The present invention relates to a process for highly stereoselective synthesis of sertraline and sertraline intermediate.
BACKGROUND OF THE INVENTION
U.S. Patent No. 4,536,518, which is herein incorporated by reference, disclosed cis-isomeric derivatives of 4-phenyl-1,2,3,4-tetrahydro-1 -naphthalenamine and their pharmaceutically acceptable salts. These compounds act to block the synaptosomal uptake of serotonin (5-hydroxy-tryptamine), thereby alleviating serotonin abnormalities at central receptor sites. Among them sertraline, chemically (1 S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-/V-methyl-1-naphthalenamine is a selective serotonin reuptake inhibitor (SSRI). Sertraline is represented by the following structure:

Processes for the preparations of sertraline, it's pharmaceutically acceptable salts and related compounds were described in U.S. Patent No. 4,536,518, U.S. Patent No. 6,552,227, PCT publication No. WO 99/57093 A1, U.S. Patent No. 6,232,501, U.S. Patent No. 6,034,274 and PCT publication No. WO 01/16089.
The key step in the preparation of sertraline or a salt thereof is the hydrogenation of the racemic 4-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl-1(2H)-naphthalenimine of formula A:

N-CH3 c,
Cl
Sertraline hydrochloricle may also be prepared from 4(S)-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl-1 (2H)-naphthalenimine of formula B:
N-CH3 c,
Cl
The preparation of sertraline from 4(S)-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl-1(2H)-naphthalenimine may be represented schematically as below:
4S-(3,4-Dichlorophenyl)-3,4-dihydro-N-methyl-1 (2H)-naphthalenimine
Hydrogenation
\<
1 S-cis-Sertraline + 1 R-trans-Sertraline
Conversion to hydrochloride salt
1 S-cis-Sertraline hydrochloride + 1 R-trans-Sertraline hydrochloride
Fractional crystallization
u
1 S-cis-Sertraline hydrochloride
In the above processes, the key step is the hydrogenation step.
U.S. Patent No. 4,536,518 described hydrogenation of imine compound of formula A using Pd/C at room temperature. In this step cis-(+), trans-(+)-sertralines are obtained in about 3 : 1 ratio.
U.S. Patent No. 6,552,227 described hydrogenation of imine compound of formula A using Pd/C or PtO2 at a temperature above 40°C to obtain cis-(+) and trans-(+) sertralines in higher ratio of cis-(+)-sertraline over the trans-(+) sertraline compound than that obtained in U.S. Patent No. 4,536,518. According to the processes described in the published patent application, the hydrogenation resulted in the formation of cis-(+) and trans-(+) sertralines in the ratio at the maximum of 12:1.

PCT publication No. WO 99/57093 A1 described hydrogenation of imine compound of formula A using Pd applied on a carrier pre-treated with an alkyl halide to obtain cis-(+) and trans-(+) isomers in the ratio of at the maximum of 19 : 1.
U.S. Patent No. 6,232,501 describes hydrogenation of 4-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl-1 (2H)-naphthalenimine or 4-(3,4-dichloro phenyl)-3,4-dihydro-N-methyl-1(2H)-naphthalenimine-N-oxide to obtain cis -trans sertraline using copper containing catalyst. The hydrogenation is required to carried out at very high pressure (10-15 bars) and/or at high temperatures (100°C-150°C).
U.S. Patent No. 6,034,274 describes hydrogenation of 4-(3,4-dich1oro phenyl)-3,4-dihydro-N-methyl-1(2H)-naphthalenimine'N-oxide to obtain cis -trans sertraline, followed by conversion into hydrochloride salts and fractional crystallization of cis (+)-sertraline hydrochloride.
WO 01/16089 describes reductive amination of 4-(3,4-dichlorophenyl)-3,4-dihydro-1-(2H)-naphthalenone to obtain cis - trans sertraline, followed by conversion into hydrochloride salts and fractional crystallization of cis (+)-sertraline hydrochloride.
U.S. Patent No. 6,506,940 described the conversion of one stereoisomer of sertraline into another stereoisomers via 4-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl-1 (2H)-naphthalenimine.
U.S. Patent No. 6,723,878 described a method of hydrogenation of 4-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl-1(2H)-naphthalenimine in the presence of a dehalogenating agent to obtain cis - trans sertraline. The process requires high pressures.
Deschloro impurities of Sertraline, namely cis-(+)-4-(3 or 4-chlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine and cis-(+)-4-phenyl-1,2,3,4-tetrahydro-N-methyl-naphthalenamine are common impurities of sertraline and formed when hydrogenation is carried out at high temperature and / or high pressures.
WO 03/099761 describes reductive amination of 4-(3,4-dichlorophenyl)-3,4-dihydro-1 -(2H)-naphthalenone with methylamine to obtain cis - trans sertraline, followed by conversion into hydrochloride salts and fractional crystallization of cis (+)-sertraline hydrochloride.

According to the present invention, it has been found that the imine compounds of above mentioned compounds can be hydrogenated in a highly stereoselective manner in a simple procedure to obtain the cis-isomers of sertraline.
DETAILED DESCRIPTION OF THE INVENTION
According to one aspect of the present invention, there is provided a process for preparing cis-(+)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine of formula I:

which comprises hydrogenating 4-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl-1(2H)-naphthalenimine of formula II:

with palladium supported on an alkaline earth metal carbonate to obtain substantially pure cis-dH^S^-dichlorophenyO-I^.S^-tetrahydro-N-methyl-naphthalenamine of formula I.
The preferable alkaline earth metal carbonate is CaCO3 or BaCO3 and more preferable being CaCO3.
The hydrogenation reaction is preferably carried out at the pressure below about 2 Kg, more preferably at below about 1 Kg and still more preferably at about 0.1 - 1 kg.
Preferably the hydrogenation reaction is carried out at about 10 - 40°C, more preferably at about 15 - 40°C and still more preferably at about 15 - 35°C.

Preferably the hydrogenation reaction is carried out in a solvent selected from alcohols, ketones, hydrocarbon solvents, ester solvents, tetrahydrofuran, water and a mixture thereof, more preferable solvent is selected from alcoholic solvent, water and a mixture thereof. Preferable alcoholic solvent is selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and n-butyl alcohol, more preferable alcoholic solvent is methanol or ethanol. Preferable ketonic solvent is selected from acetone, methyl isobutyl ketone and methyl ethyl ketone, more preferable ketonic solvent is acetone. Preferable hydrocarbon solvent is toluene. Preferable ester solvent is ethyl acetate.
The words "substantially pure cis" refers to cis-isomer having its trans-isomer content in about 4% or less of the contents of the cis and trans isomers put together.
Preferably "substantially pure cis" refers to cis-isomer having its trans-isomer content in less than about 2%, more preferably to cis-isomer having its trans-isomer content in less than about 1%, and still more preferably to cis-isomer having its trans-isomer content in less than about 0.5% of the contents of the cis and trans isomers put together.
The hydrogenation of 4-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl-1(2H)-naphthalenimine if carried out according to prior art resulted in the formation of the mixture of cis-(+)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine and trans-(+)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine with trans-(+)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro -N-methyl-naphthalenamine in substantial content. In such a case, there is required to separate the undesired trans-(+)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine from the desired cis-(+)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine and then subject to resolution step to obtain sertraline or a salt thereof. The separation of trans-(+)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine from the desired cis-(+)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine requires the additional steps of a) conversion of the mixture of cis-(+)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine and trans-(+)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine isomers into their salts such as hydrochloride salts, b) fractional crystallization of the desired salt (HCI) of cis-(+)-4-(3I4-dichlorophenyl)-1,2,3l4-tetrahydro-N-

methyl-naphthalenamine, and c) neutralization of the separated salt to convert to free base of cis-(+)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine. The separated cis-(+)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine is then subjected to resolution.
By following the highly stereoselective hydrogenation, it is now possible, as a preferred process, to avoid the aforesaid additional steps and the hydrogenated product can directly be subjected to resolution step.
Thus, the novel process makes the process highly productive, commercially viable. Because of the highly stereoselective nature of the process of the invention, sertraline or a salt thereof is obtained in high yield in good purity.
According to the present invention hydrogenation can be carried preferably at low pressures and at ambient temperatures.
According to another aspect of the present invention, there is provided a process for preparing (1 S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine of formula la:

which comprises hydrogenating 4(S)-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl-1(2H)-naphthalenimine of formula lla:


with palladium supported on an alkaline earth metal carbonate to obtain substantially pure (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine of formula la.
The preferable alkaline earth metal carbonate is CaCO3 or BaCO3 and more preferable being CaCO3.
The hydrogenation reaction is preferably carried out at the pressure below about 2 Kg, more preferably at below about 1 Kg and still more preferably at about 0.1 -1 kg.
Preferably the hydrogenation reaction is carried out at about 10 - 40°C, more preferably at about 15 - 40°C and still more preferably at about 15 - 35°C.
Preferably the hydrogenation reaction is carried out in a solvent selected from alcohols, ketones, hydrocarbon solvents, ester solvents, tetrahydrofuran, water and a mixture thereof, more preferable solvent is selected from alcoholic solvent, water and a mixture thereof. Preferable alcoholic solvent is selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and n-butyl alcohol, more preferable alcoholic solvent is methanol or ethanol. Preferable ketonic solvent is selected from acetone, methyl isobutyl ketone and methyl ethyl ketone, more preferable ketonic solvent is acetone. Preferable hydrocarbon solvent is toluene. Preferable ester solvent is ethyl acetate.
The hydrogenation of 4(S)-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl-1(2H)-naphthalenimine if carried out according to prior art resulted in the formation of the mixture of (1S-cis)-4»(3,4»dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine and (1 R-trans)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine with (1S-trans)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine in substantial content. In such a case, there is required to separate the undesired (1R-trans)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine from the desired (1 S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine to obtain sertraline or a salt thereof. The separation of (1R-trans)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine from the desired (IS-cisH^S^-dichlorophenyO-i^^^-tetrahydro-N-methyl-naphthalenamine requires the additional steps of a) conversion of the mixture of (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine and (1 R-trans)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine isomers into

their salts such as hydrochloride salts, and b) fractional crystallization of the desired isomer (1 S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthaienamine as salt.
By following the highly stereoselective hydrogenation, it is now possible, as a preferred process, to avoid the aforesaid additional steps.
Thus, the novel process makes the process highly productive, commercially viable. Because of the highly stereoselective nature of the process of the invention, sertraline or a salt thereof is obtained in high yield in good purity.
According to another aspect of the present invention, there is provided a process for preparing (1 R-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine of formula Ib:

which comprises hydrogenating 4(R)-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl-1(2H)-naphthalenimine of formula Mb:

with palladium supported on an alkaline earth metal carbonate to obtain substantially pure (1R-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine of formula Ib.

(1 R-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine obtained can be subjected to isomerisation by known methods to obtain desired isomer of sertraline.
The preferable alkaline earth metal carbonate is CaCO3 or BaCO3 and more preferable being CaCO3.
The hydrogenation reaction is preferably carried out at the pressure below about 2 Kg, more preferably at below about 1 Kg and still more preferably at about 0.1-1 kg.
Preferably the hydrogenation reaction is carried out at about 10- 40°C, more preferably at about 15 - 40°C and still more preferably at about 15 - 35°C.
Preferably the hydrogenation reaction is carried out in a solvent selected from alcohols, ketones, hydrocarbon solvents, ester solvents, tetrahydrofuran, water and a mixture thereof, more preferable solvent is selected from alcoholic solvent, water and a mixture thereof. Preferable alcoholic solvent is selected from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and n-butyl alcohol, more preferable alcoholic solvent is methanol or ethanol. Preferable ketonic solvent is selected from acetone, methyl isobutyl ketone and methyl ethyl ketone, more preferable ketonic solvent is acetone. Preferable hydrocarbon solvent is toluene. Preferable ester solvent is ethyl acetate.
The invention will now be further described by the following examples, which are illustrative rather than limiting.
Example 1 Step-I:
The mixture of 4-(3,4-Dichlorophenyl)-3,4-dihydro-N-methyl-1(2H)-naphthalenimine (10 gm), 5% Pd/CaCO3 (grade-21, 0.6 gm), water (2 ml) and methanol (150 ml) is taken in a hydrogenation flask and then subjected to hydrogenation under a hydrogen pressure of 0.5 Kg at 20 - 35°C for 3 hours 30 minutes. The catalyst is removed by filtration and the solvent is evaporated completely under vacuum to obtain cis-(+)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine. (cis-(+): trans-(+): 99.8 : 0.2).
To the above reaction mass ethyl acetate (65 ml) and water (20 ml) are added and the pH is adjusted to 9.5 - 11.0 with aqueous sodium hydroxide (50%). The organic layer is washed with 10% sodium chloride solution (20 ml)

and then subjected to carbon treatment. Then the reaction mass is heated to 45 - 50°C, D-(-)-mandelic acid (2.9 gm) is added at 45 - 50°C and stirred for 2 hours at the same temperature. The mass is cooled to 25 - 35°C, stirred for 12 hours at 25 - 35°C, then cooled to 0 - 5°C and stirred for 1 hour at the same temperature. Filtered the mass and washed with ethyl acetate, methanol (15 ml) is added and then heated to reflux. The contents are stirred for 1 hour at reflux and cooled to 25 - 35°C. Then the reaction mass is cooled to 0 - 5°C and stirred for 1 hour at 0 - 5°C. Filtered the solid, washed with methanol and dried to give 4.6 gm of (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4"tetrahydro-N-methyl-naphthalenamine mandelate (trans-(+): not detected). Step-ll:
Water (30 ml) and ethyl acetate (35 ml) are added to (1S-cis)-4-(3,4-
dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine mandelate
(obtained in step-l), cooled to 10 - 18°C and aqueous sodium hydroxide (50%) is slowly added for 1 hour 30 minutes at 10- 18°C (to adjust the pH to 9.5 -11.0). The contents are stirred for 30 - 45 minutes, separated the aqueous layer and discarded it. Activated carbon (0.25 gm) is added to the reaction mass, stirred for 15 - 30 minutes, filtered and washed with ethyl acetate (5 ml). Distilled off ethyl acetate under reduced pressure until the mass temperature reaches to 50 -55°C, n-butanol (30 ml) is added, stirred for 30 minutes, cooled to 5 - 15°C and then cone, hydrochloric acid is slowly added during 20 minutes at 5 - 15°C (to adjust the pH to below 2). The contents are stirred for 3 hours at 5 - 15°C, filtered the mass and washed with diisopropyl ether (5 ml). Diisopropyl ether (30 ml) is added to the solid, cooled to 5 - 15°C and stirred for 1 hour at 5 - 15°C. Filtered the solid and dried at 45 - 50°C to give 2.5 gm of sertraline hydrochloride (HPLC purity: 99.9%).
Example 2
The mixture of 4(S)-(3,4-Dichlorophenyl)-3,4-dihydro-N-methyl-1(2H)-naphthalenimine (10 gm), 5% Pd/CaCO3 (grade-21, 0.6 gm), water (2 ml) and methanol (150 ml) is taken in a hydrogenation flask and then subjected to hydrogenation under a hydrogen pressure of 0.5 Kg at 20 - 35°C for 3 hours 30 minutes. Then filtered the mass and washed with methanol to obtain (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine (1S-cis : 1S-trans : 99.8 : 0.2). The resulting mass is distilled under vacuum and then

subjected to carbon treatment. Cone, hydrochloric acid is added to the reaction mass at 10°C to adjust the pH below 2 and stirred for 2 hours at 10°C. The resulting mass is centrifuged, washed with methanol, the wet cake is slurried in methanol (40 ml) and dried to give 8 gm of (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine hydrochloride (1 R-trans: not detected).
Example 3
Example 1 is repeated by using the solvent ethanol in step-l instead of methanol to give 2.4 gm of sertraline hydrochloride (HPLC purity: 99.8%).
Example 4
Example 1 is repeated by using the solvent acetone in step-l instead of methanol to give 2.3 gm of sertraline hydrochloride (HPLC purity: 99.7%).
Example 5 Step-l:
The mixture of 4-(3,4-Dichlorophenyl)-3,4-dihydro-N-methyl-1(2H)-naphthalenimine (10 gm), 5% Pd/CaCO3 (grade-21, 0.6 gm), water (2 ml) and methanol (100 ml) is taken in a hydrogenation flask and then subjected to hydrogenation under a hydrogen pressure of 0.5 Kg at 20 - 35°C for 3 hours 30 minutes. Then filtered the mass and washed with methanol to obtain cis-(+)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine (cis-(+) : trans-(+): 99.7 : 0.3). The resulting mass is distilled under vacuum and then subjected to carbon treatment. Cone, hydrochloric acid is added to the reaction mass at 10°C to adjust the pH below 2 and stirred for 2 hours at 10°C. The resulting mass is centrifuged, washed with methanol, the wet cake is slurried in methanol (40 ml) and dried to give 8 gm of cis-(+)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine hydrochloride (trans-(+): not detected). Step-l I:
Ethyl acetate (60 ml) and water (40 ml) are added to cis-(+)-4-(3,4-dichlorophenyO-i^^^-tetrahydro-N-methyl-naphthalenamine hydrochloride (obtained in step-l) and the contents are cooled to 10 - 20°C. Then 50% aqueous sodium hydroxide (7.8 ml) is added at 10 - 20°C during 1 hour 30 minutes (pH: 9.5 - 11.0), stirred for 1 hour, the aqueous layer is separated and discarded it. The ethyl acetate layer is washed with distilled water (14 ml) and discarded the aqueous layer. The contents are heated to 40 - 50°C, D-(-)-

mandelic acid (2.8 gm) is added, stirred for 2 hours at 40 - 50°C and then stirred at 25 - 30°C for 12 hours. The reaction mass is cooled to 0 - 5°C, filtered the mass and washed with ethyl acetate (6.3 ml). Methanol (20 ml) is added to the wet cake, heated to reflux temperature and refluxed for 30 - 45 minutes. Then the reaction mass is cooled to 0 - 5°C and stirred for 2 hours at the same temperature. The resulting solid is filtered, washed with 7 ml of methanol and dried at 60 - 65°C to give 4.2 gm of (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine mandelate. Step-Ill:
Water (25 ml) and ethyl acetate (30 ml) are added to (1S-cis)-4-(3,4-
dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine mandelate
(obtained in step-ll), cooled to 10 - 18°C and 50% aqueous sodium hydroxide (2.6 ml) is slowly added for 1 hour 30 minutes at 10 - 18°C (pH: 9.5 - 11.0). The contents are stirred for 30 - 45 minutes, separated the aqueous layer and discarded it. Activated carbon (0.3 gm) is added to the reaction mass, stirred for 15-30 minutes, filtered and washed with ethyl acetate (5 ml). Distilled off ethyl acetate under reduced pressure until the mass temperature reaches to 50 -55°C, n-butanol (30 ml) is added, stirred for 30 minutes, cooled to 5 - 15°C and then cone, hydrochloric acid (1.5 ml) is slowly added during 45 minutes at 5 -15°C (pH: 1.0). The contents are stirred for 3 hours at 5 - 15°C, filtered the material, washed with diisopropyl ether (40 ml) and dried at 45 - 50°C to give 2.1 gm of sertraline hydrochloride (HPLC purity: 99.8%).

We claim:
1. A process for the preparation of cis-(+)-4-(3,4-dichlorophenyl)-1,2,3,4-
tetrahydro-N-methyl-naphthalenamine of formula I:
HN-CH3
Cl
HN-CH3
Cl
which comprises hydrogenating 4-(3)4-dichlorophenyl)-3)4-dihydro-N-methyl-1(2H)-naphthalenimine of formula II:
N-CH3
Y^c,
Cl
N-CH3
ci
with palladium supported on an alkaline earth metal carbonate to obtain substantially pure cis-(+)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine of formula I.
2. The process as claimed in claim 1, wherein the alkaline earth metal
carbonate is CaCO3 or BaCO3.
3. The process as claimed in claim 2, wherein the alkaline earth metal
carbonate is CaCO3.
4. The process as claimed in claim 1, wherein the hydrogenation reaction is
carried out at the pressure below about 2 Kg.
5. The process as claimed in claim 4, wherein the hydrogenation reaction is
carried out at the pressure below about 1 Kg.
6. The process as claimed in claim 5, wherein the hydrogenation reaction is
carried out at the pressure about 0.1-1 Kg.

7. The process as claimed in claim 1, wherein the hydrogenation reaction is
carried out at about 10 - 40°C.
8. The process as claimed in claim 7, wherein the hydrogenation reaction is
carried out at about 15 - 40°C.
9. The process as claimed in claim 8, wherein the hydrogenation reaction is
carried out at about 15 - 35°C.
10. The process as claimed in claim 1, wherein the hydrogenation reaction is
carried out in a solvent selected from alcohols, ketones, hydrocarbon
solvents, esters, tetrahydrofuran, water and a mixture thereof.
11. The process as claimed in claim 10, wherein the solvent is selected from
alcoholic solvent, water and a mixture thereof.
12. The process as claimed in claim 11, wherein the alcoholic solvent is selected
from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and n-butyl
alcohol.
13. The process as claimed in claim 12, wherein the alcoholic solvent is
methanol or ethanol.
14. The process as claimed in claim 10, wherein the ketonic solvent is selected
from acetone, methyl isobutyl ketone and methyl ethyl ketone.
15. The process as claimed in claim 14, wherein the ketonic solvent is acetone.
16. The process as claimed in claim 10, wherein the hydrocarbon solvent is
toluene.
17. The process as claimed in claim 10, wherein the ester solvent is ethyl
acetate.
18. The process as claimed in claim 1, wherein the product obtained has trans
isomer in about 4% or less of the contents of the cis and trans isomers put
together.
19. The process as claimed in claim 18, wherein the product obtained has trans
isomer in less than about 2% of the contents of the cis and trans isomers put
together.
20. The process as claimed in claim 19, wherein the product obtained has trans
isomer in less than about 0.5% of the contents of the cis and trans isomers
put together.
21. The process as claimed in claim 20, wherein the product obtained has trans
isomer undetected.

22. A process for the preparation of (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-
tetrahydro-N-methyl-naphthalenamine of formula la:

which comprises hyclrogenating 4(S)-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl-1(2H)-naphthalenimine of formula lla:

with palladium supported on an alkaline earth metal carbonate to obtain substantially pure (1S-cis)-4-(3)4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine of formula la.
23. The process as claimed in claim 22, wherein the alkaline earth metal
carbonate is CaCO3 or BaCO3.
24. The process as claimed in claim 23, wherein the alkaline earth metal
carbonate is CaCO3.
25. The process as claimed in claim 22, wherein the hydrogenation reaction is
carried out at the pressure below about 2 Kg.
26. The process as claimed in claim 25, wherein the hydrogenation reaction is
carried out at the pressure below about 1 Kg.
27. The process as claimed in claim 26, wherein the hydrogenation reaction is
carried out at the pressure about 0.1-1 Kg.

28. The process as claimed in claim 22, wherein the hydrogenation reaction is
carried out at about 10 - 40°C.
29. The process as claimed in claim 28, wherein the hydrogenation reaction is
carried out at about 15 - 40°C.
30. The process as claimed in claim 29, wherein the hydrogenation reaction is
carried out at about 15 - 35°C.
31. The process as claimed in claim 22, wherein the hydrogenation reaction is
carried out in a solvent selected from alcohols, ketones, hydrocarbon
solvents, esters, tetrahydrofuran, water and a mixture thereof.
32. The process as claimed in claim 31, wherein the solvent is selected from
alcoholic solvent, water and a mixture thereof.
33. The process as claimed in claim 32, wherein the alcoholic solvent is selected
from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and n-butyl
alcohol.
34. The process as claimed in claim 33, wherein the alcoholic solvent is
methanol or ethanol.
35. The process as claimed in claim 31, wherein the ketonic solvent is selected
from acetone, methyl isobutyl ketone and methyl ethyl ketone.
36. The process as claimed in claim 35, wherein the ketonic solvent is acetone.
37. The process as claimed in claim 31, wherein the hydrocarbon solvent is
toluene.
38. The process as claimed in claim 31, wherein the ester solvent is ethyl
acetate.
39. The process as claimed in claim 22, wherein the product obtained has 1R-
trans isomer in about 4% or less of the contents of the 1S-cis and 1R-trans
isomers put together.
40. The process as claimed in claim 39, wherein the product obtained has 1R-
trans isomer in less than about 2% of the contents of the 1S-cis and 1R-
trans isomers put together.
41. The process as claimed in claim 40, wherein the product obtained has 1R-
trans isomer in less than about 0.5% of the contents of the 1S-cis and 1R-
trans isomers put together.
42. The process as claimed in claim 41, wherein the product obtained has 1R-
trans isomer undetected.

43. A process for the preparation of (1R-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine of formula Ib:
HN-CH.
Ib

which comprises hydrogenating 4(R)-(3t4-dichlorophenyl)-3,4-dihydro-N-methyl-1(2H)-naphthalenimine of formula lib:
N-ChL
lib

with palladium supported on an alkaline earth metal carbonate to obtain substantially pure (IR-cisM-^^ichlorophenylH^.S^-tetrahydro-N-methyl-naphthalenamine of formula Ib.
44. The process as claimed in claim 43, wherein the alkaline earth metal
carbonate is CaCO3 or BaCO3.
45. The process as claimed in claim 44, wherein the alkaline earth metal
carbonate is CaCO3.
46. The process as claimed in claim 43, wherein the hydrogenation reaction is
carried out at the pressure below about 2 Kg.
47. The process as claimed in claim 46, wherein the hydrogenation reaction is
carried out at the pressure below about 1 Kg.
48. The process as claimed in claim 47, wherein the hydrogenation reaction is
carried out at the pressure about 0.1-1 Kg.

49. The process as claimed in claim 43, wherein the hydrogenation reaction is
carried out at about 10 - 40°C.
50. The process as claimed in claim 49, wherein the hydrogenation reaction is
carried out at about 15 - 40°C.
51. The process as claimed in claim 50, wherein the hydrogenation reaction is
carried out at about 15 - 35°C.
52. The process as claimed in claim 43, wherein the hydrogenation reaction is
carried out in a solvent selected from alcohols, ketones, hydrocarbon
solvents, esters, tetrahydrofuran, water and a mixture thereof.
53. The process as claimed in claim 52, wherein the solvent is selected from
alcoholic solvent, water and a mixture thereof.
54. The process as claimed in claim 53, wherein the alcoholic solvent is selected
from methanol, ethanol, isopropyl alcohol, tert-butyl alcohol and n-butyl
alcohol.
55. The process as claimed in claim 54, wherein the alcoholic solvent is
methanol or ethanol.
56. The process as claimed in claim 52, wherein the ketonic solvent is selected
from acetone, methyl isobutyl ketone and methyl ethyl ketone.
57. The process as claimed in claim 56, wherein the ketonic solvent is acetone.
58. The process as claimed in claim 52, wherein the hydrocarbon solvent is
toluene.
59. The process as claimed in claim 52, wherein the ester solvent is ethyl
acetate.
60. The process as claimed in claim 1, further comprises (c) resolving the cis-
(+)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine
formed in step (b) to obtain (1 S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-
tetrahydro-N-methyl-naphthalenamine and optionally converting to a
pharmaceutically acceptable salt by a known method.
61. The process as claimed in claim 60, wherein resolving agent used in the
resolution is D-(-)-mandelic acid and the pharmaceutically acceptable salt is
sertraline hydrochloride.
62. The process as claimed in claim 1, further comprises (c) crystallizing cis-(+)-
4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine from
the reaction mass obtained in step(b) as hydrochloride salt, converting the

salt into cis-(+)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-
naphthalenamine free base using a base, resolving cis-(+)-4-(3,4-
dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine to obtain (1S-
cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine
and optionally converting to a pharmaceutically acceptable salt.
63. The process as claimed in claim 62, the base used to convert cis-(+)-4-(3,4-
dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-naphthalenamine hydrochloride
salt to cis-(+)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-
naphthalenamine free base is sodium hydroxide, the resolution agent used in resolution step is D-(-)-mandelic acid and the pharmaceutically acceptable salt is sertraline hydrochloride.
DATED: 15 September 2006

(Dr. B. PARTHASARADHI REDDY) Chairman & Managing Director