WO2009007995A1 - Procédé de préparation de zolpidém et de son intermédiaire - Google Patents

Procédé de préparation de zolpidém et de son intermédiaire Download PDF

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Publication number
WO2009007995A1
WO2009007995A1 PCT/IN2008/000266 IN2008000266W WO2009007995A1 WO 2009007995 A1 WO2009007995 A1 WO 2009007995A1 IN 2008000266 W IN2008000266 W IN 2008000266W WO 2009007995 A1 WO2009007995 A1 WO 2009007995A1
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formula
range
temperature
period
hours
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PCT/IN2008/000266
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English (en)
Inventor
Rajendiran Chinnapillai
Ravikumar Reddy Nallamaddi
Veera Reddy Arava
Venkateswarlu Jasti
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Suven Life Sciences Limited
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Publication of WO2009007995A1 publication Critical patent/WO2009007995A1/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 an improved process for the preparation of 6- methyl-2- [4-methylphenyl] imidazo [ 1 ,2-a]pyridine-3 -N,N-dimethyl acetamide having formula (1).
  • the compound of formula (1) has adopted name "Zolpidem”.
  • the present invention also relates to novel intermediate of the formula (2)
  • R represents methyl, ethyl, propyl, butyl, isopropyl, isobutyl or tertiary butyl group.
  • the novel intermediate of formula (T) is used in preparation of Zolpidem having formula (V).
  • Zolpidem is useful in the treatment of anxiety, sleep disorders and convulsion. Background of the Invention
  • Zolpidem disclosed in EP 50563 (equivalent to US 4382938) is assigned to synthelabo (France). It is a selective benzodiazepine receptor agonist not related chemically to benzodiazepines. Zolpidem shows both high affinity and selectivity towards non-benzodiazepine-2-receptors, which means an improved activity for the treatment of anxiety, sleep disorders and convulsion.
  • 6-Methyl-2-(4-methylphenyl)imidazo[l,2-a]pyridine of the formula (7) was prepared by the reaction of toluene of the formula (3) with chloroacetylchloride of the formula (4) under Friedel-crafts acylation conditions followed by condensation with 2- amino-5-methylpyridine of the formula (6).
  • EP 50563 describes the process for the preparation of Zolpidem, using synthetic process as depicted in Scheme -2.
  • This approach involves the preparation of key intermediate 6-methyl-2-[4- methylphenyl]imidazo[l,2-a]pyridine-3-acetonitrile of the formula (10), by using the disclosed procedures of GB 991589 and GB 1076089.
  • the amino methylation of the imidazopyridine of the formula (7) yields the 3-dimethylamino derivative of the formula (8), which is alkylated with methyliodide to obtain the quaternary ammoinium salt of the formula (9), which is then reacted with sodium cyanide to give the corresponding nitrile of the formula (10).
  • the 6-methyl-2-[4-methylphenyl]irnidazo[l,2-a]pyridine of the formula (T) is formylated using oxalylchloride and dimethylformamide to obtain the aldehyde derivative of the formula (13) which is reduced with sodium borohydride to yield the corresponding alcohol of the formula (14).
  • Alcohol derivative of the formula (14) is reacted with p-toluenesulfonylchloride in the presence of pyridine to obtain the quaternary ammonium salt of the formula (15), which is reacted with cyanide ion to yield the 6-methyl-2-[4-methylphenyl]imidazo[l,2-a]pyridine-3-acetonitrile of the formula (10).
  • the resulting acetonitrile intermediate of the formula (10) transformed into acid of the formula (12) by base hydrolysis, which is amidated using CDI and dimethylamine to give Zolpidem of the formula Qj.
  • Zolpidem of formula (1) was prepared by the reaction of 6-methyl-2-[4- methylphenyl]imidazo[l,2-a]pyridine of the formula (T) with N,N-dimethyl-2,2- dimethoxyacetamide of the formula (16) to yield 3 -substituted hydroxy derivative of the formula (17),
  • the hydroxyl group of formula (17) is converted into chloro derivative of the formula (18), by using thionylchloride.
  • the chloro derivative of formula (18) is converted into formula (T), by subsequent reduction with sodiumborohydride.
  • the present invention relates to the novel intermediate of the formula (2), which is useful for the preparation of Zolpidem of the formula (1)
  • R represents methyl, ethyl, propyl, butyl, isopropyl or tertiary butyl group.
  • the present invention also provides process for preparation of the novel intermediate of the formula (2),
  • R represents methyl, ethyl, propyl, butyl, isopropyl or tertiary butyl group.
  • the present invention provides an improved process for the preparation of Zolpidem of formula (V)
  • R represents methyl, ethyl, propyl, butyl, isopropyl or tertiary butyl group c) treating the intermediate of the formula (2) with sodium cyanide at a temperature in the range of 10 to 100 0 C for the period of 1 to 6 hours to get acetonitrile derivative of imidazopyridine of formula (10)
  • the present invention provides an improved process for the preparation of Zolpidem avoiding use of the expensive methyliodide, sodiumborohydride and CDI In another aspect, the present invention provides an improved process for the preparation of Zolpidem using inexpensive readily available and easy to handle reagents.
  • the present invention provides an improved process for the preparation of Zolpidem which can be readily scaled up and which does not require a special purification step to obtain pure Zolpidem.
  • the present invention provides an improved process for the preparation of Zolpidem, which is simple, convenient, economical and environmentally safe.
  • the present invention relates to the novel intermediate of the formula (2), which is useful for the preparation of Zolpidem of the formula (1).
  • R represents methyl, ethyl, propyl, butyl, isopropyl or tertiary butyl group.
  • R represents methyl, ethyl, propyl, butyl, isopropyl or tertiary butyl group.
  • R represents methyl, ethyl, propyl, butyl, isopropyl or tertiary butyl group c) treating the intermediate of the formula (2) with sodium cyanide at a temperature in the range of 10 to 100 0 C for the period of 1 to 6 hours to get acetonitrile derivative of imidazopyridine of formula (10) d) hydrolyzing the acetonitrile derivative of the formula (10) using dilute sulfuric acid solution at a temperature in the range of 50 to 150 0 C for the period of 2 to 8 hours to give the acid derivative of formula (12)
  • Scheme - 6 illustrates an improved process for preparation of Zolpidem of the formula (V), by the present invention.
  • the reaction temperature may range from 10 to 100 0 C and preferably at a temperature in the range from 50 to 55 0 C.
  • the duration of the reaction may range from 2 to 5 hours, preferably from a period of 3 to 4 hours.
  • the obtained dimethylaminomethyl derivative of imidazopyridine of the formula (8) is treated with alkylchloroformate in a halogenated solvent to obtain formula (T).
  • the alkylchloroformate used in the reaction can be selected from the methylchloroformate, ethylchloroformate or butylchloroformate and preferably using ethylchloroformate.
  • the amount of alkylchloroformate used in the reaction may be in the range of 1.0 to 3.0 molar equivalents and preferably using 1.2 to 1.5 molar equivalents.
  • the halogenated solvent used in the reaction can be selected from dichloromethane, dichloroethane or chloroform and preferably using dichloromethane.
  • the reaction temperature may range from -5 to 20 0 C and preferably at a temperature in the range from 0 to 5 0 C.
  • the duration of the reaction may range from 15 minutes to 2 hours, preferably from a period of 30 to 45 minutes.
  • the formed solid of formula (2) is dissolved in water and basified to adjust the pH around 8.0 and treated with sodium cyanide to get the nitrile derivative of formula (10).
  • the amount of sodium cyanide used in the reaction is 1.0 to 2.0 molar equivalents of compound of formula (8) and preferably in an amount of 1.1 to 1.4 molar equivalents.
  • the base used in the reaction can be selected from potassium carbonate, sodium bicarbonate, sodium hydride or sodium hydroxide and preferably using sodium hydroxide.
  • the reaction temperature may range from 10 to 100 0 C and preferably at a temperature in the range from 50 to 55 0 C.
  • the duration of the reaction may range from 1 to 6 hours, preferably from a period of 3 to 4 hours.
  • the nitrile derivative of formula (10) is converted into corresponding acid of formula (12) by means of hydrolysis.
  • the hydrolysis reaction is carried out in presence of dilute sulfuric acid.
  • the percentage of sulfuric acid in the reaction is ranging from 10% to 70% and preferably about 50%.
  • the amount of sulfuric acid used in the reaction will be in the range of 10 to 30 molar equivalents, preferably 15 to 20 molar equivalents.
  • the reaction temperature may range from 50 to 150 0 C and preferably at a temperature in the range from 90 to 110 0 C.
  • the duration of the reaction may range from 2 to 8 hours, preferably from a period of 4 to 5 hours.
  • the acid of formula (12) is treated with an organic base and pivaloylchloride in suitable solvent followed by dimethylamine to get Zolpidem.
  • the solvent used in the reaction can be selected from dichloromethane, dichloroethane or chloroform and preferably using dichloromethane.
  • the volume of solvent used in the reaction is range of 20 to 50 volumes, preferably about 30 to 40 volumes.
  • the organic base used in the reaction can be selected from triethylamine, diisopropylethylamine, pyridine or N-methylmorpholine, for about 1.5 molar equivalents to 3.0 molar equivalents and preferably triethylamine is used as organic base for about 2.0 molar equivalents.
  • Pivaloylchloride is used in the reaction about 1.0 to 2.0 molar equivalents, preferably 1.5 molar equivalents for a period of about 10 to 60 minutes and preferably about 30 minutes.
  • the amount of dimethylamine used in the reaction may be about 1.5 to 3.5 molar equivalents, preferably about 2.0 molar equivalents.
  • the reaction temperature may range from -10 to 20 0 C and preferably at a temperature in the range from 5 to 10 0 C.
  • IR spectra (cm "1 ): 2921, 2895, 2249, 1500, 1386, 1343, 824, 799;
  • the 6-methyl-2-(4-methylphenyl)imidazo[l,2-a]pyridine-3-acetic acid of the formula (12) is prepared without isolation and purification of intermediate products thereby saving the time and increasing the productivity.
  • Zolpidem is prepared from acid of the formula (12) using pivaloylchloride as a coupling reagent instead of CDI which makes the process cheaper, simple and safe
  • the total yield of the Zolpidem is 55 to 60% in two-step process from 6-methyl-2- (4-methylphenyl)imidazo[l,2-a]pyridine of formula (T) instead of five-step process with 40 - 45% yield, thereby making then process economical.

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

Abstract

La présente invention porte sur un procédé perfectionné pour la préparation du 6-méthyl-2-[4-méthylphényl]imidazo[l,2-a]pyridine-3-N,N-diméthyl acétamide représenté par la formule (1). Le composé de formule (1) a reçu le nom de « Zolpidém ». La présente invention porte également sur un nouvel intermédiaire de la formule (2) et sur un procédé permettant de le préparer. Dans la formule, R représente méthyle, éthyle, propyle, butyle, isopropyle, isobutyle ou butyle tertiaire. Le nouvel intermédiaire de formule (2) est utilisé dans la préparation du Zolpidém ayant la formule (1). Le Zolpidém est utile dans le traitement de l'anxiété, des troubles du sommeil et des convulsions.
PCT/IN2008/000266 2007-07-09 2008-04-28 Procédé de préparation de zolpidém et de son intermédiaire WO2009007995A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1470/CHE/2007 2007-07-09
IN1470CH2007 2007-07-09

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WO2009007995A1 true WO2009007995A1 (fr) 2009-01-15

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN113264932A (zh) * 2021-05-28 2021-08-17 湖南千金湘江药业股份有限公司 一种唑吡坦的制备方法
CN114249724A (zh) * 2020-09-25 2022-03-29 鲁南制药集团股份有限公司 一种唑吡坦中间体的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE255942C (fr) *
GB991589A (en) * 1963-04-30 1965-05-12 Selvi & C Lab Bioterapico Novel [1,2-ª‡]imidazopyridines and a process for the manufacture thereof
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

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE255942C (fr) *
GB991589A (en) * 1963-04-30 1965-05-12 Selvi & C Lab Bioterapico Novel [1,2-ª‡]imidazopyridines and a process for the manufacture thereof
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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
GEORGE P ET AL: "Le zolpidem: Un nouvel hypnotique de structure imidazo[1,2-alpha]pyridine", ACTUAL. CHIM. THER., vol. 18, 1 January 1991 (1991-01-01), pages 215 - 239, XP002900936 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
CN114249724A (zh) * 2020-09-25 2022-03-29 鲁南制药集团股份有限公司 一种唑吡坦中间体的制备方法
CN113264932A (zh) * 2021-05-28 2021-08-17 湖南千金湘江药业股份有限公司 一种唑吡坦的制备方法

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