Title of Invention

NOVEL METHOD TO PREPARE SERTRALINE HYDROCHLORIDE

Abstract A process for the preparation of Sertraline of the formula I which comprises the sequential series of steps that involve (a) stereoselective reductive amination by reacting 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-naphthalen-l-one (DCPT) of formula II with methylamine, in the presence of a Lewis acid such as hereinbefore described, at temperature between 5 °C to 40 °C for Lewis acid condensation and subsequent reduction by reacting with reducing agents such as hereinbefore described at temperature between 9 °C to 11°C; (b) separation in any manner of substantially geometrically pure racemic (±) cis stereoisomer III, from a mixture of cis (III) and Trans (IV) isomers as salt; (c) resolution of substantially geometrically pure racemic (±) cis stereoisomer III cis-base as (1 S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1 -naphthalenamine, by employing suitable resolving agents such as tartaric acid, mandelic acid and camphor sulfonic acid; (d) formation of hydrochloride salt from ls-cis-free base as (lS-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1 -naphthalenamine hydrochloride(Sertraline).
Full Text FORM -2
THE PATENTS ACT, 1970
(39 of 1970)
COMPLETE SPECIFICATION

27.07.2007

Novel method to prepare Sertraline hydrochloride.
Cadila Healthcare Ltd., 'Zydus Tower', Satellite cross Roads,
Gandhinagar - Sarkhej Highway, Ahmedabad - 380 015, Gujarat, India.

Original
567/MUM/2003
02/06/03

GRANTED
8-1-2004

This invention particularly describes and ascertains the nature of this invention and the manner in which it is to be performed:

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Field of invention:
The present invention relates to a novel process for preparing a naphthaienamine derivative represented by formula (I), (+) (l S-cis)-N-methy]-4-(3,4-dichloroplenyl)-l,2,3,4-tetrahydro-1-naphthaienamine hereinafter referred to as "Sertraline" and its add addition salts.
Background of the invention:
Sertraline hydrochloride, (+) (l S-cis)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-1-naphthaienamine hydrochloride, has the following structural chemical formula:

Sertraline hydrochloride has been approved under the brand name "Zoloft" by the U. S. Food and Drug Administration, for the treatment of depression, obsessive-compulsive disorder, and panic disorder. Sertraline hydrochloride is marketed in other countries under various brand names, with additional uses as an anti-depressant and anorectic agent.
Sertraline hydrochloride is a valuable pharmaceutical substance, and the pharmaceutical compositions containing this compound are useful in the treatment of depression and other dependence / anxiety related disorders (US 4,536,518 and 5,248,699).
There are several processes known for manufacturing Sertraline and its acid addition salts. The key intermediate in most of these processes, is 4-(3,4-dichlorophenyI)-3,4-dihydro-l-(2H)naphthalen-l-one or 4-(3,4-dichlorophenyl)tetralone (hereinafter referred to as DCPT). The synthesis of DCPT is described in US 4,029,731, 5,019,655, 4,045,488; European Patent application no. 30,081 and in2hur. Org. Khim., 18, 870 (1982).






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Various aspects of Sertraline polymorphs are also disclosed in US 4. 536. 517; US 5, 734, 083; JP 2000/026378 and 026379; WO 0032551 and WO 0172684.
Welch et al. (US 4,536,518) initially reported the use and method of preparation of Sertraline hydrochloride and related compounds. In the process DCPT is reacted with methyl amine in THF at 0 °C to 5 °C and is followed by dropwise addition of titanium tetrachloride. After filtration of the reaction mixture, the filtrate obtained was hydrogenated using 10 % Pd/C catalyst at atmospheric pressure and room temperature. The residue was dissolved in anhydrous ether and was treated with gaseous hydrogen chloride to obtain Sertraline HC1 salt, which contains about 70 % cis-racemate and 30 %. trans-racemate. Cis-racemate of the desired compound is selectively crystallized out by dissolving the mixture in hot methanol (40 x based on the starting tetralone) and addition of a 30 times amount of diethyl ether. The primary yield is 48 %, which is increased to 68 % by working up the mother liquor obtaining a second crop of the title compound. The cis isomer is resolved into (IS) and (IR) using D(-)-mandelic acid to get Sertraline mandelate.
There are several disadvantages in the above-described process. The commercial
realization / scale-up involves additional working time, working power and energy due to
large solvent circulation and the work-up of secondary generation mother liquor.
Hydrogenation leads to a mixture of cis-racemate (IE) and trans-racemate (IV) isomers in the
ratio of 50:50 to 70:30, and an additional resolution step is needed. During isolation excess
amount of solvents is needed. The use of TiCl4 in the process demands careful handling due
to its extreme reactivity with water. Further, it is corrosive, can contaminate the product with
titanium, and is associated with potential hazards. Another drawback is that during use of
methyl amine, the reactor temperature has to be kept below 5 °C. Additionally addition of
TiCl4 to reactor is exothermic, resulting in a sensitive reactor conditions e.g. efficient cooling.
US 4,855,500 uses hydratable /reusable molecular sieves, instead of TiCU, thereby
giving pure product imine in a unique one-step method with high yields.
Recently, Indian patent application no. 748/CAL/99, has disclosed the reaction of 4-
(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)-naphthalone with methyl amine under reducing
atmosphere in the presence of hydrogen under a pressure of 200-1000 psi and a reducing
agent such as raney Nickel at a temperature ranging from room temperature to 100 °C. The

yields are average in the range of 41 % to 50 %.


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The reductive step is associated with the generation of a stereocenter and hence methods have been developed to include stereoselective reduction of the compound of the formula (II) using microbial flora (European Patent application no. 0997535) or in the presence of copper-containing catalyst (WO 9947486). US 5,463,126 discloses a method using ionic hydrogenation to selectively form the desired cis-lS stereoisomer. US 6,034,274 discloses stereoselective reduction of N-oxide DCPT, obtained by using compound of formula (II) with methylhydroxyl-amine and followed by hydrogenation in the presence of Raney-Nickel.
The above methods of selective reduction are commercially less viable, as these involve
relatively higher processing costs.
European Patent application no. 0947499) uses N-methylformamide instead of N-

methylamine, for stereoselective reduction.
Hence, it is desirable to have a process to prepare Sertraline and its acid addition salts, which is commercially viable, relatively safe, with high yields of desired stereoisomer.
Summary of the invention :
The present invention provides a method to prepare / manufacture Sertraline and its acid addition salts using a process, which is devoid of the above stated disadvantages in the prior art.
The main objective of the present invention is to provide a novel process to prepare Sertraline hydrochloride ie. (+)(l S-cis)-4-(3,4-dichorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-phthalenamine hydrochloride, in three steps.
The particular objective of the present invention is to provide a one pot process for substantially geometrically pure racemic cis (±) of formula (III), via stereoselective reductive animation, by condensing methyl amine in the presence of a Lewis acid and subsequent reduction.
Another objective of the present invention is to provide a process for substantially geometrically pure racemic (±) (III) by condensation of 4-(3,4-dichlorophenyl)-3,4-dihydro-l-(2H)-naphthalen-l-one (DCPT) of the formula (II) with a solution of methyl amine in


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organic solvents in the presence of titanium(IV)isopropoxide, followed by reduction with sodium borohydride in-situ.
Yet another objective of the present invention is to provide a novel process for substantially geometrically pure racemic (±) of formula (III), by using minimum amount of solid reagents (CH3NH2.HCI) at ambient temperature, thereby, reducing environmental pollution and minimizing costs.
Optionally, the present invention provides a process to isolate substantially geometrically pure racemic (±) of formula (III), from a mixture of cis (±) and trans (±) isomers.
Still another objective of the present invention is to reveal process for the resolution of substantially geometrically pure cis (±) isomer (III).
The preferred objective of the present invention is to provide a novel, simple, safe, cost-effective and alternative process to manufacture Sertraline.
Detailed Description of the invention :
Accordingly, the present invention provides a process to prepare compounds of the formula I, in either racemic or optically active (+) or (-) forms, and their salts. More particularly, the present invention provides a process to prepare Sertraline. The key step in the present invention is the stereoselective reductive amination of DCPT II with methylamine or its salt, in the presence of Lewis acid and a reducing agent
The process comprises of the following sequential series of steps:
(1) Stereospecific reductive amination by reacting DCPT with methylamine
hydrochloride in a suitable solvent and a suitable organic base in the presence of a Lewis acid. Subsequently, the reaction mixture is reduced with a suitable reducing agent in situ. (2) Seperation of substantially geometrically pure racemic (±) cis stereoisomer III, from a mixture of cis (III) and trans (IV) isomers, as an acid addition salt.

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(3) Resolution of substantially geometrically pure racemic (±) cis stereoisomer (III) base with suitable resolving agents and regenerating optically pure (+) (lS-cis) free base.
(4) Formation of hydrochloride salt from (+) (lS-cis) free base as (+)(lS-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyI-l-phthaIenamine hydrochloride
SCHEME I

The reaction may be carried out in the presence of a protic or aprotic solvent(s) or a mixture of solvent(s), selected from methanol, ethanol, propanol, toluene, hexane, cyclohexane, tetrahydrofuran, diethyl ether and the like The choice of the Lewis acids may be Titanium (IV) alkoxides eg. propoxide, isopropoxide, ethoxide, methoxide in a molar ratio of 1 to 5, with respect to DCPT of formula II. The reaction temperature may range from 5 oC

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to the reflux temperature of the solvent(s) used (Synthetic Communications 2000, 30, 2001
and J. Chem. Soc. Perkin Trans. 1, ] 998, 2527).
Suitable organic bases such as 1,5-Diazabicyclo [4,3,0] non-5-ene(DBN), 1,8 -
diazabicyclo-[5,4,0] undec-7-ene (DBU), 1,4-Diazabicyclo [2,2,2] octane (DABCO), triethyl
amine and di isopropyl ethyl amine and the like may be used) The molar ratio of organic base
to DCPT may be 1 to 10.
While the use of methylamine hydrochloride salt requires lesser amount of the
solvent, the use of methylamine gas requires large volume of solvents due to its lesser
solubility at ambient temperatures. Indeed, condensation of methylamine in large volume of
solvents cooled at -10 °C or below is an extremely time consuming and an expensive
process.
The in-situ reduction may be effected in the presence of a reducing agent such as
lithium borohydride, sodium borohydride, lithium aluminum hydride, or hydrogenation in the presence of Raney Nickel, 5 - 10 % Pd/C and such other catalysts known. The amount of reducing agent may be in the range from 1 to 20 equivalents(preferably 2-5 equivalents). The reaction may be carried out in the presence of an inert atmosphere such as N2, He or Ax. The reaction time may range from 5 minutes to 72 hours, preferably from 1 to 48 hours.
It is preferred that in the process disclosed in the invention, methanol or ethanol is used as solvent, and sodium borohydride or lithium borohydride is used as a reducing agent.
It is more preferred that methanol is used as a solvent, and sodium borohydride is used as an in-situ reducing agent. Separation of substantially geometrically pure racemic (±) cis and trans isomers is effected via its salts, especially hydrochloride salt and refluxing in solvents eg. methanol, ethanol, propanol, methylene chloride, 1,2-dichloroethane and mjxtures thereof. The characterization of substantially geometrically pure cis (±) III isomer was carried out by 1H NMR, HPLC and melting point of its HCI salt (m.p. 280 °C).
Resolution of the substantially geometrically pure racemic (±) of formula (III) may be carried out with an optically active acid by standard techniques well known to those skilled in the art. Mixture of stereoisomers may be resolved by conventional methods such as microbial resolution, resolving the diastereomeric salts formed with chiral acids or chiral bases. The method used here involves treatment with an alcoholic solution of chiral acid to form


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diastereoisomeric salts. The chiral acid may be selected from the group consisting of tartaric
acid, mandelic acid, lactic acid, camphorsulfonic acid, amino acids and the like?)
The preferred method involves the use of D (-) mandelic acid in an alcoholic solvent(s) (methanol, ethanol or isopropanol) in the presence of some moisture (0.1 to 2 %).
The resulting cis chiral acid addition salt is further converted into free cis-base by standard techniques well-known to those skilled in the art, which is further converted to the acid addition salt. According to the process disclosed in the invention, hydrogen chloride in methanol, ethanol or isopropanol is used as an alcoholic solution of mineral acid to get the final product Sertraline hydrochloride.
The reaction of chiral 4S (+) DCPT with methylamine hydrochloride as disclosed above gives (+) (lS-cis)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l-naphthalenamine hydrochloride, ie Sertrahne.HCl, in one step by employing above disclosed stereoselective reductive amination invention.
Scheme II

The process of this invention has the following advantages :
1. The present process provides one-pot process to prepare cis isomer of Sertraline from DCPT and methylamine, followed by reduction in-situ.
2. The desired substantially geometrically pure racemic (±) of formula (III) cis-compound is formed with better selectivity (70 -85 %).
3. The solid nature of methylamine salt is easier to handle and avoids the use of low temperatures and high pressure, required to dissolve methylamine gas in non-


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aqueous media. This results in better control over the process and hence advancement over the known art.
4. The yield of the final product is around 40 % to 70 %.
5. The described process involves condensation of a methylamine hydrochloride salt with DCPT in the presence of, titanium (IV) isopropoxide, which is relatively mild compared to TiCI4 or less pyrophoric compared to 10 % Pd-C and Raney Nickel used in earlier processes.
6. Titanium (IV) isopropoxide is readily available, less corrosive, and generates less heat during reaction, which effects the overall cooling costs.
7. Use of smaller amount of methylamine hydrochloride decreases the possibility of environmental pollution.
8. The solid handling and smaller amount of methylamine hydrochloride use effects the overall volume efficiency of the process, provides improved safety and is also cost effective.
The Sertraline.HCl produced according to the process described in the present invention is useful for the treatment of depression, obsessive-compulsive disorder and panic disorder in patients, who are in need thereof. The pharmaceutical composition containing Sertraline.HCl prepared according to the process described in the present invention is useful for treating the patients suffering from mental disorders mentioned above.
The present invention is illustrated by the following examples, which are not intended to limit the effective scope of the invention and the claims.
Example 1
To a solution of 1.45 g (5 m.mole) DCPT in 15 ml of methanol under nitrogen atmosphere, 0.64 g (9.4 m.mole) of Methylamine hydrochloride, 0.96 g (9.4 m.mole) of methylamine and 2.75 g (9.4 m.mole) of titanium (IV) isopropoxide, were added and stirred at 25-30 °C for 8 -9 hours. After monitoring the disappearence of DCPT, the reaction mixture was subsequently charged with 0.277 g (7.05 m.mole) NaBH4 in small lots, by maintaining the temperature between 10 - 15 °C for half an hour. The reaction mixture was subsequently stirred for 3

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hours and filtered through a filtration cloth. The solid residue was washed with 10-35 ml methanol, and the combined filtrate was concentrated into an oily residue, charged with 15 ml of D. M. water and 20 ml of ethylacetate and stirred for 30 minutes. The lower aqueous layer was separated and re-extracted with 20 ml ethyl acetate. The organic extracts were then combined, dried over anhydrous Na2SO4 and concentrated to get an oily product (free base of mainly cis(±) isomer). The oil was dissolved in isopropylalcohol, and the pH was adjusted to 1-2 using cone HC1 and subsequent reflux gave mainly (±) Cis-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-l-naphthalenamine (III,1.25g, 73 % yield) solid in the form of its hydrochloride (m.p. 280 °C).
Example 2
The procedure described in example I was repeated except that toluene was employed as a solvent in lieu of methanol and substantially the same results were achieved. In this particular case, the final product obtained (68 %) eg, mainly (±) cis-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-1-naphthalenamine.HCl, is identical in every respect with the product of Example I.
Example 3
The procedure described in example I was repeated except that absolute ethanol was used as a solvent in lieu of methanol. In this particular case, the final product obtained (75 %) eg, mainly (±)cis-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l-naphthalenamine.HCl, is identical in every respect with the product of Example I.
Example 4
The procedure described in earlier Example I and Example III was repeated except the work-up procedure of the reaction mixture. After completion of the reaction stirring, NaBH4 was added and the reaction mixture was quenched into aqueous ammonia, the resulting solid was filtered and washed with dichloromethane (25 ml). The aqueous layer is reextracted (25 ml) with dichloromethane and the combined organic layer was treated with dil HC1. The aqueous layer was reextracted with dichloromethane and combined with organic layer. Basification of aqueous layer with sodium hydroxide to pH 10-12 and extracting the base with

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dichloromethane (2 x 50 ml) gave 1.5 g of crude base. Purification of crude base as HC1 salt, and refluxing in ] ,2-dichloroethane as described in Example I gave 1.1 g (64 % yield) of mainly (±) cis-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l-naphthalenamine.HCl (III), m.p 281 °C. In this particular case, the final product obtained, was identical in every respect with the product of Example I.
Example 5
The procedures as described in Example 1 or Example 3 were repeated, except that the molar ratio of methylamine hydrochloride was changed to 1 equivalent with respect to DCPT, to form 0.4 g (22 % yield) of the desired product. In this particular case, the final product obtained eg. mainly (±) cis-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-l-naphthalenamine.HCl (III) was found to be identical in every respect with the product of Example I.
Example 6
The procedure described in Example 1 or Example 3 were repeated except that the molar ratio of methylamine hydrochloride was taken to be 5 equivalent with respect to DCPT. Here 65 % yield of the desired product was obtained. In this particular case, the final product obtained eg. mainly (±) cis-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-l-naphthalenamine.HCl (III, m.p. 280 - 282 °C) was found to be identical in every respect with the product of example I.
Example 7
The procedure as described in Example 1 or Example 3 were repeated except that the molar ratio of Titanium (IV) isopropoxide was taken to be 1.5 times with respect to DCPT. It yielded 0.28 g (16 % yield) of the desired product. In this particular case, the final product obtained eg. mainly (±) cis-4-(3,4-dichlorophenyl)-l,2,3,4-tetraliydro-N-methyl-l-naphthalenamine.HCl (III, m.p. 281 - 283 °C) was found to be identical in every respect with the product of example I.

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Example 8
The procedure as described in Example 1 or Example 3 were repeated with a different molar concentration of Titanium (IV) isopropoxide fixed at 2.5 times with respect to DCPT 0.5 g (29% yield) of the desired isomer (III) was obtained. In this particular case, the final product obtained eg. mainly (±) cis-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l-naphthalenamine.HCl (III, m.p. 281 - 283 °C) was found to be identical in every respect with the product of example I.
Example 9
The procedure as described in Example 1 or Example 3 were repeated except that here methylamine hydrochloride is prepared insitu by starting with a suitable amount of methylamine gas and purging with dry HCL gas. Methylamine hydrochloride was freshly prepared by charging 100 ml methylamine and 100 ml methanol solution into a round bottom flask A, and cooling. Meanwhile HCL gas was generated by adding cone H2SO4 solution to HC1 solution, and was purged through the solution present in Flask A to get crystalline precipitates of methylamine hydrochloride.
To a solution of 1.45 g (4.7 m.mole) DCPT in 15 ml methanol solution. Freshly prepared 0.64 g (9.4 ni.mole) methylamine Iwdrochloride was introduced. To the resulting mass 0.96 g (9.4 m.mole) of triethylamine and 2.75 g (9.4 ramole) of titanium (IV) isopropoxide, were added and stirred at 25-30 °C for 8 - 9 hours. After monitoring the disappearance of DCPT, the reaction mixture was subsequently charged with 0.277 g (7.05 m.mole) NaBH4 in small lots, by maintaining the temperature between 10 - 15 °C for half an hour. The reaction mixture was subsequently stirred for 3 hours and filtered through a filtration cloth. The solid residue was washed with 10-15 ml methanol, and the combined filtrate was concentrated into an oily residue, charged with 15 ml of D. M. water and 20 ml of ethylacetate and stirred for 30 minutes ..The lower aqueous layer was separated and re-extracted with 20 ml ethyl acetate. The organic extracts were then combined, dried over anhydrous Na2S04 and concentrated to get an oily product (free base of mainly cis(±) isomer. The oil was dissolved in isopropylalcohol, and the pH was adjusted to 1-2 using cone HC1 to give mainly cis (±) III (1.25g, 73 % 3'ield) solid in the form of its hydrochloride. Refluxing the salt in dichloromethane further purified the cis isomer. In this particular case, the final product obtained eg. mainly (±) cis-4-

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(3,4-dichIorophenyl)-l,2,3,4-tetrahydro-N-methy]-l-naphthalenamine.HC] (111, m.p. 281 -283 °C) was found to be identical in every respect with the product of Example 1.
Example 10
To 10 ml solution of methylamine in methanol (25 %) solution under nitrogen atmosphere, 2.83 g (10. m.mole) of titanium (IV) isopropoxide, were added dropwise and stirred at 25-30 °C for half an hour. A solution of 1.45 g (4.7 m.mole) DCPT in 15 ml of methanol was added and stirred for another 6-8 hours. After monitoring the disappearence of DCPT, the reaction mixture was subsequently charged with 0.190 g (5 m.mole) NaBH4 in small lots, by maintaining the temperature between 10 - 15 °C for half an hour. The reaction mixture was subsequently stirred for 3 hours and filtered through a filtration cloth. The solid residue was washed with 10-15 ml methanol, and the combined filtrate was concentrated into an oily residue, charged with 15 ml of D. M. water and 20 ml of ethylacetate and stirred for 30 minutes. The lower aqueous layer was separated and re-extracted with 20 ml ethyl acetate. The organic extracts were then combined, dried over anhydrous Na2SO4 and concentrated to get an oily product (free base of mainly cis(±) isomer). The oil was dissolved in ethanol, and the pH was adjusted to 1-2 using cone HC1 to give mainly cis (±) III (0.75g, 23 % yield) solid in the form of its hydrochloride. In this particular case, the final product obtained eg. mainly (±) cis-4-(3,4-dichlorophenyl)-ls2,3,4-tetrahydro-N-methyl-l-naphthalenamine.HCl was found to be identical in every respect with the product of example I.
Example 11
The procedure as mentioned in Example 10 was repeated with methylamine in absolute ethanol as a solvent, instead of methanol. 0.4, g (23 %yield) of the desired product was obtained. In this particular case, the final product obtained eg. mainly (±) cis-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l-naphthalenamine.HCl was found to be identical in every respect with the product of example I.


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Example 12
The procedure as mentioned in Example 10 or Example 11 were repeated with methylamine in toluene (12 % solution) as a solvent.0.7 g (41 % yield) of the desired product was obtained. In this particular case, the final product obtained eg. mainly (±) cis-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-l-naphthalenamine.HCl was found to be identical in every respect with the product of example I.
Example 13
Similarly variation of the molar ration of Titanium (IV) isoproproxide in Example 10, Example 11, or Example 12 and modified workup procedure as described in Example 4, gave identical results with comparable yields. In all these cases, the final product obtained eg. mainly (±) cis-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l-naphthalenamine.HCl was found to be identical in every respect with the product of example I.
Example 14
The procedure as mentioned in Example 10 and Example 11 were repeated now with the concentration of methylamine gas in the molar ratio 5 as compared to DCPT. In this particular case, the final product obtained eg. mainly (±) cis-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-1-naphthalenamine.HCl (60 %) was found to be identical in every respect with the product of Example I.
Example 15
The procedure as mentioned in Example 10 and Example 11 were repeated with the molar ratio of methylamine gas at 50 as compared to the concentration of DCPT. In this particular case, the final product obtained eg. mainly (±) cis-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-1-naphthalenamine.HCl was found to be identical in every respect with the product of Example I.


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Resolution of mainly (±) cis-4-(3,4-dichIoropheny])-l,2,3,4-letrahydro-N-methyl-l-naphthalenamine (III), with D(-) Mandelic Acid.
To a solution of (±) III cis free base (45 g) in 500 ml of isopropyl alcohol, D-(-) Mandelic acid (22 g) dissolved in 90 ml isopropyl alcohol Avas added. The moisture content of the reaction varied between 0.1 % to 2 %. The reaction mixture was heated and allowed to cool. The resultant mass was then filtered off and washed with isopropylalcohol, dried, and washed with acetone (m.p. 180 - 182 °C). The resultant mass was further purified by repeated recrystallization to constant m.p. (185 °C to 187 °C). Subsequently dichloromethane (100 ml) was charged to this ppt, and heated at 30-35 °C and stirred for 15 minutes. Finally 10 % NaOH solution (50 ml) was added dropwise and stirred untill two clear layers are separated. The dichloromethane layer is separated. The aqueous layer is reextracted with dichloromethane, organic layers are combined, and concentrated to give 15.3 g (68 %) optically pure (ee > 99 %) is cis free base.
Example 17
Sertraline formation to (+) (15'-cis)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l-naphthalenamine.HCl, using cone HC1.
To 3 g of sertraline free base was charged 8 v/wt isopropyl alcohol and stirred until a clear solution was obtained. The solution was heated to 55 °C and cone HC1 was charged dropwise until a pH of 2 was obtained. The subsequent mixture was refluxed at 75 °C for 2 hours, and allowed to cool to room temperature. The resultant mass was filtered at suction and dried in an oven for 2 hours at 70 - 80 °C, which gave 2.2 g (65 % yield) of Sertraline (SOR + 40°C, 1 % solutionin 0.05 N HC1 in methanol, m.p. 247 -249 °C).
Example 18
Sertraline formation to (+) (l5'-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine.HCl, using dry HC1 gas.
The same procedure as mentioned in Exampfe 17 was carried out with dry HCl gas instead of cone HCl solution. 3 g (88 % yield) of the desired product was obtained. In this

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particular case, the final product obtained eg. mainly (lS-cis)-4-(3,4-dichlorophenyi)-l,2,3,4-tetrahydro-N-methyl-1-naphthalenamine.HCl was found to be identical in every respect with the product of Example 17.
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 intended within the scope of the presentinvention.


We claim:
1. A process for the preparation of Sertraline of the formula I which comprises the sequential series of steps that involve
(a) stereoselective reductive amination by reacting 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-naphthalen-l-one (DCPT) of formula II with methylamine, in the presence of a Lewis acid such as hereinbefore described, at temperature between 5 °C to 40 °C for Lewis acid condensation and subsequent reduction by reacting with reducing agents such as hereinbefore described at temperature between 9 °C to 11°C;


(b) separation in any manner of substantially geometrically pure racemic (±) cis stereoisomer III, from a mixture of cis (III) and Trans (IV) isomers as salt;
(c) resolution of substantially geometrically pure racemic (±) cis stereoisomer III cis-base as (1 S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1 -naphthalenamine, by employing suitable resolving agents such as tartaric acid, mandelic acid and camphor sulfonic acid;


(d) formation of hydrochloride salt from ls-cis-free base as (lS-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1 -naphthalenamine hydrochloride(Sertraline).

2. A process as claimed in clam 1 wherein the substantially geometrically pure racemic (±) cis stereoisomer III or its salt is formed as a major isomer in one pot and in one step via stereoselective reductive amination.
3. A process as claimed in any preceding claim wherein said Lewis acid is selected from titanium (IV) alkoxides such as titanium (IV) isopropoxide, titanium (IV) propoxides and titanium (IV) ethoxide.
4. A process as claimed in any preceding claim wherein said reducing agent is selected from sodium bofohydride and lithium borohydride.
5. A process as claimed in any preceding claim wherein said solvent is either protic or aprotic or mixtures thereof, such as isopropanol, methanol, ethanol,
propoanol, butanol, toluene, tetrahydrofuran, cyclohexane, hexane and diethyl
A process as claimed in claim 1 dr 2 wherein the molar ratio of methyl amine is in the range of 5 to 50 with respect to DCPT in a condensed solution in a solvent.
7. A process as claimed in claim 3 wherein the molar ratio of said Lewis acid is 1 to 5 with respect to said DCPT.

8. A process as claimed in any preceding claim wherein said Lewis acid condensation is carried out at a temperature in the range of 5°C to 40°C whereas the temperature for reduction is preferably 10°C.
9. A process as claimed in claim in any preceding claim wherein the separation of substantially geometrically pure racemic (±) cis stereoisomer III from the mainly cis is effected by stirring ior refluxing in methanol, ethanol, ethylene glycol, 1,2-dichloro etahne and dichloromethane or from mixtures of these solvents.
[10. A process as claimed in claim in any preceding claim wherein the separation of substantially geometrically pure racemic (±) cis stereoisomer III is carried out by using a member independently selected from molar the group consisting of tarataric acid, mandelic acid and camphor sulfonic acid.
11. A process as claimed in claim 1 for the preparation of Sertraline substantially as herein described with reference to the foregoing examples.
Dated this the 2nd day of June 2003.
H.SUBRAMANIAM Of Subramaniam, Nataraj & Associates Attorneys for the applicants


Documents:

567-mum-2003-cancelled pages(8-1-2004).pdf

567-mum-2003-claims(granted)-(8-1-2004).doc

567-mum-2003-claims(granted)-(8-1-2004).pdf

567-mum-2003-correspondence(24-11-2004).pdf

567-mum-2003-correspondence(ipo)-(7-10-2004).pdf

567-mum-2003-form 1(2-6-2003).pdf

567-mum-2003-form 1(24-11-2004).pdf

567-mum-2003-form 19(2-7-2003).pdf

567-mum-2003-form 2(granted)-(8-1-2004).doc

567-mum-2003-form 2(granted)-(8-1-2004).pdf

567-mum-2003-form 3(2-6-2003).pdf


Patent Number 207052
Indian Patent Application Number 567/MUM/2003
PG Journal Number 40/2008
Publication Date 03-Oct-2008
Grant Date 21-May-2007
Date of Filing 02-Jun-2003
Name of Patentee CADILA HEALTHCARE LIMITED
Applicant Address ZYDUS TOWER, SATELITE CROSS ROADS, AHMEDABAD,
Inventors:
# Inventor's Name Inventor's Address
1 VIDYA BHUSHAN LOHRAY CADILA HEALTHCARE LIMITED, ZYDUS TOWERS, SATELLITE CROSS ROAD, AHMEDABAD 380 015
2 BRAJ BHUSHAN LOHRAY CADILA HEALTHCARE LIMITED, ZYDUS TOWERS, SATELLITE CROSS ROAD, AHMEDABAD 380 015
3 BIPIN PANDEY CADILA HEALTHCARE LIMITED., ZYDUS TOWER, SATELITE CROSS ROADS, AHMEDABAD - 380 015.
PCT International Classification Number A61K 31/135
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA