WO2010122576A1 - Procédé amélioré pour la préparation de 6-méthyl-2-[4-méthyl-phényl] imidazo [1, 2-a ] pyridine-3-n, n-diméthyle acétamide - Google Patents

Procédé amélioré pour la préparation de 6-méthyl-2-[4-méthyl-phényl] imidazo [1, 2-a ] pyridine-3-n, n-diméthyle acétamide Download PDF

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Publication number
WO2010122576A1
WO2010122576A1 PCT/IN2010/000245 IN2010000245W WO2010122576A1 WO 2010122576 A1 WO2010122576 A1 WO 2010122576A1 IN 2010000245 W IN2010000245 W IN 2010000245W WO 2010122576 A1 WO2010122576 A1 WO 2010122576A1
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WO
WIPO (PCT)
Prior art keywords
methyl
imidazo
zolpidem
acid
phenyl
Prior art date
Application number
PCT/IN2010/000245
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English (en)
Inventor
Jyothi Basu Abbineni
Babu Rao Konudula
Satish Babu Gadupudi
Sabapathy Kanaga
Original Assignee
Matrix Laboratories Ltd
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Publication date
Application filed by Matrix Laboratories Ltd filed Critical Matrix Laboratories Ltd
Publication of WO2010122576A1 publication Critical patent/WO2010122576A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • TITLE Improved Process for the preparation of 6-methyl-2-[4-methyl phenyl] imidazo [1, 2-a] pyridine-3-N, N-dimethyl acetamide.
  • the present invention relates to an improved process for the preparation of tartaric acid salt of N,N,6-trimethyl-2-p-tolylimidazo[l,2-a] pyridine-3 -acetamide (Zolpidem).
  • Zolpidem tartrate marketed under the trade name Ambien is a non-benzodiazepine hypnotic of the imidazopyridine class. Chemically, Zolpidem is N,N,6-trimethyl-2-p- tolylimidazo[l,2-a] pyridine-3-acetamide L-(+)-tartrate (2:1). It has the following structure:
  • Zolpidem tartrate is a white to off-white crystalline powder that is sparingly soluble in water, alcohol, and propylene glycol. Its hypnotic effects are similar to those of the benzodiazepine class of drugs, but it is molecularly distinct from the classical benzodiazepine molecule and is classified as an imidazopyridine.
  • Zolpidem is a short- acting non benzodiazepine hypnotic that potentiates gamma-amino butyric acid (GABA), an inhibitory neurotransmitter, by binding to gamma-amino butyric acid (GABA A ) receptors at the same location as benzodiazepines. It is indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation.
  • WO 2009/007995 Al assigned to Suven Life Sciences Ltd also claims process for the preparation of Zolpidem via novel intermediate.
  • This patent application also discloses process for the preparation of 2-[6-methyl-2-(4-methyl-phenyl)-imidazo[l,2-a]pyridin-3- yl]-acetic acid of formula (IV) from the compound of [6-methyl-2-(4-methyl-phenyl)- imidazo[l,2-a]pyridin-3-yl]-acetonitrile, formula (H) by hydrolysis in the presence of sulfuric acid.
  • the main object of the present invention is to provide an improved process for the preparation of the compound 2-[6-methyl-2-(4-methyl-phenyl)-imidazo[l,2-a]pyridin-3- yl]-acetic acid, and its further conversion to Zolpidem.
  • the main aspect of the present invention is to provide an improved process for the preparation of 2-[6-methyl-2-(4-methyl-phenyl)-imidazo[l,2-a]pyridin-3-yl]-acetic acid, an intermediate used in the preparation of Zolpidem tartarate, the process comprising hydrolysis of [6-methyl-2-(4-methyl-phenyl)-imidazo [l,2-a]pyridin-3-yl]-acetonitrile using mineral acid mixture in a solvent to give 2-[6-methyl-2-(4-methyl-phenyl)- imidazo[l,2-a]pyridin-3-yl]-acetic acid and further conversion into Zolpidem or its pharmaceutically acceptable salt.
  • the present invention relates to an improved process for the preparation of 2-[6-methyl- 2-(4-methyl-phenyl)-imidazo[l,2-a]pyridin-3-yl]-acetic acid and further conversion of the said compound to tartarate salt of 6-methyl-2-[4-methylphenyl] imidazo [1, 2-a] pyridine-3-N,N-dimethyl acetamide [Zolpidem].
  • the present invention provides an improved process for the preparation of Zolpidem tartarate schematically represented in Scheme-2, comprising the steps of: a) hydrolyzing [6-methyl-2-(4-methyl-phenyl)-imidazo [l,2-a]pyridin-3-yl]-acetonitrile of formula II using mineral acid to give 2-[6- methyl-2-(4-methyl-phenyl)- imidazo[l,2-a]pyridin-3-yl]-acetic acid of formula (IV); b) treating compound of formula (IV) with halogenating agent, condensing with dimethylamine to give Zolpidem; and c) treating Zolpidem with pharmaceutically acceptable acid to obtain Zolpidem acid addition salt.
  • [6-methyl-2-(4-methyl-phenyl)-imidazo [1,2- a]pyridin-3-yl]-acetonitrile is hydrolysed in a solvent preferably water, in the presence of a mineral acid.
  • Mineral acid is selected from sulfuric acid, hydrochloric acid or mixtures thereof preferably sulphuric acid and hydrochloric acid mixture. Reaction is carried out at
  • Compound of formula (IV) obtained above is treated with a halogenating agent and condensed with dimethylamine insitu.
  • Compound of formula (IV) is treated with a halogenating agent in a solvent mixture at 40-45 0 C.
  • Halogenating agent is selected from thionyl chloride, phosphorous trichloride and phosphorous oxychloride preferably phosphorous oxychloride.
  • Solvent used for carrying out reaction is selected from chlorinated solvents, aromatic solvents such as methylene dichloride, chloroform, carbon tetrachloride, toluene or mixtures thereof preferably methylene dichloride, toluene mixture. Contents are cooled to ambient temperature and added to 40% aq. dimethylamine solution below 15°C. The reaction is maintained for 40-80 min preferably 60 min at 10-25°C preferably 15-20 0 C.
  • Compound Zolpidem is isolated in DM water.
  • Zolpidem obtained in the above step is converted to pharmaceutically acceptable acid addition salts such as fumaric acid, malic acid, tartaric acid preferably tartaric acid by treating Zolpidem with acid addition salt in an alcoholic solvent.
  • the alcoholic solvent is selected from methanol, ethanol, propanol preferably methanol.
  • the obtained Zolpidem tartarate has improved yield and enhanced purity.
  • reaction mass was added to 40% aqueous dimethyl amine (1130 ml) solution at 0-5°C. Temperature of the reaction mass was raised to 15-20 0 C and maintained for 60 min. Layers were separated and organic layer was concentrated. DM water was added to the residue. Solid obtained was filtered and washed with toluene. The wet cake was dried at 55-60 0 C under reduced pressure to obtain (N, N, 6-trimethyl-2-(4-methylphenyl)-imidazo-(l, 2a)-pyridine)-3- acetamide.
  • N,N-6-trimethyl-2-(4-methylphenyl)-imidazo-(l, 2a)-pyridine)-3-acetamide (75 gms) was dissolved in methanol (375 ml).
  • L-tartaric acid solution (18 gms of acid in 1 15 ml methanol) was added under nitrogen atmosphere and maintained for about 4 hrs at 24- 26°C. Reaction mass was cooled to 0-5 0 C under nitrogen atmosphere. Solid obtained was filtered and washed with methanol (25 ml). The wet cake was dried under vacuum to obtain Zolpidem Tartrate.

Abstract

La présente invention concerne un procédé amélioré pour la préparation d'acide 2-[6-méthyl-2-(4-méthyl-phényl)-imidazo [1,2-a] pyridin-3-yl]-acétique, et pour la conversion de ce composé en sel tartrate de 6-méthyl-2-[4-méthylphényl] imidazo [1, 2-a] pyridine-3-n, n-diméthyle acétamide [Zolpidem].
PCT/IN2010/000245 2009-04-20 2010-04-16 Procédé amélioré pour la préparation de 6-méthyl-2-[4-méthyl-phényl] imidazo [1, 2-a ] pyridine-3-n, n-diméthyle acétamide WO2010122576A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN904/CHE/2009 2009-04-20
IN904CH2009 2009-04-20

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WO2010122576A1 true WO2010122576A1 (fr) 2010-10-28

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111057053A (zh) * 2018-10-17 2020-04-24 复旦大学 一种唑吡坦的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4382938A (en) 1980-10-22 1983-05-10 Synthelabo Imidazo[1,2-a] pyridine derivatives and their application as pharmaceuticals
WO2004087703A1 (fr) 2003-03-12 2004-10-14 Sun Pharmaceutical Industries Limited Procede de preparation de n,n,6-trimethyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine-3-acetamide
US20070027180A1 (en) 2005-09-19 2007-02-01 Padi Pratap R Process for preparing zolpidem
WO2009007995A1 (fr) 2007-07-09 2009-01-15 Suven Life Sciences Limited Procédé de préparation de zolpidém et de son intermédiaire

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4382938A (en) 1980-10-22 1983-05-10 Synthelabo Imidazo[1,2-a] pyridine derivatives and their application as pharmaceuticals
WO2004087703A1 (fr) 2003-03-12 2004-10-14 Sun Pharmaceutical Industries Limited Procede de preparation de n,n,6-trimethyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine-3-acetamide
US20070027180A1 (en) 2005-09-19 2007-02-01 Padi Pratap R Process for preparing zolpidem
WO2009007995A1 (fr) 2007-07-09 2009-01-15 Suven Life Sciences Limited Procédé de préparation de zolpidém et de son intermédiaire

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111057053A (zh) * 2018-10-17 2020-04-24 复旦大学 一种唑吡坦的制备方法
CN111057053B (zh) * 2018-10-17 2022-07-08 复旦大学 一种唑吡坦的制备方法

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