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WO2010076763A2 - Procédé amélioré de préparation de sertraline - Google Patents

Procédé amélioré de préparation de sertraline Download PDF

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Publication number
WO2010076763A2
WO2010076763A2 PCT/IB2009/055979 IB2009055979W WO2010076763A2 WO 2010076763 A2 WO2010076763 A2 WO 2010076763A2 IB 2009055979 W IB2009055979 W IB 2009055979W WO 2010076763 A2 WO2010076763 A2 WO 2010076763A2
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WO
WIPO (PCT)
Prior art keywords
sertraline
cis
imine
catalyst
hydrogenation
Prior art date
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Ceased
Application number
PCT/IB2009/055979
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English (en)
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WO2010076763A3 (fr
Inventor
Vilas Vasant Pandit
Rajesh Naik
Pravin Karnik
Nitin Pawar
Pranay Shah
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Piramal Enterprises Ltd
Original Assignee
Piramal Healthcare Ltd
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Filing date
Publication date
Application filed by Piramal Healthcare Ltd filed Critical Piramal Healthcare Ltd
Publication of WO2010076763A2 publication Critical patent/WO2010076763A2/fr
Anticipated expiration legal-status Critical
Publication of WO2010076763A3 publication Critical patent/WO2010076763A3/fr
Ceased legal-status Critical Current

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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

Definitions

  • 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.
  • 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®.
  • cyclohexylamine, sertraline which is structurally represented above exist in at least two isomeric forms: cis trans
  • the carbon atoms are chiral in 1- and 4-positions.
  • sertraline has the (IS, 4S)-configuration.
  • 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.
  • 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 (NaBH 4 ) used for the conversion of sertraline- 1-imine to sertraline, gives ( ⁇ )-cis/ trans ratio of 1:1.
  • NaBH 4 sodium borohydride
  • 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 10-100 0 C 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 PtO 2 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 (100-150 0 C) 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 60 0 C 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 20-50 0 C 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.
  • a catalyst selected from palladium or platinum
  • a dehalogenation inhibitor such as an ester of phosphorous or hypophosphorous acid
  • 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
  • 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 (CaCO 3 ) and barium carbonate (BaCO 3 ) within a temperature range of 10-40 0 C 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%.
  • alkaline earth metal carbonate selected from calcium carbonate (CaCO 3 ) and barium carbonate (BaCO 3 )
  • 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 80-150 0 C and 5-20 bar.
  • 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.
  • Pd/alumina catalyst for such conversion of imine in the above mentioned trickle bed reactor.
  • 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.
  • 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.
  • 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.
  • 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.
  • the process comprises converting the ( ⁇ )-cis racemate of sertraline to cis (IS, 4S) sertraline mandelate salt or cis (IS, 4S) sertraline hydrochloride.
  • the hydrogenation reaction 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.
  • 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.
  • the hydrogenation reaction is carried out in an autoclave (pressure reactor).
  • the process comprises the hydrogen pressure of the autoclave in said hydrogenation step to be about 10 - 20 kg, preferably 10 kg.
  • 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.
  • 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:
  • 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:
  • 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.
  • 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 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 H 2 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.
  • 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.

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

Abstract

La présente invention concerne un procédé de préparation de (±)-cis-4-(3,4-dichlorophényl)-1,2,3,4-tétrahydro-N-méthyl-1-naphtalènamine (sertraline) et/ou d'un sel d'addition d'acide pharmaceutiquement acceptable de celle-ci qui comprend l'hydrogénation de 4-(3,4-dichlorophényl)-3,4-dihydro-N-méthyl-1-naphtalènimine (sertraline-1-imine) en présence d'un solvant polaire en utilisant du palladium/alumine en tant que catalyseur à une température dans la plage de 25°C à 35°C pour obtenir la (±)-cis/trans-sertraline avec le (±)-cis racémate de sertraline en tant que produit principal.
PCT/IB2009/055979 2009-01-02 2009-12-29 Procédé amélioré de préparation de sertraline Ceased WO2010076763A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN9/MUM/2009 2009-01-02
IN9MU2009 2009-01-02

Publications (2)

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WO2010076763A2 true WO2010076763A2 (fr) 2010-07-08
WO2010076763A3 WO2010076763A3 (fr) 2012-09-07

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Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19812054A1 (de) * 1998-03-19 1999-09-23 Hoechst Schering Agrevo Gmbh Verfahren zur Herstellung 4-substituierter cis-Cyclohexylamine
US7276629B2 (en) * 2003-04-14 2007-10-02 Teva Pharmaceutical Industries Ltd. Hydrogenation of imine intermediates of sertraline with catalysts
CA2576097C (fr) * 2005-06-03 2009-10-27 Hetero Drugs Limited Synthese hautement stereoselective de sertraline

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