WO2004087703A1 - Procede de preparation de n,n,6-trimethyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine-3-acetamide - Google Patents

Procede de preparation de n,n,6-trimethyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine-3-acetamide Download PDF

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Publication number
WO2004087703A1
WO2004087703A1 PCT/IN2004/000057 IN2004000057W WO2004087703A1 WO 2004087703 A1 WO2004087703 A1 WO 2004087703A1 IN 2004000057 W IN2004000057 W IN 2004000057W WO 2004087703 A1 WO2004087703 A1 WO 2004087703A1
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Prior art keywords
compound
formula
preparation
mixed anhydride
formula iii
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PCT/IN2004/000057
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English (en)
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WO2004087703A8 (fr
Inventor
Samir Rameshchandra Shah
Kartik Shantilal Patel
Rajeev Budhdev Rehani
Rajamannar Thennati
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Sun Pharmaceutical Industries Limited
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Publication of WO2004087703A1 publication Critical patent/WO2004087703A1/fr
Publication of WO2004087703A8 publication Critical patent/WO2004087703A8/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

  • the present invention relates to a process for the preparation of N,N,6-trimethyl-2-(4- methylphenyl)-imidazo[l,2-a]pyridine-3-acetamide, commonly known as zolpidem (INN name), compound of formula I.
  • N,N,6-trimethyl-2-(4-methylphenyl)-imidazo[l,2- a]pyridine-3-acetamide is indicated for the short term treatment of insomnia.
  • United States patent number 4382938 (referred to herein as '938, Indian reference not available) exemplifies a process for the preparation of compound of formula I, by reacting compound of formula II with dimethyl amine in the presence of carbonyldiimidazole.
  • the amidation reaction can also be carried out by reacting compound of formula II with thionyl chloride followed by reaction with dimethyl amine. It has been reported that the reaction product of compound of formula II with thionyl chloride gives a black tar which requires additional purification steps, thus making the process unsuitable for industrial scale production.
  • the process of the present invention prepares compound of formula I through a novel mixed anhydride, compound of formula III, without the use of carbonyldiimidazole.
  • patent number 4794185 (Indian reference not available) describes a process for the preparation of compound of formula I by reacting ⁇ -hydroxy-N,N- dimethyl-acetamide derivative with thionyl chloride followed by reduction with sodium borohydride.
  • the drawback of this process is that the intermediate used to prepare ⁇ - hydroxy-N,N-dimethyl-acetamide viz., N,N-dimethyl-2.2-dimethoxy-acetamide is less stable as it is sensitive towards traces of water and acid.
  • the process of the present invention prepares compound of formula I using novel mixed anhydride, compound of formula III.
  • the stability of mixed anhydride, compound of formula III, of the present invention has been found to be superior to the intermediates reported in prior art.
  • An object of the present invention is to provide a novel process for the preparation of compound of formula I, from stable mixed anhydride, compound of formula III.
  • Another object of the present invention is to provide stable mixed anhydride, compound of formula III, and its process of preparation.
  • the present invention provides a process for the preparation of N,N,6- trimethyl-2-(4-methylphenyl)-imidazo [l,2-a]pyridine-3-acetamide,compound of formula
  • R is selected from Cito C 6 linear or branched alkyl groups and substituted phenyl groups.
  • compound of formula I may be converted to an acid addition salt such as hemitartrate or tartrate.
  • the present invention also provides mixed anhydride, compound of formula III,and its process of preparation, comprising reacting compound of formula II, with RCOX;
  • N,N,6-trimethyl-2-(4-methylphenyl)- imidazo[l,2-a]pyridine-3-acetamide, compound of formula I is obtained by reacting mixed anhydride, compound of formula III, with dimethylamine.
  • novel mixed anhydride, compound of formula III, of the present invention may be prepared by reaction of compound of formula II with RCOX wherein R is selected from Cito C 6 linear or branched allcyl and substituted phenyl groups, preferably pivaloyl and isobutyl groups and X is a halo group, such as chloro, bromo, fluoro & iodo, preferably chloro.
  • RCOX wherein R is selected from Cito C 6 linear or branched allcyl and substituted phenyl groups, preferably pivaloyl and isobutyl groups and X is a halo group, such as chloro, bromo, fluoro & iodo, preferably chloro.
  • the mixed anhydride, compound of formula III may be isolated followed by nucleophilic addition reaction with dimethylamine to yield compound of formula I.
  • compound of formula I may be prepared by reacting compound of formula II with RCOX followed by insitu addition of dimethylamine.
  • the reaction of mixed anhydride, compound of formula III, with dimethylamine may be carried out at about -10 to 100 °C, preferably the reaction is carried out at about -10 to 50°C.
  • reaction of mixed anhydride, compound of formula III, with dimethylamine may be carried out in an organic solvent in the presence of base.
  • the organic solvent may be selected from non-polar, polar, polar aprotic or polar protic solvents, preferably polar aprotic to non-polar solvent(s).
  • the polar aprotic to non-polar solvent(s) may be selected from ethers such as diethylether, di-isopropylether, diphenylether, dioxane, tetrahydrofuran and the like; linear or cyclic aliphatic or aromatic hydrocarbons such as n-hexane, n-heptane, cyclohexane, methylcyclohexane, toluene, ethylbenzene, xylene and the like; aliphatic or aromatic halogenated hydrocarbons such as methylene dichloride, ethylene dichloride, tetrachloroethane, trichloroethane, chlorobenzene, dichlorobenzene and the like; amides such as acetamide
  • the base is preferably non-nucleophilic base selected from organic and inorganic bases such as linear and cyclic amines selected from C ⁇ -4 lower alkyl tertiary amines e.g. trimethylamine triethylamine, l,8-diazabicyclo[5.4.0] undec-7-ene, tetramethylguanidine, pyridine, substituted pyridine, dimethylamino pyridine, lutidine and the like; and carbonates or bicarbonates of alkali or alkaline earth metals such as sodium, potassium, lithium, calcium, barium and the like.
  • organic and inorganic bases such as linear and cyclic amines selected from C ⁇ -4 lower alkyl tertiary amines e.g. trimethylamine triethylamine, l,8-diazabicyclo[5.4.0] undec-7-ene, tetramethylguanidine, pyridine, substituted pyridine, dimethylamino
  • mixed anhydride, compound of formula III may be prepared from compound of formula II with RCOX followed by reaction of mixed anhydride, compound of formula III, with dimethylamine insitu at about -10 to 100 °C, preferably at about -10 to 50°C.
  • the process for the preparation of mixed anhydride, compound of formula III may be carried out by treating compound of formula II with RCOX wherein R is selected from Cito C 6 linear or branched alkyl groups and substituted phenyl groups and X is a halo group; in an organic solvent in the presence of base.
  • the organic solvent may be selected from non-polar, polar, polar aprotic or polar protic solvents, preferably polar aprotic to non-polar solvent(s).
  • the polar aprotic to non-polar solvent(s) may be selected from ethers such as diethylether, di-isopropylether, diphenylether, dioxane, tetrahydrofuran and the like; linear or cyclic aliphatic or aromatic hydrocarbons such as n-hexane, n-heptane, cyclohexane, methylcyclohexane, toluene, ethylbenzene, xylene and the like; aliphatic or aromatic halogenated hydrocarbons such as methylene dichloride, ethylene dichloride, tetrachloroethane, trichloroethane, chlorobenzene, dichlorobenzene and the like; amides such as acetamide
  • the base is preferably non-nucleophilic base selected from organic and inorganic bases such as linear and cyclic amines selected from C ⁇ -4 lower alkyl tertiary amines e.g. trimethylamine triethylamine, l,8-diazabicyclo[5.4.0] undec-7-ene, tetramethylguanidine, pyridine, substituted pyridine, dimethylamino pyridine, lutidine and the like; and carbonates or bicarbonates of alkali or alkaline earth metals such as sodium, potassium, lithium, calcium, barium and the like.
  • organic and inorganic bases such as linear and cyclic amines selected from C ⁇ -4 lower alkyl tertiary amines e.g. trimethylamine triethylamine, l,8-diazabicyclo[5.4.0] undec-7-ene, tetramethylguanidine, pyridine, substituted pyridine, dimethylamino
  • Compound of formula II used in the preparation of compound of formula III may be prepared as per any prior art method such as United States patent number 4382938. Further, the compound of formula I may be converted to acid addition salts such as acetic, citric, malic, succinic, maleic, fumaric, oxalic, tartaric, alkyl or aryl sulfonic, pamoic, xinafoic, ascorbic and the like or mineral acids such as hydrochloric, hydrobromic, sulfuric and the like.
  • acid addition salts such as acetic, citric, malic, succinic, maleic, fumaric, oxalic, tartaric, alkyl or aryl sulfonic, pamoic, xinafoic, ascorbic and the like or mineral acids such as hydrochloric, hydrobromic, sulfuric and the like.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention a trait à un procédé de préparation d'un composé de N,N,6-triméthyl-2-(4-méthylphényl)-imidazo [1,2-a]pyridine-3-acétamide, représenté par la formule (I). Ledit procédé consiste à faire réagir un anhydride mélangé, représenté par la formule (III), avec de la diméthylamine. Dans la formule (III), R est sélectionné parmi les groupes alkyle linéaires ou ramifiés C1 à C6 et les groupes phényle substitués.
PCT/IN2004/000057 2003-03-12 2004-03-11 Procede de preparation de n,n,6-trimethyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine-3-acetamide WO2004087703A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN271MU2003 2003-03-12
IN271/MUM/2003 2003-03-12

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WO2004087703A1 true WO2004087703A1 (fr) 2004-10-14
WO2004087703A8 WO2004087703A8 (fr) 2004-11-25

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PCT/IN2004/000057 WO2004087703A1 (fr) 2003-03-12 2004-03-11 Procede de preparation de n,n,6-trimethyl-2-(4-methylphenyl)-imidazo[1,2-a]pyridine-3-acetamide

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007040995A1 (fr) * 2005-10-03 2007-04-12 Mallinckrodt Inc. Procédé pour la préparation de polymorphes de zolpidem hémitartrate et tartrate
WO2009007995A1 (fr) * 2007-07-09 2009-01-15 Suven Life Sciences Limited Procédé de préparation de zolpidém et de son intermédiaire
WO2010122576A1 (fr) 2009-04-20 2010-10-28 Matrix Laboratories Ltd Procédé amélioré pour la préparation de 6-méthyl-2-[4-méthyl-phényl] imidazo [1, 2-a ] pyridine-3-n, n-diméthyle acétamide

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001038327A2 (fr) * 1999-11-22 2001-05-31 EGIS Gyógyszergyár Rt. Procede de preparation de 6-methyl-2-(4-methyl-phenyl)-imidazo[1,2-a]pyrimidine-3-(n,n-dimethyl-acetamide) et d'intermediaires
WO2001080857A1 (fr) * 2000-04-24 2001-11-01 Teva Pharmaceutical Industries Ltd. Zolpidem hemitartrate
EP1172364A1 (fr) * 2000-07-14 2002-01-16 Dinamite Dipharma S.p.A. (in abbreviated form Dipharma S.p.A.) Procédé pour la préparation de 2-phényl-imidazo[1,2-a]pyridine 3-acétamides

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001038327A2 (fr) * 1999-11-22 2001-05-31 EGIS Gyógyszergyár Rt. Procede de preparation de 6-methyl-2-(4-methyl-phenyl)-imidazo[1,2-a]pyrimidine-3-(n,n-dimethyl-acetamide) et d'intermediaires
WO2001080857A1 (fr) * 2000-04-24 2001-11-01 Teva Pharmaceutical Industries Ltd. Zolpidem hemitartrate
EP1172364A1 (fr) * 2000-07-14 2002-01-16 Dinamite Dipharma S.p.A. (in abbreviated form Dipharma S.p.A.) Procédé pour la préparation de 2-phényl-imidazo[1,2-a]pyridine 3-acétamides

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007040995A1 (fr) * 2005-10-03 2007-04-12 Mallinckrodt Inc. Procédé pour la préparation de polymorphes de zolpidem hémitartrate et tartrate
JP2009510163A (ja) * 2005-10-03 2009-03-12 マリンクロッド・インコーポレイテッド ヘミ酒石酸および酒石酸ゾルピデム多形の製造方法
WO2009007995A1 (fr) * 2007-07-09 2009-01-15 Suven Life Sciences Limited Procédé de préparation de zolpidém et de son intermédiaire
WO2010122576A1 (fr) 2009-04-20 2010-10-28 Matrix Laboratories Ltd Procédé amélioré pour la préparation de 6-méthyl-2-[4-méthyl-phényl] imidazo [1, 2-a ] pyridine-3-n, n-diméthyle acétamide

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