WO2006027658A2 - Process for the preparation of sertraline hydrochloride form ii - Google Patents

Process for the preparation of sertraline hydrochloride form ii Download PDF

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WO2006027658A2
WO2006027658A2 PCT/IB2005/002603 IB2005002603W WO2006027658A2 WO 2006027658 A2 WO2006027658 A2 WO 2006027658A2 IB 2005002603 W IB2005002603 W IB 2005002603W WO 2006027658 A2 WO2006027658 A2 WO 2006027658A2
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Prior art keywords
sertraline
cis
acetonitrile
hydrochloride
sertraline hydrochloride
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PCT/IB2005/002603
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French (fr)
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WO2006027658A3 (en
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Bakulesh Mafatlal Khamar
Indravadan Ambalal Modi
Murali Rajappa
K. N. Shashikala
Radha Achanath
Abhay Chheda
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Bakulesh Mafatlal Khamar
Indravadan Ambalal Modi
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Publication of WO2006027658A2 publication Critical patent/WO2006027658A2/en
Publication of WO2006027658A3 publication Critical patent/WO2006027658A3/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
    • C07C209/24—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds
    • C07C209/26—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds by reduction with hydrogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/82—Purification; Separation; Stabilisation; Use of additives
    • C07C209/84—Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • 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

  • This invention relates to a process for the preparation of racemic sertraline and sertraline hydrochloride form II.
  • Sertraline (IS, 4S)-4-(3, 4-dichlorophenyl)-l, .2, 3, 4- tetrahydro-N-metihyl-1-naphthalenamine, commonly known as Sertraline, is marketed in the form of its hydrochloride salt. Sertraline is used in the treatment of depression, obsessive-compulsive disorder and panic disorder. It is a novel inhibitor of serotonin reuptake in the brain. The structure of sertraline hydrochloride is given below.
  • Sertraline hydrochloride exhibits polymorphism. Several polymorphic forms of sertraline hydrochloride have been prepared and are described in many publications.
  • US patent 5,734,083 discloses another crystalline polymorph, which is reported to exhibit improved bioavailability as compared to form I sertraline hydrochloride.
  • the said novel polymorph is designated polymorph Ti.
  • US patent 6,452,054 and US patent 6,500,987 disclose novel polymorphic forms of solvated and hydrated forms of sertraline hydrochloride which are designated as VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV and XVI.
  • US 6,495,721 and US application 2004/0030190 disclose novel methods for the preparation of sertraline hydrochloride form II, wherein a solution of free base in n-butanol is treated with gaseous hydrogen chloride.
  • form II is also prepared by crystallization of solvate and hydrate forms of sertraline hydrochloride from a solvent selected form the group consisting of acetone, t-butyl-methyl ether, cyclohexane, n-butanol and ethyl acetate.
  • WO 01/32601 discloses novel polymorphic forms denoted as CSC2 and CSCl.
  • the patent also discloses processes to prepare amorphous form and polymorphic forms I, II, V and Ti of sertraline hydrochloride.
  • sertraline hydrochloride form II is prepared by dissolving sertraline free base in ketone, seeding the solution with crystals of polymorphic form II and adding a solution of hydrogen chloride.
  • the ketone used is acetone, methyl ethyl ketone or methyl isobutyl ketone.
  • WO 02/096859 relates to the preparation of sertraline hydrochloride form II by- dissolving the sertraline base into ethyl acetate, adding isopropanol as a solvent, followed by addition of hydrogen chloride dissolved in ethyl acetate or in gaseous form, and then isolating and drying to yield sertraline hydrochloride form II.
  • WO 03/099761 discloses a method for the preparation of sertraline hydrochloride form II, wherein a solution of the free base in 2-propanol is treated with 2- propanolic hydrochloric acid to obtain a viscous gel. The resulting mixture is further diluted with diisopropyl ether to obtain a crystalline product.
  • Sertraline hydrochloride form II is generally prepared from cis (+) sertraline base or sertraline mandelate.
  • the cis (+) sertraline base is obtained by resolution of cis sertraline racemates using D (-) mandelic acid.
  • US Patent 4536518 discloses a process for preparation of sertraline, wherein the tetralone intermediate is condensed with methylamine in an aprotic solvent in the presence of TiCU, which is then hydrogenated in the presence of 10% Pd/C to a mixture of cis and trans racemates. The cis and trans isomers are separated by fractional crystallization.
  • US patent 4855500 discloses a process for the preparation of sertraline, which involves condensing tetralone with methylamine in the presence of a hydratable molecular sieve as catalyst, whereby water is effectively removed by the catalyst and the desired ketimine final product is readily obtained in pure form and in high yield.
  • the US patent 6034274 relates to a process for preparing sertraline and its acid addition salts, wherein N-methyl-[4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-napthalenamine]-N-oxide is hydrogenated in an inert solvent in the presence of a catalyst, then the resulting mixture is treated with alcoholic solution of a mineral acid, the resulting cis-racemic acid salt is converted to the free cis-base by standard techniques well-known to those skilled in the art, resolved, then the cis- (+)- base is converted to the acid addition salt.
  • WO 99/57093 discloses a process for the preparation of sertraline hydrochloride, wherein the imine is subjected to hydrogenation in the . presence of a palladium-charcoal catalyst, which is pretreated with an alkali halide to obtain racemic sertraline with a purity of 85-95%.
  • WO 01/16089 disclose a process for the preparation of sertraline hydrochloride, wherein the tetralone intermediate is treated with methylamine under reducing atmosphere in presence of Raney nickel to produce the intermediate amine. The resulting amine is converted to sertraline hydrochloride by known process.
  • the US patent 6232500 discloses a process for the preparation of sertraline, which involves a condensation reaction between tetralone intermediate and monomethylamine in a solvent such as an alcohol or a mixture of two or more alcohols.
  • a solvent such as an alcohol or a mixture of two or more alcohols.
  • the resulting imine is hydrogenated using Pd/CaC ⁇ 3 catalyst.
  • the resulting racemic mixture is resolved and finally crystallized.
  • US patent 6723878 discloses a process for the preparation of sertraline, wherein the ketimine is hydrogenated in the presence of a dehalogenation inhibitors (like triphenyl phosphite or Trimethyl phosphite) and Pd/ graphite as a catalyst.
  • a dehalogenation inhibitors like triphenyl phosphite or Trimethyl phosphite
  • US 2003/0166970 discloses a process 1 to prepare sertraline hydrochloride, wherein the imine is hydrogenated in the presence of Pd/ graphite to obtain sertraline having a cis/trans ratio greater than 12:1.
  • the literature procedures for the preparation of racemic sertraline have several disadvantages.
  • the ketimine is prepared by treating the tetralone intermediate with gaseous methylamine in the presence of dehydrating agents such as TiCl 4 and molecular sieves.
  • dehydrating agents such as TiCl 4 and molecular sieves.
  • the addition of methylamine gas to a solution containing tetralone is not convenient.
  • the use of TiCl 4 is hazardous and also results in by products such as titanium dioxide.
  • the use of molecular sieves as catalyst is not economical. Therefore there exist a need for an improved process that eliminates the disadvantages of the prior art processes for the synthesis of racemic sertraline.
  • the literature procedures for the preparation of sertraline hydrochloride form II have several disadvantages.
  • the present invention discloses a novel method for the preparation of racemic sertraline starting from the known tetralone and cis(+) sertraline hydrochloride form II from cis(+) sertraline mandelate.
  • the present invention provides a new method for preparing cis(+)sertraline hydrochloride form- II, in which the tetralone intermediate is treated with aqueous methylamine in a closed vessel at temperature of 70-80°C for 40-50 h.
  • the imine obtained is suspended in methanol and subjected to hydrogenation using Pd/ BaSCU catalyst for about 24h.
  • the resulting mass is treated with methanolic HCl to precipitate cis-(+/-)sertraline hydrochloride.
  • Conversion of cis-(+/-)sertraline hydrochloride to its cis-(+)-sertraline mandelate salt is effected by reacting with aqueous sodium hydroxide and subsequent treatment of free base with D-(-)-mandelic acid.
  • Cis-(+)-sertraline hydrochloride form-II is obtained from cis-(+)-sertraline mandelate by conversion of mandelate salt to cis-(+)-sertraline base and further dissolving base in a solvent and reacting with hydrogen chloride.
  • the process does not need any seeding.
  • the solvent is selected from the class of nitriles such as acetonitrile, propionitrile , preferably acetonitrile and mixtures thereof.
  • the crystallization of sertraline hydrochloride from acetonitrile is rapid and does not involve the intermediate gel formation.
  • the tetralone [I] is prepared by a known literature method and is purified by crystallization to a purity of at least 98%.
  • the present invention provides a method for the preparation of ketimine [II] without the use of titanium tetrachloride and molecular sieves.
  • the process employs aqueous methylamine.
  • the tetralone is converted to imine by reaction with aqueous methylamine having concentration 25-40%; preferably 35-40%.
  • the reaction is carried out at 70 - 80°C for 40-50 hours.
  • the imine is isolated by filtration.
  • the imine is • purified by leaching with methanol .
  • the purified imine [II] is then reduced by catalytic hydrogenation preferably at or below 35 0 C and at pressure of 4-5 kg for about 24 hours using Pd/BaSO4as catalyst in methanol to a mixture of cis and trans sertraline racemates.
  • the reduction of imine using Pd/BaS ⁇ 4 results in cis/trans ratio greater than 3:1.
  • the solution is treated with methanolic HCl to precipitate the cis-(+/-)-sertraline hydrochloride [III].
  • cis-(+/-)-sertraline hydrochloride [III] is converted to cis-(+/-)-sertraline base [IV] by standard techniques well known in art ('518 patent).
  • cis(+/-)-sertraline base is resolved using D-(-)-mandelic acid in ethyl acetate.
  • the cis-(+)-sertraline mandelate salt [V] obtained is treated with aqueous sodium hydroxide to yield cis-(+)-sertraline base [VI].
  • cis (+) sertraline hydrochloride form II is prepared from either cis-(+)-sertraline freebase [VI] or cis-(+)-sertraIine mandelate [V].
  • Cis-(+)-sertraline freebase [VI] or ⁇ s-(+)-sertraIine mandelate [V] is taken in acetonitrile and gaseous hydrogen chloride is bubbled through the mixture at room temperature (25 - 27 0 C) for 30 min. The temperature is raised during the passing of HCl gas to about 45°C. The addition of hydrogen chloride is continued until pH ⁇ 2 is reached. The crystalline solid formed is filtered to yield cis-(+)-sertraline hydrochloride polymorph II of formula-[VII].
  • Tetralone(50g) aqueous mono methylamine solution (40%, 150ml) and DM water (150ml) are charged into a closed vessel.
  • the mixture is heated to 75-90 0 C under stirring for 40 hours, after which the mixture is cooled to 20-25 0 C, filtered, washed with water (100ml) followed by methanol
  • Sertraline-1 -imine (12g) in methanol (60ml) is hydrogenated in the presence of catalyst Pd/BaSCU
  • Sertraline-1-imine (1Og) in tetrahydrofuran (80ml) is subjected to hydrogenation in the presence of catalyst Pd/BaSO 4 (0.2g) at 25-27°C and at a pressure of 4 kg for 6 hours.
  • the catalyst is removed by filtration. THF is removed completely, the resulting mass (sertraline free base) is taken in IPA (80ml), and hydrogen chloride gas is purged at 20-25 0 C until pH 2 is attained.
  • the precipitated solid is filtered (8.8g), which contains 83% of cis isomer, 8% of trans isomer, 5% of tetralone, and 3.4% of other impurities.
  • Cis- (IS) (IR) - N-methyl- 4- (3, 4-dichlorophenyl)- 1, 2, 3, 4 - tetra hydro - 1 - naphthalenamine hydrochloride (cis-(+/-)-sertraline hydrochloride) (100Og; 2.9 mol) is slurried in ethyl acetate (TL) and treated with 15% a ⁇ jueous NaOH (3L) to yield a solution of cis-racemate freebase in ethyl acetate!
  • the ethyl acetate solution is treated with D-(-)-Mandelic acid (30Og; 1.97mol).
  • the resulting mixture is refluxed for Ih and then cooled to room temperature (25°C).
  • the solid obtained is filtrated, washed with ethyl acetate to yield crude mandelate salt (55Og).
  • the crude mandelate salt (55Og) is slurried in methanol (2.5L) at 60 - 64°C for 1 hour.
  • the resulting mixture is cooled to room temperature and filtered to obtain pure mandelate salt (475g).
  • the purified cis mandelate salt (45Og) is suspended in ethyl acetate (2.25L).
  • the suspension is treated with 10% aqueous NaOH solution (IL) to obtain a clear solution.
  • IL aqueous NaOH solution
  • the ethyl acetate layer is separated, washed with water (2X500ml) and the solvent evaporated under reduced pressure to yield cis(+) sertraline free base.
  • the cis (+) sertraline free base (30Og; 0.98mol) is dissolved in acetonitrile (2.25L) and hydrogen chloride is bubbled through the solution at 25-27°C.
  • HCl HCl
  • the temperature of the reaction mixture raises form 25 to 5O 0 C.
  • the addition of HCl is continued until pH 2 is reached.
  • the crystalline solid thus formed is filtered , washed with acetonitrile (2X300ml) and dried at 6O 0 C under vacuum.
  • the cis (+) sertraline hydrochloride (305 g) obtained is characterized by IR, XRD and DSC and found to be polymorphic form II.
  • sertraline hydrochloride form II To a suspension of sertraline mandelate (15g; 0.0327mol) in acetonitrile (100ml), Hydrogen chloride is bubbled at 25-27°C. During the addition of HCl, the temperature of the reaction mixture raises form 24 to 45 0 C. The addition of HCl is continued until pH 2 is reached. The crystalline solid thus formed is filtered , washed with acetonitrile (2X20ml) and dried at 60°C under vacuum. The cis (+) sertraline hydrochloride (8 g) obtained is characterized by IR, XRD and DSC and found to be polymorphic form II.
  • the cis (+) sertraline free base (44Og; 1.4mol) is dissolved in n-butanol (5L) and the resulting solution is cooled to 5°C.
  • Butanol containing anhydrous hydrogen chloride (16%W/W; 380ml) is added slowly, maintaining the temperature between 5-10°C.
  • the resulting gelatinous precipitate is stirred and slowly allowed to attain room temperature (25°C) over a period of 3 hours.
  • the crystalline solid thus formed is filtered, washed with butanol and dried at 60°C under vacuum.
  • the cis(+) sertraline hydrochloride (41Og) obtained is characterized by IR, XRD and DSC and found to be polymorphic form II.

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  • Organic Chemistry (AREA)
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Abstract

The present invention relates to a novel method for preparation of sertraline hydrochloride form II from sertralone on an industrial scale.

Description

FIELD OF THE INVENTION:
This invention relates to a process for the preparation of racemic sertraline and sertraline hydrochloride form II.
BACKGROUND OF THE INVENTION:
(IS, 4S)-4-(3, 4-dichlorophenyl)-l, .2, 3, 4- tetrahydro-N-metihyl-1-naphthalenamine, commonly known as Sertraline, is marketed in the form of its hydrochloride salt. Sertraline is used in the treatment of depression, obsessive-compulsive disorder and panic disorder. It is a novel inhibitor of serotonin reuptake in the brain. The structure of sertraline hydrochloride is given below.
Figure imgf000003_0001
(+)-cis-sertraline hydrochloride
Sertraline hydrochloride exhibits polymorphism. Several polymorphic forms of sertraline hydrochloride have been prepared and are described in many publications.
The US patent 4,536,518 describes the preparation of sertraline hydrochloride wherein ethyl acetate/ether solution of the free base is treated with gaseous hydrogen chloride. In a US patent 5,248,699 it is stated that the material obtained in '518 patent is form II. The '699 patent also discloses four other polymorphs designated as forms I, III, IV and V.
US patent 5,734,083 discloses another crystalline polymorph, which is reported to exhibit improved bioavailability as compared to form I sertraline hydrochloride. The said novel polymorph is designated polymorph Ti.
US patent 6,452,054 and US patent 6,500,987 disclose novel polymorphic forms of solvated and hydrated forms of sertraline hydrochloride which are designated as VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV and XVI.
US 6,495,721 and US application 2004/0030190 disclose novel methods for the preparation of sertraline hydrochloride form II, wherein a solution of free base in n-butanol is treated with gaseous hydrogen chloride. According to US 6,495,721 form II is also prepared by crystallization of solvate and hydrate forms of sertraline hydrochloride from a solvent selected form the group consisting of acetone, t-butyl-methyl ether, cyclohexane, n-butanol and ethyl acetate.
WO 01/32601 discloses novel polymorphic forms denoted as CSC2 and CSCl. The patent also discloses processes to prepare amorphous form and polymorphic forms I, II, V and Ti of sertraline hydrochloride. According to this patent, sertraline hydrochloride form II is prepared by dissolving sertraline free base in ketone, seeding the solution with crystals of polymorphic form II and adding a solution of hydrogen chloride. The ketone used is acetone, methyl ethyl ketone or methyl isobutyl ketone.
WO 02/096859 relates to the preparation of sertraline hydrochloride form II by- dissolving the sertraline base into ethyl acetate, adding isopropanol as a solvent, followed by addition of hydrogen chloride dissolved in ethyl acetate or in gaseous form, and then isolating and drying to yield sertraline hydrochloride form II.
WO 03/099761 discloses a method for the preparation of sertraline hydrochloride form II, wherein a solution of the free base in 2-propanol is treated with 2- propanolic hydrochloric acid to obtain a viscous gel. The resulting mixture is further diluted with diisopropyl ether to obtain a crystalline product.
Sertraline hydrochloride form II is generally prepared from cis (+) sertraline base or sertraline mandelate. The cis (+) sertraline base is obtained by resolution of cis sertraline racemates using D (-) mandelic acid. Several methods for the preparation of racemic sertraline are known in literature and the.following paragraphs briefly describe them.
US Patent 4536518 discloses a process for preparation of sertraline, wherein the tetralone intermediate is condensed with methylamine in an aprotic solvent in the presence of TiCU, which is then hydrogenated in the presence of 10% Pd/C to a mixture of cis and trans racemates. The cis and trans isomers are separated by fractional crystallization.
US patent 4855500 discloses a process for the preparation of sertraline, which involves condensing tetralone with methylamine in the presence of a hydratable molecular sieve as catalyst, whereby water is effectively removed by the catalyst and the desired ketimine final product is readily obtained in pure form and in high yield.
The US patent 6034274 relates to a process for preparing sertraline and its acid addition salts, wherein N-methyl-[4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-napthalenamine]-N-oxide is hydrogenated in an inert solvent in the presence of a catalyst, then the resulting mixture is treated with alcoholic solution of a mineral acid, the resulting cis-racemic acid salt is converted to the free cis-base by standard techniques well-known to those skilled in the art, resolved, then the cis- (+)- base is converted to the acid addition salt.
WO 99/57093 discloses a process for the preparation of sertraline hydrochloride, wherein the imine is subjected to hydrogenation in the. presence of a palladium-charcoal catalyst, which is pretreated with an alkali halide to obtain racemic sertraline with a purity of 85-95%.
WO 01/16089 disclose a process for the preparation of sertraline hydrochloride, wherein the tetralone intermediate is treated with methylamine under reducing atmosphere in presence of Raney nickel to produce the intermediate amine. The resulting amine is converted to sertraline hydrochloride by known process.
The US patent 6232500 discloses a process for the preparation of sertraline, which involves a condensation reaction between tetralone intermediate and monomethylamine in a solvent such as an alcohol or a mixture of two or more alcohols. The resulting imine is hydrogenated using Pd/CaCθ3 catalyst. The resulting racemic mixture is resolved and finally crystallized.
US patent 6723878 discloses a process for the preparation of sertraline, wherein the ketimine is hydrogenated in the presence of a dehalogenation inhibitors (like triphenyl phosphite or Trimethyl phosphite) and Pd/ graphite as a catalyst.
US 2003/0166970 discloses a process 1 to prepare sertraline hydrochloride, wherein the imine is hydrogenated in the presence of Pd/ graphite to obtain sertraline having a cis/trans ratio greater than 12:1.
The literature procedures for the preparation of racemic sertraline have several disadvantages. In the above processes the ketimine is prepared by treating the tetralone intermediate with gaseous methylamine in the presence of dehydrating agents such as TiCl4 and molecular sieves. The addition of methylamine gas to a solution containing tetralone is not convenient. The use of TiCl4 is hazardous and also results in by products such as titanium dioxide. The use of molecular sieves as catalyst is not economical. Therefore there exist a need for an improved process that eliminates the disadvantages of the prior art processes for the synthesis of racemic sertraline. The literature procedures for the preparation of sertraline hydrochloride form II have several disadvantages. Most of these procedures use mixture of solvents like ethyl acetate/ diethyl ether; acetone/isopropyl alcohol; isopropyl alcohol/ethyl acetate and 2- propanol/iso propyl ether. Some of the processes also require seeding. It is also seen that in the above processes; sertraline hydrochloride initially forms a gel, which on stirring crystallizes.
By following the procedures described in the in '518 and '721 patents, we were unable to consistently obtain sertraline hydrochloride form II. Therefore, there exists a need for preparing sertraline hydrochloride form II, that is easily reproducible and does not involve gel formation.
SUMMARY OF THE INVENTION
The present invention discloses a novel method for the preparation of racemic sertraline starting from the known tetralone and cis(+) sertraline hydrochloride form II from cis(+) sertraline mandelate.
The present invention provides a new method for preparing cis(+)sertraline hydrochloride form- II, in which the tetralone intermediate is treated with aqueous methylamine in a closed vessel at temperature of 70-80°C for 40-50 h. The imine obtained is suspended in methanol and subjected to hydrogenation using Pd/ BaSCU catalyst for about 24h. The resulting mass is treated with methanolic HCl to precipitate cis-(+/-)sertraline hydrochloride. Conversion of cis-(+/-)sertraline hydrochloride to its cis-(+)-sertraline mandelate salt is effected by reacting with aqueous sodium hydroxide and subsequent treatment of free base with D-(-)-mandelic acid.
Cis-(+)-sertraline hydrochloride form-II is obtained from cis-(+)-sertraline mandelate by conversion of mandelate salt to cis-(+)-sertraline base and further dissolving base in a solvent and reacting with hydrogen chloride. The process does not need any seeding. The solvent is selected from the class of nitriles such as acetonitrile, propionitrile , preferably acetonitrile and mixtures thereof. The crystallization of sertraline hydrochloride from acetonitrile is rapid and does not involve the intermediate gel formation.
DETAILED DESCRIPTION OF THE INVENTION
The process of the present invention is depicted in the following
Figure imgf000008_0001
cis(-)sertraline D(-)mandelate
Figure imgf000008_0002
cis(+) sertraline D(-)mandelate cis-(+/-)-sertraline base
HCI gas
_cis(+)sertraline aq. NaOH acetorϋtrϊle"" hydrochloride D(-) Mandelic ethyl acetate form I acid
Figure imgf000008_0003
cis-(+)-sertraline base cis-(+)-sertraline hydrochloride polymorph Il
The tetralone [I] is prepared by a known literature method and is purified by crystallization to a purity of at least 98%. The present invention provides a method for the preparation of ketimine [II] without the use of titanium tetrachloride and molecular sieves. The process employs aqueous methylamine. According to the present invention the tetralone is converted to imine by reaction with aqueous methylamine having concentration 25-40%; preferably 35-40%. The reaction is carried out at 70 - 80°C for 40-50 hours. On completion of the reaction, the imine is isolated by filtration. The imine is • purified by leaching with methanol . The purified imine [II] is then reduced by catalytic hydrogenation preferably at or below 350C and at pressure of 4-5 kg for about 24 hours using Pd/BaSO4as catalyst in methanol to a mixture of cis and trans sertraline racemates. The reduction of imine using Pd/BaSθ4 results in cis/trans ratio greater than 3:1. After filtering the catalyst, the solution is treated with methanolic HCl to precipitate the cis-(+/-)-sertraline hydrochloride [III]. The cis-(+/-)-sertraline hydrochloride [III] is converted to cis-(+/-)-sertraline base [IV] by standard techniques well known in art ('518 patent). Thus cis(+/-)-sertraline base is resolved using D-(-)-mandelic acid in ethyl acetate. The cis-(+)-sertraline mandelate salt [V] obtained is treated with aqueous sodium hydroxide to yield cis-(+)-sertraline base [VI].
In most of the literature processes sertraline hydrochloride initially forms a gel, which crystallizes only on intense stirring. Such gel formation generally causes problem in maintaining the temperature of the reaction mass and controlling the rate of addition of HCl (either gas or as solution). Our experiments using the procedure described in '518 patent for the preparation of sertraline form-II, wherein sertraline free base was dissolved in ethyl acetate, diluted with ether and was acidified with gaseous hydrogen chloride does not produce form-II as is claimed in the patent.
Experiments were performed to repeat the procedure described in example-5 in US 6,495,721 , wherein sertraline base was dissolved in n-butanol and gaseous hydrogen chloride was purged through the solution until pH 0.5 was reached. The resulting gel-like solid was stirred for 2.5 hours to obtain a fine crystalline solid. The material obtained after filtration and drying was found to be form I instead of form-II as claimed in '721 patent.
Surprisingly we found that, carrying out the process described in example-5 in '721 patent at a lower temperature resulted in form II. The cis-(+)-sertraline free base is dissolved in n-butanol and the solution was cooled to 5°C. Butanol containing hydrogen chloride was added slowly, maintaining the temperature between 5-10°C. The gelatinous precipitate formed was stirred , vigorously and allowed to attain a temperature of 20°C over a period of 3 hours. The crystalline solid formed was filtered, washed with n-butanol and dried at 60°C to obtain sertraline hydrochloride form-II. Alternatively cis (+) sertraline hydrochloride form II is prepared from either cis-(+)-sertraline freebase [VI] or cis-(+)-sertraIine mandelate [V]. Cis-(+)-sertraline freebase [VI] or άs-(+)-sertraIine mandelate [V] is taken in acetonitrile and gaseous hydrogen chloride is bubbled through the mixture at room temperature (25 - 270C) for 30 min. The temperature is raised during the passing of HCl gas to about 45°C. The addition of hydrogen chloride is continued until pH < 2 is reached. The crystalline solid formed is filtered to yield cis-(+)-sertraline hydrochloride polymorph II of formula-[VII].
The present invention is illustrated with following examples without limiting, the scope of the invention.
Example-1
Preparation of sertraline-1-itnine (ketimine)
Tetralone(50g), aqueous mono methylamine solution (40%, 150ml) and DM water (150ml) are charged into a closed vessel. The mixture is heated to 75-900C under stirring for 40 hours, after which the mixture is cooled to 20-250C, filtered, washed with water (100ml) followed by methanol
(100ml) to yield crude imine (52g) with 93-95% purity. M.P.- 143-145°C.
Example-2
Preparation ofracemic sertraline hydrochloride in methanol
Sertraline-1 -imine (12g) in methanol (60ml) is hydrogenated in the presence of catalyst Pd/BaSCU
(0.24g) at 25-27°C and at a pressure of 4 kg for 8 hours. The catalyst is removed by filtration through celite bed, washed the cake with methanol (30ml). The resulting filtrate is treated with methanolic hydrochloride (20%, 8ml) to precipitate cis-sertraline hydrochloride racemate (9.2g) with 94% purity,
ExampIe-3
Preparation ofracemic sertraline hydrochloride in tetrahydrofuran.
Sertraline-1-imine (1Og) in tetrahydrofuran (80ml) is subjected to hydrogenation in the presence of catalyst Pd/BaSO4 (0.2g) at 25-27°C and at a pressure of 4 kg for 6 hours. Upon completion of the reaction, the catalyst is removed by filtration. THF is removed completely, the resulting mass (sertraline free base) is taken in IPA (80ml), and hydrogen chloride gas is purged at 20-250C until pH 2 is attained. The precipitated solid is filtered (8.8g), which contains 83% of cis isomer, 8% of trans isomer, 5% of tetralone, and 3.4% of other impurities.
Example-4
Preparation ofracemic sertraline hydrochloride in toluene Sertraline-1-imine (1Og) in toluene (50ml) is subjected to hydrogenation in the presence of catalyst Pd/BaSθ4 (0.2g) at 25-27°C and at a pressure of 4 kg for 8 hours. Catalyst is removed by filtration, washed with toluene (30ml). The resulting solution is treated with hydrochloric acid. The solid formed is filtered, washed with toluene to yield crude sertraline hydrochloride racemate (5.2g), which melts at 278-280°C.
Example-5
Preparation of sertraline mandelate;
Cis- (IS) (IR) - N-methyl- 4- (3, 4-dichlorophenyl)- 1, 2, 3, 4 - tetra hydro - 1 - naphthalenamine hydrochloride (cis-(+/-)-sertraline hydrochloride) (100Og; 2.9 mol) is slurried in ethyl acetate (TL) and treated with 15% aαjueous NaOH (3L) to yield a solution of cis-racemate freebase in ethyl acetate! The ethyl acetate solution is treated with D-(-)-Mandelic acid (30Og; 1.97mol). The resulting mixture is refluxed for Ih and then cooled to room temperature (25°C). The solid obtained is filtrated, washed with ethyl acetate to yield crude mandelate salt (55Og). The crude mandelate salt (55Og) is slurried in methanol (2.5L) at 60 - 64°C for 1 hour. The resulting mixture is cooled to room temperature and filtered to obtain pure mandelate salt (475g).
Example-6
Preparation of cis (+) sertraline hydrochloride form II:
The purified cis mandelate salt (45Og) is suspended in ethyl acetate (2.25L). The suspension is treated with 10% aqueous NaOH solution (IL) to obtain a clear solution. The ethyl acetate layer is separated, washed with water (2X500ml) and the solvent evaporated under reduced pressure to yield cis(+) sertraline free base.
The cis (+) sertraline free base (30Og; 0.98mol) is dissolved in acetonitrile (2.25L) and hydrogen chloride is bubbled through the solution at 25-27°C. During the addition of HCl, the temperature of the reaction mixture raises form 25 to 5O0C. The addition of HCl is continued until pH 2 is reached. The crystalline solid thus formed is filtered , washed with acetonitrile (2X300ml) and dried at 6O0C under vacuum. The cis (+) sertraline hydrochloride (305 g) obtained is characterized by IR, XRD and DSC and found to be polymorphic form II.
Example-7
Preparation of sertraline hydrochloride form II: To a suspension of sertraline mandelate (15g; 0.0327mol) in acetonitrile (100ml), Hydrogen chloride is bubbled at 25-27°C. During the addition of HCl, the temperature of the reaction mixture raises form 24 to 450C. The addition of HCl is continued until pH 2 is reached. The crystalline solid thus formed is filtered , washed with acetonitrile (2X20ml) and dried at 60°C under vacuum. The cis (+) sertraline hydrochloride (8 g) obtained is characterized by IR, XRD and DSC and found to be polymorphic form II.
Example-8
Preparation of sertraline hydrochloride form II using n-butanol:
The cis (+) sertraline free base (44Og; 1.4mol) is dissolved in n-butanol (5L) and the resulting solution is cooled to 5°C. Butanol containing anhydrous hydrogen chloride (16%W/W; 380ml) is added slowly, maintaining the temperature between 5-10°C. The resulting gelatinous precipitate is stirred and slowly allowed to attain room temperature (25°C) over a period of 3 hours. The crystalline solid thus formed is filtered, washed with butanol and dried at 60°C under vacuum. The cis(+) sertraline hydrochloride (41Og) obtained is characterized by IR, XRD and DSC and found to be polymorphic form II.

Claims

We claim:
1. A process for preparation of of cis-(+)-sertraline hydrochloride- form II comprising:
(a) Reaction of sertralone with aqueous methylamine to obtain the corresponding ketimine,
(b) Reduction of the ketimine using Pd/BaSθ4 in organic solvent at or below 350C and treatment of resulting mass with methanolic hydrochloric acid to precipitate cis-(+/- )-sertraline hydrochloride,
(c) Conversion of cis-(+)-sertraline mandelate salt to cis-(+)-sertraline . hydrochloride form-II either directly or optionally via cis-(+)- sertraline base.
2. A process as claimed in claim l(c) "wherein, cis-(+)-sertraline hydrochloride form-II is prepared
(a) From cis-(+)- sertraline base by addition of butanolic HCl at 5-100C followed by stirring at 20-250C for 3 hours.
(b) From cis-(+)- sertraline base by passing HCl gas in acetonitrile at 25-500C till pH=2 followed by filtration, washing with acetonitrile and drying the product.
(c) From cis-(+)-sertraline mandelate salt by passing HCl gas in acetonitrile at 25-450C till pH=2 followed by filtration, washing with acetonitrile and drying the product.
3. A process as claimed in claim l(a) wherein, reaction is carried out at about 400C -100°C, preferably at about 75°C - 90°C.
4. A process as claimed in claim l(a) wherein, concentration of aqueous mono methylamine solution is 25-40%, preferably 35-40% and molar equivalent of aqueous monomethyl amine solution used is between 10-30, preferably 10-20.
5. A process as claimed in claim 1 wherein, organic solvent used in the reduction of ketimine is selected from C1-C3 alcohols such as methanol, ethers such as tetra hydro furan, hydrocarbons such as toluene or esters such as ethyl acetate.
6. A process as claimed in claim 2 wherein, cis-(+)-sertraline mandelate salt or cis-(+)-sertraline base is suspended in solvent selected from the group of nitriles such as acetonitrile, propionitrile or mixtures thereof, preferably acetonitrile.
PCT/IB2005/002603 2004-09-06 2005-09-05 Process for the preparation of sertraline hydrochloride form ii WO2006027658A2 (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007119247A2 (en) * 2006-04-17 2007-10-25 Unichem Laboratories Limited 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)
WO2007124920A1 (en) * 2006-04-28 2007-11-08 Sandoz Ag Process for the preparation of [4(s,r)-(3,4-dichlorophenyl)-3,4-dihydro-1(2h)-naphthalen-1-ylidene]methylamine
EP1862447A2 (en) * 2006-06-01 2007-12-05 Hetero Drugs Limited Novel processes for preparing sertraline hydrochloride crystalline forms
CN103524354A (en) * 2013-10-23 2014-01-22 山东鲁药制药有限公司 Method for preparing sertraline hydrochloride

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6234500B1 (en) * 1997-10-31 2001-05-22 Steven E. Aufrance Pneumatic device for adjusting wheel camber

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6234500B1 (en) * 1997-10-31 2001-05-22 Steven E. Aufrance Pneumatic device for adjusting wheel camber

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007119247A2 (en) * 2006-04-17 2007-10-25 Unichem Laboratories Limited 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)
WO2007119247A3 (en) * 2006-04-17 2009-05-14 Unichem Lab Ltd 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)
WO2007124920A1 (en) * 2006-04-28 2007-11-08 Sandoz Ag Process for the preparation of [4(s,r)-(3,4-dichlorophenyl)-3,4-dihydro-1(2h)-naphthalen-1-ylidene]methylamine
EP1862447A2 (en) * 2006-06-01 2007-12-05 Hetero Drugs Limited Novel processes for preparing sertraline hydrochloride crystalline forms
EP1862447A3 (en) * 2006-06-01 2008-09-10 Hetero Drugs Limited Novel processes for preparing sertraline hydrochloride crystalline forms
CN103524354A (en) * 2013-10-23 2014-01-22 山东鲁药制药有限公司 Method for preparing sertraline hydrochloride

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