Title of Invention	AN IMPROVED METHOD FOR MANUFACTURE OF N-[4-(3,4-DICHLORPHENYL)-3,4-DIHYDRO-1(2H) NAPHTHALENYLIDENE] METHANAMINE
Abstract	Process for preparation of compound of formula (I) by the reaction of compound of formula (III), with a solution of methylamine in water or in a mixture of water and a water miscible organic solvent at temperature between 30º C to 80º C and at atmospheric pressure. The solution of methylamine in water has a strength of between 20% to 40% w/v. Methylamine is employed in molar proportions of 2 to 20 moles per mole of compound of formula (III). Also according to the invention there is provided a process for preparation of sertraline hydrochloride of formula (II) by the reduction of compound of formula (I).

Title of Invention

AN IMPROVED METHOD FOR MANUFACTURE OF N-[4-(3,4-DICHLORPHENYL)-3,4-DIHYDRO-1(2H) NAPHTHALENYLIDENE] METHANAMINE

Abstract

Process for preparation of compound of formula (I) by the reaction of compound of formula (III), with a solution of methylamine in water or in a mixture of water and a water miscible organic solvent at temperature between 30º C to 80º C and at atmospheric pressure. The solution of methylamine in water has a strength of between 20% to 40% w/v. Methylamine is employed in molar proportions of 2 to 20 moles per mole of compound of formula (III). Also according to the invention there is provided a process for preparation of sertraline hydrochloride of formula (II) by the reduction of compound of formula (I).

Full Text	FORM2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION (See section 10; rule 13) 1. TITLE OF INVENTION An Improved Method For Manufacture Of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) Naphthalenylidene] Methanamine 2. LUPIN LIMITED, (b) of 159 C.S.T. Road, Kalina, Santacruz (East), Mumbai - 400 098, Maharashtra, India, (c) an Indian Company The following specification particularly describes the nature of this invention and the manner in which it is to be performed 18-8-2005 An Improved Method For Manufacture Of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) Naphthalenylidene] Methanamine FIELD OF THE INVENTION The present invention relates to an improved method for the manufacture of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I), which is a key intermediate for the antidepressant drug, Sertraline hydrochloride. BACKGROUND OF THE INVENTION The chemical entity (lS,4S)-4-(3,4-dichlorphenyl)-l,2,3,4-tetrahydro-N-methyl-l naphthalenylamine hydrochloride, generically known as sertraline hydrochloride of formula (II), is an antidepressant drug useful for the treatment of panic disorder and obsessive compulsive disorder. -V Many methods have been reported for synthesis of sertraline hydrochlorideMost of the methods utilize N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylideneTmethanamine of formula (I) as an intermediate. 2 The synthesis of compound of formula (I) in turn has been achieved in several ways. A summary of the reported methods for synthesis of compound of formula (I) is given hereinbelow. 1. The first method for synthesis of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I) was disclosed by Welch et. al. in US Patent No. 4,536,518, which comprises condensation of the tetralone of formula (III) with an appropriate primary amine, viz. methylamine in the presence of an acid catalyst like titanium tetrachloride to give the corresponding imine, viz. N~[4-(3,4-dichlorphenyl)-3,4-dihydro-1(2H) naphthalenylidene] methanamine of formula (I). The imine thus obtained is subjected to catalytic hydrogenation or reduction with a metal hydride complex to give sertraline as a racemic mixture of cis and trans isomers, from which the desired cis isomer is separated. 3 Example 1 of US Patent 4,536,518 describes the method for synthesis of compound (I) wherein a solution of tetralone of formula (III) in tetrahydrofuran is treated with monomethylamine followed by dropwise addition of titanium tetrachloride and the mixture agitated at room temperature for 17 hours under an inert gas atmosphere to give the ketimine compound of formula (I). The product is isolated by distilling off excess methylamine and trituration of the residue with hexane. However, this method suffers from a serious drawback in that it utilizes titanium tetrachloride, which is not only toxic but also corrosive. It is harmful if swallowed, inhaled or absorbed through the skin. It also causes burns and is very destructive of mucous membranes and can cause permanent damage to the eyes, if splashed into the eyes. It might be mentioned that compound of formula (I) is a Schiff s base and its method of synthesis from the corresponding ketone compound (III) is an equilibrium reaction wherein the equilibrium has to be shifted to the right side, which is normally achieved by removal of water formed in the reaction through azeotropic distillation or other means. 2. An improvement over the method described in US Patent No. 4,536,518 has been reported in US Patent No. 4,855,500 by Spavins et. al. wherein the Schiff s base formation is carried out by reaction of tetralone of formula (III) with monomethylamine under pressure 4 and in presence of molecular sieves, which acts as a dehydrating agent and pushes the equilibrium to the right side. However, this method also suffers from several drawbacks, viz. (a) the reaction is carried out under pressure; (b) utilizes methylamine gas, which is cumbersome to handle; (c) is specific about the pore size of the molecular sieves used; and (d) utilizes solvents such as ethers which by virtue of containing peroxides are prone to explosion as well as solvents like benzene, chloroform, carbon tetrachloride etc. which are not only carcinogenic but also not recommended for use in an industrial manufacture. y 3. A further improvement in the process was disclosed by Simig et. al. in PCT Application No. WO 99/57095 wherein the tetralone of formula (III) is treated with methylamine in the absence of a dehydrating agent and in presence of lower alkanol as solvent. Even though, this method has advantage in that: (a) no dehydrating agent is used; (b) reaction is carried out in an alcoholic jjolvent; and (c) an alcoholic solution of methylamine rather than a gas is used, however, a limitation of this process is that the reaction is carried under pressure, which renders the method commercially unattractive. 4. Yet another method for synthesis of compound (I) is disclosed by Thomman et. al. in PCT Application No. WO 00/26181 wherein the tetralone of formula (III) is treated with methylamine in an alcoholic solvent and in the presence of a acid catalyst such as p-toluenesulphonic acid, hydrochloric acid, sulfuric acid etc. 5. In a method described by Colberg et. al. in US Patent No. 6,232,500 the imine of formula (I) has been prepared by reaction of the tetralone of formula (III) with methylamine in an alcoholic solvent having a boiling point under the reaction conditions greater than 55 ° C. This patent claims that the inventive merit lies in selection of a suitable solvent for reaction i.e. an alcohol in which the product formed i.e. (I) has high, solubility which results in shifting the equilibrium to the right hand side. 5 However, this method like earlier methods is also associated with the same limitations enumerated hereinearlier. 6. In a method described by Thommen et. al. in PCT Application No. WO 01/36377 wherein, the imine of formula (I) has been prepared by reaction of tetralone of formula (III) with methylamine gas in alcoholic solvent under pressure. This method also suffers from the same limitations associated with US Patent No. 6,232,500. 7. In a method described by Laitinen et. al. in US Patent Application No. 2003/0013768, wherein imine of formula (I) has been prepared by carrying out the reaction of tetralone of formula (III) with methylamine in an amide solvent in the presence of acid catalyst such as formic acid, acetic acid, sulfuric acid, hydrochloric acid, scandium triflate etc. From the foregoing, it would be evident that the prior art methods for the preparation of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I), suffer from one or more of the following limitations, viz. i) Utilization of corrosive and toxic chemicals like, titanium tetrachloride; ii) Requires anhydrous conditions wherein the equilibrium is shifted towards the product through removal of water using dehydrating agents such as molecular sieves, acids etc., which leads to increase in the cost of manufacture; iii) Requires pressure reactors; iv) Use of methylamine gas, which is cumbersome to handle in large-scale manufacture; v) Requires tedious isolation techniques; and vi)Utilizes solvents such as ethers which by virtue of containing peroxides are prone to explosion as well as solvents like benzene, chloroform, carbontetrachloride etc. which are not only carcinogenic but not recommended for use in an industrial manufacture. 6 Thus, there exist a need for an improved method for manufacture of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I), which is simple, convenient, cost effective and avoids use of toxic chemicals and hazardous solvents and is moreover, environmentally harmless. OBJECTS OF THE INVENTION An object of the present invention is to provide a method of manufacture of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I), which overcomes the limitations associated with the prior art methods. Another object of the present invention is to provide a method of manufacture of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I), which is simple, convenient, cost effective and environmentally harmless. Yet another object of the present invention is to provide a method for manufacture of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I) which avoids utilization of corrosive and toxic chemicals. A further object of the present invention is to provide a method for manufacture of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I) which does not utilize any dehydrating agent. Yet further object of the present invention is to prepare N-[4-(3,4-dichlorphenyl)-3,4-dihydro-1(2H) naphthalenylidene] methanamine of formula (I) which does not require pressure conditions. Another object of the present invention is to provide a method for manufacture of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I) which does not require anhydrous conditions. 7 Yet another object of the present invention is to provide a method for manufacture of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I) which does not require any catalyst and can be carried out in aqueous medium. A further object of the present invention is to provide a method for manufacture of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I) which which can be isolated by simple and convenient techniques. In their endeavor to achieve the abovementioned objectives the present inventors have found to their surprise that the tetralone of formula (III) can be reacted with an aqueous solution of methylamine under atmospheric pressure conditions in water or a mixture of water and an organic solvent. While the conversion of the tetralone of formula (III) to the imine compound (I) could be carried out in water as a solvent, however, it was found advantageous to carry out the reaction in a mixture of water and an organic solvent, specially solvents which are miscible with water. SUMMARY OF THE INVENTION Thus the present invention relates to a process for the preparation of a compound of formula (I), comprising reaction of a compound of formula (III), with a solution of methylamine in water or in a mixture of water and a water miscible organic solvent at temperature between 30 ° C to 80 ° C and at atmospheric pressure. The water-miscible solvents are selected from lower aliphatic alcohols, cyclic ethers, acyclic ethers, aprotic solvents such as amides, nitriles, sulfolane and the like. The reaction in essence takes place in an aqueous medium or in a medium consisting of a mixture of water and an organic solvent with no added catalyst or agents for removal of water from the reaction mixture. An advantage of the process of the present invention is that, unlike the prior art methods wherein either methylamine gas or its solution in an alcohol is used, the imine compound (I) can be obtained from the corresponding tetralone (III) through utilization of commercially available and inexpensive aqueous solution of methylamine having strength of between 20-40 % w/v. The reaction is carried out under atmospheric pressure conditions and most importantly does not require any special technique or addition of any agent to drive out water from the reaction mixture. In particular the reaction is carried out in presence of a substantial amount of water, which contrary to the teachings of the prior art provides compound (I) in high yield and purity. 9 In the process of the invention the product i.e. N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I) precipitates out from the reaction mixture, which can be easily isolated by filtration. According an aspect of the present invention there is provided a process for preparation of compound of formula (I), with a solution of methyl amine in water or a mixture of water and an organic solvent at atmospheric pressure and at a temperature of between 30 ° C and 80 ° C, which is environmentally harmless and avoids use of corrosive, toxic, hazardous and carcinogenic chemicals and solvents. In another aspect, the present invention provides a simple method for isolation of compound of formula (I), 10 with a solution of methyl amine in water or a mixture of water and an organic solvent at atmospheric pressure and at a temperature of between 30 ° C and 80 ° C, and filtering the compound of formula (I) from the reaction mixture. DETAILED DESCRIPTION OF INVENTION The starting material for the preparation of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I) viz. the tetralone of formula (III) is a known compound and can be prepared by any one of the methods described in US Patent No. 4,536,518 and US Patent No. 6,054,614. In a typical embodiment, the tetralone (III) is suspended in water or a mixture of water and water miscible organic solvent at room temperature. To the suspension is added an aqueous 11 solution of methylamine whereafter the reaction mixture is agitated at a temperature between 30°Cto80°C till the completion of the reaction. The aqueous solution of methylamine is available commercially in strengths varying from 20 % to 40 % w/v. A solution of any strength could be used in the process of the present invention. The methylamine is typically employed in molar proportions in excess of the equimolar quantities. Typically it is employed in molar proportions of between 2 moles to 20 moles per mole of the compound of formula (III). The water miscible solvents are those, which have complete miscibility with water in all proportions. Such solvents include lower aliphatic alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol etc.; cyclic ethers such as tetrahydrofuran, dioxane, etc.; acyclic ethers such as diglyme, 1,2-dimethoxyethane etc.; aprotic solvents like amides, nitriles and sulfolane. Suitable amides that can be employed include N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, methylformamide etc.; suitable nitriles that can be employed include acetonitrile, propionitrile etc. Of all the solvents lower aliphatic alcohols and amides are preferrecf Of the lower aliphatic alcohols methanol, and of the amide solvents N-methylpyrrolidontrale the most preffered solvents. As mentioned hereinbefore, the conversion of tetralone (III) to the imine compound (I) can be carried out in pure water as a solvent or in a mixture of water and any of the water miscible organic solvents mentioned above. However, since reaction rate is found to be faster when water miscible solvent is utilized, it is preferred to carry out the conversion in presence of such solvents.Typically the water miscible solvent can be employed in proportion of between 1 time to 10 times volume/gm of the tetralone of formula (III). 12 The reaction can be carried out at a temperature of between 30 ° C to 80 ° C. However, it is preferable to carry out the reaction at a temperature of 65 ° C ± 5 ° C. In one embodiment, one mole of compound of formula (III) is suspended in a water miscible-solvent such as methanol. Volume of methanol employed is in the ratio of 5 times volume per gm of compound of formula (III). The aqueous solution of methylamine (4 moles) is added to the reaction mixture and reaction mixture is heated to 65 ° C + 5 ° C for 4 to 6 hours. The reaction is monitored by HPLC till completion of the reaction and the reaction mixture is cooled to 20 ° C ± 5 ° C. The reaction mixture is stirred for a period of 2-3 hours at same temperature and the precipitated solid filtered and dried to give compound of formula (I) In another embodiment, one mole of compound of formula (III) is suspended in water. Volume of water employed is in the ratio of 5 times volume per gm of compound of formula (III). The aqueous solution of methylamine (4 moles) is added to the reaction mixture and reaction mixture is heated to 65 ° G ± 5 ° C for 20 to 24 hours. The reaction is monitored by HPLC till completion of the reaction and the reaction mixture is cooled to 20 ° C ± 5 ° C. The reaction mixture is stirred for a period of 2-3 hours at same temperature and the precipitated solid filtered and dried to give compound of formula (I). The compound of formula (I) thus obtained has purity greater than 95 %. As mentioned hereinearlier, compound of formula (I) is a valuable intermediate for the antidepressant drug sertraline hydrochloride of formula (II). The present inventors have found it advantageous to use the wet/moist compound of formula (I) i.e. without drying obtained by the process of the present invention for synthesis of sertraline hydrochloride of formula (II) in high chemical and optical purity. Thus according to a further aspect here is provided a process for preparation of sertraline hydrochloride of formula (II), 13 comprising the steps of (a) reduction of compound of formula (I), with sodium borohydride in a lower aliphatic alcohol solvent at a temperature ranging between 0 ° C to reflux temperature to give a racemic mixture of cis isomer of formula (Ha), NHMe and trans isomer of formula (lib), (b) reacting the mixture of (Ha) and (lib) with an aqueous solution of hydrochloric acid to form the corresponding hydrochloride salt (lie) and (lid), (c) separation of the cis isomer of formula (IIe) from the trans isomer of formula (IId) by crystallization from a lower aliphatic alcohol, (d) neurealizing the cis hydrochloride isomer of formula (IIe) with alkali to form the free base of formula (Ha), (e) reacting the free base (IIa) with mandelic acid in an organic solvent selected from an alkylacetate, or a lower aliphatic alcohol to give mandelic acid salts (IIe) and (IK), 15 (f) separation of isomer of formula (He) from the isomer (Ilf) by crystallization from the lower aliphatic alcohol solvent, (g) reacting the isomer of formula (He) with aqueous alkali solution to give compound (1 S,4S)-4-(3,4-dichlorphenyl)-l,2,3,4-tetrahydro-N-methyl-l naphthalenylamine, (h) dissolving the compound obtained in step (g), (lS,4S)-4-(3,4-dichlorphenyi)-1,2,3,4-tetrahydro-N-methyl-l naphthalenylamine in a suitable organic solvent and passing hydrogen chloride gas through the solution to give (lS,4S)-4-(3,4-dichlorphenyl)-l,2,3,4-tetrahydro-N-methyl-l naphthalenylamine hydrochloride of formula (II). The wet/moist compound of formula (I) is reduced to the corresponding amine i.e. cis and trans racemic sertraline of formula (Ha) and (lib) either through catalytic hydrogenation or reduction with metal hydride complex, as per the method described in US Patent No. 4,536,518. The racemic compound of formula (Ila), if desired is further resolved to give the desired optical isomer (II). , imine compound of formula (I) is reduced with sodium borohydride, in a suitable alcoholic solvent to give the amine compound of formula (Ha) and (lib). Typically, a mixture containing the imine compound of formula (I), methanol and sodium borohydride is agitated under reflux to form the cis and trans racemic sertraline of formula (Ha) and (lib). The cis and trans isomers are treated with hydrochloric acid to form the corresponding hydrochloride salt (lie) and (lid). The cis (lie) and trans (lid) isomers are separated by crystallization from a suitable organic solvent. The cis racemic hydrochloride salt of formula (lie) is neutralized with aqueous alkali solution to give the free base, i.e. cis racemic seertraline of formula (Ila). Cis racemic sertraline of formula (Ila), is dissolved in a suitable organic solvent and agitated with mandelic acid to form mixture of diasteriomeric salt (He) and (Ilf). 17 The mixture of salt is crystallized from organic solvent such as alkyl acetate so that salt of formula (He) precipitates out and salt of formula (Ilf) remains in solution. Salt of formula (He) is further hydrolyzed to give (lS,4S)-4-(3,4-dichlorphenyl)-l,2,3,4-tetrahydro-N-methyl-1 naphthalenylamine hydrochloride of formula (II). The invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention. Example 1 Preparation ofN-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine (I): To a solution of 100 gm (0.34 mole) of tetralone of formula (III) in methanol (500 ml) is added 50 ml (0.65 mole) of a 40 % solution of methylamine at room temperature. The reaction mixture is heated to 65 ° C and agitated at 65 ° C ± 5 ° C for 6 hours, when the reaction is complete. The reaction mixture is cooled to 20 ° C and agitated at the same temperature for 2 hrs. The precipitated solid is filtered, washed with 100 ml methanol and dried below 50 ° C under reduced pressure to give 92 gm (88 %) of the title compound, having purity greater than 95 %. H NMR (CDC13, 200 MHz): 8 2.1 (2H, m); 8 2.48 (2H, m); 8 3.3 (3H, s); 8 4.1 (1H, m); 8 6.8-8.2 (7H, m). IR (KBr, cm"1): 763, 830, 1467, 1624, 1677, 2930, 3025, 3443. 18 Example 2 Preparation ofN-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine (I): To a solution of 250 gm (0.86 mole) of tetralone of formula (III) in 250 ml of N-mehtyl pyrrolidine is added 500 ml (6.5 mole) of a 40 % solution of methylamine at room temperature. The reaction mixture is heated to 75 ° C and agitated at 75 ° C ± 5 ° C for 5 hours, when the reaction is complete. The reaction mixture is cooled to 20 ° C and agitated at the same temperature for 2 hrs. The precipitated solid is filtered, washed with 100 ml methanol and dried below 50 ° C under reduced pressure to give 242 gm (82.6 %) of the title compound, having purity greater than 95 %. Example 3 Preparation ofN-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine (I): To a solution of 100 gm (0.34 mole) of tetralone of formula (III) in N,N-dimethylformamide (100 ml) is added 250 ml (3.25 mole) of a 40 % solution of methylamine at room temperature. The reaction mixture is heated to 70 ° C and agitated at 70 ° C ± 5 ° C for 8 hours, when the reaction is complete. The reaction mixture is cooled to 20 ° C and agitated at the same temperature for 2 hrs. The precipitated solid is filtered, washed with 100 ml methanol and dried below 50 ° C under reduced pressure to give 88 gm (84.2 %) of the title compound, having purity greater than 95 %. Example 4 Preparation ofN-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine (I): 100 gm (0.34 mole) of tetralone of formula (III) is suspended in 250 ml (3.25 mole) of a 40 % solution of methylamine at room temperature. The reaction mixture is heated to 80 ° C and 19 agitated at 80 ° C ± 5 ° C for 24 hours, when the reaction is complete. The reaction mixture is cooled to 20 ° C and agitated at the same temperature for 2 hrs. The precipitated solid is filtered, The crude product is slurred in 100 ml methanol and refiltered and dried below 50 ° C under reduced pressure to give 79 gm (75.6 %) of the title compound, having purity greater than 95 %. Example 5 Preparation of cis racemic sertraline hydrochloride (lie): To a suspension of 261 gm (0.86 mole) of imine of formula (I) in methanol (1250 ml), is added sodium borohydride (25 gm, 0.66 mole) in lots at 0 to 5 ° C. The reaction mixture is heated to reflux for 6 hours, and after completion of the reaction, the reaction mixture is cooled to room temperature. Aqueous solution of hydrochloric acid (625 ml, 1:1) is added dropwise to the reaction mixture and stirred for two hours. The solid, which precipitates out is filtered and dried to give 110 gm (35%) of cis racemic sertraline of formula (lie) as a hydrochloride salt. Example 6 Preparation of (IS, 4S)-4-(3,4-dichlorphenyl)-l, 2,3,4-tetrahydro-N-methyl-l naphthalenylamine hydrochloride (II): Step 1: To a solution of 105 gm (0.31 mole) of cis racemic sertraline hydrochloride (lie) in water (525 ml), is added ethylacetate (1050 ml). Aqueous solution of sodium hydroxide (10 %) is added to the solution till pH of the solution is 10. After complete addition of sodium hydroxide, ethylacetate layer is separated. Mandelic acid (49.35 gm, 0.32 mole) is added to the ethylacetate layer and the solution is agitated at 40 ° C ± 5 ° C for two hours. Cool the solution to room temperature. Filter the precipitated solid and dry it to give 60gm (85%) of mandelic salt of (lS,4S)-4-(3,4-dichlorphenyl)-l,2,3,4-tetrahydro-N-methyl-l naphthalenylamine of formula (IIe). 20 Step 2: To a solution of 40 gm of the mandelic salt obtained in Stepl in water (200 ml) is added ethyl acetate (200 ml). To the solution is added a 10% aqueous solution of sodium hydroxide (40 ml). After the complete addition, the reaction mixture is agitated, for 15 mns and the layers allowed to separate. The ethyl acetate layer is separated from the aqueous phase, dried over anhydrous sodium sulfate and the solution separated from sodium sulfate. To the solution is bubbled hydrogen chloride gas till a pH of 1.0 is attained. Thereafter, the reaction mixture is agitated for 3 hours and the precipitated solid filtered and dried to give 25 gm (83%) of (lS,4S)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l- napthalenylamine i. .e sertraline hydrochloride of formula (II), having an optical purity of 99.2%. We claim, comprising reaction of compound of formula (III), 1. A process for preparation of compound of formula (I), with a solution of methylamine in water or in a mixture of water and a water miscible organic solvent at temperature between 30 ° C to 80 ° C and at atmospheric pressure. 2. The process of claim 1, wherein the water-miscible organic solvent is selected from lower aliphatic alcohols; cyclic ethers; acyclic ethers; aprotic solvents such as amides; nitriles and sulfolane. 3. The process according to any one of claims 1 and 2, wherein the lower aliphatic alcohol is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol and ferf-butanol. 4. The process according to any one of claims 1 and 2, wherein the cyclic ether is selected from tetrahydrofuran or dioxane. 5. The process according to any one of claims 1 and 2, wherein the acyclic ether is selected from diglyme or 1,2-dimethoxyethane. 6. The process according to any one of the claims 1 and 2, wherein the amide is selected from N-methylpyrrolidone, N,N-dimethylformamide, methylformamide or N,N-dimethylacetamide. 7. The process according to any one of the claims 1 and 2, wherein the nitrile is selected from acetonitrile or propionitrile. 8. The process of claim 1, wherein the solution of methylamine in water has a strength of between 20 % to 40 % w/v. 9. The process according to any one of claims 1 and 7, wherein methylamine is employed in molar proportions of 2 to 20 moles per mole of compound of formula (III). 10. A process for preparation of sertraline hydrochloride of formula (II), comprising the steps of reduction of compound of formula (I), with sodium borohydride in a lower aliphatic alcohol solvent selected from methanol, ethanol n-propanol, isopropanol. n-butanol, sec-butanol, ter-butanol at a temperature ranging between 0 ° C to reflux temperature to give a racemic mixture of cis isomer of formula (Ha), i. (Ha) and trans isomer of formula (lib), reacting the mixture of (Ha) and (lib) with an aqueous solution of hydrochloric acid to form the corresponding hydrochloride salt (lie) and (lid), b. Racemic cis Racemic trans 25 separation of the cis isomer of formula (II c) from the trans isomer of formula (II d) by crystallization from a lower aliphatic alcohol selected from methanol, ethanol n-propanol, isopropanol. n-butanol. sec.-butanol, ter-butanol: neutralizing the cis hydrochloride isomer of formula (II c) with alkali selected from sodium hydroxide and potassium hydroxide to form the free base of formula (II a) reacting the free base (II a) with mandelic acid in an organic solvent selected from an alkyl acetate such as ethvlacetate. or a lower aliphatic alcohol selected from methanol, ethanol n-prooanol. isopropanol, n-butanol, sec-butanol, ter-butanol to give mandeJic acid salts (U e) and (U f) separation of isomer of formula (II e) from the isomer (II f) by crystallization from the lower aliphatic alcohol solvent selected from methanol, ethanol n-oropanol, isopropanol, n-butanol, sec-butanol, ter-butanol. reacting the isomer of formula (II e) with aqueous alkali solution selected from sodium hydroxide and potassium hydroxide to give compound (IS, 4S)-4-(3,4-dichlorophenyl-l, 2,3,4-tetrahydro-N-methyl-l-naphthalenylamine, dissolving the compound obtained in stepj^(IS, 4S)-4-(3,4-dichlorophenyl-1, 2,3,4-tetrahydro-N-methyl-l-naphthalenylamine in a suitable organic solvent selected from alkyl acetate such as ethvlacetate and passing hydrogen chloride gas through the solution to give (IS, 4S)-4-(3,4-dichlorophenyl-l, 2,3,4-tetrahydro-N-methyl-l-naphthalenylamine hydrochloride of formula (11)./ Dated this 27n day of May 2004 Dr. Sanchita Ganguli Of S. Majumdar & Co. (Applicant Agent"s)

Full Text

FORM2
THE PATENTS ACT, 1970 (39 of 1970)
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. TITLE OF INVENTION
An Improved Method For Manufacture Of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) Naphthalenylidene] Methanamine
2. LUPIN LIMITED, (b) of 159 C.S.T. Road, Kalina, Santacruz (East), Mumbai - 400 098, Maharashtra, India, (c) an Indian Company
The following specification particularly describes the nature of this invention and the manner
in which it is to be performed

18-8-2005

An Improved Method For Manufacture Of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) Naphthalenylidene] Methanamine
FIELD OF THE INVENTION
The present invention relates to an improved method for the manufacture of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I), which is a key intermediate for the antidepressant drug, Sertraline hydrochloride.
BACKGROUND OF THE INVENTION
The chemical entity (lS,4S)-4-(3,4-dichlorphenyl)-l,2,3,4-tetrahydro-N-methyl-l naphthalenylamine hydrochloride, generically known as sertraline hydrochloride of formula (II), is an antidepressant drug useful for the treatment of panic disorder and obsessive compulsive disorder.

-V
Many methods have been reported for synthesis of sertraline hydrochlorideMost of the methods utilize N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylideneTmethanamine of formula (I) as an intermediate.
2

The synthesis of compound of formula (I) in turn has been achieved in several ways. A summary of the reported methods for synthesis of compound of formula (I) is given hereinbelow.
1. The first method for synthesis of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I) was disclosed by Welch et. al. in US Patent No. 4,536,518, which comprises condensation of the tetralone of formula (III) with an appropriate primary amine, viz. methylamine in the presence of an acid catalyst like titanium tetrachloride to give the corresponding imine, viz. N~[4-(3,4-dichlorphenyl)-3,4-dihydro-1(2H) naphthalenylidene] methanamine of formula (I). The imine thus obtained is subjected to catalytic hydrogenation or reduction with a metal hydride complex to give sertraline as a racemic mixture of cis and trans isomers, from which the desired cis isomer is separated.
3

Example 1 of US Patent 4,536,518 describes the method for synthesis of compound (I) wherein a solution of tetralone of formula (III) in tetrahydrofuran is treated with monomethylamine followed by dropwise addition of titanium tetrachloride and the mixture agitated at room temperature for 17 hours under an inert gas atmosphere to give the ketimine compound of formula (I). The product is isolated by distilling off excess methylamine and trituration of the residue with hexane.
However, this method suffers from a serious drawback in that it utilizes titanium tetrachloride, which is not only toxic but also corrosive. It is harmful if swallowed, inhaled or absorbed through the skin. It also causes burns and is very destructive of mucous membranes and can cause permanent damage to the eyes, if splashed into the eyes.
It might be mentioned that compound of formula (I) is a Schiff s base and its method of synthesis from the corresponding ketone compound (III) is an equilibrium reaction wherein the equilibrium has to be shifted to the right side, which is normally achieved by removal of water formed in the reaction through azeotropic distillation or other means.
2. An improvement over the method described in US Patent No. 4,536,518 has been reported in US Patent No. 4,855,500 by Spavins et. al. wherein the Schiff s base formation is carried out by reaction of tetralone of formula (III) with monomethylamine under pressure
4

and in presence of molecular sieves, which acts as a dehydrating agent and pushes the equilibrium to the right side.
However, this method also suffers from several drawbacks, viz.
(a) the reaction is carried out under pressure;
(b) utilizes methylamine gas, which is cumbersome to handle;
(c) is specific about the pore size of the molecular sieves used; and
(d) utilizes solvents such as ethers which by virtue of containing peroxides are prone to
explosion as well as solvents like benzene, chloroform, carbon tetrachloride etc. which are not
only carcinogenic but also not recommended for use in an industrial manufacture.
y
3. A further improvement in the process was disclosed by Simig et. al. in PCT Application
No. WO 99/57095 wherein the tetralone of formula (III) is treated with methylamine in the
absence of a dehydrating agent and in presence of lower alkanol as solvent.
Even though, this method has advantage in that:
(a) no dehydrating agent is used;
(b) reaction is carried out in an alcoholic jjolvent; and
(c) an alcoholic solution of methylamine rather than a gas is used,
however, a limitation of this process is that the reaction is carried under pressure, which renders the method commercially unattractive.
4. Yet another method for synthesis of compound (I) is disclosed by Thomman et. al. in PCT Application No. WO 00/26181 wherein the tetralone of formula (III) is treated with methylamine in an alcoholic solvent and in the presence of a acid catalyst such as p-toluenesulphonic acid, hydrochloric acid, sulfuric acid etc.
5. In a method described by Colberg et. al. in US Patent No. 6,232,500 the imine of formula (I) has been prepared by reaction of the tetralone of formula (III) with methylamine in an alcoholic solvent having a boiling point under the reaction conditions greater than 55 ° C. This patent claims that the inventive merit lies in selection of a suitable solvent for reaction i.e. an alcohol in which the product formed i.e. (I) has high, solubility which results in shifting the equilibrium to the right hand side.
5

However, this method like earlier methods is also associated with the same limitations enumerated hereinearlier.
6. In a method described by Thommen et. al. in PCT Application No. WO 01/36377 wherein,
the imine of formula (I) has been prepared by reaction of tetralone of formula (III) with
methylamine gas in alcoholic solvent under pressure.
This method also suffers from the same limitations associated with US Patent No. 6,232,500.
7. In a method described by Laitinen et. al. in US Patent Application No. 2003/0013768,
wherein imine of formula (I) has been prepared by carrying out the reaction of tetralone of
formula (III) with methylamine in an amide solvent in the presence of acid catalyst such as
formic acid, acetic acid, sulfuric acid, hydrochloric acid, scandium triflate etc.
From the foregoing, it would be evident that the prior art methods for the preparation of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I), suffer from one or more of the following limitations, viz.
i) Utilization of corrosive and toxic chemicals like, titanium tetrachloride;
ii) Requires anhydrous conditions wherein the equilibrium is shifted towards the product through removal of water using dehydrating agents such as molecular sieves, acids etc., which leads to increase in the cost of manufacture;
iii) Requires pressure reactors;
iv) Use of methylamine gas, which is cumbersome to handle in large-scale manufacture;
v) Requires tedious isolation techniques; and
vi)Utilizes solvents such as ethers which by virtue of containing peroxides are prone to
explosion as well as solvents like benzene, chloroform, carbontetrachloride etc.
which are not only carcinogenic but not recommended for use in an industrial
manufacture.
6

Thus, there exist a need for an improved method for manufacture of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I), which is simple, convenient, cost effective and avoids use of toxic chemicals and hazardous solvents and is moreover, environmentally harmless.
OBJECTS OF THE INVENTION
An object of the present invention is to provide a method of manufacture of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I), which overcomes the limitations associated with the prior art methods.
Another object of the present invention is to provide a method of manufacture of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I), which is simple, convenient, cost effective and environmentally harmless.
Yet another object of the present invention is to provide a method for manufacture of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I) which avoids utilization of corrosive and toxic chemicals.
A further object of the present invention is to provide a method for manufacture of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I) which does not utilize any dehydrating agent.
Yet further object of the present invention is to prepare N-[4-(3,4-dichlorphenyl)-3,4-dihydro-1(2H) naphthalenylidene] methanamine of formula (I) which does not require pressure conditions.
Another object of the present invention is to provide a method for manufacture of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I) which does not require anhydrous conditions.
7

Yet another object of the present invention is to provide a method for manufacture of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I) which does not require any catalyst and can be carried out in aqueous medium.
A further object of the present invention is to provide a method for manufacture of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I) which which can be isolated by simple and convenient techniques.
In their endeavor to achieve the abovementioned objectives the present inventors have found to their surprise that the tetralone of formula (III) can be reacted with an aqueous solution of methylamine under atmospheric pressure conditions in water or a mixture of water and an organic solvent. While the conversion of the tetralone of formula (III) to the imine compound (I) could be carried out in water as a solvent, however, it was found advantageous to carry out the reaction in a mixture of water and an organic solvent, specially solvents which are miscible with water.
SUMMARY OF THE INVENTION
Thus the present invention relates to a process for the preparation of a compound of formula (I),

comprising reaction of a compound of formula (III),

with a solution of methylamine in water or in a mixture of water and a water miscible organic solvent at temperature between 30 ° C to 80 ° C and at atmospheric pressure.
The water-miscible solvents are selected from lower aliphatic alcohols, cyclic ethers, acyclic ethers, aprotic solvents such as amides, nitriles, sulfolane and the like.
The reaction in essence takes place in an aqueous medium or in a medium consisting of a mixture of water and an organic solvent with no added catalyst or agents for removal of water from the reaction mixture.
An advantage of the process of the present invention is that, unlike the prior art methods wherein either methylamine gas or its solution in an alcohol is used, the imine compound (I) can be obtained from the corresponding tetralone (III) through utilization of commercially available and inexpensive aqueous solution of methylamine having strength of between 20-40
% w/v.
The reaction is carried out under atmospheric pressure conditions and most importantly does not require any special technique or addition of any agent to drive out water from the reaction mixture. In particular the reaction is carried out in presence of a substantial amount of water, which contrary to the teachings of the prior art provides compound (I) in high yield and purity.
9

In the process of the invention the product i.e. N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I) precipitates out from the reaction mixture, which can be easily isolated by filtration.
According an aspect of the present invention there is provided a process for preparation of compound of formula (I),

with a solution of methyl amine in water or a mixture of water and an organic solvent at atmospheric pressure and at a temperature of between 30 ° C and 80 ° C, which is environmentally harmless and avoids use of corrosive, toxic, hazardous and carcinogenic chemicals and solvents.
In another aspect, the present invention provides a simple method for isolation of compound of formula (I),
10

with a solution of methyl amine in water or a mixture of water and an organic solvent at atmospheric pressure and at a temperature of between 30 ° C and 80 ° C, and filtering the compound of formula (I) from the reaction mixture.
DETAILED DESCRIPTION OF INVENTION
The starting material for the preparation of N-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine of formula (I) viz. the tetralone of formula (III) is a known compound and can be prepared by any one of the methods described in US Patent No. 4,536,518 and US Patent No. 6,054,614.
In a typical embodiment, the tetralone (III) is suspended in water or a mixture of water and water miscible organic solvent at room temperature. To the suspension is added an aqueous
11

solution of methylamine whereafter the reaction mixture is agitated at a temperature between 30°Cto80°C till the completion of the reaction.
The aqueous solution of methylamine is available commercially in strengths varying from 20 % to 40 % w/v. A solution of any strength could be used in the process of the present invention.
The methylamine is typically employed in molar proportions in excess of the equimolar quantities. Typically it is employed in molar proportions of between 2 moles to 20 moles per
mole of the compound of formula (III).
The water miscible solvents are those, which have complete miscibility with water in all proportions. Such solvents include lower aliphatic alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol etc.; cyclic ethers such as tetrahydrofuran, dioxane, etc.; acyclic ethers such as diglyme, 1,2-dimethoxyethane etc.; aprotic solvents like amides, nitriles and sulfolane. Suitable amides that can be employed include N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, methylformamide etc.; suitable nitriles that can be employed include acetonitrile, propionitrile etc.
Of all the solvents lower aliphatic alcohols and amides are preferrecf Of the lower aliphatic alcohols methanol, and of the amide solvents N-methylpyrrolidontrale the most preffered solvents.
As mentioned hereinbefore, the conversion of tetralone (III) to the imine compound (I) can be carried out in pure water as a solvent or in a mixture of water and any of the water miscible organic solvents mentioned above.
However, since reaction rate is found to be faster when water miscible solvent is utilized, it is preferred to carry out the conversion in presence of such solvents.Typically the water miscible solvent can be employed in proportion of between 1 time to 10 times volume/gm of the tetralone of formula (III).
12

The reaction can be carried out at a temperature of between 30 ° C to 80 ° C. However, it is preferable to carry out the reaction at a temperature of 65 ° C ± 5 ° C.
In one embodiment, one mole of compound of formula (III) is suspended in a water miscible-solvent such as methanol. Volume of methanol employed is in the ratio of 5 times volume per gm of compound of formula (III). The aqueous solution of methylamine (4 moles) is added to the reaction mixture and reaction mixture is heated to 65 ° C + 5 ° C for 4 to 6 hours. The reaction is monitored by HPLC till completion of the reaction and the reaction mixture is cooled to 20 ° C ± 5 ° C. The reaction mixture is stirred for a period of 2-3 hours at same temperature and the precipitated solid filtered and dried to give compound of formula (I)
In another embodiment, one mole of compound of formula (III) is suspended in water. Volume of water employed is in the ratio of 5 times volume per gm of compound of formula (III). The aqueous solution of methylamine (4 moles) is added to the reaction mixture and reaction mixture is heated to 65 ° G ± 5 ° C for 20 to 24 hours. The reaction is monitored by HPLC till completion of the reaction and the reaction mixture is cooled to 20 ° C ± 5 ° C. The reaction mixture is stirred for a period of 2-3 hours at same temperature and the precipitated solid filtered and dried to give compound of formula (I).
The compound of formula (I) thus obtained has purity greater than 95 %.
As mentioned hereinearlier, compound of formula (I) is a valuable intermediate for the antidepressant drug sertraline hydrochloride of formula (II).
The present inventors have found it advantageous to use the wet/moist compound of formula (I) i.e. without drying obtained by the process of the present invention for synthesis of sertraline hydrochloride of formula (II) in high chemical and optical purity.
Thus according to a further aspect here is provided a process for preparation of sertraline hydrochloride of formula (II),
13

comprising the steps of
(a) reduction of compound of formula (I),

with sodium borohydride in a lower aliphatic alcohol solvent at a temperature ranging between 0 ° C to reflux temperature to give a racemic mixture of cis isomer of formula (Ha),
NHMe

and trans isomer of formula (lib),

(b) reacting the mixture of (Ha) and (lib) with an aqueous solution of hydrochloric acid to form the corresponding hydrochloride salt (lie) and (lid),

(c) separation of the cis isomer of formula (IIe) from the trans isomer of formula (IId) by crystallization from a lower aliphatic alcohol,
(d) neurealizing the cis hydrochloride isomer of formula (IIe) with alkali to form the free base of formula (Ha),
(e) reacting the free base (IIa) with mandelic acid in an organic solvent selected from an alkylacetate, or a lower aliphatic alcohol to give mandelic acid salts (IIe) and (IK),
15

(f) separation of isomer of formula (He) from the isomer (Ilf) by crystallization from the lower aliphatic alcohol solvent,
(g) reacting the isomer of formula (He) with aqueous alkali solution to give compound (1 S,4S)-4-(3,4-dichlorphenyl)-l,2,3,4-tetrahydro-N-methyl-l naphthalenylamine,
(h) dissolving the compound obtained in step (g), (lS,4S)-4-(3,4-dichlorphenyi)-1,2,3,4-tetrahydro-N-methyl-l naphthalenylamine in a suitable organic solvent and passing hydrogen chloride gas through the solution to give (lS,4S)-4-(3,4-dichlorphenyl)-l,2,3,4-tetrahydro-N-methyl-l naphthalenylamine hydrochloride of formula (II).
The wet/moist compound of formula (I) is reduced to the corresponding amine i.e. cis and trans racemic sertraline of formula (Ha) and (lib)

either through catalytic hydrogenation or reduction with metal hydride complex, as per the method described in US Patent No. 4,536,518. The racemic compound of formula (Ila), if desired is further resolved to give the desired optical isomer (II).
, imine compound of formula (I) is reduced with sodium borohydride, in a suitable alcoholic solvent to give the amine compound of formula (Ha) and (lib). Typically, a mixture containing the imine compound of formula (I), methanol and sodium borohydride is agitated under reflux to form the cis and trans racemic sertraline of formula (Ha) and (lib). The cis and trans isomers are treated with hydrochloric acid to form the corresponding hydrochloride salt (lie) and (lid).

The cis (lie) and trans (lid) isomers are separated by crystallization from a suitable organic solvent.
The cis racemic hydrochloride salt of formula (lie) is neutralized with aqueous alkali solution to give the free base, i.e. cis racemic seertraline of formula (Ila).
Cis racemic sertraline of formula (Ila), is dissolved in a suitable organic solvent and agitated with mandelic acid to form mixture of diasteriomeric salt (He) and (Ilf).
17

The mixture of salt is crystallized from organic solvent such as alkyl acetate so that salt of formula (He) precipitates out and salt of formula (Ilf) remains in solution. Salt of formula (He) is further hydrolyzed to give (lS,4S)-4-(3,4-dichlorphenyl)-l,2,3,4-tetrahydro-N-methyl-1 naphthalenylamine hydrochloride of formula (II).
The invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
Example 1
Preparation ofN-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine
(I):
To a solution of 100 gm (0.34 mole) of tetralone of formula (III) in methanol (500 ml) is added 50 ml (0.65 mole) of a 40 % solution of methylamine at room temperature. The reaction mixture is heated to 65 ° C and agitated at 65 ° C ± 5 ° C for 6 hours, when the reaction is complete. The reaction mixture is cooled to 20 ° C and agitated at the same temperature for 2 hrs. The precipitated solid is filtered, washed with 100 ml methanol and dried below 50 ° C under reduced pressure to give 92 gm (88 %) of the title compound, having purity greater than 95 %.
*H NMR (CDC13, 200 MHz): 8 2.1 (2H, m); 8 2.48 (2H, m); 8 3.3 (3H, s); 8 4.1 (1H, m); 8
6.8-8.2 (7H, m).
IR (KBr, cm"1): 763, 830, 1467, 1624, 1677, 2930, 3025, 3443.
18

Example 2
Preparation ofN-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine
(I):
To a solution of 250 gm (0.86 mole) of tetralone of formula (III) in 250 ml of N-mehtyl pyrrolidine is added 500 ml (6.5 mole) of a 40 % solution of methylamine at room temperature. The reaction mixture is heated to 75 ° C and agitated at 75 ° C ± 5 ° C for 5 hours, when the reaction is complete. The reaction mixture is cooled to 20 ° C and agitated at the same temperature for 2 hrs. The precipitated solid is filtered, washed with 100 ml methanol and dried below 50 ° C under reduced pressure to give 242 gm (82.6 %) of the title compound, having purity greater than 95 %.
Example 3
Preparation ofN-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine
(I):
To a solution of 100 gm (0.34 mole) of tetralone of formula (III) in N,N-dimethylformamide (100 ml) is added 250 ml (3.25 mole) of a 40 % solution of methylamine at room temperature. The reaction mixture is heated to 70 ° C and agitated at 70 ° C ± 5 ° C for 8 hours, when the reaction is complete. The reaction mixture is cooled to 20 ° C and agitated at the same temperature for 2 hrs. The precipitated solid is filtered, washed with 100 ml methanol and dried below 50 ° C under reduced pressure to give 88 gm (84.2 %) of the title compound, having purity greater than 95 %.
Example 4
Preparation ofN-[4-(3,4-dichlorphenyl)-3,4-dihydro-l(2H) naphthalenylidene] methanamine
(I):
100 gm (0.34 mole) of tetralone of formula (III) is suspended in 250 ml (3.25 mole) of a 40 % solution of methylamine at room temperature. The reaction mixture is heated to 80 ° C and
19

agitated at 80 ° C ± 5 ° C for 24 hours, when the reaction is complete. The reaction mixture is cooled to 20 ° C and agitated at the same temperature for 2 hrs. The precipitated solid is filtered, The crude product is slurred in 100 ml methanol and refiltered and dried below 50 ° C under reduced pressure to give 79 gm (75.6 %) of the title compound, having purity greater than 95 %.
Example 5
Preparation of cis racemic sertraline hydrochloride (lie):
To a suspension of 261 gm (0.86 mole) of imine of formula (I) in methanol (1250 ml), is added sodium borohydride (25 gm, 0.66 mole) in lots at 0 to 5 ° C. The reaction mixture is heated to reflux for 6 hours, and after completion of the reaction, the reaction mixture is cooled to room temperature. Aqueous solution of hydrochloric acid (625 ml, 1:1) is added dropwise to the reaction mixture and stirred for two hours. The solid, which precipitates out is filtered and dried to give 110 gm (35%) of cis racemic sertraline of formula (lie) as a hydrochloride salt.
Example 6
Preparation of (IS, 4S)-4-(3,4-dichlorphenyl)-l, 2,3,4-tetrahydro-N-methyl-l naphthalenylamine hydrochloride (II):
Step 1: To a solution of 105 gm (0.31 mole) of cis racemic sertraline hydrochloride (lie) in
water (525 ml), is added ethylacetate (1050 ml). Aqueous solution of sodium hydroxide (10
%) is added to the solution till pH of the solution is 10. After complete addition of sodium
hydroxide, ethylacetate layer is separated. Mandelic acid (49.35 gm, 0.32 mole) is added to
the ethylacetate layer and the solution is agitated at 40 ° C ± 5 ° C for two hours. Cool the
solution to room temperature. Filter the precipitated solid and dry it to give 60gm (85%) of
mandelic salt of (lS,4S)-4-(3,4-dichlorphenyl)-l,2,3,4-tetrahydro-N-methyl-l
naphthalenylamine of formula (IIe).
20

Step 2: To a solution of 40 gm of the mandelic salt obtained in Stepl in water (200 ml) is
added ethyl acetate (200 ml). To the solution is added a 10% aqueous solution of sodium
hydroxide (40 ml). After the complete addition, the reaction mixture is agitated, for 15 mns
and the layers allowed to separate. The ethyl acetate layer is separated from the aqueous
phase, dried over anhydrous sodium sulfate and the solution separated from sodium sulfate.
To the solution is bubbled hydrogen chloride gas till a pH of 1.0 is attained. Thereafter, the
reaction mixture is agitated for 3 hours and the precipitated solid filtered and dried to give 25
gm (83%) of (lS,4S)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l-
napthalenylamine i. .e sertraline hydrochloride of formula (II), having an optical purity of 99.2%.

We claim,
comprising reaction of compound of formula (III),

1. A process for preparation of compound of formula (I),

with a solution of methylamine in water or in a mixture of water and a water miscible organic solvent at temperature between 30 ° C to 80 ° C and at atmospheric pressure.

2. The process of claim 1, wherein the water-miscible organic solvent is selected from lower aliphatic alcohols; cyclic ethers; acyclic ethers; aprotic solvents such as amides; nitriles and sulfolane.
3. The process according to any one of claims 1 and 2, wherein the lower aliphatic alcohol is selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol and ferf-butanol.
4. The process according to any one of claims 1 and 2, wherein the cyclic ether is selected from tetrahydrofuran or dioxane.
5. The process according to any one of claims 1 and 2, wherein the acyclic ether is selected from diglyme or 1,2-dimethoxyethane.
6. The process according to any one of the claims 1 and 2, wherein the amide is selected from N-methylpyrrolidone, N,N-dimethylformamide, methylformamide or N,N-dimethylacetamide.
7. The process according to any one of the claims 1 and 2, wherein the nitrile is selected from acetonitrile or propionitrile.
8. The process of claim 1, wherein the solution of methylamine in water has a strength of between 20 % to 40 % w/v.
9. The process according to any one of claims 1 and 7, wherein methylamine is employed in molar proportions of 2 to 20 moles per mole of compound of formula (III).

10. A process for preparation of sertraline hydrochloride of formula (II),

comprising the steps of reduction of compound of formula (I),

with sodium borohydride in a lower aliphatic alcohol solvent selected from methanol, ethanol n-propanol, isopropanol. n-butanol, sec-butanol, ter-butanol at a temperature ranging between 0 ° C to reflux temperature to give a racemic mixture of cis isomer of formula (Ha),

i. (Ha)
and trans isomer of formula (lib),

reacting the mixture of (Ha) and (lib) with an aqueous solution of hydrochloric acid to form the corresponding hydrochloride salt (lie) and (lid),

b. Racemic cis Racemic trans
25

separation of the cis isomer of formula (II c) from the trans isomer of formula (II d) by crystallization from a lower aliphatic alcohol selected from methanol, ethanol n-propanol, isopropanol. n-butanol. sec.-butanol, ter-butanol:
neutralizing the cis hydrochloride isomer of formula (II c) with alkali selected from sodium hydroxide and potassium hydroxide to form the free base of formula (II a)
reacting the free base (II a) with mandelic acid in an organic solvent selected from an alkyl acetate such as ethvlacetate. or a lower aliphatic alcohol selected from methanol, ethanol n-prooanol. isopropanol, n-butanol, sec-butanol, ter-butanol to give mandeJic acid salts (U e) and (U f)

separation of isomer of formula (II e) from the isomer (II f) by crystallization from the lower aliphatic alcohol solvent selected from methanol, ethanol n-oropanol, isopropanol, n-butanol, sec-butanol, ter-butanol.
reacting the isomer of formula (II e) with aqueous alkali solution selected from sodium hydroxide and potassium hydroxide to give compound (IS, 4S)-4-(3,4-dichlorophenyl-l, 2,3,4-tetrahydro-N-methyl-l-naphthalenylamine,
dissolving the compound obtained in stepj^*(IS, 4S)-4-(3,4-dichlorophenyl-1, 2,3,4-tetrahydro-N-methyl-l-naphthalenylamine in a suitable organic solvent selected from alkyl acetate such as ethvlacetate and passing hydrogen chloride gas through the solution to give (IS, 4S)-4-(3,4-dichlorophenyl-l, 2,3,4-tetrahydro-N-methyl-l-naphthalenylamine hydrochloride of formula (11)./

Dated this 27n day of May 2004
Dr. Sanchita Ganguli
Of S. Majumdar & Co.
(Applicant Agent"s)

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Patent Number

213528

Indian Patent Application Number

606/MUM/2004

PG Journal Number

09/2008

Publication Date

29-Feb-2008

Grant Date

07-Jan-2008

Date of Filing

31-May-2004

Name of Patentee

LUPIN LIMITED

Applicant Address

159 C.S.T. ROAD, KALINA, SANTACRUZ(EAST), MUMBAI-400 098,

Inventors:

#	Inventor's Name	Inventor's Address
1	BHANU, MANJUNATH NARAYAN	LUPIN LIMITED, SURVEY NO. 46A/47A, NANDE VILLAGE, TALUKA, MULSHI, PUNE-411 042,
2	MAHAJAN, DEEPAK PUNA	LUPIN LIMITED, SURVEY NO. 46A/47A, NANDE VILLAGE, TALUKA, MULSHI, PUNE-411 042, MAHARASHTRA, INDIA
3	JAIN, AJINATH MURLIDHAR	LUPIN LIMITED, SURVEY NO. 46A/47A, NANDE VILLAGE, TALUKA, MULSHI, PUNE-411 042, MAHARASHTRA, INDIA

PCT International Classification Number

C07D38/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA