WO2010076763A2

WO2010076763A2 - An improved process for the manufacture of sertraline

Info

Publication number: WO2010076763A2
Application number: PCT/IB2009/055979
Authority: WO
Inventors: Vilas Vasant Pandit; Rajesh Naik; Pravin Karnik; Nitin Pawar; Pranay Shah
Original assignee: Piramal Healthcare Ltd
Current assignee: Piramal Enterprises Ltd
Priority date: 2009-01-02
Filing date: 2009-12-29
Publication date: 2010-07-08
Anticipated expiration: 2011-07-02
Also published as: WO2010076763A3

Abstract

A process for preparing (±)-cis-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1- naphthalenamine (sertraline) and/or a pharmaceutically acceptable acid addition salt thereof comprising hydrogenation of 4-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl-1- naphthalenimine (sertraline-1-imine) in the presence of a polar solvent using palladium / alumina as a catalyst at a temperature ranging from 25°C to 35°C to obtain (±)-cis/trans- sertraline with the (±)-cis racemate of sertraline as the major product.

Description

AN IMPROVED PROCESS FOR THE MANUFACTURE OF SERTRALINE

FIELD OF INVENTION

The present invention relates to a process for the manufacture of Sertraline (4-(3,4- dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l-naphthalenamine) and, in particular, to an improved method for the hydrogenation of 4-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl- 1-naphthalenimine (sertraline- 1-imine) to obtain (±)-cis/trans-sertraline with the (±)-cis racemate of sertraline as the major product in high yield and purity.

BACKGROUND OF ART

Cyclohexylamines can be used, inter alia, as antioxidants and as pharmaceutically active substances. An important cyclohexylamine is sertraline: cis (IS, 4S)-4-(3,4- dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l-naphthalenamine, see Merck Index: Twelfth Edition 1996, No. 8612, is known as an antidepressant. The preparation of this compound is described in U.S. Patent No. 4,536,518. The hydrochloride salt is commercially available under the registered trademarks name Lustral® and Zoloft®.

The cyclohexylamine, sertraline which is structurally represented above exist in at least two isomeric forms:

cis trans

In another non-symmetrical substitution at the cyclohexyl ring, the carbon atoms are chiral in 1- and 4-positions. According to the R,S-nomenclature by Cahn, Ingold and Prelog, sertraline has the (IS, 4S)-configuration.

cis (±.) sertraline trans (+.) sertraline

Sertraline is obtained on treating the sertralone (4-(3,4-dichlorophenyl)-3,4-dihydro-l- naphthalenone) with methylamine to yield the Schiff base of sertralone, sertraline- 1- imine ("imine") by the elimination of water, which is then subjected to catalytic hydrogenation in accordance with the schematic as given below.

Several processes for the preparation of sertraline are known in the prior art. US patent no. 4,536,518 discloses a two-step synthesis of sertraline hydrochloride from sertralone. The first step comprises of condensation of sertralone with methyl amine in the presence of an acid catalyst to yield the Schiff base of sertralone, sertraline- 1-imine, that is reduced to sertraline (amine) in the second step. The reduction process is carried out at room temperature for two hours over 10% Pd/C catalyst under 1 atmosphere hydrogen pressure to yield (+)-cis/trans sertraline diastereoisomers in the ratio of 3:1. The patent also discloses that another reducing reagent, sodium borohydride (NaBH₄) used for the conversion of sertraline- 1-imine to sertraline, gives (±)-cis/ trans ratio of 1:1.

PCT Application Publication No. WO 99/57093 is directed to a process of selective hydrogenation of sertraline- 1-imine with a palladium catalyst supported onto a carrier which is preferably in the form of 5-30% by wt. of Pd loaded on charcoal pretreated with an alkyl halide to obtain (±)-cis and (±)-trans sertraline diastereoisomers in the ratio of about 19:1 [yield of (±)-cis product varies from 85-95%] and wherein the total dechlorinated contaminant side products amounts to less than 0.5%. The hydrogenation is carried out at a temperature range of 10-100⁰C with a hydrogen pressure of 1-25 atmospheres and is continued until the starting material, sertraline- 1-imine is consumed. The invention suffers from a serious drawback in using alkyl halide for said process since halogenated reagents are often not environment friendly and thus render the process industrially non- viable. US Patent no. 6,552,227 describes a process for the hydrogenation of sertraline- 1-imine by using Pd/C or PtO₂ as the catalyst at a temperature of about 40°C-80°C and 1 atmosphere hydrogen pressure to obtain cis (±)- and trans (±)-sertraline in a ratio of about 12:1.

US Patent No. 6,232,501 describes that the hydrogenation of sertraline- 1-imine or sertraline- 1-imine N-oxide is carried out at very high pressure (10-15 bars) and/or at high temperature (100-150⁰C) using copper containing catalyst, to give (±)-cis/ trans ratio of 95:5.

US Patent no. 6,034,274 describes hydrogenation of sertralin- 1-imine N-oxide under 1 atmosphere hydrogen pressure in an inert solvent in the presence of Raney nickel as the catalyst at a temperature of 25°C, followed by treating the resulting mixture with an alcoholic solution of hydrogen chloride, converting the resulting cis-racemic acid addition salt to the free base, resolving and then converting the resulting (+)-cis-sertraline base to acid addition salt.

PCT Application Publication No. WO 01/116089 is related to a process involving reductive amination of sertralone, wherein said process involves reacting sertralone with methyl amine in hydrogen atmosphere at a pressure of 450-500 psi and temperature of 60⁰C in the presence of Raney nickel as the catalyst to obtain a mixture of cis- and trans- sertraline, followed by separating the cis isomers from the mixture by fractional crystallization in methanol followed by resolution of the cis isomers by known method with mandelic acid, isopropyl alcohol and hydrogen chloride to yield the desired cis-(lS, 4S) isomer of sertraline.

US Patent no. 6,723,878 describes a process for the preparation of cis-sertraline, comprising hydrogenating sertraline- 1-imine under a hydrogen pressure of 2-5 bar and a temperature of 20-50⁰C in the presence of a catalyst selected from palladium or platinum, and a dehalogenation inhibitor such as an ester of phosphorous or hypophosphorous acid to drastically reduce the formation of dehalogenated by- products to less than 0.1% and to enhance the (±)-cis- and (±)-trans sertraline ratio to as high as 97:3.

PCT Application Publication No. WO 03/099761 discloses the reductive amination of 4- (3,4-dichlorophenyl)-3,4-dihydro-l-naphthalenone (sertralone) by a mixture of methylamine salt and alkaline formate in the presence of at least one inorganic salt of lithium or beryllium or magnesium or aluminum in a media of N-methyl formamide or

1 ,2-dichlorobenzene or a mixture of N-methyl formamide and 1 ,2-dichlorobenzene under inert atmosphere and wherein the product obtained hydrolyses to cis- and trans- isomers of sertraline hydrochloride that are isolated separately with a minimum content of opposite geometric isomer.

PCT Application Publication No. WO 2006/129324 is related to a process for hydrogenation of sertraline- 1-imine using 5% palladium supported on alkaline earth metal carbonate selected from calcium carbonate (CaCO₃) and barium carbonate (BaCO₃) within a temperature range of 10-40⁰C and a hydrogen pressure of 0.1-1 Kg that lead to a substantially pure cis isomer with the trans isomer content of <0.5%.

US patent no. 7,276,629 (hereinafter referred to as US '629 patent) relates to a process for preparing sertraline from sertraline- 1-imine ("imine") comprising the step of hydrogenating sertraline- 1-imine in the presence of a catalyst in a trickle bed reactor. The catalyst used for hydrogenation of the imine to the amine is carried out using cobalt or nickel containing catalyst which is prepared by calcining it on an aluminum-silica support and wherein the hydrogenating temperature and pressure is maintained at about 80-150⁰C and 5-20 bar. Importantly, said US '629 patent also discloses as a comparative example, the use of Pd/alumina catalyst for such conversion of imine in the above mentioned trickle bed reactor. However, in spite of carrying out the hydrogenation reaction using

Pd/alumina catalyst in the special reaction vessel such as the trickle bed reactor, the yield obtained was only about 63% of (±)-cis racemate of sertraline. This patent, thus teaches away from the use of Pd/alumina as catalyst for conversion of sertraline- 1-imine to sertraline. It is clearly apparent from the above discussions that though there exists several methods for the synthesis of sertraline enriched with the (±)-cis isomer content there remains an obvious need in the art for improvement on processes for the stereoselective synthesis of sertraline in high yields and with high (±)-cis-isomer content involving simple and effective imine conversion steps for better yield and purity of the resulting amine i.e. sertraline.

OBJECTS OF THE INVENTION

Thus, a basic object of the present invention is to provide an improved process for the synthesis of (±)-cis-sertraline and/ or a pharmaceutically acceptable acid addition salt thereof involving convenient and effective imine conversion steps for achieving good yield and purity of (±)-cis-sertraline.

Another object of the present invention is to provide an improved process for the preparation of (±)-cis- sertraline and/ or a pharmaceutically acceptable acid addition salt thereof, which affords sertraline having a high content of the (±)-cis isomer of sertraline.

Another object of the present invention is to provide an improved process for the preparation of (±)-cis sertraline that is convenient wherein the synthesis can be accomplished by hydrogenation method using palladium on alumina as the catalyst and moderate reaction conditions and yet achieving high yields.

Another object of the present invention is to provide an improved process for the preparation of (±)-cis sertraline that would include the use of simple pressure reactor, such as an autoclave, thus making the process cost effective.

Another object of the present invention is to provide an improved process for the preparation of (±)-cis sertraline that would be economical and can be accomplished with crude sertraline- 1 -imine as the substrate. Yet another object of the present invention is to provide an improved process for the preparation of (±)-cis sertraline with the undesirable dehalogenated side products in reduced amount.

Still another object of the present invention is to provide an improved process for the manufacture of (±)-cis sertraline that would result in highly pure product.

SUMMARY OF THE INVENTION

Thus according to the basic aspect of the present invention there is provided a process for preparing sertraline and/ or a pharmaceutically acceptable acid addition salt thereof comprising the step of hydrogenating 4-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl-l- naphthalenimine ("sertraline- 1-imine") using palladium supported on alumina as the catalyst in an autoclave in the presence of a polar solvent and at a temperature ranging from 25°C to 35°C to obtain (±)-cis/trans-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N- methyl-1-naphthalenamine (sertraline) with the cis racemate of sertraline as the major product.

In accordance with another aspect of the present invention, the product, racemic cis (+) sertraline can be further resolved using a chiral acid and then directly converted to a pharmaceutically acceptable acid addition salt e.g. hydrochloride.

In accordance with the above aspect of the present invention, the process comprises converting the (±)-cis racemate of sertraline to cis (IS, 4S) sertraline mandelate salt or cis (IS, 4S) sertraline hydrochloride.

In accordance with another aspect of the present invention in the process for preparing sertraline and/ or a pharmaceutically acceptable acid addition salt thereof the hydrogenation reaction is carried out using 5% palladium on alumina (Pd/alumina) as the catalyst. In accordance with the above aspect of the present invention, the process comprises the loading of catalyst for said hydrogenation reaction to be 2.5-7.5 wt. % with respect to the substrate, sertraline- 1-imine, more preferably 3 wt. % loading of the catalyst.

In accordance with another aspect of the present invention in the process for preparing sertraline and/ or a pharmaceutically acceptable acid addition salt thereof the hydrogenation reaction is carried out in an autoclave (pressure reactor).

In accordance with the above aspect of the present invention the process comprises the hydrogen pressure of the autoclave in said hydrogenation step to be about 10 - 20 kg, preferably 10 kg.

In accordance with another aspect of the present invention, in the process for preparing sertraline and/ or a pharmaceutically acceptable acid addition salt thereof, the solvent for said hydrogenation reaction is selected from a polar solvent. The polar solvent may be selected from an alcohol, for example, methanol, ethanol or a ketone for example, methyl ethyl ketone.

In accordance with another aspect of the present invention in the process for preparing sertraline and/ or a pharmaceutically acceptable acid addition salt thereof the hydrogenation reaction is completed in about 28-30 hrs.

In accordance with another aspect of the present invention in the process for preparing sertraline and/ or a pharmaceutically acceptable acid addition salt thereof the "imine" charged in the autoclave could be used directly as obtained from the preceding step without any purification which significantly reduced the number of steps which makes the process cost effective and industrially viable. DETAILED DESCRIPTION OF THE INVENTION

The invention as described herein before thus basically involves subjecting the 4-(3,4- dichlorophenyl)-3 ,4-dihydro-N-methyl- 1 -naphthalenimine (sertraline- 1 -imine) as obtained without further purification from the preceding step of the reaction between sertralone and methyl amine to a hydrogenation step with Pd/alumina as the catalyst with a catalyst charging of preferably 3 wt.% with respect to sertraline- 1 -imine in an autoclave (pressure reactor) under 10 kg hydrogen pressure and a temperature range of 25-35°C whereby a mixture of (±)-cis sertraline and (±)-trans sertraline with a high ratio of Cis: Trans :: 87%: 5% (determined by HPLC) is attained. The method is schematically presented as follows:

(±)- cis-sertraline -(Major) Sertralιne-1 -ιmιne

+ (±)- trans-sertraline(Minor)

According to the present invention, the starting compound, sertraline- 1 -imine can be obtained by reacting 4-(3,4-dichlorophenyl)-3,4-dihydro-l-naphthalenone (sertralone) with methyl amine in the presence of an acid catalyst such as that disclosed in the prior art.

The hydrogenation catalyst used in the process of this invention has a 5 + 0.2% palladium content loaded on 95% alumina support where the particle size distribution is as follows:

DlO: 5-8 microns D50: 18-20 microns D90: 33-35 microns Bet Surface Area: Surface Area: 200-250 m²/gm Pore Volume: 0.5-0.7 gm/cc Average Pore Size: 90-100 A⁰

Hydrogenation is carried out in an autoclave (pressure reactor) in a polar solvent. The polar solvent may be selected from an alcohol, for example, methanol, ethanol or a ketone for example, methyl ethyl ketone. The amount of catalyst used is 2.5- 7.5 wt. % with respect to the sertraline- 1-imine, 3 wt. % charging of the catalyst in autoclave is preferable. Hydrogenation is carried out at a temperature in the range of 25-35°C under 10- 20 kg hydrogen pressure, over a period of 28-30 hours resulting in the decrease of the starting compound, sertraline- 1-imine content to < 0.1%.

The hydrogenation is followed by filtering the catalyst and distilling out the solvent completely. The (±)-cis sertraline is resolved using a chiral acid, for example, D (-) mandelic acid in an alcohol, for example, ethanol to obtain the corresponding D (-) mandelate salt, which is finally hydrolysed to get the active cis-(lS, 4S) sertraline.

The details of the invention, its objects and advantages are explained hereunder in greater detail in relation to non-limiting exemplary illustrations as per the following examples:

Example 1: Preparation of cisdS, 4S) Sertraline Mandelate using methanol

A mixture of 4-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl-l-naphthalenimine (sertraline- l-imine)( 100 g), 5% Pd/alumina (3 g) in methanol (1200 ml) was charged in an autoclave and subjected to hydrogenation at a pressure of 10 kg and temperature in the range of 26-29°C for 28-30 hours till the sertraline- 1-imine content was less than 0.1%.

After reduction, the catalyst was filtered, washed with methanol. The filtrate was charcoalised, filtered and then washed again with methanol. The filtrate was then distilled out completely under vacuum.

Yield: 91.52% (±)-cis isomer and 6.54% (+)- trans isomer Dehalogenated product content: 0.23%.

D-(-) mandelic acid (27.5 g) in ethanol (600 ml) was added to the crude base obtained after hydrogenation and heated to a temperature in the range of 50-55⁰C with stirring for 2 hours. The reaction mixture was cooled to a temperature in the range of 15-20⁰C, stirred for 1 hour and then filtered. The filtrate was washed with ethyl alcohol, suck dried well & again dried at a temperature in the range of 50-55⁰C under vacuum. Crude sertraline mandelate was then further purified by recrystallisation from methanol to obtain 55 g of pure cis (IS, 4S)- 4-(3,4dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l- naphthalenamine mandelate salt. Yield 31%, Purity: 99.23%.

Example 2: Preparation of Sertraline Hydrochloride from cis (1S,4S) Sertraline Mandelate Cis-(lS,4S)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l- naphthalenamine mandelate salt (45 g) as obtained in example 2 was added to ethyl acetate (280 ml) and cooled. The pH of the resulting solution was adjusted to 9-10 using 10% caustic solution. The aqueous layer was separated and extracted with ethyl acetate. The organic layer was given water wash to wash out the free sodium hydroxide. Ethyl acetate was distilled out partially. The reaction mixture was heated to a temperature in the range of 60-65⁰C and concentrated hydrochloric acid (20.5 ml) was added to convert it into sertraline hydrochloride. The reaction mixture was slowly cooled to a temperature in the range of 25-30⁰C and then filtered, the residue was washed with ethyl acetate, dried at a temperature in the range of 50-55⁰C under vacuum to give 29 g of cis (IS, 4S)-4-(3,4- dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l-naphthalenamine hydrochloride [cis (IS, 4S) Sertraline Hydrochloride]. The product passed the quality control test as per European Pharmacopoeia (EP). Chiral purity=99.96% Example 3: Preparation of CisdS, 4S) Sertraline Mandelate using methyl ethyl ketone

A mixture of 4-(3,4-dichlorophenyl)-3,4-dihydro-N-methyl-l-naphthalenimine (sertraline- 1 -imine) (25 g, dry), 5% Pd/alumina (0.75g), in methyl ethyl ketone (MEK) (250 ml) was charged in an autoclave and subjected to hydrogenation at a pressure of 8- 10 kg and temperature in the range of 25-35°C for 17.5 hours till sertraline- 1 -imine content was less than 0.1%. 85-90% of (±)-cis isomer and 5-8% of (±)-trans isomer was obtained. The catalyst was washed with methyl ethyl ketone and combined filtrate with the washings was distilled out completely under vacuum. D (-) mandelic acid (7 g) in ethanol (150ml) was added to the crude base and the mixture was heated to a temperature in the range of 77-78°C and was stirred for 2 hours. The reaction mixture was then cooled to a temperature in the range of 15-20⁰C, stirred for 1 hour and then filtered. The filtrate was given ethanol wash (2 x 25 ml), suck dried well and then dried at a temperature in the range of 50-55⁰C under vacuum. Further purification was carried out by dissolving the crude cis mandelate salt in (100ml) methanol at refluxing temperature. Methanol was distilled out at 60-70⁰C (keeping 60 ml volume). The resulting mixture was cooled to 0-5⁰C and then stirred for 1 hour and filtered. The residue was given (10 ml) methanol wash, suck dried well and dried at 50- 55°C under vacuum to obtain 9.7 g of cis (IS, 4S)-4-(3, 4-dichlorophenyl)-l,2,3,4- tetrahydro-N-methyl-1-naphthalenamine mandelate salt. Yield: 26%, cis isomer purity: 97.67%, trans isomer: nil, imine: 0.01%.

The above obtained cis-(lS, 4S)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N-methyl-l- naphthalenamine mandelate salt was converted to cis-(lS, 4S) sertraline hydrochloride by following the procedure as described in the Example 2.

The table given below explains the effect of different catalysts used in the hydrogenation step of the present process of this invention. The table clearly indicates that the use of palladium/ alumina as catalyst is advantageous over other known catalysts, which can be used for the conversion of sertraline- 1 -imine to the corresponding amine. Table 1: Comparative data on different kinds of Catalyst used for reduction

The results presented in the above table illustrate that: 1) Using Pd/C as catalyst trans isomer formation is 10-15%, affecting yield of the desired product. 2) Using Pd/CaCO₃ or Pd/alumina as catalyst yields and other process analysis are comparable. However, the rate of reaction is better when Pd/alumina is used as the catalyst as compared to Pd/CaCO₃ when used as the catalyst Also, Pd/alumina is effective in catalysing a crude imine solution as compared to the prior art WO 2006/129324 whereby purified imine is converted to the cis racemate using Pd/CaCO₃. Based on the above study results, it is evident that use of Pd/alumina as the catalyst for the hydrogenation of sertraline- 1-imine is significantly advantageous over other hydrogenation catalysts reported in the prior art as discussed herein.

It is thus possible by way of the present invention to achieve the much-desired synthesis of sertraline enriched in its cis (+) isomer content, a key step in the manufacture of cis - (IS, 4S) sertraline hydrochloride. The process of invention is convenient and economical thereby being advantageous for executing the synthesis of cis (+) sertraline in a pressure reactor (autoclave) using 5% Pd/ alumina as the catalyst in high yields with high content of the desired (±)-cis isomer at an industrial scale.

The process stands to be energy efficient and easy operable for industry whereby the reaction is carried out at mild temperatures of 25-35°C, under 10 kg of H₂ pressure in an autoclave without calling for any kind of special reactor such as trickle bed reactor to affect the transformation of sertraline- 1-imine to the desired (+) cis isomer of sertraline in higher amount.

Importantly and most advantageously the process does not involve any special reactor or high temperatures and is thus found to be highly beneficial for wide industrial application and use in manufacture of sertraline and/ or a pharmaceutically acceptable acid addition salt thereof.

Claims

WE CLAIM:

1. A process for preparing (+)-cis-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-N- methyl-1-naphthalenamine (sertraline) and/or a pharmaceutically acceptable acid addition salt thereof comprising hydrogenation of 4-(3,4-dichlorophenyl)-3,4- dihydro-N-methyl-1-naphthalenimine (sertraline- 1-imine) in the presence of a polar solvent using palladium/alumina as a catalyst at a temperature ranging from 25°C to 35°C to obtain (±)-cis/trans-sertraline with the (±)-cis racemate of sertraline as the major product.

2. The process as claimed in claim 1, wherein the catalyst for said hydrogenation of sertraline- 1-imine comprises 5% palladium/alumina and loading of said catalyst is 2.5-7.5 wt. % with respect to sertraline- 1-imine.

3. The process as claimed in claim 2, wherein the loading of said catalyst is 3 wt. % with respect to sertraline- 1-imine.

4. The process as claimed in any one of the preceding claims, wherein the palladium in the palladium/alumina catalyst has a particle size distribution as Dio: 5-8 microns, D50: 18-20 microns, D₉0: 33-35 microns.

5. The process as claimed in any one of the preceding claims, wherein the surface area of said palladium/alumina catalyst is 200-250 m²/gm, the pore volume in the range of 0.5-0.7 gm/cc and average pore size in the range of 90-100 A⁰.

6. The process as claimed in claim 1, wherein said hydrogenation of sertraline- 1-imine is carried out in an autoclave (pressure reactor).

7. The process as claimed in claim 1, wherein said hydrogenation of sertraline- 1-imine is carried out under a hydrogen pressure of 10-20 kg.

8. The process as claimed in claim 7, wherein the hydrogen pressure is 10 kg.

9. The process as claimed in claim 1, wherein the polar solvent is selected from an alcohol or a ketone.

10. The process as claimed in claim 9, wherein the alcohol is methanol.

11. The process as claimed in claim 9, wherein the ketone is methyl ethyl ketone.

12. The process as claimed in claim 1, wherein the percentage (%) of (+) cis sertraline obtained from the hydrogenation of sertraline- 1-imine ranges from 85-90%.

13. The process as claimed in claim 1, wherein said process further comprises converting the cis (+) racemate of sertraline to cis (IS, 4S) sertraline mandelate salt or cis (IS, 4S) sertraline hydrochloride.

14. A process for preparing sertraline and/or a pharmaceutically acceptable acid addition salt thereof substantially as herein described and illustrated with reference to the accompanying examples.