined with the washings. This combined solution was then concentrated under vacuum at ~50°C to get a residue which was dissolved in toluene (350 ml) and used as such in the next step.

[84] Example 3: Preparation of cis- racemate sertraline hydrochloride

[85] A mixture of Schiff base in toluene and palladium on carbon catalyst was hy- drogenated for 3-4 hours under 3-4 psi hydrogen pressure. The catalyst was filtered and washed with toluene (75 ml x 2) under nitrogen atmosphere and concentrated under vacuum at 50 to 60 °C to obtain a residue which was again diluted with toluene (175 ml) and warmed to 35-40°C. Concentrated hydrochloric acid (11 ml) was added to adjust pH to 1-2 to obtain the precipitate. The reaction mass was cooled to 25 °C. It was filtered and washed with toluene (50 ml x 2 ) and dried under vacuum at 35 to 40 °C to obtain the product (Yield 97.6 %).

[86] Quality:

[87] Dehalo-impurity: 0.65 % w/w (by HPLC)

[88] Example 4; Preparation of sertraline mandelate

[89] A mixture of aqueous sodium hydroxide (11.56 g) and water (46 ml), cis- racemate of sertraline hydrochloride (22 g) and ethyl acetate (220 ml) was stirred at 25 to 30 °C to get a clear solution. The layers were separated and the organic layer was concentrated under vacuum at 40 to 45 °C to obtain a residue.

[90] To the above residue, denatured sprit (100 ml) and ( R )- (-)-mandelic acid (11.71 g) were added and the resultant mixture was stirred at 50 to 52 °C for 2 hours. It was cooled to room temperature and filtered. The wet cake so obtained was recrystallized with denatured sprit (280 ml) at 80-85 °C to produce sertraline mandelate (Yield: 63% on net basis). [91] Quality:

[92] Dehalo-impurity: 0.08 % w/w (by HPLC)

[93] Example 5: Preparation of sertraline hydrochloride

[94] A mixture of sertraline mandelate (9.5 g), ethyl acetate (80 ml) and 10% aqueous sodium hydroxide solution (15 ml) was stirred at room temperature to get a clear solution. The layers were separated and the organic layer was concentrated under vacuum to obtain a residue. The residue so obtained was treated with concentrated hydrochloric acid (1.9 ml) at 55 to 60 °C and stirred for 2 hours to give a solid. The solid so obtained was filtered, washed with ethyl acetate (10 ml x 2) and dried under vacuum at 30 - 35°C to produce sertraline hydrochloride (Yield : 91 %).

[95] Quality:

[96] Dehalo-impurity: 0.11 % w/w (by HPLC)

[97] Cis-sertraline: -99.8 %

[98] Trans racemate: Not detected

[99] Example 6: Preparation of sertraline hydrochloride

[100] Sertraline mandelate (35 g) was dissolved in ethyl acetate (1575 ml) at room temperature and a solution of sodium hydroxide (10%, 61 ml of water) was added to it. The reaction mixture was stirred at 20-25°C for about 1 hour. The layers were separated and the organic layer was washed with demineralized water (435 ml). To the organic layer, activated carbon (1.75 g) was added and it was stirred for 30 minutes at 20-25°C. The reaction mixture was filtered through celite bed and the bed was washed with ethyl acetate (140 ml). The filtrate was dried using sodium sulphate. To the ethyl acetate layer, diethyl ether (1890 ml) was added and the resultant mixture was stirred for 5-10 minutes at 20-25°C. Dry hydrogen chloride gas was purged through the reaction mixture while maintaining the pH at about 1. The reaction mixture was further stirred at 20-25°C for about 12 hours. The separated product was filtered, and washed with diethyl ether (2 x 210 ml). The final product was initially dried at room temperature and then at 35-40°C using vacuum.

[101] Yield: 22.1 g

[102] Example 7; Preparation of stable sertraline hydrochloride Form II

[103] Sertraline hydrochloride (1.0 g) obtained as per the process of Example 6, was suspended in methyl isobutyl ketone (20 ml) at room temperature and the reaction mixture was heated slowly to 80°C. The reaction mixture was stirred at 80°C for about 2 hours and then cooled to room temperature. The product was filtered and dried under vacuum.

[104] The XRD pattern as per Figure 1 showed it to be a Form II of sertraline hydrochloride.

[105] Example 8 -.Preparation of purestable Form II of sertraline hydrochloride [106] A: Preparation of sertraline mandelate

[107] The product obtained in step B), Example 1, cis-(lS,lR)-N-methyl-4-(3,4-dichloro phenyl)-l, 2,3, 4-tetrahydro-l -naphthalenamine hydrochloride (175 g) was partitioned between 20% aqueous NaOH (450 ml) and toluene (750 ml) in presence of methylamine (about 3 ml) to yield a solution of the cis-racemate free base in toluene. After complete recovery of toluene, the reaction mixture was dissolved in denatured spirit (about 200 ml) and treated with D(-) mandelic acid (40 g) at 60 - 65°C. The resulting mixture was warmed at 50 - 55°C for about 3 hrs and cooled to 10°C to yield a white crystalline solid. This solid was separated by filtration and then recrystallized from hot denatured spirit to get pure sertraline mandelate salt.

[108] Yield: 34 g

[109] B: Preparation of pure sertraline hydrochloride

[110] Mandelate salt (40 g) obtained in step A) above was suspended in ethyl acetate (1.08 lit). The ethyl acetate suspension was treated with 10% aqueous sodium hydroxide solution, thereby converting the mandelate salt to sertraline free base. The resulting ethyl acetate solution was then dried, diluted with diethyl ether (1.08 lit) and then treated with dry hydrogen chloride gas to give gelatinous suspension, which was left overnight to crystallize. The product was separated by filtration, washed with diethyl ether (2 x 160 ml), and dried to get pure sertraline hydrochloride.

[Ill] C: Conversion to pure stable Form II sertraline hydrochloride

[112] Sertraline hydrochloride (25 g) obtained in Part B) above was suspended in methyl isobutyl ketone (500 ml) and the resulting suspension was heated to 60 - 80°C for about 3 hours. After cooling the reaction mixture to room temperature, a white crystalline hydrochloride salt of sertraline separated out. The product was filtered and washed with methyl isobutyl ketone and dried under vacuum to get pure, stable sertraline hydrochloride Form II.

[113] Yield: 22.5 g

[114] HPLC Purity: Cis-sertraline hydrochloride 99.85% w/w

[115] Dehalo-impurity: not detectable by HPLC

[116] While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention.

Claims

[1] A process for the preparation of Schiff s base of Formula II,

FORMULA II the process comprising: a) obtaining a solution of tetralone of Formula IV in one or more solvents;

FORMULA IV b) purging methylamine gas through the solution obtained in step a); c) passing the solution obtained in step b) through a column packed with anhydrous molecular sieves; and d) isolating the Schiff s base of Formula II by the removal of the solvent.

[2] The process of claim 1, wherein the solvent comprises one or more of aromatic hydrocarbons, primary alcohols, polar aprotic solvents, or mixtures thereof.

[3] The process of claim 2, wherein the aromatic hydrocarbon comprises one or more of toluene, xylene, and benzene.

[4] The process of claim 2, wherein the primary alcohol comprises one or more of methanol, ethanol, n-propanol and isopropanol.

[5] The process of claim 2, wherein the polar aprotic solvent comprises one or more of tetrahydrofuran, acetonitrile and 1,4-dioxane.

[6] The process of claim 1, wherein the solution is passed through the column at a temperature from about 30°C to about 120°C.

[7] A process for the preparation of cis-(-) sertraline or a pharmaceutically acceptable salt thereof, the process comprising: a) treating a solution of tetralone of Formula IV

FORMULA IV in one or more solvents, with methylamine gas in the presence of activated molecular sieves to get a solution of Schiff base of Formula II;

FORMULA II b) concentrating the solution of step (a) until pH of the solution is from about 7.0 to about 8.0; c) reducing the product of step (b) with a reducing agent to get cis- racemate of sertraline or a pharmaceutically acceptable salt thereof; and d) resolving the product of step c) with a chiral reagent to get cis-(-) sertraline or a pharmaceutically acceptable salt thereof.

[8] The process of claim 7, wherein the organic solvent comprises one or more of aromatic hydrocarbons, primary alcohols, polar aprotic solvents, or mixtures thereof.

[9] The process of claim 7, wherein the reducing agent comprises one or more of palladium on carbon, palladium acetate, palladium chloride, Raney nickel, platinum oxide, platinum chloride, ruthenium and rhodium.

[10] The process of claim 9, wherein the reducing agent is Raney nickel.

[11] The process of claim 7, wherein the chiral reagent comprises one or more of mandelic acid, tartaric acid, or derivatives thereof.

[12] The process of claim 7, further comprising converting cis-(-) sertraline into stable Form II of sertraline hydrochloride.

[13] The process of claim 7, further comprising forming the product into a finished dosage form.

[14] Cis-(-) sertraline or a pharmaceutically acceptable salt thereof having dehalo- impurity of Formula III less than 0.2% by HPLC prepared by the process of claim 7.

FORMULA III

[15] A process for the preparation of stable Form II of sertraline hydrochloride, the process comprising: a) treating a solution of tetralone of Formula IV

FORMULA II b) concentrating the solution of step (a) until pH of the solution is from about 7.0 to about 8.0; c) hydrogenating the Schiff s base of Formula II with Raney nickel catalyst in the presence of hydrogen pressure; d) isolating cis-racemate of sertraline hydrochloride from reaction mass; e) converting the product of step d) to cis-racemate of sertraline free base; f) treating the free base with D-(-)-mandelic acid to get mandelate salt of cis-sertraline; g) converting the mandelate salt of cis-sertraline to cis-sertraline free base; h) treating the cis-sertraline free base with a source of hydrogen chloride to get sertraline hydrochloride; i) suspending the sertraline hydrochloride in an organic solvent comprising one or both of methyl isobutyl ketone and N,N-dimethylacetamide; and j) isolating the Form II of sertraline hydrochloride.

[16] The process of claim 15, further comprising forming the product into a finished dosage form.

[17] Stable Form II of sertraline hydrochloride having more than 99.0% of cis-(-) sertraline hydrochloride and dehalo-impurity of Formula III less than 0.1% by HPLC prepared by the process of claim 15.

[18] Stable Form II of sertraline hydrochloride having more than 99.5% of cis-(-) sertraline hydrochloride and dehalo-impurity of Formula III less than 0.05% by HPLC prepared by the process of claim 15.

[19] The process of claim 15, wherein the stable Form II of sertraline hydrochloride has the X-ray diffraction pattern of Figure 1.

[20] Cis-(-) sertraline hydrochloride having more than 99% of cis-(-) sertraline hydrochloride and dehalo-impurity of Formula III less than 0.1% by HPLC.

[21] Cis-(-) sertraline hydrochloride of claim 20 having more than 99.5% of cis-(-) sertraline hydrochloride and dehalo-impurity of Formula III less than 0.05% by HPLC.

[22] Stable Form II of sertraline hydrochloride having a purity of more than 99.5% of cis-(-) sertraline hydrochloride and dehalo-impurity of Formula III less than 0.05% by HPLC.

[23] A pharmaceutical composition comprising: a therapeutically effective amount of pure stable Form II of sertraline hydrochloride having a purity more than 99.5% of cis-(-) sertraline hydrochloride and the dehalo-impurity of Formula III less than 0.05% by HPLC; and one or more pharmaceutically acceptable carriers, excipients or diluents.

[24] A method of treating anxiety-related disorders, symptoms associated with premenstrual disorders and late luteal phase dysphoric disorder in a warm-blooded animal, the method comprising administering a pharmaceutical composition that includes pure stable Form II of sertraline hydrochloride having a purity more than 99.5% of cis-(-) sertraline hydrochloride and dehalo-impurity of Formula III less than 0.05% by HPLC.