Novel process for preparing (+)-cis-sertraline WO 2001068566

Novel process for preparing (+)-cis-sertraline  WO 2001068566 

http://www.google.com/patents/WO2001068566A1?cl=en

The methods of the present invention for making (+)-cis-sertraline allow sertraline-precipitant, or sertraline-mandelate, to be made directly from the sertraline racemate resulting from the hydrogenation, reduction, of the sertraline- 1-imine. This improved, efficient and cost effective purification is possible when the sertraline racemate has a relatively high cis/trans ratio, such as, about 8:1 to about 12:1, as well as when the content of dechlorinated-sertraline side products is low, such as, less than about 1%. The methods of the present invention successfully eliminate the need for several purification steps prior to selectively precipitating (+)-cis-sertraline with an optically active selective precipitant.

Sertraline hydrochloride, (lS-cis)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N- methyl-1-naphthalenamine hydrochloride, having the formula

Sertraline hydrochloride

is the active ingredient in Zoloft®, a medication approved by the U.S. Food and Drug Administration, for the treatment of depression, obsessive-compulsive disorder and panic disorder.

Sertralone

U.S. Patent No. 4,536,518 describes a synthesis of sertraline hydrochloride from sertralone. The process for synthesizing sertraline hydrochloride from sertralone comprises two steps. First, sertralone is condensed with methyl amine in the presence of an acid catalyst, to yield the Schiff base of sertralone, sertraline- 1-imine.

Sertraline 1-imine

The imine, or Schiff base, is then reduced to sertraline. The reduction process of U.S. Patent No. 4,536,518 comprises the hydrogenation of sertraline- 1-imine concentrate at room temperature for two hours over 10% Pd/C catalyst in an atmosphere of hydrogen (1 atm pressure). The product is a racemic mixture of the cis and trans diastereomers ("(±)- cis/trans-sertraline") in the ratio of approximately 3 to 1. This hydrogenation step can introduce a number of contaminants, including dechlorinated side-products, if not carefully controlled. One very problematic group of side products are dechlorinated- sertraline derivatives. It is desirable to have a hydrogenation method that reduces the amount of dechlorinated-sertraline side products or eliminates these side products.

The purification of cis-sertraline from (±)-cis/trans-sertraline as described in the '518 patent is relatively complicated and expensive requiring multiple recrystallizations, and the (±)-cis/trans-sertraline so produced has a cis/trans ratios lower than 3:1. It is therefore desirable to have a method of initially making cis/trans-sertraline base from sertraline- 1-imine with cis/trans ratios greater than 3:1. It is also desirable to have a simple and cost effective purification of (+)-cis-sertraline from (±)-cis/trans-sertraline base or from (±)-cis/trans-sertraline hydrochloride.

EXAMPLES

EXAMPLE 1 Step 1: Preparation of sertraline- 1-imine (Schiff base):

Sertralone (100 g) was dissolved in toluene (1400 mL) and the solution so obtained was cooled to 0-5 °C. Methyl amine gas (38.7 g) was bubbled through the solution while maintaining the temperature between 0-5 °C. To the above solution, TiCl₄(20 mL) was added dropwise while maintaining the temperature below 10°C. The reaction mixture was allowed to warm to room temperature and then was stirred at room temperature for 3 hours. Upon completion of the reaction, TiO₂ was removed by filtration and the filtrate was evaporated to dryness. The solid obtained after evaporation was sertraline- 1-imine (101.17 g; yield 100%).

Step 2: Preparation of (drVcis/trans-sertraline (sertraline racemate) free base:

A slurry of sertraline- 1-imine (Schiff base) (10 g) in t-butyl-methyl-ether (MTBE) (270 mL) was hydrogenated in the presence of Pd/C (10% loading) at 40 °C, at 1 atm H₂ pressure. After approximately 5 hours the reaction was complete. Filtration of the reaction mixture through a cellite pad and evaporation of the solvent afforded (±)- cis/trans-sertraline free base (sertraline racemate free base) (10 g) as an oil.

Step 3: Preparation of crude f+)-sertraline mandelate:

Sertraline racemate free base (75.6 g) was dissolved in ethanol (760 mL) and the solution heated to about 50°C. (D)-Mandelic acid (37.6 g) was added and the solution was heated to reflux. The mixture was cooled to room temperature and stirred for 3 hours. Filtration and washing with ethanol followed by drying at about 60 °C afforded the product crude (+)-sertraline mandelate, in 83.7% yield (40.7g), 94.6% SS-sertraline, 3.01% RR-sertraline.

The optical purity of the (+)-sertraline mandelate was established by chiral HPLC.

Step 4: Preparation of (+)-sertraline mandelate crystals

Crude (+)-sertraline mandelate (40 g) was crystallized from ethanol (920 mL). The hot solution was treated with active carbon, filtrated and cooled to room temperature. The obtained solid was isolated by filtration and washed with ethanol. After drying, the (+)-sertraline-mandelate crystals are obtained in 82.8 % yield (31.95 g) 99.0% SS- sertraline by area, no i-R-sertraline was detected.

Step 5: Preparation of (+ -sertraline hydrochloride Form N:

The crude (+)-sertraline mandelate crystals in toluene were partitioned between a 10% aqueous solution of ΝaOH and toluene. The organic solution was washed with water and the solvent was evaporated to dryness to give (+)-sertraline base (6.9 g). The solution of (+)-sertraline base (3.7 g) in ethanol (18.5 mL) was acidified with hydrogen chloride gas while keeping the temperature at about 10°C. Then the mixture was cooled to room temperature and stirred for 2 hours. After filtration, washing of the solid with ethanol and drying, (+)-sertraline hydrogen chloride ((+)-sertraline HCl) Form N was obtained (3.16 g, yield 82.7%>), 99.6% SS-sertraline by area, no i-i?-sertraline was detected.

The procedure of steps 3-5 was performed 5 times as described above. Table 2 includes the specific conditions and results of these 5 experiments.

Table 2.

EXAMPLE 2: OPTICAL RESOLUTION (±)-Sertraline hydrochloride (5 g) was dissolved in ethanol (20 mL) and KOH powder (85%>) was added to the solution. The slurry was stirred at room temperature for 2.5 hrs. After stirring the solids were removed by filtration and the solution was treated with D-(-)-mandelic acid (2.66 g). Precipitation occurred and the stirring was continued for 24 hours. (+)-Sertraline-mandelate was isolated by filtration and washed with ethanol and then dried to yield 2.70 g of (+)-sertraline-mandelate.

Optical purity of (+)-sertraline-mandelate was established by chiral HPLC methods. Table 3 provides additional data and reaction conditions concerning the optical resolution of sertraline. In Table 3, the % Enantiomer RR is the percent area of the RR- enantiomer as determined by chiral HPLC; Chiracel OD-H, 250 x 4.6 nm, 5μ, column temperature 5°C. In Table 3, the Yield %> is the yield of optical resolution, based on the % SS-enantiomer of sertraline hydrochloride practically obtained against the theoretical SS-sertraline hydrochloride enantiomer that could be obtained. The yield was calculated based on the optical purity of (±)-sertraline hydrochloride obtained. In Table 3, the Assay % is the percent of SS-sertraline hydrochloride as determined by chiral HPLC method using SS-sertraline hydrochloride as the standard.

Although certain presently preferred embodiments of the invention have been described herein, it will be apparent to those skilled in the art to which the invention pertains that variations and modifications of the described embodiments may be made without departing from the spirit and scope of the invention. Accordingly, it is intended that the invention be limited only to the extent required by the appended claims and the applicable rules of law.

PATENT CITATIONS

Cited Patent	Filing date	Publication date	Applicant	Title
US4536518 *	Nov 1, 1979	Aug 20, 1985	Pfizer Inc.	Antidepressant derivatives of cis-4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine
US5463126 *	Jul 3, 1992	Oct 31, 1995	Pfizer Inc.	Process for preparing sertraline

Reference
1	*	See also references of EP1268369A1

Citing Patent	Filing date	Publication date	Applicant	Title
WO2002102761A1 *	Jun 14, 2002	Dec 27, 2002	Ilpo Laitinen	A novel process for the preparation of (is-cis) -4-(3, 4-dichlorophenyl) -1, 2, 3, 4 - tetrahydro-n-methyl-1-naphthalenamine
WO2004092110A2 *	Apr 14, 2004	Oct 28, 2004	Mordechay Hershowitz	Hydrogenation of imine intermediates of sertraline with catalysts
WO2005023752A2 *	Sep 7, 2004	Mar 17, 2005	Ben-Zion Dolitzky	A recycling process for preparing sertraline
WO2005121074A2 *	Jun 9, 2005	Dec 22, 2005	Keshav Deo	Processes for the preparation of sertraline hydrochloride
WO2007119247A2 *	Sep 12, 2006	Oct 25, 2007	Dayalji Chauhan Ajay	Improved manufacturing procedure for the preparation of polymorphic form ii of cis-(1s)-n-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-napthleneamine hydrochloride (sertraline hydrochloride)
US6723878	Jun 14, 2002	Apr 20, 2004	Orion Corporation Fermion	Method for preparing sertraline
US7262327 *	Sep 7, 2004	Aug 28, 2007	Teva Pharmaceutical Industries Ltd.	Recycling process for preparing sertraline
US7276629	Apr 14, 2004	Oct 2, 2007	Teva Pharmaceutical Industries Ltd.	Hydrogenation of imine intermediates of sertraline with catalysts

* Cited by examiner

US 7326794, Process for the Preparation of High Purity Perindopril and Intermediates Used in its Synthesis

US 7326794

http://www.google.com/patents/US7326794

Process for the Preparation of High Purity Perindopril and Intermediates Used in its Synthesis

Les Laboratoires Servier, Courbevoie Cedex, France

Perindopril 3 is used in treating cardiovascular problems, and other related patents from this company on this compound were reviewed recently (Org. Process Res. Dev. 2008, 12, 146). This patent extends the work covered in the earlier patents and involves the same route that is shown in Reaction 1.

Reaction 1

The process involves acylation of 1a to give 1b that is activated using SOCl2 to form 1c, and this is coupled with 2 to form 3 that is isolated by formation of the tert-butyl salt in 45% yield. The main claim of this patent specifically mentions the synthesis of 3 or the salt that is free from contamination by the benzyl esters 4a and 4b. These compounds are present when DCC is used as a coupling reagent in the alternative synthesis from 1c and the Ts salt of the benzyl ester of 2 Benzyl Esters.The patent also describes the synthesis of the methyl and ethyl analogues of 1b and 1c (R1 = OMe or OEt) from the corresponding chloroformates and Et3N is used in place of K2CO3 in step (a). The But analogue is formed by using (BOC)2O in place of the chloroformates and K2CO3. All of these compounds are novel, and basic 1H NMR data are given for them.

Preparation of Perindopril Eburmine

Example 5 Acylation of perhydroindole-2-carboxylic acid using N-[2-(ethoxycarbonyl)butyl]-N-ethoxycarbonylalanine

To a solution of N-[2-(ethoxycarbonyl)butyl]-N-ethoxycarbonylalanine (10.1 g, 35 mmol) in dichloromethane (35 mL) thionyl chloride (4.2 mL, 6.9 g, 58 mmol) was added in drops at 0-5° C. It was stirred at ambient temperature for 2-3 h. The solvent was evaporated to give a reddish oil. The residue was dissolved in THF (37.5 mL) and it was added to a suspension of perhydroindole-2-carboxylic acid (4.7 g, 28 mmol) in THF (37.5 mL). The suspension was refluxed with stirring for 4-4.5 h until a brownish solution was formed. After evaporation of the solvent the residue was dissolved in ethyl acetate (120 mL), t-butylamine (2.8 mL, 1.95 g, 27 mmol) in ethyl acetate (60 mL) was added slowly to the stirred solution resulting in separation of a crystalline mass. The mixture was heated until a solution was formed, then treated with charcoal. The crystalline product obtained after cooling was filtered to give perindopril eburmine (6.8 g, 55%).

Example 6 Acylation of perhydroindole-2-carboxylic acid using N-[2-(ethoxycarbonyl)butyl]-N-methoxycarbonylalanine

Perindopril eburmine was prepared analogously to Example 5, using N-[2-(ethoxycarbonyl)butyl]-N-methoxycarbonylalanine (3.4 g, 12.5 mmol) and perhydroindole-2-carboxylic acid (1.7 g, 10 mmol). The crystalline product obtained was filtered to give perindopril eburmine (2.4 g, 54%).

Example 7 Acylation of perhydroindole-2-carboxylic Acid Using N-[2-(ethoxycarbonyl)butyl]-N-t-buthoxycarbonylalanine

Perindopril eburmine was prepared analogously to Example 5, using N-[2-5 (ethoxycarbonyl)butyl]-N-t-buthoxycarbonylalanine (0.69 g, 2.2 mmol) and perhydroindole-2-carboxylic acid (0.29 g, 1.7 mmol). The crystalline product obtained was filtered to give perindopril eburmine (0.37 g, 49%).

Example 8 Acylation of perhydroindole-2-carboxylic acid using N-[2-(ethoxycarbonyl)butyl]-N-benzyloxycarbonylalanine

Perindopril eburmine was prepared analogously to Example 5, using N-[2-(ethoxycarbonyl)butyl]-N-benzyloxycarbonylalanine (1.41 g, 4 mmol) and perhydroindole-2-carboxylic acid (0.51 g, 3 mmol). The crystalline product obtained was filtered to give perindopril eburmine (0.60 g, 45%).

Example 9 Acylation of perhydroindole-2-carboxylic acid using N-[2-(ethoxycarbonyl)butyl]-N-ethoxycarbonylalanine

To a solution of N-[2-(ethoxycarbonyl)butyl]-N-ethoxycarbonylalanine (1.45 g, 5 mmol) in dichloromethane (7.5 mL) thionyl chloride (0.6 mL, 0.98 g, 8.5 mmol) was added dropwise at 0-5° C. It was stirred at ambient temperature for 2-3 h. The excess of thionyl chloride and the sulphur dioxide and hydrogen chloride formed was eliminated in slight vacuo. To the dichloromethane solution thus obtained was added perhydroindole-2-carboxylic acid (0.71 g, 4.2 mmol) and dichloromethane (5.0 mL). The suspension was refluxed with stirring for 2 h until a brownish solution was formed. After evaporation of the solvent the residue was dissolved in ethyl acetate (20 mL), whereupon t-butylamine (0.42 mL, 0.29 g, 4.05 mmol) in ethyl acetate (5.0 mL) was added slowly to the stirred solution resulting in separation of a crystalline mass. The mixture was heated until a solution was formed, then treated with charcoal. The crystalline product obtained after cooling was filtered to give perindopril eburmine (0.64 g, 35%).

Cited Patent	Filing date	Publication date	Applicant	Title
US4914214 *	Sep 16, 1988	Apr 3, 1990	Adir Et Cie	Process for the industrial synthesis of perindopril
US6835843	Apr 5, 2001	Dec 28, 2004	Les Laboratoires Servier	Method for synthesis of perindopril and its pharmaceutically acceptable salts
US7060842	Jul 23, 2002	Jun 13, 2006	Les Laboratoires Servier	Method for synthesis of (2S, 3aS, 7aS)-1-{(S)-alanyl}-octahydro-1H -indole-2-carboxylic acid derivatives and use for synthesis of perindopril
US20040248814	Jul 23, 2002	Dec 9, 2004	Pau Cid	Process for the preparation of perindopril, its analgous compounds and salts therof using 2,5 dioxo-oxazolidine intermediate compounds
DE19721290A1	May 21, 1997	Dec 11, 1997	Krka Tovarna Zdravil D D	ACE-inhibiting substituted alanyl-derivatives of e.g. proline preparation
EP0308341A1	Sep 16, 1988	Mar 22, 1989	Adir Et Compagnie	Process for the industrial synthesis of perindopril and for its principal synthesis intermediates
EP1256590A1	Jul 23, 2002	Nov 13, 2002	Les Laboratoires Servier S.A.	Method for synthesis of (2S,3aS,7aS)-1-(S)-alanyl-octahydro-1H-indole-2- carboxylic acid derivatives and use in the synthesis of perindopril
EP1279665A2	Jul 23, 2002	Jan 29, 2003	Adir	A process for the preparation of perindopril, its analogous compounds and salts thereof using 2,5-dioxo-oxazolidine intermediate compounds
GB2095252A				Title not available
WO2001058868A1	Apr 5, 2001	Aug 16, 2001	Adir	Method for synthesis of perindopril and its pharmaceutically acceptable salts

Reference
1		Vincent, et al., Drug Design and Discovery, 1992, 9, Nov. 28.
2		Vincent, M., et al., "Synthesis and Ace Inhibitory Activity of the Stereoisomers of Perindopril (S9490) and Perindoprilate (S 9780)" Drug Design and Discovery, Hardwood Academic Publishers GmbH, vol. 9, No. 1, 1992, pp. 11-28 XP000885876 ISSN: 1055-9612, p. 11-p. 13.

US 7276629...........Catalytic Hydrogenation of Imine Intermediates of Sertraline

US. 7276629

http://www.google.com/patents/US7276629

Catalytic Hydrogenation of Imine Intermediates of Sertraline

Sertraline hydrochloride, (1S-cis)-4-(3,4 dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride, having the formula:

is approved, under the trademark Zoloft®, by the U.S. Food and Drug Administration, as a serotonin re-uptake inhibitor for the treatment of depression, obsessive-compulsive disorder, panic disorder and post-traumatic disorder. Only cis sertraline is therapeutically active.

U.S. Pat. No. 4,536,518 describes a synthesis of sertraline hydrochloride from sertralone having the following formula:

The process for synthesizing sertraline from sertralone has two steps. First, sertralone is condensed with methyl amine in the presence of an acid catalyst, to yield the Schiff base of sertralone, “sertraline-1-imine”:

The imine is then reduced to sertraline. The reduction process of U.S. Pat. No. 4,536,518 involves the hydrogenation of sertraline-1-imine concentrate at room temperature for two hours over 10% Pd/C catalyst in an atmosphere of hydrogen (1 atm pressure). The product is a racemic mixture of the cis and trans diastereoisomers (“(±)-cis/trans-sertraline”) in the ratio of approximately 3 to 1. The '518 patent discloses that reduction with NaBH₄ gives a cis:trans ratio of about 1:1.

Two publications, WO 01/30742 and WO 98/27050, disclose the stereoselective reduction of sertraline-imine derivatives. The publication, WO 01/30742, discloses replacing the methyl group of sertraline 1-imine with an optionally substituted bulky benzyl group to increase the cis to trans ratio during hydrogenation, followed by additional steps of converting the bulky group to a methyl group. Additionally, the publication, WO 01/30742, discloses: “The reduction may be performed using complex hydrides (e.g. NaBH₄) or by hydrogenation. Reduction performed by catalytic hydrogenation tends to give better selectivity that reduction using the complex hydrides. For example, aliquots of N-[4-(3,4 dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]-benzylamine were reduced with NaBH₄ and Raney nickel/H₂ respectively, and subsequently reductively alkylated with formaldehyde, whereafter the cis/trans ratio was analyzed. The result was a ratio of 53.8/46.2 using NaBH₄ compared to 82.9/17.1 for Raney nickel/H₂ which clearly demonstrates the selectivity for the catalytic hydrogenation. An even higher selectivity with a cis/trans ratio of 93.5/6.5 has been observed using palladium on carbon.”

The publication, WO 98/27050, discloses obtaining sertraline by reducing an N-oxide derivative of the imine. In Example 1, the N-oxide derivative is hydrogenated with Raney nickel catalyst, while in Example 2 a 10% palladium on carbon is used as a catalyst. A cis product with an 81% yield is obtained in both instances. According to WO 98/27050, the N-oxide group may then be removed by addition of HCl to the N-oxide compound in ethanol.

The publication, WO 01/16089, discloses a process of reductive amination of sertralone to cis and trans sertraline. In Example 1, sertralone is reduced in the presence of Raney nickel and methylamine. The yield provided in Example 1 is 48–51% of the cis isomer.

The publication, WO 99/57093, discloses a process of selective hydrogenation with a palladium catalyst pretreated with an alkyl halide. The publication discloses that the process of the '518 patent may lead to 10% of dechlorinated side products, while the process of the publication has a “total amount of said contaminated by-products . . . below 0.5%.” In regards to the cis/trans ratio, the ratio provided is 85–95% in the description of the invention. Alkyl halides however are problematic for use on an industrial scale since halogenated reagents are often not environmentally friendly.

U.S. Pat. No. 6,593,496 discloses preparing sertraline-I imine by reacting sertralone with monomethylamine and either titanium tetrachloride or molecular sieves. The hydrogenation illustrated in scheme 1 is carried out with a palladium catalyst in THF.

In US 2003/0105364, a process is provided for obtaining optically pure sertralone through chromatography. The examples do not illustrate hydrogenation.

In US 2003/0166970, a process for making (±)-sertraline with a cis/trans ratio of greater than about 3:1 is provided by hydrogenation of sertraline-1-imine at a temperature of at least about 40° C. using a palladium or a platinum catalyst.

Sertraline 2 is a widely used antidepressant drug, and patents on various aspects of its synthesis have been covered previously ( Org. Process Res. Dev.2005, 9, 537). The hydrogenation of 1 to 2 is a key step in the synthesis and produces two pairs of enantiomers; one cis and the other trans (Reaction 1). Only one of the cis isomers is active, and hence a stereoselective hydrogenation step is highly desirable. Some processes produce about 25% of the trans pair, and a further process loss arises by removal of one or both of Cl groups during hydrogenation. This patent describes the use of commercial Ni catalyst (e.g., G69 from Süd-Chemie) and also proprietary Co catalysts. The patent states that G69 is preferred although the claims cover both Ni and Co catalysts and the patent gives details of the preparation of the Co catalysts. The reaction is carried out in trickle-bed reactor or in a batch reactor with a variety of solvents being used. A process operated at 65 °C and 5 bar pressure using G69 in MeOH gave a 100% conversion of 1 with a selectivity to cis- 2 of 79.8%. This is understood to be less than other commercial catalysts.

Reaction 1

The option of using the racemic mixture of 1 is also covered in the patent. The resolution of 2was carried out by preparation of the d-(−)-mandelate and crystallisation and isolation of (+)-sertraline mandelate.

EXAMPLE 1 Preparation of the Proprietary Cobalt Catalyst

The catalyst was prepared using the incipient wetness impregnation of alumina-silica. The support precursor catalyst reduction purchased from Saint-Gobain NorPro (Stow, Ohio) was first calcined at 500° C. for 12 hours before impregnation. Characteristics of the support SA3 135 is given in Table 5. Calcined SA-3 135 (5 grams), granules 1–1.2 mm, was charged into glass flask and evaporated at P=0.02 bar and 25° C. over 1 hour. An aqueous solution of cobalt nitrate (4.0 ml) containing 4.36 g of Co(NO₃)₂×6H₂O (98%), purchased from Aldrich (Milwaukee, Wis.), was added dropwise so that surface of all the granules was saturated by the salt solution. The catalyst was dried at 120° C. for 4 hours and calcined at 500° C. for 4 hours.

The Energy Dispersive X-Ray (“EDX”) analysis indicated the contents of Co, Al, Si, 0: 15.0, 35.8, 13.8 and 35.4% wt., respectively. The XRD patterns of the material were evident for the existence of the phase Co₃O₄: (peaks at 2θ:18.96, 31.24, 36.68, 38,78, 44.75, 57.55). The average crystal size of CoO estimated in XRD study was 50 nm. The catalyst had surface area 11 m²/g, with an average pore diameter 183 angstroms.

The catalyst (2.3 g) was loaded into a tubular stainless steal reactor (6 mm ID and 150 mm length). In the stream of hydrogen at GHSV (gas hour space velocity) 2500 h⁻¹, the temperature was gradually ramped to 500° C., (5° C./min), and then the temperature was maintained constant at 500° C. for 4 hours. The operating conditions of catalyst reduction were selected over Temperature Programmed Reduction (“TPR”) studies carried out in AMI-100 Catalyst Characterization System from Zeton-Altamira (Pittsburgh, Pa.).

The XRD analysis of the reduced catalysts indicates the existence of the phase Co and CoO (peaks at 2θ: 36.8, 42.47, 61.41, 73.69). After the completion of the catalyst reduction, the temperature in the reactor was decreased to 120° C., and the total pressure of hydrogen was increased to 8 bar. A solution containing N-methyl-4(3,4-dichlorophenyl)-1-(−2H)-naphtalenimine (Imine) in tetrahydrofuran (THF), purchased from BioLab (99.5%), having a concentration of 30 g/L was then fed with hydrogen to the reactor. The rate of the solution feed was 25 g/h and the rate of hydrogen feed was 150 ml/mm.

(The products were analyzed by GC HP6890 (Palo Alto, Calif.): capillary column DB-17, 30 m×0.53 mm×1μ. The initial temperature was 160° C. for 26 minutes, and then the temperature was increased at a rate of 30° C./min to 250° C.).

The results of the GC analysis under conditions mentioned above are shown in table 7, which indicates that the imine was completely hydrogenated to a mixture containing: cis-(1S,4S)-N-Methyl-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphtalenamine(cis-Sertraline) as the major component, trans-(1S,4R)-N-Methyl-4(3,4-dichlorophenyl)-1,2,3,4-.tetrahydro-1-naphtalenamine(trans-Sertraline), (1S,4S)-N-Methyl-4(3-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphtalenamine(DCS-1), (1S,4S)-N-Methyl-4-(4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphtalenamine(DCS-2) and Sertralone.

The content of cis-sertraline in the product of imine hydrogenation was 91%.

TABLE 5
The characteristics of the support SA 3135
	Parameter	Value
	Aluminum oxide, % wt	79–81
	Silicon oxide, % wt	17–19
	Sodium oxide, % wt	0.2–0.4
	Ferric oxide, % wt	0.3–0.5
	Titanium dioxide, % wt	0.4–0.5
	Magnesium oxide, % wt	0.1–0.3
	Potassium oxide, % wt	0.1–0.3
	Surface area, m2/g	12.5
	Particle density, g/cc	1.1

EXAMPLE 2

A catalyst containing 11% cobalt by weight was prepared and reduced as in Example 1, but 3.2 g instead of 4.36 g of Co(NO₃)₂×6H₂O was used for the preparation of the aqueous solution. The hydrogenation was carried out under conditions as provided in Example 1. The content of cis-sertraline in the product of imine hydrogenation was 91%.

EXAMPLE 3

The catalyst containing 25% of cobalt by weight was prepared by carrying out the incipient wetness impregnation process twice. The first impregnation was followed by drying at 120° C. for 4 hours, and then calcination at 500° C. for 4 hours was carried out as in Example 1. S Scanning Electronic Microscopy (“SEM”) analysis indicated that the catalyst had 15% of Cobalt (5 g) impregnated for the second time by 4 ml of aqueous solution contained 2.2 g of Co(NO₃)₂×6H₂O. The catalyst was dried and calcinated as mentioned above. The cobalt content after twofold impregnation was 25.1% (Scanning Electronic Microscopy (“SEM”) analysis). The catalyst (2.3 g) was charged in a tubular stainless steal reactor and reduced by hydrogen as in Example 1. The hydrogenation of imine was carried out under operating conditions mentioned as in Example 1. The content of cis-Sertraline in the product was 87% (Table 6).

EXAMPLE 4

Example 3 was repeated with the temperature of hydrogenation being increased to 150° C. and the feed rate of solution being increased to 40 g/hr. The content of cis-sertraline was 88.8% (Table 6).

TABLE 6
The experimental results of Imine hydrogenation in a trickel bed reactor
	GC analysis, % area
		T	Cis-
Examples	Catalyst	(° C.)	SRT	Trans-SRT	DCS-1 + DCS-2	Imine	SRT-one
1	15% Co	120	91.0	7.0	0.1	Not detected	0.3
	SA-
	3135
2	11% Co	120	90.4	7.1	0.1	Not detected	0.2
	SA-
	3135
3	25% Co	120	87.0	9.4	0.1	Not detected	0.7
	SA-
	3135
4*	25% Co	150	88.8	7.0	0.1	Not detected	0.3
	SA-
	3135
The content of imine in THF was 30 g/L, the feed of the solution was 25 g/h and the feed of hydrogen was 150 ml/min (* the feed the Imine solution was 40 g/h).

EXAMPLE 5 Resolution

(±)-Sertraline hydrochloride (5 g) was dissolved in ethanol (20 mL) and KOH powder (85%) was added to the solution. The slurry was stirred at room temperature for 2.5 hrs. After stirring the solids were removed by filtration and the solution was treated with D-(−)-mandelic acid (2.66 g). Precipitation occurred and the stirring was continued for 24 hours. (+)-Sertraline-mandelate was isolated by filtration and washed with ethanol and then dried to yield 2.70 g of (+)-sertraline-mandelate.

EXAMPLE 6

The catalyst G-69 (2.9 g) was loaded into a tubular stainless steal reactor (6 mm ID and 150 mm length). In the stream of hydrogen at GHSV (gas hour space velocity) 2500h⁻¹, the temperature was gradually ramped to 150° C., (5° C./min), and then the temperature was maintained constant at 150° C. for 2 hours. After catalyst pre-treatment, the temperature in the reactor was decreased to 90° C., and the total pressure of hydrogen was increased to 8 atmospheres. A solution containing N-methyl-4(3,4-dichlorophenyl)-1-(−2H)-naphtalenimine (Imine) in tetrahydrofuran (THF), purchased from BioLab (99.5%), having a concentration of 30 g/L was then fed with hydrogen to the reactor. The rate of the solution feed was 250 g/h and the rate of hydrogen feed was 150 ml/mm. The content of cis -sertraline in the product of imine hydrogenation was 86%.

US2486361 *	Oct 20, 1944	Oct 25, 1949	Union Oil Co	Catalytic conversion of hydrocarbons
US3860532 *	Jun 5, 1972	Jan 14, 1975	Nippon Oil Co Ltd	Method for preparing silica-alumina catalysts for the conversion of hydrocarbon
US4536518	Nov 1, 1979	Aug 20, 1985	Pfizer Inc.	Antidepressant derivatives of cis-4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine
US6034274 *	Dec 15, 1997	Mar 7, 2000	Richter Gedeon	Process for preparing a naphtalenamine derivative
US6232501 *	Mar 16, 1999	May 15, 2001	Ciba Specialty Chemicals Corporation	Process for the cis-selective catalytic hydrogenation of cyclohexylidenamines
US6593496	May 30, 2000	Jul 15, 2003	Pfizer Inc	Process for preparing sertraline from chiral tetralone
US20030105364	Sep 18, 2002	Jun 5, 2003	Laurent Berger	Process for the preparation of optically pure or enriched racemic tetralone
US20030166970	Feb 12, 2003	Sep 4, 2003	Marioara Mendelovici	Novel process for preparing (+)-cis-sertraline
EP1059287A1	Jun 5, 2000	Dec 13, 2000	Pfizer Products Inc.	Process for preparing sertraline from chiral tetralone
WO1998027050A1	Dec 15, 1997	Jun 25, 1998	Iren Fellegvari	Process for preparing a naphtalenamine derivative
WO1999047486A1	Mar 16, 1999	Sep 23, 1999	Markus Benz	Process for the cis-selective catalytic hydrogenation of cyclohexylidenamines
WO1999057093A1	May 5, 1999	Nov 11, 1999	Laszlo Balazs	Process for the preparation of sertraline and its 1,r-stereoisomer
WO2001009080A1	Jul 20, 2000	Feb 8, 2001	Markus Benz	Process for the cis-selective catalytic hydrogenation of cyclohexylidenamines
WO2001016089A1	Aug 28, 2000	Mar 8, 2001	Sharad Kumar Vyas	A process for the preparation of cis-(1s,4s)-n-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine hydrochloride
WO2001030742A1	Oct 20, 2000	May 3, 2001	Gea Farmaceutisk Fabrik As	Improved synthesis of racemic sertraline
WO2001049638A2	Jan 1, 2001	Jul 12, 2001	Trinadha Rao Chitturi	A process for converting stereoisomers of sertraline into sertraline
WO2001068566A1	Mar 14, 2001	Sep 20, 2001	Neomi Gershon	Novel process for preparing (+)-cis-sertraline
WO2002102761A1	Jun 14, 2002	Dec 27, 2002	Ilpo Laitinen	A novel process for the preparation of (is-cis) -4-(3, 4-dichlorophenyl) -1, 2, 3, 4 - tetrahydro-n-methyl-1-naphthalenamine

NON-PATENT CITATIONS

Reference
1	*	Rathousky et al., Applied Catalysis A: General, 79 (1991), pp. 167-180.
2	*	The Merck Index, 12th edition (1996), Budavari ed., Merck & Co. Inc., Whitehouse Station, NJ, entry No. 8612.

Citing Patent	Filing date	Publication date	Applicant	Title
WO2010076763A2 *	Dec 29, 2009	Jul 8, 2010	Piramal Healthcare Limited	An improved process for the manufacture of sertraline