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WO2007102167A1 - Procédé de synthèse de la forme polymorphique anhydre de l'olanzapine - Google Patents

Procédé de synthèse de la forme polymorphique anhydre de l'olanzapine Download PDF

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Publication number
WO2007102167A1
WO2007102167A1 PCT/IN2006/000142 IN2006000142W WO2007102167A1 WO 2007102167 A1 WO2007102167 A1 WO 2007102167A1 IN 2006000142 W IN2006000142 W IN 2006000142W WO 2007102167 A1 WO2007102167 A1 WO 2007102167A1
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WO
WIPO (PCT)
Prior art keywords
olanzapine
methyl
amino
cyano
thiophene
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.)
Ceased
Application number
PCT/IN2006/000142
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English (en)
Inventor
Venkat Reddy Alla
Kameswara Rao Vyakaranam
Aruna Kumari Sirigiri
Srinivas Reddy Bodapati
Ranadheer Reddy Billa
Raghumitra Alla
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.)
Lee Pharma Ltd
Original Assignee
Lee Pharma 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 Lee Pharma Ltd filed Critical Lee Pharma Ltd
Publication of WO2007102167A1 publication Critical patent/WO2007102167A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the invention pertains to the process of obtaining OLANZAPINE Form - II, having a process of preparation resulting in anhydrous form..
  • OLANZAPINE 2-methyl-4-(4-methyl-l-piperazinyl)-10H ⁇ thieno [2,3-b][l,5] benzodiazepine is useful in the treatment of psychotic disorders.
  • Oianzapine was described for the first time in the European Patent EP 0454436BI.
  • One of the methods for preparation of Olanzapine is based on condensation of 4-amino-2-methyl-10H- thieno [2,3-b][l, 5] benzodiazepine with N-methyl piperazine in dimethyl sulfoxide and toluene.
  • the typical methods for preparation of Olanzapine of technical grade comprise the condensation of 6-fold molar excess of N-methyl piperazine with 4-amino-2 methyl- 1 OH- thieno- [2, 3-b] [I. 5] benzodiazepine hydrochloride in an organic solvent, e. g. dimethylsulf oxide, to which alcohol and excess of water is added after the reaction is completed, to remove unreacted substrates and impurities. The product is separated in a form of solvate with alcohol.
  • OLANZAPINE is obtained.
  • the Patent No US 5,229,382 described first polymorph of OLANZAPINE called Form I, which has been described to be metastable and not suitable for commercial use in pharmaceutical formulations such as tablets due to its color which changes over time on exposure to air.
  • the patent EP 07336335 BI reported a more stable second polymorph of Olanzapine claimed as Olanzapine polymorphic Form II which is obtained by suspending crude Olanzapine in ethyl acetate in anhydrous conditions and crystallization from this solution.
  • the existence of the two different polymorphs (Form I and Form II) has been confirmed by X ray powder diffraction patterns characterized by different interplanar spacing d and relative intensities I/Io.
  • Preparation methods were also given for a polymorph defined by the Applicant as Olanzapine Form I, by crystallization of crude Olanzapine from acetone (Preparation 5), tetrahydrofuran (Preparation 6), ethyl acetate (Preparation 7), t-butanol (Preparation 8).
  • EP 0733637 described preparation of solvate Form of Olanzapine From-II.
  • the shortcomings of earlier inventions are addressed in the present invention and a more convenient, reproducible process is described.
  • the main objective of this invention is to develop a better method of preparation for anhydrous OLANZAPINE of Form -II.
  • Step-II 4-Cyano-2-methyl-l- (2-Nitro phenyl amino) Thiophene
  • Step-III 4-amino-2-methyl-10H-Thieno [2,3-b][l,5] Benzodiazepine
  • This invention describes an improved method for the preparation of anhydrous OLANZAPINE of Form II
  • Anhydrous OLANZAPINE (Technical grade) is dissolved in Acetone at a temperature ranging from 40° C to 65° C , preferably at 50° C -60° C more preferably in the range of 55° C-58° C .
  • the ratio of Technical Olanzapine and Acetone may be 1: 10, preferably 1:7.5 and more preferably 1:5.
  • the resultant clear solution is then treated with activated carbon and stirred for 60 minutes.
  • the solvent is distilled off completely under reduced pressure.
  • An anti solvent is added and the resultant solid is filtered.
  • the anti solvent may be a lower alcohol preferably C 1 to C2; more preferably methanol.
  • the product is dried generally C 1- C4 at 65°C-70°C till constant weight.
  • the Olanzapine Form-II thus obtained was investigated by Elemental analysis, Ultra-violet spectrophotometer. Infrared absorption spectrophotometer, Proton nuclear magnetic resonance spectrometer, Carbon magnetic resonance spectrometer and mass spectrometer.
  • the polymorphism is established by the X Ray Diffraction values and are compared with the reported values. Below is the comparison of d- values of Form-II produced by the inventor and reported values.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

Du malononitrile réagit avec du propionaldéhyde en présence de poudre de soufre et de triéthylamine dans le N,N-diméthylformamide pour aboutir au 5-amino-4-cyano-2-méthylthiophène. Du 2-fluoronitrobenzène est condensé avec le 5-amino-4-cyano-2-méthylthiophène dans l'isopropanol et de la poudre d'hydroxyde de potassium pour obtenir du 4-cyano-2-méthyl-1-(2-nitrophénylamino)thiophène. La réduction du 4-cyano-2-méthyl-1-(2-nitrophénylamino)thiophène par le chlorure stanneux et l'acide chlorhydrique dans l'isopropanol, suivie d'une cyclisation, permet d'obtenir la 4-amino-2-méthyl-10H-thiéno[2,3,-b][1,5]benzodiazépine. La condensation de la 4-amino-2-méthyl-10H-thiéno[2,3,-b][1,5]benzodiazépine et de la N-méthylpipérazine en présence de diméthylsulfoxyde et le toluène permet d'obtenir de l'olanzapine de qualité technique sous forme anhydre. Le traitement de l'olanzapine technique anhydre par de l'acétone, suivi de sa précipitation à l'aide d'un anti-solvant, permet d'obtenir de l'OLANZAPINE anhydre de forme II.
PCT/IN2006/000142 2006-03-06 2006-04-25 Procédé de synthèse de la forme polymorphique anhydre de l'olanzapine Ceased WO2007102167A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN390CH2006 2006-03-06
IN390/CHE/2006 2006-03-06

Publications (1)

Publication Number Publication Date
WO2007102167A1 true WO2007102167A1 (fr) 2007-09-13

Family

ID=38474635

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2006/000142 Ceased WO2007102167A1 (fr) 2006-03-06 2006-04-25 Procédé de synthèse de la forme polymorphique anhydre de l'olanzapine

Country Status (1)

Country Link
WO (1) WO2007102167A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102225941A (zh) * 2011-06-01 2011-10-26 宁波人健医药化工有限公司 抗精神病药奥氮平的制备方法
CN102276624A (zh) * 2011-06-17 2011-12-14 大连理工大学 一种奥氮平有关物质及其制备方法和高效液相色谱分析方法
CN103848847A (zh) * 2012-12-04 2014-06-11 广东东阳光药业有限公司 一种改进制备奥氮平及其晶型ii的方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003097650A1 (fr) * 2002-05-17 2003-11-27 Institut Farmaceutyczny Procedes de preparation d'olanzapine polymorphe de forme i
WO2006030300A2 (fr) * 2004-09-17 2006-03-23 Ranbaxy Laboratories Limited Procedes de preparation d'olanzapine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003097650A1 (fr) * 2002-05-17 2003-11-27 Institut Farmaceutyczny Procedes de preparation d'olanzapine polymorphe de forme i
WO2006030300A2 (fr) * 2004-09-17 2006-03-23 Ranbaxy Laboratories Limited Procedes de preparation d'olanzapine

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102225941A (zh) * 2011-06-01 2011-10-26 宁波人健医药化工有限公司 抗精神病药奥氮平的制备方法
CN102225941B (zh) * 2011-06-01 2013-11-27 宁波人健医药化工有限公司 抗精神病药奥氮平的制备方法
CN102276624A (zh) * 2011-06-17 2011-12-14 大连理工大学 一种奥氮平有关物质及其制备方法和高效液相色谱分析方法
CN103848847A (zh) * 2012-12-04 2014-06-11 广东东阳光药业有限公司 一种改进制备奥氮平及其晶型ii的方法
CN103848847B (zh) * 2012-12-04 2018-02-06 广东东阳光药业有限公司 一种改进制备奥氮平及其晶型ii的方法

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