FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
PROCESS FOR THE PREPARATION OF (15,45)4(3,4-
DICHLOROPHENYL)-l,2,3,4-TETRAHYDRO-yV-METHYL-l
NAPHTHYLAMINE HYDROCHLORIDE
SUN PHARMACEUTICAL INDUSTRIES LTD.
A company incorporated under the laws of India having their office at ACME PLAZA, ANDHERI-KURLA ROAD, ANDHERI (E), MUMBAI-400059,
MAHARASHTRA, INDIA.
The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.

The present invention relates to a process for the preparation of (15,45)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-V-methyl-l-naphthylamine hydrochloride, compound of formula I, commonly known as sertraline hydrochloride (INN name), useful in the treatment of depression, obsessive-compulsive disorder and panic disorder.


.HCI

BACKGROUND OF THE INVENTION
Sertraline hydrochloride has two chiral centers and hence has four stereoisomeric forms, viz. (WAR), (15,45), (IRAS) & (15,4^). Of these the required stereoisomer for therapeutic purpose is the cis-(lS,4S) isomer, compound of formula I.
United States Patents No. 4,536,518 ('518 patent) and No. 4,556,676 ('676 patent) assigned to Pfizer disclose a multi-step process for the synthesis of pure (15',4.S)-4-(3.4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l-naphthylamine starting from 3,4-dichlorobenzophenone. The synthetic process involves the intermediacy of racemic 4-(3,4-dichlorophenyl)-3,4-dihydro-l(2H)-naphthalenone, a compound of formula VIII.

2

The ketone of formula VIII is condensed with methylamine to form a racemic imine mixture of formula VII. The racemic imine is then reduced by means of catalytic hydrogenation or by the use of a metal hydride complex to 4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-Af-methyl-l-naphthylamine, which is a racemic mixture of both cis and trans isomers. Separation of the trans isomers by fractional crystallization, and subsequent resolution of the separated cis-racemate with an optically active precipitant acid, such as (i?)-mandelic acid in a classical manner finally affords the desired cis-(1S,4S) enantiomer (sertraline). This process has the disadvantage that separation of the undesired isomers of formulas III, V and VI, that are co-produced, requires several steps rendering the process operationally tedious and economically unviable.
The racemic tetralone of formula VIII, is also obtained by the processes described in US 4,777,288; US 4,839,104 and WO 98/15516, and may be once again be processed to obtain sertraline isomers from which the desired cis-(1S,4S) isomer may be separated by processes described in US 4,536,518, or by following the process described in US 4,556,676, wherein the cis & trans isomers are at first separated as their racemates by column chromatography which is a tedious technique and unviable on commercial scale.
US Patent application 6,552,227 (the '227 patent, equivalent Indian reference not available) exemplifies hydrogenation of the imine of formula VI using either palladium or platinum oxide catalyst in /-butyl methyl ether (MTBE), isolation of the stereoisomeric mixture of (±)-cis/trans sertraline by evaporation of solvent, and subsequent preparation of the mandelate salt of cis-( IS, 4S) enantiomer in ethanol, purification by recrystallization in ethanol, generation of the free base and extraction in toluene, concentration and dissolution of the free base in ethanol, and finally preparation of sertraline hydrochloride by acidification using dry hydrogen chloride gas. The entire process for the preparation of sertraline hydrochloride as described in the '227 patent is once again operationally tedious.
3

In the methods described above in '518 & '676 patents, initial separation of the cis & trans isomers as racemates is inevitable, and a separate resolution process for the racemates to obtain the desired stereoisomer is essential. While in the '227 patent the cis-(15,45) isomer is isolated directly from the (±)-cis/trans sertraline mixture, the entire process for obtaining sertraline hydrochloride is still tedious. Hence a simple process that would involve minimum operations, and produce the desired cis-(1S,4S) isomer of sertraline as crystalline form I or form V, with high separation efficiency in a facile manner would be highly desirable from operational and commercial viewpoints.
OBJECT OF THE INVENTION
The object of the present invention is to develop an alternate simple, commercially viable process whereby the unwanted /raw-isomers, as well as the cis-(1R,4R) isomer could be eliminated with minimum number of operations, and render isolation of sertraline hydrochloride in a facile manner.
SUMMARY OF THE INVENTION
A process for the preparation of (15,45)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-A-methyl-1-naphthylamine hydrochloride, compound of formula 1, as crystalline form 1 or form V, comprising


.HCI
CO,H
H\..^CH,

4

II

a) hydrogenating the imine N-[4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-l(2//)-ylidene]methanamine, compound of formula VII, with Raney-nickel in an alcohol solvent to obtain stereoisomeric mixture containing (17?,4i?)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-A^-methyl-1 -naphthylamine(III), (l^^^-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-A^-methyl-l-naphthylamine(IV), (lR,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-l-naphthylamine(V) and (1S',4R)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-JV-methyl-1 -naphthylamine(VI);

CI CI CI CI


III IV V VI
VII
b) adding water, less than 1 molar equivalent of (R)-mandelic acid with respect to the compound of formula VII, to the stereoisomeric mixture of step (a). heating, cooling to selectively crystallize the (7?)-mandelate of (lS,4S)~4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-jV-methyl-l -naphthylamine, of formula II;
c) reacting the (70-mandelate salt of (1S',4S)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-.N-methyl-1 -naphthylamine, compound of formula II, with hydrochloric acid and isolating the product.
5

Or
generating the free base from the (R)-mandelate salt of (15,45)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l-naphthylamine of formula II, and treating with amine hydrochloride salt in suitable solvent.
DETAILED DESCRIPTION OF THE INVENTION
According to the process of the present invention, water and (R)-mandelic acid are added
to a stereoisomeric mixture consisting of (1R,4R)-4-(3,4-dichlorophenyl)-l,2,3,4-
tetrahydro-N-methyl-l-naphthylamine(III), (lS,4S)-4-(3-4-dichlorophenyl)-!, 2,3,4-
tetrahydro-N-methyl-l-naphthylamine(IV), (lR,4S)-4-(3,4-dichlorophenyl)-l,2,3,4-
tetrahydro-N-methyl-l-naphthylamine(V) and (1S,4R)-4-(3,4-dichlorophenyl)-l ,2,3,4-
tetrahydro-A^-methyl-l-naphthylamine(VI), obtained by the hydrogenation of the imine
N-[4-(3,4-dichlorophenyI)-3,4-dihydronaphthalen-1 (2H)-ylidene]methanamine of
formula VII with Raney-Nickel in an alcohol solvent, heating and cooling to selectively crystallize to selectively crystallize the (R)-mandelate of the desired cis-( 1S,4S) isomer of formula II.

Ill IV V VI
The solvent for the hydrogenation of the imine of formula VII may be selected from a Cj-C6 alkanol solvent that may be primary, secondary & tertiary, straight or branched, and a mixture thereof. Preferably the alcohol solvent is ethanol or 2-propanol, most preferably 2-propanol.
6

In the process of the present invention, water and (R)-mandelic acid are added to the mixture containing the four stereoisomers of formulas III, IV, V & VI obtained by hydrogenation of the imine of formula VII in a solvent described as above, and the mixture heated and cooled to selectively crystallize out the (R)- mandelate of the desired cis-(1S,4S) isomer of formula II. This would greatly minimize the number of operations, reduce the solvent usage and energy requirements, and render isolation of the desired cis-(1S,4S) isomer in a very facile manner.
The amount of water that is added is 0.1 to 0.5 parts with respect to the alcohol solvent used for the hydrogenation of the imine of formula VII. Preferably the quantity of water to be added is 0.2 to 0.4 parts with respect to the alcohol solvent used for the hydrogenation of the imine of formula VII.
In the process of the present invention, (^)-mandelic acid is added is 0.5 to 0.8 molar equivalents with respect to the imine of formula VII. Preferably the quantity of (R)-mandelic acid is 0.60 to 0.70 molar equivalents with respect to the imine of formula VII.
According to one embodiment of the present invention the mixture of water, (R)-mandelic acid and the stereoisomers III, IV, V and VI may be heated from about 30°C to 150°C, preferably between 40-65°C. The addition mixture may be heated for a period of 0.5 to 5 hours, then cooled upto 0°C, preferably 15 to 35°C to selectively crystallize the (R)- mandelate of the desired cis-(1S,4S) isomer of formula II.
The crystallized compound of formula II may be optionally purified by recrystallization from a suitable solvent selected from a C1-C6 alkanol solvent that may be primary, secondary & tertiary, straight or branched; a mixture thereof and a mixture with water. Preferably the solvent system is an admixture of ethanol or 2-propanol and water, most preferably 2-propanol and water in the ratio 4:1.
According to another embodiment of the present invention, the compound of formula II is
converted to (1 S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-jV-methy 1-1 -
7

naphthylamine (sertraline hydrochloride) of formula I, having crystalline nature corresponding to polymorphic form I or polymorphic form V of sertraline hydrochloride.
The conversion may be carried out by treating with concentrated hydrochloric acid in an alcohol solvent selected from a C1-C6 alkanol solvent that may be primary, secondary & tertiary, straight or branched; a mixture thereof and a mixture with water.
For obtaining (1S,4S)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l-
naphthylamine (sertraline hydrochloride) of formula I, having crystalline nature corresponding to polymorphic form I the solvent system is preferably, ethanol or 2-propanol or a mixture thereof, most preferably the solvent is 2-propanol.
For obtaining (15,45)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-iV-methyl-l -
naphthylamine (sertraline hydrochloride) of formula I, having crystalline nature corresponding to polymorphic form V, the solvent system is preferably an admixture of ethanol or 2-propanol with water in the ratio 6:1 to 15:1, preferably in the ratio of 7:1 to 9:1.
The process has the flexibility to produce compound of formula I, totally devoid of the cis-(1R,4R) enantiomer, even when the compound of formula II has a contamination of the corresponding (R)-mandelate salt of the cis-(lR,4R) enantiomer upto 1.5%.
According to another embodiment of the present invention, the free base of formula IV generated from the mandelate salt of formula II may be treated with an amine hydrochloride salt in suitable solvent(s), heated and then cooled, to obtain (lS',4S)-4-(3,4-dichlorophenyl)-l ,2,3,4-tetrahydro-iV-methyl-l -naphthylamine (sertraline hydrochloride) of formula I, having crystalline nature corresponding to polymorphic form I or polymorphic form V of sertraline hydrochloride.
8

The above conversion may be carried out in suitable solvent(s) selected from C1-C6 alkanol that may be primary, secondary & tertiary, straight or branched; their mixtures and C1-C6 alkanol(s)/water mixtures.
The amine hydrochloride salt is selected from ammonium chloride or a primary amine hydrochloride having a chain of 1 to 6 carbons that may be straight or branched, taken in about 1 to 6 molar equivalents with respect to the free base of formula IV. Preferably the amine hydrochloride salt is ammonium chloride.
For obtaining (15,45)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1 -
naphthylamine (sertraline hydrochloride) of formula I, having crystalline nature corresponding to polymorphic form I the solvent system is preferably, ethanol or 2-propanol or a mixture thereof, most preferably the solvent is 2-propanol.
For obtaining (15,45)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1 -
naphthylamine (sertraline hydrochloride) of formula I, having crystalline nature corresponding to polymorphic form V the solvent system is preferably an admixture of ethanol or 2-propanol with water in the ratio 6:1 to 15:1, preferably the solvent system is 2-propanol and water in the ratio of 7:1 to 9:1.
The invention is illustrated but not restricted by the description in the following examples.
9

EXAMPLES
Example 1
Preparation of (K)-mandelate salt of (lS,4S)-4-(3,4-dichlorophenyl)-l,2,3,4-
tetrahydro-.N-methyl-1-naphthylamine of formula II



COOH

II
VII
Example I-A
N-[4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-l(2/f)-ylidene]methanamine (200g) was hydrogenated in 2-propanol (1000ml) using Raney-nickel catalyst (20g) at 70-75°C & 4kg/cm pressure. Charcoal (20g) was charged to the reaction mass, stirred for 0.5hrs, filtered and washed with 2-propanol (200ml).
i) To one part of the above solution (containing mixture of all the four stereoisomers of formulas III, IV, V & VI) (150ml equivalent to reaction on 20g of imine of formula VII) was added water (3.75ml) and (R)-mandelic acid (lOg), and the mixture heated to 50-55°C for lhr. Gradually cooled to 25-30°C filtered, and dried the mandelate salt, 9.59g (lR,4R)-enantiomer content 1.88% & trans-isomer was 6.49%). ii) To second part of the above solution (containing mixture of all the four stereoisomers of formulas III, IV, V & VI) (150ml equivalent to reaction on 20g of imine of formula VII) was added water (7.5ml) and (R)-mandelic acid (l0g), and the mixture heated to 50-55°C for lhr. Gradually cooled to 25-30°C filtered, and
10

dried the mandelate salt, 9.05g (1R,4R)- enantiomer content 1.04% & trans-isomer was 5.5%).
iii) To third part of the above solution (containing mixture of all the four stereoisomers of formulas III, IV, V & VI) (150ml equivalent to reaction on 20g of imine of formula VII) was added water (15ml) and (7?)-mandelic acid (lOg), and the mixture heated to 50-55°C for lhr. Gradually cooled to 25-30°C filtered, and dried the mandelate salt, 8.42g (1R,4R)- enantiomer content 0.55% & trans-'isomer was 3.57%).
iv) To fourth part of the above solution (containing mixture of all the four stereoisomers of formulas III, IV, V & VI) (150ml equivalent to reaction on 20g of imine of formula VII) was added water (30ml) and (7?)-mandelic acid (lOg), and the mixture heated to 50-55°C for lhr. Gradually cooled to 25-30°C filtered, and dried the mandelate salt, 7.7g (lR,4R)-enantiomer content 0.4% & trans-isomer was 2.9%).
Example 1-B
N-[4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-l(2//)-ylidene]methanamine (150g) was hydrogenated in 2-propanol (725ml) using Raney-nickel catalyst (15g) at 70-75°C & 4kg/cm2 pressure. Charcoal (15g) was charged to the reaction mass, stirred for 0.5hrs and then filtered. To the filtrate (containing mixture of all the four stereoisomers of formulas III, IV, V & VI) were added 2-propanol (150ml), water (210ml) and (#)-mandelic acid (75g) and mixture heated to reflux to obtain a clear solution. Gradually cooled to 25-30°C filtered, and dried the mandelate salt, 68g (1R,4R)-enantiomer content 1.2% & trans-isomer was 3.7%).
Example 1-C
N-[4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-1 (2H)-ylidene]methanamine (10g) was hydrogenated in 2-propanol (40ml) using Raney-nickel catalyst (lg) at 70-75°C & 4kg/cm2 pressure. Charcoal (lg) was charged to the reaction mass, stirred for 0.5hrs and then filtered and washed with 2-propanol (5ml). To the filtrate (containing mixture of all the four stereoisomers of formulas III, IV, V & VI) was added water (17.1ml) and (/?)-
11

mandelic acid (4.97g). Heated the suspension to reflux to obtain a clear solution. Gradually cooled to 10-15°C, filtered and dried the mandelate salt, 4.27g (\RAR)-enantiomer content 0.48% & trans-isomer was 2.6%).
Example 2
Preparation of (1S,4S,)-4-(3,4-dichlorophenyl)-1,2,3»4-tetrahydro-A'-methyl-1 -naphthylamine hydrochloride (sertraline hydrochloride) of formula I directly from (R)-mandelate salt of (15,45)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l-naphthylamine of formula II



OH
COOH
.HCI

II
Example 2-A
(tf)-Mandelate salt of (lS,4S)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l-naphthylamine, of formula II (l00g, as obtained in Example 1-A) was suspended in 2-propanol (800ml) and water (62ml) and added cone, hydrochloric acid (27.3ml) to the mixture. The resulting slurry was heated to 75-80°C to get a clear solution, which was then cooled gradually to 0-5°C, and the crystallized product was filtered. The wet product was suspended in 2-propanol (250ml), stirred for lhr at ambient temperature, filtered and dried to obtain to pure (lS,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylamine hydrochloride of formula 1 (53.3g). The product obtained has been
12

confirmed to be of polymorphic form V of sertraline hydrochloride by powder X-Ray diffraction spectroscopy.
Example 2-B
(R)-Mandelate salt of (lS,4S)-4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l-naphthylamine, of formula II (lOg, as obtained in Example 1-B, containing the 1.2% of the (lR,4R)-enatiomer) was suspended in 2-propanol (80ml) and water (5.9ml) and added cone, hydrochloric acid (3.19ml) to the mixture. The resulting slurry was heated to 75-80°C to get a clear solution, which was then cooled gradually to 0-5°C, and the crystallized product was filtered to obtain (1S',4S)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-JV-methyl-1 -naphthylamine hydrochloride of formula 1, 5.38g (1R,4R)-enantiomer content was found to be nil). The product obtained has been confirmed to be of polymorphic form V of sertraline hydrochloride by powder X-Ray diffraction spectroscopy.
Example 2-C
(tf)-Mandelate salt of (1S,4S)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l-naphthylamine, of formula II (l0g) was suspended in 2-propanol (80ml) and water (6.2ml) and added cone, hydrochloric acid (2.7ml) to the mixture. The resulting slurry was heated to 75-80°C to get a clear solution, which was then cooled gradually to ~40°C and seeded with sertraline HC1 form V. Further cooled to 0-5°C, and the crystallized product was filtered and dried to obtain to pure (lS,4S)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-1 -naphthylamine hydrochloride of formula 1 (6. lg). The product obtained has been confirmed to be of polymorphic form V of sertraline hydrochloride by powder X-Ray diffraction spectroscopy.
Example 2-D
(R)-Mandelate salt of (15,45)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylamine, of formula II (25g) was suspended in 2-propanol (200ml) and added cone, hydrochloric acid (7ml) to the mixture. The resulting slurry was heated to 78-82°C to get a clear solution, which was then cooled gradually to ~40°C and seeded sertraline
13

HC1 form I. Further cooled to 25-30°C, the crystallized product was filtered and dried to obtain to pure (15,45)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-iV-methyl-l-naphthylamine hydrochloride of formula 1 (15.0g). The product obtained has been confirmed to be of polymorphic form I of sertraline hydrochloride by IR and powder X-Ray diffraction spectroscopy.
Example 3
Preparation of (lS,4S)-4-(3,4-dichlorophenyl)-l,23?4-tetrahydro-N-methyl-l-naphthylamine hydrochloride (sertraline hydrochloride) of formula I from (lS,4S)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-Af-methyl-l-naphthylamine free base of formula IV using ammonium chloride



HCI

Example 3-A
To a solution of (1S',4S)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l-naphthylamine of formula IV (10g) in 2-propanol (80ml) was added a solution of ammonium chloride (2.62g) in water (10ml). Heated the solution at 78-82°C for 3hrs and then cooled gradually to 25-30°C. The crystallized product was filtered, and dried to obtain to pure (lS,4S)-4-(dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-l-naphthylamine hydrochloride of formula 1 (7.25g). The product obtained has been confirmed to be of polymorphic form V of sertraline hydrochloride by powder X-Ray diffraction spectroscopy.
14

Example 3-B
To a solution of (lS,4S)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l-naphthylamine of formula IV (l0g) in 2-propanol (80ml) was added solid ammonium chloride (6.9g). Heated the suspension at 78-82°C for 5hrs, then cooled gradually to 10°C and filtered. The solids were stirred in water (50ml) for 30min, then filtered and dried to obtain to pure (15,45)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l-naphthylamine hydrochloride of formula 1 (9.5g). The product obtained has been confirmed to be of polymorphic form I of sertraline hydrochloride by powder X-Ray diffraction spectroscopy.
15

We claim
1. A process for the preparation of (IS,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-/V-methyl-1-naphthylamine hydrochloride, compound of formula I, as crystalline form I or form V, comprising


HCI
H\ ^CH
Formula II

a) hydrogenating the imine N-[4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-l(2/i)-ylidene]methanamine, compound of formula VII, with Raney-nickel in isopropanol to obtain stereoisomeric mixture containing (lR,4R)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-Af-methyl-l-naphthylamine(III), (1S,,4S)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-1 -naphthylamine(IV), (1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-/V-methyl-1 -naphthylamine(V) and (1S,4/?)-4-(3,4-dichloropheny 1)-l,2,3,4-tetrahydro-N-methyl-l-naphthylamine(VI);





,CH,

V

XH,

16

VII
b) adding water and less than 1 molar equivalent of (R)-mandelic acid with respect to the compound of formula VII to the stereoisomeric mixture of step (a), heating, cooling to selectively crystallize the (R)-mandelate of (IS,4S)-4-(3A-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1 -naphthylamine, compound of formula II;
c) reacting the (R)-mandelate salt of (1S',4S)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-1-naphthylamine, of formula II with hydrochloric acid in isopropanol-water solvent system and isolating crystalline form I or V of compound of formula I.
I. A process for the preparation of (lS,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-yV-nethyl-1-naphthylamine hydrochloride, compound of formula I, as crystalline form I or 0rm V, comprising

HCI
CO,H

Hx.XH,

H\ „CH.
Formula II

17

a) hydrogenating the imine N-[4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-1(2H)-ylidene]methanamine, compound of formula VII, with Raney-nickel in isopropanol to obtain stereoisomeric mixture containing (lR,4R)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1 -naphthylamine(III), (IS,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1 -naphthylamine(IV), (1R,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1 -naphthylamine(V) and (1S,4R)-4-(3,4-dichlorophenyl )-1,2,3,4-tetrahydro-iV-methyl-1 -naphthylamine(VI);

CI CI CI CI

III IV V VI

VII
b) adding water and less than 1 molar equivalent of (R)-mandelic acid with respect to the compound of formula VII to the stereoisomeric mixture of step (a), heating. cooling to selectively crystallize the (R)-mandelate of (IS,4S)-4-(3.4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1 -naphthylamine, compound of formula II;
c) converting compound of formula II to (lS,4S)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-A^-methyl-1-naphthylamine, compound of formula IV;
18

d) treating compound of formula IV with amine hydrochloride salt in suitable solvent^) and isolating crystalline form I or form V of compound of formula I.

3. A process as claimed in claim 2 wherein suitable solvent(s) is -, selected from C1-C6
alkanol; their mixtures and C1-C6 alkanol(s)/water mixtures.
Dated this 2nd July 2007

19

ABSTRACT
A process for the preparation of (IS,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylamine hydrochloride, compound of formula I, as crystalline form I or form V directly from compound of formula II or by treating the free base of compound of formula II with amine hydrochloride salt in suitable solvent(s).

HCI

Hv.CH,

H\ ^CH.
Formula II

To

The Controller of Patents, The Patent Office, Mumbai-400 013.

20