WO2007071421A1 - An improved process for the preparation of sertraline - Google Patents

An improved process for the preparation of sertraline Download PDF

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Publication number
WO2007071421A1
WO2007071421A1 PCT/EP2006/012393 EP2006012393W WO2007071421A1 WO 2007071421 A1 WO2007071421 A1 WO 2007071421A1 EP 2006012393 W EP2006012393 W EP 2006012393W WO 2007071421 A1 WO2007071421 A1 WO 2007071421A1
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WO
WIPO (PCT)
Prior art keywords
hydrochloride
salt
sertraline
methanol
amide
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PCT/EP2006/012393
Other languages
French (fr)
Inventor
Ramana Kintali
Raji Nair
Pravin Barve
Original Assignee
Sandoz Ag
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Publication date
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Publication of WO2007071421A1 publication Critical patent/WO2007071421A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/44—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers
    • C07C209/52—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers by reduction of imines or imino-ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the present invention relates to an improved process for the preparation of sertraline and its pharmaceutically acceptable salts.
  • Sertraline hydrochloride chemically known as (1S-cis)-4-(3,4dichlorophenyl)-1, 2,3,4- tetrahydro-N-methyl-1-naphthalenamine hydrochloride is described in EP 30 081.
  • racemic sertraline can be obtained by hydrogenating N-[4-(3,4- dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (Schiff base) with 10% Pd/C catalyst at atmospheric pressure or by sodium borohydride (NaBH 4 ) in an alcohol preferably methanol.
  • WO 99/36394 describes a synthesis of sertraline by reductive amination which involves combining racemic 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone with monomethylamine and a suitable hydrogenation catalyst, such as Pd/CaCO 3 , under a hydrogen atmosphere, in an alcohol.
  • a suitable hydrogenation catalyst such as Pd/CaCO 3
  • WO 99/47486 describes a synthesis of racemic sertraline by hydrogenating its corresponding imine compound (Schiff base) in presence of a copper-containing catalyst like copper chromite, copper zinc oxide, copper boride or copper urushibara catalysts. It is further described that copper catalysts containing other elements like aluminium, chromium, zinc, barium, manganese, zirconium, vanadium, molybdenum, titanium, tantalum, niobium, tungsten, nickel, cobalt, bismuth, tin, antimonium, hafnium, rhenium, iron, cadmium, lead and/or germanium can also be used for hydrogenation.
  • a copper-containing catalyst like copper chromite, copper zinc oxide, copper boride or copper urushibara catalysts. It is further described that copper catalysts containing other elements like aluminium, chromium, zinc, barium, manganese, zirconium, vanadium, molybdenum
  • WO 01/30742 describes a synthesis of racemic sertraline by hydrogenating its corresponding N-benzyl imine compound (Schiff base) in presence of Raney nickel, Pd/C or Rh/C and an alcohol. Methylation of the corresponding compound followed by debenzylation gives racemic sertraline.
  • US 6,593,496 describes a synthesis of sertraline as its (+) enantiomer which comprises, reacting optically pure (+)enantiomer of 4-(3,4-dichlorophenyl)-3,4dihydro-1(2H)- napthalenone or an optically enriched (+) mixture of the (+) and (-)enantiomers, with monomethylamine and either titanium tetrachloride or molecular sieves followed by hydrogenating the obtained ketimine in presence of a Pd catalyst.
  • WO 01/68566 describes a process for the preparation of sertraline with a cis/trans ratio of greater than about 3:1 comprising hydrogenating sertraline-1-imine at a temperature of at least about 40 0 C using a catalyst selected from the group consisting of palladium and platinum in an organic solvent selected from the group consisting of ethanol, tetrahydrofuran, toluene, isopropanol, n-butanol, ethyl acetate, acetone, methanol, and t- butyl-methyl ether, and mixtures thereof.
  • the said patent also claims other catalyst like palladium on carbon, palladium on graphite, palladium on carbon paste, and PtO 2 .
  • the present invention relates to a process for preparing sertraline or its pharmaceutically acceptable salts which is substantially free of impurities and directly resolving the cis racemate without any purification to get pure required enantiomer of Sertraline or its pharmaceutically acceptable salts.
  • the present invention relates to a process for the preparation of (1S-cis)-4-(3,4- dichlorophenyl)-1 ,2,3,4-tetrahydro-N -methyl-1-naphthalenamine or its hydrochloride salt by catalytic hydrogenation of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalene-1- ylidene]methyl-amine or a salt thereof in presence of an amine salt and/or an amide salt.
  • Sertraline prepared according to the invention has a high purity with a content of deschlorosertraline of less than 0.1area% without any purification step.
  • Palladium and platinum are preferably used as hydrogenation catalyst in the process according to the invention.
  • the amine and/or amide salt preferably derives from an organic amine and/or organic amide and a mineral acid.
  • Suitable amine and/or amide salts are N,N-dimethylamine hydrochloride, N,N-diethylamine hydrochloride, diphenylamine hydrochloride, pyridium hydrochloride, N- methyl acetamide hydrochloride and/or N,N-dimethyl acetamide hydrochloride.
  • the process of the present invention is carried out as follows: a) addition of a solution of an amine salt in C 1 -C 5 alcohol to a mixture of N-[4-(3,4- dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (Schiff base) and Ci-C 5 alcohol under stirring; b) addition of a catalyst like palladium on carbon or platinum on carbon as a slurry in C 1 - C5 alcohol to the reaction solution of step (a); c) stirring the reaction mixture of step (b) under hydrogen pressure at about 2-5 kg pressure; d) filtration of reaction mass of step (c ) and washing the catalyst with C 1 -C 5 alcohol; e) acidifying the filtrate of step (d) by addition of hydrochloric acid followed by concentrating under reduced pressure; f) isolating the solid from the residue of step (e) by stirring in an aromatic hydrocarbon solvent and washing the solid with water; g) drying the obtained solid from
  • Suitable C 1 -C 5 alcohols for the process of the invention include methanol, ethanol, propanol, isopropanol, n-butanol, n-pentanol. Methanol is the preferred C 1 -C 5 alcohol.
  • the reaction mixture was diluted by addition of 500 ml of methanol, filtered through hyflo bed and washed with 500 ml of methanol.
  • the filtrate was acidified to pH 1-2 with hydrochloric acid.
  • Solvent was distilled off from filtrate under reduced pressure and 500 ml of toluene was added to the residue under stirring for about 15 minutes.
  • the separated solid was filtered , washed with water (300 ml). The solid was dried under reduced pressure at 50- 55°C for 5 hours to give the title compound. Yield: 65 grams with cis/trans ratio: 99:0.9, Purity: 99 area%, deschloro impurity:0.09 area%
  • the reaction mixture was diluted by addition of 1 litere of methanol, filtered through hyflo bed and washed with 500 ml of methanol.
  • the filtrate was acidified to pH 1-2 with 33ml of hydrochloric acid.
  • Solvent was distilled off from filtrate under reduced pressure and 500 ml of toluene was added to the residue under stirring for about 15 minutes.
  • the separated solid was filtered , washed with water (300 ml). The solid was dried under reduced pressure at 50-55 0 C for 5 hours to give the title compound. Yield: 65 grams with cis/trans ratio: 99:0.9, Purity: 99 area%, deschloro impurity:0.09 area%
  • the reaction mixture was diluted by addition of 100 ml of methanol, filtered through hyflo bed and washed with 100 ml of methanol.
  • the filtrate was acidified to pH 1-2 with 3 ml of hydrochloric acid.
  • Solvent was distilled off from filtrate under reduced pressure and 50 ml of toluene was added to the residue under stirring for about 15 minutes.
  • the separated solid was filtered , washed with water (30 ml). The solid was dried under reduced pressure at 50- 55°C for 5 hours to give the title compound. Yield: 8.5 grams with cis/trans ratio: 99:0.9, Purity: 99 area%, deschloro impurity:0.03 area%

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to a process for preparing sertraline of high purity by hydrogenating the corresponding imine compound (Schiff base) in the presence of amine salt and/or amide salt using a catalyst preferably a palladium or platinum catalyst.

Description

An improved process for the preparation of Sertraline
The present invention relates to an improved process for the preparation of sertraline and its pharmaceutically acceptable salts.
Sertraline hydrochloride chemically known as (1S-cis)-4-(3,4dichlorophenyl)-1, 2,3,4- tetrahydro-N-methyl-1-naphthalenamine hydrochloride is described in EP 30 081. According to this patent racemic sertraline can be obtained by hydrogenating N-[4-(3,4- dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (Schiff base) with 10% Pd/C catalyst at atmospheric pressure or by sodium borohydride (NaBH4) in an alcohol preferably methanol.
WO 99/36394 describes a synthesis of sertraline by reductive amination which involves combining racemic 4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone with monomethylamine and a suitable hydrogenation catalyst, such as Pd/CaCO3 , under a hydrogen atmosphere, in an alcohol.
WO 99/47486 describes a synthesis of racemic sertraline by hydrogenating its corresponding imine compound (Schiff base) in presence of a copper-containing catalyst like copper chromite, copper zinc oxide, copper boride or copper urushibara catalysts. It is further described that copper catalysts containing other elements like aluminium, chromium, zinc, barium, manganese, zirconium, vanadium, molybdenum, titanium, tantalum, niobium, tungsten, nickel, cobalt, bismuth, tin, antimonium, hafnium, rhenium, iron, cadmium, lead and/or germanium can also be used for hydrogenation.
WO 01/30742 describes a synthesis of racemic sertraline by hydrogenating its corresponding N-benzyl imine compound (Schiff base) in presence of Raney nickel, Pd/C or Rh/C and an alcohol. Methylation of the corresponding compound followed by debenzylation gives racemic sertraline.
US 6,593,496 describes a synthesis of sertraline as its (+) enantiomer which comprises, reacting optically pure (+)enantiomer of 4-(3,4-dichlorophenyl)-3,4dihydro-1(2H)- napthalenone or an optically enriched (+) mixture of the (+) and (-)enantiomers, with monomethylamine and either titanium tetrachloride or molecular sieves followed by hydrogenating the obtained ketimine in presence of a Pd catalyst.
WO 01/68566 describes a process for the preparation of sertraline with a cis/trans ratio of greater than about 3:1 comprising hydrogenating sertraline-1-imine at a temperature of at least about 400C using a catalyst selected from the group consisting of palladium and platinum in an organic solvent selected from the group consisting of ethanol, tetrahydrofuran, toluene, isopropanol, n-butanol, ethyl acetate, acetone, methanol, and t- butyl-methyl ether, and mixtures thereof. The said patent also claims other catalyst like palladium on carbon, palladium on graphite, palladium on carbon paste, and PtO2.
The main disadvantage of all known prior art processes is the formation of impurities mainly deschlorosertraline during the preparation of racemic Sertraline hydrochloride which requires purification techniques like two to three recrystalizations to minimize these impurities and resolving the cis racemate to get the final compound. These purification methods affect the yield of the final product.
The present invention relates to a process for preparing sertraline or its pharmaceutically acceptable salts which is substantially free of impurities and directly resolving the cis racemate without any purification to get pure required enantiomer of Sertraline or its pharmaceutically acceptable salts.
Accordingly, the present invention relates to a process for the preparation of (1S-cis)-4-(3,4- dichlorophenyl)-1 ,2,3,4-tetrahydro-N -methyl-1-naphthalenamine or its hydrochloride salt by catalytic hydrogenation of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalene-1- ylidene]methyl-amine or a salt thereof in presence of an amine salt and/or an amide salt.
Sertraline prepared according to the invention has a high purity with a content of deschlorosertraline of less than 0.1area% without any purification step.
Palladium and platinum are preferably used as hydrogenation catalyst in the process according to the invention. The amine and/or amide salt preferably derives from an organic amine and/or organic amide and a mineral acid. Suitable amine and/or amide salts are N,N-dimethylamine hydrochloride, N,N-diethylamine hydrochloride, diphenylamine hydrochloride, pyridium hydrochloride, N- methyl acetamide hydrochloride and/or N,N-dimethyl acetamide hydrochloride.
Typically the process of the present invention is carried out as follows: a) addition of a solution of an amine salt in C1-C5 alcohol to a mixture of N-[4-(3,4- dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine (Schiff base) and Ci-C5 alcohol under stirring; b) addition of a catalyst like palladium on carbon or platinum on carbon as a slurry in C1- C5 alcohol to the reaction solution of step (a); c) stirring the reaction mixture of step (b) under hydrogen pressure at about 2-5 kg pressure; d) filtration of reaction mass of step (c ) and washing the catalyst with C1-C5 alcohol; e) acidifying the filtrate of step (d) by addition of hydrochloric acid followed by concentrating under reduced pressure; f) isolating the solid from the residue of step (e) by stirring in an aromatic hydrocarbon solvent and washing the solid with water; g) drying the obtained solid from step (f) under reduced pressure at 50-550C.
Suitable C1-C5 alcohols for the process of the invention include methanol, ethanol, propanol, isopropanol, n-butanol, n-pentanol. Methanol is the preferred C1-C5 alcohol.
Examples
Example 1
To a mixture of 100 grams (0.328 moles) of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)- naphthalenylidenejmethanamine (Schiff base) and methanol (1.8 liters) a solution of pyridinium hydrochloride (46 grams, 0.393 moles) in methanol (100 ml) was added under stirring. A slurry of 4 grams of Pd/C (50 % wet) with methanol (100 ml) was added and the contents were stirred under hydrogen pressure (2-3 kg pressure) at 25-35°C for about 6 hours. The reaction mixture was diluted by addition of 500 ml of methanol, filtered through hyflo bed and washed with 500 ml of methanol. The filtrate was acidified to pH 1-2 with hydrochloric acid. Solvent was distilled off from filtrate under reduced pressure and 500 ml of toluene was added to the residue under stirring for about 15 minutes. The separated solid was filtered , washed with water (300 ml). The solid was dried under reduced pressure at 50- 55°C for 5 hours to give the title compound. Yield: 65 grams with cis/trans ratio: 99:0.9, Purity: 99 area%, deschloro impurity:0.09 area%
Example 2
To a mixture of 100 grams (0.328 moles) of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)- naphthalenylidene]methanamine (Schiff base) and methanol (1.8 liters) a solution of N1N- dimethylacetamide hydrochloride (48 grams.0.393 moles) in methanol (100 ml) was added under stirring. A slurry of 8 grams of Pd/C (50 % wet) with methanol (100 ml) was added and the contents were stirred under hydrogen pressure (2-3 kg pressure) at 25-35°C for about 4 hours. The reaction mixture was diluted by addition of 1 litere of methanol, filtered through hyflo bed and washed with 500 ml of methanol. The filtrate was acidified to pH 1-2 with 33ml of hydrochloric acid. Solvent was distilled off from filtrate under reduced pressure and 500 ml of toluene was added to the residue under stirring for about 15 minutes. The separated solid was filtered , washed with water (300 ml). The solid was dried under reduced pressure at 50-550C for 5 hours to give the title compound. Yield: 65 grams with cis/trans ratio: 99:0.9, Purity: 99 area%, deschloro impurity:0.09 area% Example 3
To a mixture of 10 grams (0.0328 moles) of N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)- naphthalenylidenejmethanamine (Schiff base) and methanol (180 ml) a solution of pyridinium hydrochloride (5.5 grams,0.047 moles) in methanol (10 ml) was added under stirring. A slurry of 0.8 grams of Pt/C (5 % wet) with methanol (10 ml) was added and the contents were stirred under hydrogen pressure (2-3 kg pressure) at 25-350C for about 30 minutes. The reaction mixture was diluted by addition of 100 ml of methanol, filtered through hyflo bed and washed with 100 ml of methanol. The filtrate was acidified to pH 1-2 with 3 ml of hydrochloric acid. Solvent was distilled off from filtrate under reduced pressure and 50 ml of toluene was added to the residue under stirring for about 15 minutes. The separated solid was filtered , washed with water (30 ml). The solid was dried under reduced pressure at 50- 55°C for 5 hours to give the title compound. Yield: 8.5 grams with cis/trans ratio: 99:0.9, Purity: 99 area%, deschloro impurity:0.03 area%

Claims

Claims
1. A process for the preparation of (1S-cis)-4-(3,4-dichlorophenyl)-1 ,2,3,4-tetrahydro-N - methyl-1-naphthalenamine or its hydrochloride salt by catalytic hydrogenation of N-[4- (3,4-dichloro-phenyl)-3,4-dihydro-1(2H)-naphthalene-1-ylidene]methylamine or a salt thereof in presence of an amine salt and/or an amide salt.
2. A process according to claim 1 , wherein the amine salt and/or amide salt derive from an organic amine and/or organic amide and a mineral acid.
3. A process according to claims 1 to 2, wherein the amine salt is N,N-dimethylamine hydrochloride, N,N-diethylamine hydrochloride, diphenylamine hydrochloride and/or pyridinium hydrochloride.
4. A process according to claims 1 to 2, wherein the amide salt is N-methyl acetamide hydrochloride and/or N,N-dimethyl acetamide hydrochloride.
5. A process according to claims 1 to 6, wherein the catalyst used for catalytic hydrogenation is palladium or platinum.
PCT/EP2006/012393 2005-12-23 2006-12-21 An improved process for the preparation of sertraline WO2007071421A1 (en)

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GB0526444.5 2005-12-23
GBGB0526444.5A GB0526444D0 (en) 2005-12-23 2005-12-23 Sertraline acid addition salt, its prepartion and its use in the preparation of sertraline hydrochloride form ll

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3989756A (en) * 1973-09-06 1976-11-02 Nippon Kayaku Kabushiki Kaisha Process for the production of halogenated aromatic primary amines
EP0347796A2 (en) * 1988-06-22 1989-12-27 Hoechst Aktiengesellschaft Preparation process of 4-chloro-2,5-dimethoxy-aniline
US4960936A (en) * 1987-12-31 1990-10-02 Ciba-Geigy Corporation Process for the preparation of halogenated aromatic primary amines
US5068436A (en) * 1989-03-10 1991-11-26 E. I. Du Pont De Nemours And Company Hydrogenation of halonitrobenzenes without dehalogenation
WO1999057093A1 (en) * 1998-05-05 1999-11-11 EGIS Gyógyszergyár Rt. Process for the preparation of sertraline and its 1,r-stereoisomer
WO2002102761A1 (en) * 2001-06-15 2002-12-27 Orion Corporation Fermion A novel process for the preparation of (is-cis) -4-(3, 4-dichlorophenyl) -1, 2, 3, 4 - tetrahydro-n-methyl-1-naphthalenamine
US6593496B1 (en) * 1999-06-09 2003-07-15 Pfizer Inc Process for preparing sertraline from chiral tetralone

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3989756A (en) * 1973-09-06 1976-11-02 Nippon Kayaku Kabushiki Kaisha Process for the production of halogenated aromatic primary amines
US4960936A (en) * 1987-12-31 1990-10-02 Ciba-Geigy Corporation Process for the preparation of halogenated aromatic primary amines
EP0347796A2 (en) * 1988-06-22 1989-12-27 Hoechst Aktiengesellschaft Preparation process of 4-chloro-2,5-dimethoxy-aniline
US5068436A (en) * 1989-03-10 1991-11-26 E. I. Du Pont De Nemours And Company Hydrogenation of halonitrobenzenes without dehalogenation
WO1999057093A1 (en) * 1998-05-05 1999-11-11 EGIS Gyógyszergyár Rt. Process for the preparation of sertraline and its 1,r-stereoisomer
US6593496B1 (en) * 1999-06-09 2003-07-15 Pfizer Inc Process for preparing sertraline from chiral tetralone
WO2002102761A1 (en) * 2001-06-15 2002-12-27 Orion Corporation Fermion A novel process for the preparation of (is-cis) -4-(3, 4-dichlorophenyl) -1, 2, 3, 4 - tetrahydro-n-methyl-1-naphthalenamine

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