WO2010122576A1 - Improved process for the preparation of 6-methyl-2-[4-methyl phenyl] imidazo [1, 2-a] pyridine-3-n, n-dimethyl acetamide. - Google Patents
Improved process for the preparation of 6-methyl-2-[4-methyl phenyl] imidazo [1, 2-a] pyridine-3-n, n-dimethyl acetamide. Download PDFInfo
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- 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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- methyl
- imidazo
- zolpidem
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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.
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Abstract
The present invention relates to an improved process for the preparation of 2-[6-methyl- 2-(4-methyl-phenyl)-imidazo [ 1,2-a]pyridin-3-yl] -acetic acid and further conversion of the said compound to tartarate salt of 6-methyl-2-[4-methylphenyl] imidazo [I, 2-a] pyridine- 3 -N, N-dimethyl acetamide [Zolpidem].
Description
TITLE: Improved Process for the preparation of 6-methyl-2-[4-methyl phenyl] imidazo [1, 2-a] pyridine-3-N, N-dimethyl acetamide.
FIELD OF THE INVENTION
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).
BACKGROUND OF THE INVENTION
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:
Formula 1
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 (GABAA) receptors at the same location as benzodiazepines. It is indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation.
US Patent number 4,382,938 assigned to Synthelabo dislosed Zolpidem generically. The synthetic scheme given in US 4,382,938 is as shown in Scheme- 1. The main
disadvantage of this process is that it employs very expensive, toxic, intermediate carbonyl-diimidazole and hence industrially non-viable.
Scheme- 1
PCT publication WO 2004/087703 claims process for the preparation of Zolpidem by reacting mixed anhydride with dimethyl amine. This patent application also discloses single step 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 6-methyl-2-para-tolyl-imidazo[l,2- a]pyridin-3-yl)-acetonitrile of formula II by using Con. hydrochloric acid.
US 2007/0027180 Al claims process for the preparation of Zolpidem comprising the steps of, reacting 3-(N,N-dimethylaminomethyl)-6-methyl-2-(4-methylphenyl)-imidazo- [l,2-a]-pyridine with an alkyl halide and without isolating any intermediate, reacting with an alkali metal cyanide, then reacting with a base to form 6-methyl-2-(4-methylphenyl)- imidazo-[l,2-a]-pyridine-3-acetic acid. This patent application 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 formula II by base hydrolysis.
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 prior art processes do not provide Zolpidem with high yield and purity. Therefore, there is a need in the art for an economical and industrially feasible process for the preparation of Zolpidem.
OBJECT OF THE INVENTION
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.
SUMMARY OF THE INVENTION
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.
DETAILED DESCRIPTION OF THE INVENTION
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].
In one embodiment, 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.
Condensation ..
Dlmethylamine
Scheme-2
According to the present invention, [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
80-120°C preferably 90-105°C. After completion of the reaction, mass is cooled to ambient temperature and pH of the reaction mass is adjusted to 3.0-5.0. The solid obtained is filtered and washed with water. Wet cake is dried to obtain compound 2-[6- methyl-2-(4-methyl-phenyl)-imidazo[l,2-a]pyridin-3-yl]-acetic acid of formula (IV).
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 40-450C. 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 15-200C. 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.
According to the present invention, the obtained Zolpidem tartarate has improved yield and enhanced purity.
The following examples are given to illustrate the present invention, but however are not intended to limit the scope of the invention in any way.
Example 1
Preparation of [6-methyl-2-(4-methyl-phenyl)-imidazo[l, 2-a]pyridin-3-yl]-acetic acid.
Sulphuric acid (40 gms) was added slowly to DM water (120 ml) in a RB flask followed by HCl (20 ml). [6-methyl-2-(4-methyl-phenyl)-imidazo[l,2-a]pyridin-3-yl]-acetonitrile (10 gms) was added to the reaction mixture and slowly heated to 90-1050C. Reaction was maintained for about 36 hrs and the resulting reaction mass was cooled to 25-35°C. pH of the reaction mass was adjusted to 3.8 - 4.2 by using NaOH solution. Reaction contents were slowly heated to 45-48°C. The solid obtained was filtered and washed with hot
water (100 ml). Wet solid was dried at 65-70°C for 10 hr to yield 10 gms of 2-[6-methyl- 2-(4-methyl-phenyl)-imidazo[ 1 ,2-a]pyridin-3-yl]-acetic acid.
Example 2 Preparation of (N, N, 6-trimethyl-2-(4-methylphenyl)-imidazo-(l, 2a)-pyridine)-3- acetamide
Methylene dichloride (500 ml) was added to toluene (100 ml) into an RB flask at 25- 35°C. Contents were cooled to 10-150C and of phosphorous oxychloride (250gms) was added. To the solution, [6-methyl-2-(4-methyl-phenyl)-imidazo [1, 2-a] pyridin-3-yl]- acetic acid (100 gms) was added. Temperature of the reaction mass was raised to 40- 45°C and maintained the reaction mass for 26-28 hours. Reaction mass was cooled to room temperature and methylene dichloride (200 ml) was added. The reaction mass was added to 40% aqueous dimethyl amine (1130 ml) solution at 0-5°C. Temperature of the reaction mass was raised to 15-200C 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 55-600C under reduced pressure to obtain (N, N, 6-trimethyl-2-(4-methylphenyl)-imidazo-(l, 2a)-pyridine)-3- acetamide.
Example 3
Preparation of Zolpidem Tartrate
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 0-50C under nitrogen atmosphere. Solid obtained was filtered and washed with methanol (25 ml). The wet cake was dried under vacuum to obtain Zolpidem Tartrate.
Claims
1. An improved process for the preparation of Zolpidem tartarate comprising the steps of: a) hydrolyzing [6-methyl-2-(4-methyl-phenyl)-imidazo [l,2-a]pyridin-3-yI]- acetonitrile of formula II using mineral acid in a solvent 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 tartaric acid in a solvent to obtain Zolpidem tartarate.
2. The process according to claim 1, wherein the mineral acid used for hydrolysis is selected from sulfuric acid, hydrochloric acid or mixtures thereof.
3. The process according to claim 2, wherein the mineral acid mixture is sulphuric acid and hydrochloric acid mixture.
4. The process according to claim 1, wherein the solvent used for hydrolysis is DM water.
5. The process according to claim 1, wherein the halogenating agent is selected from thionyl chloride, phosphorous oxychloride.
6. The process according to claim 5, wherein halogenating agent is phosphorous oxychloride.
7. The process according to claim 1, wherein the solvent used for salt formation is methanol.
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| Application Number | Priority Date | Filing Date | Title |
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| IN904/CHE/2009 | 2009-04-20 | ||
| IN904CH2009 | 2009-04-20 |
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| WO2010122576A1 true WO2010122576A1 (en) | 2010-10-28 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111057053A (en) * | 2018-10-17 | 2020-04-24 | 复旦大学 | Preparation method of zolpidem |
Citations (4)
| 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 (en) | 2003-03-12 | 2004-10-14 | Sun Pharmaceutical Industries Limited | Process for the preparation of 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 (en) | 2007-07-09 | 2009-01-15 | Suven Life Sciences Limited | Process for preparing zolpidem and its intermediate |
-
2010
- 2010-04-16 WO PCT/IN2010/000245 patent/WO2010122576A1/en active Application Filing
Patent Citations (4)
| 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 (en) | 2003-03-12 | 2004-10-14 | Sun Pharmaceutical Industries Limited | Process for the preparation of 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 (en) | 2007-07-09 | 2009-01-15 | Suven Life Sciences Limited | Process for preparing zolpidem and its intermediate |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111057053A (en) * | 2018-10-17 | 2020-04-24 | 复旦大学 | Preparation method of zolpidem |
| CN111057053B (en) * | 2018-10-17 | 2022-07-08 | 复旦大学 | Preparation method of zolpidem |
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