Title of Invention	PROCESS FOR THE PREPARATION OF SERTRALINE HYDROCHLORIDE
Abstract	The invention disclosed in this application relates to an improved process for the preparation of cis- (1 S, 4S)-N-methyl-4- (3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1- naphthaleneamine hydrochloride, commonly known as sertraline, from its racemic mixture by employing (R)-naproxen and its conversion to sertraline hydrochloride by novel methods which are environmentally friendly.

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Title : An Improved Process for the Preparation of Seatrain Hydrochloride Applicant: Divi"s Laboratories Limited Inventors : Katta Hari Babu & Mysore Aswathanarayana Rao Abstract: The invention disclosed in this application relates to an improved process for the preparation of cis- (IS, 4S)-N-methyl-4- (3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-naphthaleneamine, commonly known as sertraline, from its racemic mixture by employing (R)-naproxen and its conversion to sertraline hydrochloride by novel methods which are environmentally friendly.Sertraline hydrochloride is therapeutically useful in treating depression and obsessional disorders. Introduction : The present invention relates to an improved process for the preparation of cis- (IS, 4S)-N-methyl-4- (3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-naphthaleneamine hydrochloride commonly known as Sertraline hydrochloride. Sertraline prepared by the process of the present invention has the Formula-I given below . See the Merck Index, 13* Edn., page 1518, No.8541: Sertraline is therapeutically useful in treating depression and obsessional disorders. It was first described in the US patent no 4,536,518. Background Several processes for the preparation of sertraline are reported in the patent literature. U.S. Pat. No. 4,536,518 discloses a process for the synthesis of Sertraline hydrochloride. The process involves the reduction of the imine of the Formula-II, by either catalytic hydrogenation or metal hydride to form N-methyl -4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine which is a mixture of four isomers, namely, cis- (IS), cis-(IR), trans- (IS), and trans- (IR) isomers. The cis isomers are separated from trans isomers by fractional crystallization. The cis isomers thus obtained are a mixture of cis-(IS) enantiomer (Sertraline, Formula -I) and cis- (IR) enantiomer of the Formula -HI. The U.S. Pat. No. 4,536,518 describes a resolution method to obtain cis- (IS) enantiomer by using D (-) mandelic acid and cis- (IR) enantiomer by using L (+) mandelic acid. The "518" patent also mentions (+)-10-camphorsulfonic acid or (-)-lO-camphorsulfonic acid as other possible resolving agents without giving any details. However, (D) and (L)-mandelic acid are preferred over (+) and (-)-camphorsulfonic acid and (D)-mandelic acid is further preferred, according to the U.S. Pat. No. 6,552,227 B2. The U.S. Pat. No 4,556,676 describes a resolution method for trans isomers of sertraline where trans- (IS) enantiomer was obtained using L (+) mandelic acid and trans- (IR) enantiomer by using D (-) mandelic acid. The sertraline base is converted to its hydrochloride salt generally by gaseous hydrogen chloride as described in the U.S. Pat. Nos. 4,536,518; 4,556,676; 6,495,721; and 6,500,987. The U.S. Pat. No. 6,495,721 also describes the use of hydrogen chloride dissolved in isopropanol, whereas the U.S. Pat. No. 6,500,987 describes the use of concentrated hydrochloric acid to prepare the hydrochloride salt. Mandelic acid darkens and decomposes on prolonged exposure to light (The Merck Index, 13"^ Edn., page 1518, No.8541). It is also expensive. Hydrogen chloride, either in gaseous form or as solution, used in the process described in the prior art is corrosive, hazardous and environmentally unfriendly. /" Hence, It is desirable to explore alternatives to mandelic acid as resolving agents. It is also desirable to explore alternatives to hydrogen chloride which are environmentally more friendly. Objectives of the present invention The main objective of the present invention is to provide an improved process for the preparation of cis- (IS, 4S)-N-methyl-4- (3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-naphthaleneamine having the Formula-I, commonly known as sertraline. Another objective of the present invention is to provide an improved process for the preparation of cis- (IS, 4S)-N-methyl-4- (3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-naphthaleneamine hydrochloride, commonly known as sertraline hydrochloride, employing reagents which are environmentally friendly and is less demanding in effluent treatment, particularly avoiding the use of corrosive hydrogen chloride gas. Still another objective of the present invention is to provide an improved process for the preparation of cis- (IS, 4S)-N-methyl-4- (3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-naphthaleneamine hydrochloride, commonly known as sertraline hydrochloride, wherein the salt formation is almost immediate and gives good crystalline material in 2-3 hours. We have now found that (R)-naproxen of the Formula-IV is an excellent alternative to D (-) mandelic acid for the resolution of cis racemic mixture of sertraline. (R)-Naproxen is available as a byproduct during the manufacture of the anti¬inflammatory drug (S)-naproxen by the resolution of the racemic mixture (R,S)-naproxen. (R)-naproxen is not useful as anti-inflammatory agent. It is the inactive isomer of naproxen. It also can be recovered and reused. Since (R)-naproxen is a chiral carboxylic acid it is useful for the resolution of racemic mixture of sertraline base. We have found that (R)-naproxen forms salt readily with cis- (IS)-sertraline and the salt is less soluble than the corresponding mandelic acid salt in organic solvents such as ethanol. Further, (R)-naproxen is stable and does not undergo discoloration and degradation like mandelic acid (The Merck Index, 13"^ Edn., page 1518, No.8541). The (R)-naproxen is also less expensive than D (-) mandelic acid. Sertraline base can be re liberated from its salt with (R)- naproxen very easily by using any common alkali and extracted into an organic solvent. On evaporation of the solvent sertraline base remains as a liquid residue and can be converted to its salt form immediately. We have observed that the conversion of sertraline base to its hydrochloride salt can be achieved more conveniently by using ammonium chloride or alkyl ammonium chlorides, which are environmentally more friendly than the corrosive hydrogen chloride used previously. We have also further observed that trimethylchlorosilane (TMSCl) is also a safe source of hydrogen chloride and an excellent reagent for the conversion of sertraline to its hydrochloride salt. Description of the invention Accordingly the present invention provides an improved process for the preparation of cis- (IS, 4S)-N-methyl-4- (3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-naphthaleneamine having the Formula-I, commonly known as sertraline and its hydrochloride salt. which comprises (i) treating the racemic mixture of cis - sertraUne base solution in an organic solvent with (R)- naproxen with or without an additional organic solvent, stirring the mixture at a temperature in the range of 0 to 60°C for a period in the range of 0.5 to 6 hrs, (ii) recovering the crystalline salt formed by filtering, washing and drying if required , ( iii) suspending the resultant salt in an organic solvent which is water immiscible and treating the resulting suspension in the organic solvent with an aqueous alkali, (iv) recovering the cis- (IS)-sertraline base by extraction with an organic solvent, washing, drying and removing the solvent and (v) converting the residue oicis- (IS)-sertraline into its hydrochloride salt. The cis ^racemic sertraline hydrochloride used as the starting material may be prepared by the process described in U.S. Pat. No. 4,536,518. It is dissolved in an organic solvent such as diethyl ether, diisopropyl ether, ethyl acetate, dichloromethane, toluene etc, preferably ethyl acetate, and treated with aqueous solution of an alkali such as sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate etc., to liberate the free base. The organic layer containing sertraline base is treated with one equivalent of (R)-naproxen while stirring. To this is added a second organic solvent such methanol, ethanol, isopropyl alcohol, acetone, acetonitrile, etc. preferably ethanol, in which the (R)-naproxen salt of cis- (S)-sertraline is less soluble. The reaction mixture is stirred at a temperature of 0 - 60*^ C for 0. 5 to 6 hours to precipitate the (R)-naproxen salt of cis- (IS)-sertraline. The salt precipitate is filtered and suspended in an organic solvent which is water-immiscible, such as diethyl ether, diisopropyl ether, ethyl acetate, dichloromethane, toluene etc., preferably ethyl acetate, and treated with aqueous solution of an alkali such as sodium hydroxide, sodium carbonate, potassium hydroxide, potassium carbonate etc. The organic layer is separated and the aqueous layer extracted with an organic solvent. The pooled organic layers are washed with water and dried over anhydrous Na2S04 . The organic solution is concentrated to obtain cis- (IS)-sertraline. It can be converted to cis- (IS)-sertrahne hydrochloride by the process described in U.S. Pat. No. 4,536,518 or as described herein. According to U.S. Pat. No. 4,536,518, seratraline hydrochloride is prepared by passing excess hydrogen chloride gas to a solution of sertraline base in a solvent such as ether to obtain sertraline hydrochloride to give initially a gelatinous suspension, which on further stirring overnight gives crystalline sertraline hydrochloride. According to another embodiment of the present invention there is provided an improved process for the preparation of sertraline hydrochloride which comprises treating the free base of sertraline with an aqueous solution of alkylammoniumchloride or ammonium chloride in the presence of a solvent. According to yet another embodiment of the present invention there is provided an improved process for the preparation of sertraline hydrochloride which comprises treating the free base of sertraline with trimethylchlorosilane in the presence of a solvent. The alkylammoniumchloride salts which can be used include primary, secondary or tertiary alkylammoniumchlorides having Ci to Cio carbons, especially tributylammoniumchloride. Trimethylchlorosilane (TMSCl) is also an excellent and a safe source for hydrogen chloride. It is also soluble in a wide range of organic solvents. On treating sertraline base with saturated aqueous solution of ammoniumchloride at room temperature sertraline hydrochloride salt precipitates almost immediately. Since alkylammoniumchlorides are soluble in organic solvents, the reaction can be conducted in a suitable solvent. For example, tributylammoniumchloride is dissolved in ethyl acetate (EtOAc) and treated with sertraline, which is also soluble in EtOAc, to obtain sertraline hydrochloride salt. The embodiments of the present invention are further described in the following examples. However, these are not intended in any way to limit the scope of the present invention. Example-1 Preparation of Cis- (IS)-sertraline hydrochloride using (R)-naproxen and ammonium chloride O-y-racemic sertraline hydrochloride [c/5-(lS)-N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-1-naphthalenamine hydrochloride and c/5-(lR)-N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-naphthalenamine hydrochloride] (50 g, 0.146 moles) was suspended in 300 mL ethyl acetate (EtOAc) to which was added 400 ml of 10% NaOH and the reaction mixture was stirred. From the two clear layers obtained , the organic layer containing the free base was separated. The aqueous layer was extracted with 300 mL EtOAc. The pooled EtOAc solution was washed with water and dried over anhydrous Na2S04 . To this solution was added solid (R)-naproxen (33.5 g, 0.146 mole), followed by 300 mL ethanol. The reaction mixture was warmed to 50°C for 5 minutes to get a clear solution. The solution was stirred for 4 to 5 hours at room temperature, to obtain white crystalline (R)-naproxen salt oi cis- (lS)-N-methyl-4- (3,4-dichlorophenyl)-1,2,3,4-tetrahydro-l-naphthalenamine. The salt was filtered, washed with 25 mL ethanol and dried (m.p. 120 -122° C, 37.3 g.). The naproxen salt so obtained was suspended in 150 mL EtOAc and treated with 10 % NaOH until the solution was alkaline (pH>10). The EtOAc layer was separated, the aqueous layer was extracted with 150 mL EtOAc. The pooled EtOAc solution was washed with water and dried over anhydrous Na2S04 . The solution was concentrated to obtain free sertraline base as a colourless oil. hydrochloric acid to a pH of about 2.0 and stirred for about 10 mins. The crystalline precipitate of (R) - naproxen was filtered, washed with water and dried. (11.2 gm; M.P.151-153°C ; Optical Rotation : -64.3°, C=l in CHCI3). The oily sertraline base was treated with 200 ml saturated solution of ammonium chloride. The reaction mixture was stirred for 2-3 hours at room temperature. The crystalline sertraline hydrochloride salt obtained was filtered, washed with water and dried (20 g, 40% yield, m.p. 247 -248° C). Exainple-2 Preparation of cis- (IS)-sertraline hydrochloride using tributylammonium chloride Cw-racemic sertraline hydrochloride [cw-(lS)-N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-1-naphthalenamine hydrochloride and cw-(lR)-N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-naphthalenamine hydrochloride] (50 g, 0.146 moles) was suspended in 300 mL ethyl acetate (EtOAc) to which was added 400 mL of 10% NaOH and the reaction mixture was stirred. From the two clear layers obtained , the organic layer containing the free base was separated. The aqueous layer was extracted with 300 mL EtOAc. The pooled EtOAc solution was washed with water and dried over anhydrous Na2S04 . To this solution was added solid (R)-naproxen (33.5 g, 0.146 mole), followed by 300 mL ethanol. The reaction mixture was warmed to 50°C for 5 minutes to get a clear solution. The solution was stirred for 4 to 5 hours at room temperature, to obtain white crystalline (R)-naproxen salt of cis- (lS)-N-methyl-4- (3,4-dichlorophenyl)-1,2,3,4-tetrahydro-l-naphthalenamine. The salt was filtered, washed with 25 mL ethanol and dried (m.p. 120 -122° C, 37.3 g.). The naproxen salt so obtained was suspended in 150 mL EtOAc and treated with 10 % NaOH until the solution was alkaline (pH>10). The EtOAc layer was separated, the aqueous layer was extracted with 150 mL EtOAc. The pooled EtOAc solution was washed with water and dried over anhydrous NaiSOA . The solution was concentrated to obtain free sertraline base as a colourless oil. The oily sertraline base was again dissolved in EtOAc (150 mL). To this was added a solution of tributylammoniumchloride (18.3 g, 0.083 mol) in EtOAc (50 mL). The reaction mixture was stirred for 2-3 hours at room temperature. The crystaUine sertraline hydrochloride salt obtained was filtered, washed with EtOAc and dried (19.0 g., 38.0 % , m.p. 250"-25l"^C). Example-3 Preparation of cis- (IS)-sertraline hydrochloride using trimethylchlorosilane C«-racemic sertraline hydrochloride [c/.s"-(lS)-N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-1-naphthalenamine hydrochloride and c/5"-(lR)-N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-naphthalenamine hydrochloride] (50 g, 0.146 moles) was suspended in 300 mL ethyl acetate (EtOAc) to which was added 400 mL of 10% NaOH and the reaction mixture was stirred. From the two clear layers obtained , the organic layer containing the free base was separated. The aqueous layer was extracted with 300 mL EtOAc. The pooled EtOAc solution was washed with water and dried over anhydrous Na2S04. To this solution was added solid (R)-naproxen (33.5 g, 0.146 mole), followed by 300 mL ethanol. The reaction mixture was warmed to 50*^C for 5 minutes to get a clear solution. The solution was stirred for 4 to 5 hours at room temperature, to obtain white crystalline (R)-naproxen salt of cis- (lS)-N-methyl-4- (3,4-dichlorophenyl)-1,2,3,4-tetrahydro-l-naphthalenamine. The salt was filtered, washed with 25 mL ethanol and dried (m.p. 120 -122^ C, 37.3 g.). The naproxen salt so obtained was suspended in 150 mL EtOAc and treated with 10 % NaOH until the solution was alkaline (pH>10). The EtOAc layer was separated, the aqueous layer was extracted with 150 mL EtOAc. The pooled EtOAc solution was washed with water and dried over anhydrous Na2S04 . The solution was concentrated to obtain free sertraline base as a colourless oil. he oily sertraline base was again dissolved in EtOAc (150 mL). To this was added imethylchlorosilane (9.0 g., 0.083 mol) solution in EtOAc (50 mL). The reaction mixture was stirred for 2-3 hours at room temperature. The crystalline sertraline hydrochloride salt obtained was filtered, washed with EtOAc and dried (19.2 g., 38.4 % yield, m.p. 246 -247° C). • Advantages of the present invention 1. D (-) Mandelic acid used as the resolving agent in prior art, darkens and decomposes on prolonged exposure to light (The Merck Index, Entry No. 5757, 12"^ Edn.). It is also expensive. The present invention replaces D( -) mandelic acid with (R)-naproxen which is more stable and available as a byproduct during the manufacture of naproxen and hence less expensive. The resolving agent can also be recovered and recycled. 2. Hazardous and corrosive hydrogen chloride gas has been replaced with tributylammoniumchloride or ammonium chloride or trimethylchlorosilane which are environmentally more friendly and less demanding in effluent treatment. 3. The salt formation is almost immediate and gives good crystalline material in 2-3 hours. 4. Therefore the process is simple, convenient and less time consuming. We claim 1. An improved process for the preparation of cw-(lS,4S)-N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-naphthaleneamine of the Formula-I and its hydrochloride say, ) commonly known as sertraline hydrochloride, which comprises: (i) treating the raceme mixture of cis - sertraline base solution in an organic solvent with (R)- naproxen with or without an additional organic solvent, stirring the mixture at a temperature in the range of 0 to 60°C for a period in the range of 0.5 to 6 hrs, (ii) recovering the crystalline salt formed by filtering, washing and drag if required , (iii) suspending the salt in an organic solvent which is water immiscible and treating the resulting suspension in the organic solvent with an aqueous alkali, (iv) recovering the cis- (IS)-sertraline base by extraction with an organic solvent, washing, drying and removing the solvent and (v) converting the residue of cis- (IS)-sertraline into its hydrochloride salt. 2. An improved process as in claim 1 wherein the step (i) the organic solvent or solvents used is are selected from chlorinated hydrocarbons, aromatic or aliphatic hydrocarbons, aliphatic ethers, aliphatic alcohols, esters and mixtures thereof, in which both the c/"5-sertraline base and (R) -naproxen are soluble.

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