FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of tartaric acid
salt ofN,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

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 j drugs, but it is molecularjy distinct from the classical benzodiazepine molecule and is classified as an imidazopyridine. Zolpidem is a short-acting non benzodiazepinerhypnotic that potentiates gamrna-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.

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-
II 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 alliyl 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
ii 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 2009/007955 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]-acetonitrile5 formula (II) 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, an intermediate used in the preparation of Zolpidem and 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 if 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[l32-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 aeetamide [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 off formula (IV) with halogenating agent, condensing with
dimethylamine to give Zolpidem; and

c) treating Zolpidem with pharmaceutically acceptable acid to obtain Zolpidem acid

According to the present invention, [6-methyl-2-(4-methyl-phenyl)-imidazo [1,2-
i| a]pyridin-3-yl]-acetonitrile is hydrolysed in a solvent preferably water, in the presence of
ii 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-r'05°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 40-45°C. Halogenating agent is selected from
thionyl chloride, phosphorous trichloride and phosphorous oxychloride preferably
phosphorous oxychloridei Solvent used for carrying out reaction is selected from it 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°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
i 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-methyI-phenyl)-imidazo[l, 2-a]pyridin-3-ylj-acetic acid.

Sulphuric acid (40 gms) was added slowly to DM water (120 ml) in a RB flask followed by HC1 (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 90-105°C. 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 160 gms of 2-[6-methyl-2-(4-methyl-phenyl)-imidazo[l,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 10-15°C 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 15-20°C and maintained for 60 min. Layers were separated and organic layer was concentrated under reduced pressure. DM water was added to the residue. Solid obtained was filtered and washed with toluene. The wet cake was dried at 55-60°C 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-64rimethyl-2-(4-methylphenyl)-imidazo-(l, 2a)-pyridine)-3-acetamide (75 gms) was dissolved in methanol^ (3 75 ml). L-tartaric acid solution (18 gms of acid in 115 ml methanol) was added under nitrogen atmosphere and maintained for about 4 hrs at 24-26°C. Reaction mass was cooled to 0-5°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.

We Claim:
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-yl]-
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 compound1 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 15 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.