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EP2367806A2 - Procédé et intermediaries pour la préparation de 7-((3-chloro-6-méthyl-5,5-dioxo-6,11-dihydrodibenzo(c,f)(1,2)thiazépin-11-yl)amino)heptanoate - Google Patents

Procédé et intermediaries pour la préparation de 7-((3-chloro-6-méthyl-5,5-dioxo-6,11-dihydrodibenzo(c,f)(1,2)thiazépin-11-yl)amino)heptanoate

Info

Publication number
EP2367806A2
EP2367806A2 EP09817075A EP09817075A EP2367806A2 EP 2367806 A2 EP2367806 A2 EP 2367806A2 EP 09817075 A EP09817075 A EP 09817075A EP 09817075 A EP09817075 A EP 09817075A EP 2367806 A2 EP2367806 A2 EP 2367806A2
Authority
EP
European Patent Office
Prior art keywords
formula
tianeptine
compound
preparation
sodium salt
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP09817075A
Other languages
German (de)
English (en)
Inventor
Jagadeesh Babu Rangisetty
Manik Reddy Pullagurla
Rajesh Bhudeti
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.)
Biophore India Pharmaceuticals Pvt Ltd
Original Assignee
Biophore India Pharmaceuticals Pvt Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biophore India Pharmaceuticals Pvt Ltd filed Critical Biophore India Pharmaceuticals Pvt Ltd
Priority claimed from PCT/IN2009/000659 external-priority patent/WO2010070667A2/fr
Publication of EP2367806A2 publication Critical patent/EP2367806A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings

Definitions

  • the present invention relates to a novel process for the preparation of sodium 7-((3-Chloro-6-methyl-5,5- dioxo-6,11-dihydrodibenzo(c,f)(1 ,2)thiazepin-11-yl)amino)heptanoate and intermediates.
  • the invention also encompasses isolation of an essentially non-hygroscopic compound which is substantially pure.
  • Tianeptine is currently marketed in Europe as an antidepressant. Unlike the currently used antidepressants which inhibit the serotonin reuptake, Tianeptine enhances serotonin uptake without significant activity at any receptors or other monoamine transporters.
  • the present invention relates to a novel process for the synthesis of Tianeptine.
  • Patents describing synthetic procedures for Tianeptine are listed below.
  • FR 2104728 describes a synthetic process for the preparation of Tianeptine and its therapeutic use.
  • the patent describes the synthesis by the reaction of compound of Formula Il and ethyl-7-aminoheptanoate.
  • EP 0671173 describes the synthesis of Tianeptine by the reaction of compound of Formula III and ethyl- 7-bromoheptanoate.
  • US 6441165 describes a process for the synthesis of the intermediate of 11-amino-3-chloro-6,11-dihydro- 5,5-dioxo-6-methyldibenzo[c,f][1 ,2]thiazepine.
  • One of the objects of the invention was to provide a process for preparing of Tianeptine with improved yields. Another object of the invention was to develop a process devoid of any dinner impurity and provide an improved method for the synthesis of Tianeptine.
  • Yet another object of the invention was to develop a process for Tianeptine which is commercially viable.
  • This invention provides an alternative method for preparing Tianeptine.
  • 3-Chloro-6-methyl-dibenzo[c,f][1 , 2]thiazepin-11 (6H)-one-5,5-dioxide is reduced to give an alcohol which is further chlorinated to give compound of formula IV.
  • the compound of formula IV is condensed with 7-aminoheptanitrile in the presence of a solvent with or without a base to give an intermediate for Tianeptine which is further hydrolyzed to give Tianeptine.
  • One of the objects of the invention was to provide a process for preparing of Tianeptine with improved yields and process.
  • One object of the invention was to develop Tianeptine sodium salt which is essentially non-hygroscopic. Another object of the invention was to develop a process and thereby substantially pure Tianeptine which is devoid of any unsaturated impurity of Formula VII and dimer impurity of Formula VIII and provide an improved method for the synthesis of Tianeptine.
  • This invention also provides an alternative method for preparing Tianeptine sodium salt I from Tianeptine free acid IX.
  • the compound of formula I is prepared by hydrolysis of cyano intermediate compound of Formula-V.
  • the hydrolysis is carried out either in acidic conditions or basic conditions.
  • the reaction is carried out preferably in presence of hydrochloric acid solution.
  • the reaction is preferably carried out at room temperature to reflux conditions. Partial hydrolysis of compound of Formula-V can result in the amido compound of Formula-VI which can be further hydrolyzed either in acidic conditions or basic conditions to provide Tianeptine.
  • synthesis of the compound of Formula-V can be carried out by the reaction of 7-aminoheptanenitrile with compound of Formula IV.
  • the reaction can be performed with or without a solvent and in presence or absence of a base.
  • the reaction can be carried out at temperatures of 10-130 0 C.
  • compound of Formula-V can be synthesized by the reaction of compound of Formula-X and 7-bromoheptanenitrile.
  • the reaction can be performed with or without a solvent and in presence or absence of a base.
  • the reaction can be carried out at temperatures of 10-130 C.
  • the compound of Formula I can be obtained from compound of Formula V either in presence of Acid or basic.
  • the reaction is preferably carried out in presence of hydrochloric acid or sulfuric acid solutions at temperature ranging from 0 0 C to reflux conditions.
  • the compound of Formula Vl can also be converted to Formula I in presence of Acid solutions or basic solutions preferably in presence of hydrochloric acid or sulfuric acid solutions at temperature ranging from 0 0 C to reflux conditions.
  • the compound of Formula I is prepared from compound of Formula-IV in presence of sodium hydroxide and an alcohol or dichloromethane.
  • the reaction is carried out preferably in presence of sodium hydroxide solution added in 0.85 to 1.1 equivalents ratio and preferably 0.9 to 0.95 equivalents with respect to compound of Formula IV.
  • the reaction is carried out at -20 to 65 °C and is preferably carried out at 25-65 0 C.
  • the alcohols employed are methanol, ethanol, propanol, isopropanol, butanol preferably methanol and ethanol.
  • the alkoxide employed is sodium methoxide, sodium ethoxide, sodium propoxide, sodium butoxide and the like and preferably sodium methoxide and sodium ethoxide.
  • the compound of Formula I i.e. Tianeptine sodium is prepared from compound of Formula-X i.e. Tianeptine free acid in presence of sodium alkoxide and an alcohol or dichloromethane.
  • the reaction is carried out preferably in presence of sodium alkoxide added in 0.85 to 1.1 equivalents ratio with respect to compound of Formula IX.
  • the reaction is carried out at -20 to 65 0 C and is preferably carried out at 25-65 °C.
  • the alcohols employed are methanol, ethanol, propanol, isopropanol, butanol preferably methanol and ethanol.
  • the alkoxide employed is sodium methoxide, sodium ethoxide, sodium propoxide, sodium butoxide and the like and preferably sodium methoxide and sodium ethoxide.
  • the sodium salt I once obtained as crude can be slurried in ethyl acetate, toluene or acetonitrile and allowed to stir at -20 to 35 °C and filtered and dried under vacuum to below 1.0% and preferably below 0.5% moisture content, the product becomes essentially non-hygroscopic.
  • a non-hydroscopic product can be prepared by slurry of hygroscopic Tianeptine sodium in a suitable organic solvent preferably ethyl acetate, acetonitrile, and toluene and filtration of the compound.
  • a suitable organic solvent preferably ethyl acetate, acetonitrile, and toluene and filtration of the compound.
  • the compound when dried under vacuum to below 1.0% and preferably below 0.5% moisture content, the product becomes essentially non-hygroscopic.
  • the product prepared by the above process is substantially pure and contains impurities of compound VII and compound VIII in less than 0.1% and is essentially non-hygroscopic.
  • a suspension of compound of Formula III (58.0 g) in dichloromethane (600 ml) is cooled to 0-10 0 C, HCI gas is bubbled through the above suspension for 2-4 hour at 0-10 0 C. Upon completion of starting material, filter the precipitate and dry the solids obtained until constant weight to provide the title compound in 90-95% yield.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

Abstract

La présente invention concerne un nouveau procédé pour la préparation de 7-((3-chloro-6-méthyl-5,5-dioxo-6,11-dihydrodibenzo(c,f)(1,2)thiazépin-11-yl)amino)heptanoate de sodium et des intermédiaires. L'invention concerne en outre l'isolement d'un composé pratiquement non hygroscopique qui est sensiblement pur.
EP09817075A 2008-11-19 2009-11-18 Procédé et intermediaries pour la préparation de 7-((3-chloro-6-méthyl-5,5-dioxo-6,11-dihydrodibenzo(c,f)(1,2)thiazépin-11-yl)amino)heptanoate Withdrawn EP2367806A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
IN2841CH2008 2008-11-19
IN454CH2009 2009-03-03
PCT/IN2009/000659 WO2010070667A2 (fr) 2008-11-19 2009-11-18 Nouveau procédé pour la préparation de 7-((3-chloro-6-méthyl-5,5-dioxo-6,11-dihydrodibenzo(c,f)(1,2)thiazépin-11-yl)amino)heptanoate

Publications (1)

Publication Number Publication Date
EP2367806A2 true EP2367806A2 (fr) 2011-09-28

Family

ID=44487032

Family Applications (1)

Application Number Title Priority Date Filing Date
EP09817075A Withdrawn EP2367806A2 (fr) 2008-11-19 2009-11-18 Procédé et intermediaries pour la préparation de 7-((3-chloro-6-méthyl-5,5-dioxo-6,11-dihydrodibenzo(c,f)(1,2)thiazépin-11-yl)amino)heptanoate

Country Status (1)

Country Link
EP (1) EP2367806A2 (fr)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2010070667A2 *

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