Title of Invention


Abstract A cost effective process for preparation of highly purelS-cis Sertraline hydrochloride substantially free from trans and dehalogenated impurities is described herein; N-[4-(3,4-dichlorophenyl)-3,4-dihy dro-1 (2H)-naphthalenylidene]methanamine is catalytically hydrogenated using Raney Nickel; IS, Cis Sertraline is isolated as (D)-mandelate salt; which is purified in an alcohol; and converted to 1S Cis Sertraline hydrochloride.
Full Text FORM 2
(39 of 1970)
The Patents Rules, 2003
(See section 10 and rulel3)
"A cost effective process for production of Sertraline hydrochloride free from trans isomer and dehalogenated impurities"
(b) NATIONALITY: Indian Company incorporated under the Indian
Companies Act, 1956
(c) ADDRESS: Plot No.28,1st floor, Sector 19C, Kopri Road, Vashi,
Navi Mumbai - 400703, Maharashtra, India
The following specification particularly describes the invention and the manner in which it is to be performed:



31 JUL 2006

Technical field:
The present invention relates to a process for synthesis of Sertraline Hydrochloride which is substantially free from its trans isomer and dehalogenated impurities, by catalytic hydrogenation of N- [4-(3,4-dichlorophenyl)-3,4-dihydro-1 (2H)-naphthalenylidene] methanamine over Raney Nickel.
Background of invention: -
Sertraline is a generic name given to (1 S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine, which has a following structure of formula I.

Sertraline is marketed in the form of its hydrochloride for the treatment of depression, obsessive-compulsive disorder and panic disorder. The synthesis of Sertraline was first disclosed in U.S. Pat. No 4,536,518, which is incorporated herein by reference. The process described therein comprises a condensation reaction of 4-(3,4-dichlorophenyl)-3,4-dihydro-l (2H)-naphthalenone of formula II with monomethylamine yielding corresponding Imino compound N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l(2H)-naphthalenylidene] methanamine of Formula III.

Imino compound of formula III is reduced to racemic Sertraline base, followed by resolution to get desired lS-Cis isomer. During the reduction of imino compound III, apart from desired product, three other isomers viz. lR-Cis (IV), lR-Trans (V) and IS -Trans (VI) are formed in different proportions depending on reagents used.

Advantage of catalytic hydrogenation for conversion of imino compound to Sertraline base resulted in increase of Cis: Trans ratio and also minimized the formation of latter two isomers i.e. 1R, and IS Trans isomers. However, catalytic hydrogenation is always accompanied by dehalogenation leading to three additional impurities formula of VII, VIII & IX (and their sterioisomers); the amount of which depend on the catalyst, temperature and pressure used in the hydrogenation reaction. These impurities being structurally similar to parent compound, are difficult to remove by physical as well as by

chromatographic methods during large-scale operations.
US 3474144 describe the use of triphenyl phosphine or tritoluyl phosphine as
dehalogenation inhibitors in the catalytic reduction of aromatic chloronitro compounds. It
also has been mentioned that the use of inhibitors does not affect the original isomer
US6232501 was aimed to reduce the trans- isomer ratio by changing the catalyst. This
patent reports the hydrogenation of cyclohexylidenamines by means of copper-containing
catalyst such as copper chromite.
The catalytic hydrogenation of an imine was performed using various precious metal catalysts and an inhibitor which is selected from the group consisting hypophosphorous acid, esters of the same acid, phosphorous acid and its esters, phosphines and substituted phosphines. Metal catalysts such as platinum, platinum oxide, palladium, copper containing catalyst, and nickel etc. are known in the prior art (US Patents 6232501, 6552227, 6723878).
US6552227 primarily discloses the process for prepration of imine by reacting tetralone with methanamine in presence of TiC14 and further conversion into (±) sertraline by hydrogenating imine using platinum or palladium as catalyst.
US6723878 describes a process for preparation of sertraline by hydrogenating methanamine in presence of hydrogenation catalyst such as platinum or palladium along with dehalogenative inhibitor to reduce the dehalogenated byproducts.
Various methods have been developed to minimize the dehalogenated impurities and to increase the cis-trans isomer ratio and have been disclosed in patent US 5082970, including patent applications W09947486 (US6232501), and WO9957093.

US5082970 describes a process for recycling a trans-amine to a cis-amine. More particularly, it is concerned with a method for converting trans-isomeric sertraline to the corresponding cis-isomeric sertraline.
WO9957093 relates to a process for the preparation of cis-(lR, lS)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1 -naphthalene-1 -amine and pharmaceutically acceptable acid addition salts thereof by reducing (+/-)-4-(S,R)-[(3,4-dichlorophenyl)-3,4-dihydro-l(2H)-naphthalene-l-ylidene]-methylamine in the presence of a palladium catalyst and further conversion of the base obtained into a pharmaceutically acceptable acid addition salt. The catalyst comprises palladium applied on a carrier, containing 5-30 % by weight of palladium and pre-treated with an alkali halide.
All above methods known in the literature involve expensive precious metal catalysts. Thus it was necessary to develop a cost effective process for catalytic hydrogenation of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l(2H)-naphthalenylidene]methanamine.
PCT application WO 01/16089 discloses a process involving reductive amination of 4-(3,4-dichlorophenyl) Tetralone in presence of methylamine with Raney Nickel. Yield of racemic Cis compound is 48-51 % and nothing has been stated about the dehalogenated impurities. However in practice, due to drastic reaction conditions, lengthy reaction time and higher catalyst: substrate ratio (1:4 w/w Raney Nickel, ~500 PSI hydrogen pressure at 60°C for 16 hrs.) substantial dehalogenation was observed.
Hydrogenation with inexpensive catalyst like Raney Nickel without side reaction of dehalogenation has never been reported so far. This is because dehalogenation reaction is a common side reaction during hydrogenation with Raney Nickel (Page no.125-130, Catalytic Hydrogenation by Robert L Augustine, 1965, Page no.446-491, Practical Catalytic Hydrogenation-Techniques & Applications by Morris Freifelder, 1971, Page no.235-248, Catalytic Hydrogenation in Organic Synthesis by Paul Rylander, 1979).

So, the present invention is aimed to prepare 1 S-Cis-Sertraline Hydrochloride in a manner which is economically viable and industrially feasible.
The present invention is also aimed to develop a cost effective process by using inexpensive catalyst Nickel to perform the reduction of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1 (2H)-naphthalenylidene]methanamine
The present invention is further aimed to reduce the dehalogenated impurities by performing the reaction under moderate reaction conditions, thereby improving the Cis-Trans isomeric ratio in the final product whereby achieving the product in good yields and desired purity.
Summary of the invention:
The present invention discloses a cost effective process for production of Sertraline hydrochloride. The process involves catalytic hydrogenation of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l(2H)-naphthalenylidene]methanamine over specially prepared Raney-Nickel (Nickel Content-86 - 88 %, Nitrobenzene Activity test-60 - 80 H2 ml/gm/min, Bulk density 0.5 - 0.6 gm/cc followed by isolation of Cis isomers as hydrochloride.
Cis- Sertraline obtained by above process is further resolved by salt formation with D-Mandelic acid in ethyl acetate. Mandelate salt of IS-Cis Sertraline is insoluble in ethyl acetate is separated by filtration and subsequently converted to IS-Cis Sertraline hydrochloride. Process gives highly pure IS-Cis Sertraline hydrochloride free from lR-Cis as well as dehalogenated impurities.
Detailed description of the invention:
The present invention describes a cost effective process for preparation of IS-Cis Sertraline hydrochloride. The process of the present invention comprises the steps of;

i) catalytic hydrogenation of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l(2H)-
naphthalenylidenejmethanamine; ii) isolation of IS, Cis Sertraline as a (D)-mandelate salt and subsequent
purification of mandelate salt in an alcohol; iii) conversion of IS, Cis-Sertraline (D)-mandelate salt to IS Cis Sertraline hydrochloride. The preferred embodiment of the present invention comprises reduction of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l(2H)-naphthalenylidene]methanamine using Raney Nickel as a hydrogenating catalyst, being carried out under a hydrogen pressure range of 50-lOOpsi; preferably at lOOpsi and at a temperature range of 25-60°C, preferably at 55°C. The preferred solvent used to carry out the reaction is methanol. The catalyst is used in a quantity of 2-10%, preferably 5% of the substrate in the reaction. Reduction was carried for 30 mins to 2 hrs to give Cis-Sertraline hydrochloride, with a yield of 90.3%; substantially free of trans isomer and dehalogenated impurities.
Cis- Sertraline hydrochloride was treated with D- mandelic acid in ethyl acetate and refluxed for 2 hrs to precipitate lS-Cis Sertraline D-mandelate as solid. This solid was filtered and purified using isopropyl alcohol under reflux conditions to obtain pure 1S-Cis-Sertraline D-mandelate.
lS-Cis Sertraline D-Mandelate obtained was converted to free base using aq. Ammonia and extracted with ethylacetate and treated with HC1 in isopropanol to get lS-Cis Sertraline hydrochloride in high purity.
The present invention is further illustrated with the following examples.
Example 1 N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l(2H)-naphthalenylidene]methanamine
200 gm 4-(3,4-dichlorophenyl)-3,4-dihydro-l (2H)-naphthalenone, 400 ml methanol and 400 ml 30 % monomethyl amine in methanol were heated to reflux for 6 hrs. There after

heating discontinued and reaction mass cooled at 0-5 C , filtered and washed with 70 ml methanol and dried in vacco to yield 205 gm (98% of theoretical) of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l(2H)-naphthalenylidene]methanamine as a pale yellow solid.
Example 2
Cis-Sertraline Hydrochloride
200 gm N-[4-(3,4-dichlorophenyl)-3,4-dihydro-l(2H)-naphthalenylidene]methanamine
(Schiffs base), 900 ml methanol and 10 gm Raney Nickel were charged in an autoclave,
Vessel was pressurized to 100 PSI with hydrogen at 60°C under stirring for 1 hr.
There after vessel was cooled, depressurized and the reaction mass was filtered. Filtrate
was, acidified, cooled to 0-5°C, and filtered to give 180 gm Cis Sertraline hydrochloride.
Mother liquor upon complete removal of methanol in vacco yielded additional 23.6
grams of Cis Sertraline hydrochloride. Overall, yield was 203.6 gm (90.3% of
Contents of trans isomers and dehalogenated impurities are observed below detection
Example 3
lS-Cis Sertraline D-Mandelate
180 gm Cis-Sertraline hydrochloride was charged to mixture of 630 ml water and 900 ml ethyl acetate. Reaction mixture was made alkaline by using aqueous ammonia and pH was adjusted up to pH 10-11. Ethyl acetate layer was separated and aq. layer was extracted with ethyl acetate. D-Mandelic acid (82 grams) was added to the combined ethyl acetate extract and refluxed for 2 hrs. Insoluble lS-Cis Sertraline D-Mandelate was separated by filtration and further purified by refluxing with 30 vol. isopropanol to yield 90 grams of pure lS-Cis Sertraline D-Mandelate (75% of theoretical)

Example 4
IS-Cis Sertraline hydrochloride
IS-Cis Sertraline D-Mandelate obtained was converted to freebase using aqueous
ammonia. The sertraline free base was extracted with 900 ml ethyl acetate as per example
3 and treated with 10% HC1 in isopropanol to get 60 g Sertraline hydrochloride.
Percentage yield: 89% of theoretical
Percentage purity: NLT 99.5 %.
Contents of IR-Cis isomer and dehalogenated impurities are observed below detection

We claim,
1. A cost effective process for preparation of highly purelS-cis Sertraline
hydrochloride with a yield of 90.3% substantially free from trans and
dehalogenated impurities below detection limit, comprising the steps of;
i) catalytically hydrogenating N-[4-(3,4-dichlorophenyl)-3,4-
dihydro-l(2H)-naphthalenylidene]methanamine using specially prepared Raney Nickel catalyst in 2 to 10% with reference to the substrate; said hydrogenation reaction is carried out at 50-100 psi at temperature of between 25-60°C; and the said Raney Nickel catalyst is having a specification to have Nickel Content-86-88%, Nitrobenzene Activity test-60 - 80 H2 ml/gm/min, Bulk density 0.5 - 0.6 gm/cc;
ii) isolating IS, Cis sertraline as a (D)-mandelate salt;
iii) purifying the mandelate salt in alcohol and
iv) converting 1S, Cis-sertraline (D)-mandelate salt into IS Cis-sertraline hydrochloride.
2. The process as claimed in claim 1, wherein, hydrogenation reaction is carried out preferably at 100 psi.
3. The process as claimed in claim 1, wherein, hydrogenation reaction is carried out preferably at 55°C.
4. The process as claimed in claim 1, wherein, quantity of the catalyst used is preferably 5% with reference to the substrate.
5. The process as claimed in claim 1, wherein said alcohol used for purification of IS Cis sertraline as a (D)-mandelate salt is isopropanol.
6. A process for preparation of highly pure 1 S-cis Sertraline hydrochloride as substantially exemplified herein with reference to the foregoing examples 1-4.
Dated this 22nd day of July 2005
Dr. Gopakumar G. Nair Agent for the Applicant




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Patent Number 213312
Indian Patent Application Number 741/MUM/2005
PG Journal Number 42/2008
Publication Date 17-Oct-2008
Grant Date 27-Dec-2007
Date of Filing 22-Jun-2005
Name of Patentee WANBURY LIMITED
# Inventor's Name Inventor's Address
1 RANADE PRASAD VASUDEO 27, Bazae Peth, Rajapur 416 702 Dist Ratnagiri
3 KODURU, RAMANARASIMHA MOORTHY 4, Udayagiri, Cheddangar, Chember, Mumbai 400 089
PCT International Classification Number C07 211/42
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA