WO2007119247A2 - Procédé de production amélioré destiné à la préparation de la forme polymorphe ii de l'hydrochlorure de cis-(1s)-n-methyl-4-(3,4-dichlorophényle)-1,2,3,4-tétrahydro-1-napthlèneamine (hydrochlorure de sertraline) - Google Patents

Procédé de production amélioré destiné à la préparation de la forme polymorphe ii de l'hydrochlorure de cis-(1s)-n-methyl-4-(3,4-dichlorophényle)-1,2,3,4-tétrahydro-1-napthlèneamine (hydrochlorure de sertraline) Download PDF

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Publication number
WO2007119247A2
WO2007119247A2 PCT/IN2006/000366 IN2006000366W WO2007119247A2 WO 2007119247 A2 WO2007119247 A2 WO 2007119247A2 IN 2006000366 W IN2006000366 W IN 2006000366W WO 2007119247 A2 WO2007119247 A2 WO 2007119247A2
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Prior art keywords
dichlorophenyl
cis
hydrochloride
methyl
tetrahydro
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PCT/IN2006/000366
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English (en)
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WO2007119247A3 (fr
Inventor
Arul Ramakrishnan
Singh Rawat Ajay
Balu Wagh Manoj
Dayalji Chauhan Ajay
Arvind Chandan Payal
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Unichem Laboratories Limited
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Publication of WO2007119247A2 publication Critical patent/WO2007119247A2/fr
Publication of WO2007119247A3 publication Critical patent/WO2007119247A3/fr

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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
    • C07C209/82—Purification; Separation; Stabilisation; Use of additives
    • C07C209/86—Separation
    • C07C209/88—Separation of optical isomers
    • 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 the improved scalable and efficient manufacturing procedure for the preparation of polymorphic form II of Cis-(lS)-N-Methyl-4-(3,4- Dichlorophenyl)-l,2,3,4-tetrahydro-l-napthaleneamine hydrochloride, Sertraline 5 Hydrochloride.
  • Sertraline Hydrochloride (Zoloft) is a useful antidepressant. It blocks the synaptosomal uptake of Serotonin (5-Hydroxytryptamine) abnormalities at central receptor sites. It possess negligible monoamine oxidase inhibition anticholinergic and psychomotor stimulation activities. Effects on the cardiovascular system are minimal I Q hence it belongs to a major category of anti-depressant agent.
  • the decarboxylation stage also includes a longer reaction time, an isolation procedure involving number of steps resulting in low yield of the intermediate.
  • Imine formation stage includes a condensation reaction of 4-(3,4- dichlorophenyl)-3,4-dihydro-l-(2H)-napthalenone with gaseous monomethyla- mine (gas), which is catalysed by titanium tetrachloride yielding N-[4-(3,4- dichlorophenyl)-3 ,4-dihydro- 1 -(2H)-napthalenylidene]methanamine. Titanium tetrachloride however is extremely reactive with water and side products formed are hazardous.
  • CiS-(I S)(lR)-N-Methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetraliydro-l- napthalenamine Hydrochloride is prepared from the reduced (lS-Cis)-4-(3,4- dichloro- phenyl)-l,2,3,4-tetrahydro-N-methyl-l-napthalenamine by Hydrogen chloride gas treatment in Ether followed by crystallization.
  • EP 594666 describes two multistep processes starting from 1-N-Alkyl-naphthalene for the preparation of Sertraline and Sertraline hydrochloride as per scheme 01 and Scheme 02.
  • WO 2002096860 Al also describes a process starting from the key intermediate 4- (3,4-dichlorophenyl)-tetralone, which includes imine formation in DMF in the presence of formic acid or acetic acid at 50 0 C, followed by hydrogenation and resolution and is depicted in scheme 06
  • Another preparation disclosed in WO 2004087732 A2 also starts from the key intermediate tetralone which includes the formation of imine in Polyethylene glycol, reduction of the imine followed by the optical resolution of the obtained Cis/Trans mixture.
  • US 6723878 describes a process for the preparation of sertraline hydrochloride which starts from imine intermediate and involves reduction in the presence of a Palladium or Platinum catalyst and a dehalogenation inhibitor and finally optical resolution to give Sertraline.
  • US 6262308 provides a two step procedure for the preparation of racemic Sertraline hydrochloride starting with the key intermediate Tetralone and follows Scheme 09
  • WO 9957093 Al describes the preparation of racemic Sertraline hydrochloride from imine intermediate as follows
  • WO 003255 Al describes the preparation of Sertraline hydrochloride polymorph II from Sertraline Base by dissolving it in acetone and lowering the pH of the solution by addition of Hydrogen chloride solution, such as hydrogen chloride in isopropanol.
  • the patent further describes the recrystallisation of Sertraline hydrochloride using Dimethyl formamide or cyclohexanol.
  • US 0132828 discloses the preparation of Sertraline Form II wherein the solution of Sertraline free amine in ketonic solvent is seeded with crystals of Form II at room temperature to 55-60 0 C and hydrogen chloride solution in water or acetone is added.
  • WO 01/45692 Al describes the process for preparing Sertraline hydrochloride fo ⁇ n II from Sertraline hydrochloride form XTV or XV or form XVI.
  • WO 031099761 Al describes the preparation of form II by dissolving the Sertraline base in 2-propanol and precipitating with 1.25 molar excess of 3M 2-propanol hydrochloric acid and Diisopropyl ether. The product is recrystallised using Dimethylformamide.
  • WO 02/09859A1 disclosed the conversion of Sertraline mandelate into Sertraline base in ethylacetate. Ethylacetate is distilled off and replaced with Isopropanol. The solution of Sertraline base in Isopropanol is reacted with a solution of 12-14 % of Hydrochloric acid in Ethyl acetate at 40-65 0 C using the seed crystals of Polymorphic Form II.
  • WO 03/093217A1 describes the preparation of Form II substantially free of Form I using Sertraline base or Sertraline Mandelate in suitable solvents like n-butanol, cyclohexane, ethylacetate, acetone, hexane, t-butylmethyl ether, Dimethylformamide and mixture there of by contacting the solution or the slurry with a flow of gaseous hydrogen chloride at 30 to 60 0 C
  • the aim of the present invention is consequently to overcome the drawbacks and thus to provide an improved, scalable and efficient manufacturing procedure for the preparation of polymorphic form II of the antidepressant Cis- (lS)-N-Methyl-4-(3,4- Dichlorophenyl)-! ,2,3,4-tetrahydro-l -napthaleneamine hydrochloride (Sertraline Hydrochloride).
  • the first object of the present invention is to provide an improved, scalable manufacturing procedure for preparing polymorphic form II Sertraline hydro chloride.
  • the present invention provides an improved, scalable and efficient procedure for the preparation of polymorphic form II of Cis- (lS)-N-Methyl- 4-(3,4-Dichlorophenyl)-l,2,3,4-tetrahydro-l-napthaleneamine (Sertraline Hydrochloride), said process comprises of ;
  • R is hydrogen or C 1 ⁇ alkyl group, which can be substituted, in an alcoholic solvent in the presence of a strong base preferably chosen from metal alkali hydride wherein the product is isolated in a simplified procedure.
  • 1-napthalenamine by first converting the tetralone intermediate to the imine intermediate by reacting it with Methylammonium hydrochloride in the presence of a inorganic base such as Sodium hydroxide, Potassium hydroxide etc in an alcoholic solvent followed by its insitu reduction with sodiumborhydride.
  • a inorganic base such as Sodium hydroxide, Potassium hydroxide etc in an alcoholic solvent followed by its insitu reduction with sodiumborhydride.
  • FIGURES Figure 1 shows the XRPD of Sertraline Hydrochloride Form-II prepared using the process of the invention
  • the first step involves a neat reaction of benzoyl chloride with orthodichlorobenzene in the presence of a lewis acid such as Aluminium trichloride, Boron triflouride etc without solvent wherein the desired regioisomer 3,4-dichlorobenzophenone is separated from the undesired 2,3- dichlorobenzophenone by treatment of the crude mixture with a solvent choosen from ethyl acetate, n-propyl acetate, tertiarybutyl actetate etc.
  • a solvent choosen from ethyl acetate, n-propyl acetate, tertiarybutyl actetate etc.
  • the desired regioisomer is isolated in a reasonable yield.
  • the next step is a base catalyzed Stobbe condensation of the so prepared 3,4- dichlorobenzophenone with diethylsuccinate or dimethyl succinate in an alcoholic solvent.
  • the base is a suitable metal alkali hydride e.g. Sodium Hydride, Potassium hydride etc.
  • the reaction time for Stobbe condensation is preferably between 2 to 5 hours.
  • the isolation procedure involves removal of solvent followed by extractive
  • the next step is a hydrolysis and decarboxylation in the presence of aqueous hydrobromic acid at a temperature ranging from 115-120 0 C for 28.0-30.0 hours wherein the product is preferably isolated either by direct precipitation of the product from the reaction mixture by the addition of excess water or by simple extraction , r work up in a yield ranging from 88-95%.
  • the next step is reduction of the ' decarboxylated product by known means which is C3'clized to 4-(3,4-Dichlorophenyl)-3,4-diliydro-l-(2H)-napthalenone preferably with Sulpuric acid with or without solvent or with a mixture of Tril ⁇ ouroacetic anhydride and Boron triflouride Etherate with or without solvent at temperature ranging from 0 room temperature to reflux temperature of the used solvent wherein the cyclized product is isolated in more than 85% yield.
  • the next step of the process involves the conversion of the so formed 4-(3,4- Dichlorophenyl)-3,4-dihydro-1 -(2H)-napthalenone to Cis/Trans-N-methyl-4-(3,4-dic hlorophenyl)-l,2.3,4-tet ⁇ ahydro-l-napthalenamine by first converting the tetralone 5 intermediate to the imine intermediate by reacting it with Methylammonium hydrochloride in the presence of a inorganic base such as Sodium hydroxide, Potassium hydroxide etc in an alcoholic solvent followed by its in situ reduction with sodiumhorhydride or Pd/C. Most preferably this reaction is performed with 1.5 equivalent to 2.5 equivalent of Methylammonium hydrochloride. The most preferable base used is Potassium hydroxide.
  • Preferable reaction temperature lie between 25 to 50 0 C.
  • the next step involves the conversion of Cis/Trans-N-methyl-4-(3,4-dichlorophenyl)- 1,2,3,4-tetrahydro-l-napthalenamine to Cis(lS)(lR)-N-methyl-4-(3,4-dichloropheny I)-1, 2,3,44etrahydro-l -napthalenamine hydrochloride in which the obtained Cis/Trans free base is treated with 35% Hydrochloric acid (aqueous) in an alcoholic solvent choosen from Methanol, ethanol, propanol etc and purified from hot alcohol chosen from methanol, ethanol and propanol solvent treatment to furnish the desired Cis intermediate.
  • the next step involves the conversion of Cis(lS)(lR)-N-methyl-4-(3,4- dichlorophenyl)-l,2,3,4-tetrahydro-l-napthalenamine hydrochloride to polymorphic form II Cis(l S)-N-methyl-4-(3 ,4-dichloro ⁇ henyl)- 1 ,2,3,4-tetrahydro- 1 -napthalena mine hydrochloride (Sertraline Hydrochloride) via a simple displacement of Mandelic acid part of Cis(lS)-N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l- napthalenamine mandelate with Concentrated Hydrochloric acid.
  • Cis(l S)- N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-l-napthalenamine mandelate is prepared in a solvent chosen from the likes of Toluene, Xylene etc most preferably in Toluene at a Temperature ranging from 60 0 C temperature to reflux temperature preferably at reflux temperature of the used solvent.
  • the next step involves the insitu displacement of mandelate intermediate with Concentrated Hydrochloric acid in aqueous medium or water miscible solvent such as any solvent chosen from acetonitrile, methanol, ethanol etc at a temperature ranging from O 0 C to reflux temperature of the chosen reaction medium followed by precipitation of polymorphic form II Sertraline hydrochloride with or without seeding of the desired polymorph form II.
  • aqueous medium or water miscible solvent such as any solvent chosen from acetonitrile, methanol, ethanol etc at a temperature ranging from O 0 C to reflux temperature of the chosen reaction medium
  • the present invention provides an improved manufacturing procedure for the production of polymorphic form II Cis(lS)-N-methyl-4-(3,4-dichlorophenyl)-l,2,3,4- tetrahydro-1 -napthalenamine hydrochloride or Sertraline Hydrochloride which overcomes the drawbacks of the earlier methods.
  • the present invention thus provides a procedure to isolate the desired key raw material 3,4-dichlorobenzophenone in a cheaper and efficient way. It also provides reduced reaction time , better methods for the isolation and provides novel methodology for the preparation of some of the intermediates involved in the preparation of polymorphic form II of Sertraline hydrochloride.
  • the process of the invention also eliminates the use of hazardous and expensive Monomelhylamine gas and reagents such as Titanium tetrachloride which helps in reducing the effluent burden occurring due to the side products such as titanium dioxide.
  • the aqueous layer after separation was then acidified with concentrated hydrochloric acid (25 ml) and extracted once with Dichlorornethane (500.0 ml).
  • the Dichloromethane layer was then washed twice with water , dried over sodium sulphate and evaporated under vacuum to a Light Brown oil (74 g, 98% yield).
  • Cis/Trans-N-Methyl-4-(3,4-dichlorophenyl)-l,2,3,4-terahydro-l-(2H)-napthalenamine (25Og, 0.817 mole) was dissolved in methanol (1350 ml) and cooled between 0 to 5 0 CTo the clear reaction mixture cone.
  • HCl 250ml was charged drop wise in. ⁇ 1 hour while maintaining the temperature between 0- 10 0 C.
  • the resulting white slurry 25 was stirred for 1.0 hour at 0- 10 0 C .
  • the precipitated solid was then filtered on buchner funnel and suck dried.
  • Cis(lS)(lR)-N-Methyl-4-(3,4-dichlorophenyl)-l,2,3,4-teraliydro-l-(2H)-napthalenam ine Hydrochloride 75 g, 0.219 mol
  • Toluene 270 ml
  • a solution of Sodium hydroxide 18 g, 0.45 mol
  • water 310 ml
  • the reaction mixture was heated between 83-88 0 C for 60 minutes and then cooled to 30- 35 0 C. Then the Toluene layer was separated and washed thrice with water (300 ml).
  • the final toluene layer was diluted with extra toluene (480 ml) and D(-)-Mandelic acid (18.3g, 0.120 mol) was charged to it at 25-30 0 C.
  • the resulting reaction mass was then stirred at 100-110 0 C till the reaction mixture became clear.
  • the clear solution was then cooled to 30-35 0 C and the precipitated solid was then filtered, washed thrice with Toluene (75 ml) and dried at 75-80 0 C for 5-6 Hours. Yield : 40.0 g (80.0 % based on the desired isomer)
  • Cis(l S)(4S)-N-Methyl-4-(3,4-dichlorophenyl)-I ,2,3,4-terahydro-l -(2H)- napthalenamine mandelate to polymorphic form II of Cis (lS)(4S)-N-Mefhyl-4-(3,4- dichlorophenyl)-l ,2,3.4-terahydro-l -(2H)-napthalenamine Hydrochloride
  • Cis(lS)(4S)-N-Methyl-4-(3,4-dichlorophenyl)-l,2,3,4-terahydro-l-(2H)- napthalenamine mandelate (10.0g, 0.0218 mol) in Acetonitrile (100.0 ml) was cooled to 10-15 0 C and 1.0 g of Sertraline hydrochloride Form II seed was added.
  • Cis(l S)(4S)-N-Methyl-4-(3 ; 4-dichlorophenyl)-l ,2,3,4-terahydro-l -(2H)- napthalenamine mandelate to polymorphic form II of Cis (lS)(4S)-N-Methyl-4-(3,4- dichlorophenyl)-l,2,3,4-terahydro-l-(2H)-napthalenamine Hydrochloride

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne un procédé de production amélioré, évolutif et efficace pour la préparation de l'antidépresseur hydrochlorure de Cis-(1S)-N-Méthyl-4-(3,4-Dichlorophényle)-1,2,3,4-tétrahydro-1-napthaleneamine, hydrochlorure de sertraline de forme polymorphe II. La présente invention concerne également les procédés améliorés et modifiés de préparation, de séparation et d'isolement des produits intermédiaires clés impliqués dans la préparation de l'hydrochlorure de Sertraline de forme polymorphe II. La présente invention concerne enfin l'utilisation de nouveaux réactifs ou bien d'une de leurs combinaisons, et de nouvelles méthodologies de préparation de certains produits intermédiaires clés impliqués dans la préparation de la forme polymorphe II de l'hydrochlorure de Sertraline.
PCT/IN2006/000366 2006-04-17 2006-09-12 Procédé de production amélioré destiné à la préparation de la forme polymorphe ii de l'hydrochlorure de cis-(1s)-n-methyl-4-(3,4-dichlorophényle)-1,2,3,4-tétrahydro-1-napthlèneamine (hydrochlorure de sertraline) WO2007119247A2 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4536518A (en) * 1979-11-01 1985-08-20 Pfizer Inc. Antidepressant derivatives of cis-4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine
WO2001016089A1 (fr) * 1999-09-01 2001-03-08 Sharad Kumar Vyas Procede de preparation de chlorhydrate de cis-(1s,4s)-n-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine
WO2001068566A1 (fr) * 2000-03-14 2001-09-20 Teva Pharmaceutical Industries Ltd. Nouveau procede de preparation de (+)-cis-sertraline
WO2003099761A1 (fr) * 2002-05-10 2003-12-04 Stohandl Jiri Procede de fabrication de sertraline
WO2005012224A1 (fr) * 2003-07-15 2005-02-10 Recordati Industria Chimica E Farmaceutica S.P.A. Chlorhydrate de sertraline de forme ii et procedes de preparation associes
WO2005121074A2 (fr) * 2004-06-09 2005-12-22 Ranbaxy Laboratories Limited Procedes pour la preparation de chlorhydrate de sertraline
WO2006027658A2 (fr) * 2004-09-06 2006-03-16 Bakulesh Mafatlal Khamar Procede de preparation de la forme ii de chlorhydrate de sertraline

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4536518A (en) * 1979-11-01 1985-08-20 Pfizer Inc. Antidepressant derivatives of cis-4-phenyl-1,2,3,4-tetrahydro-1-naphthalenamine
WO2001016089A1 (fr) * 1999-09-01 2001-03-08 Sharad Kumar Vyas Procede de preparation de chlorhydrate de cis-(1s,4s)-n-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine
WO2001068566A1 (fr) * 2000-03-14 2001-09-20 Teva Pharmaceutical Industries Ltd. Nouveau procede de preparation de (+)-cis-sertraline
WO2003099761A1 (fr) * 2002-05-10 2003-12-04 Stohandl Jiri Procede de fabrication de sertraline
WO2005012224A1 (fr) * 2003-07-15 2005-02-10 Recordati Industria Chimica E Farmaceutica S.P.A. Chlorhydrate de sertraline de forme ii et procedes de preparation associes
WO2005121074A2 (fr) * 2004-06-09 2005-12-22 Ranbaxy Laboratories Limited Procedes pour la preparation de chlorhydrate de sertraline
WO2006027658A2 (fr) * 2004-09-06 2006-03-16 Bakulesh Mafatlal Khamar Procede de preparation de la forme ii de chlorhydrate de sertraline

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
QUALLICH, G.J. ET AL.: 'Friedel-Crafts Synthesis of 4-(3,4- Dichlorophenyl)-3,4-dihydro-1 (2H)-naphthalenone, a Key Intermediate in the Preparation of the Antidepressant Sertraline.' J. ORG. CHEM. vol. 55, 1990, pages 4971 - 4973 *
QUALLICH, G.J.: 'Development of the Commercial Process for Zoloft/Sertraline.' CHIRALITY 2005 vol. 17, pages S120 - S126 *

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