Title of Invention	AN IMPROVED PROCESS FOR THE PREPARATION OF ZOLPIDEM
Abstract	The invention relates to a process for the preparation of zolpidem which comprises (i) reacting zolpidic acid with a halogenating agent to get zolpidic acid chloride (ii) reacting the resulting zolpidic acid chloride with n,n-dimethyl ammonium - N1, N1-dimethylcarbamate in the presence or absence of solvent, at a temperature in a range of 0degeree to below 60degreeselsiyas.

Full Text

Field of Invention The present invention relates to an improved process for the preparation of Zolpidem. Zolpidem (CAS Registry No. 82626-48-0) is chemically, N, N, 6-trimethyl-2-(4-methyl phenyl)-imidazo[l,2-a]pyridine-3-acetamide5 represented by the Formula-I. Zolpidem hemitartrate (CAS Registry No. 99294-93-6), which is a salt of Zolpidem with L-tartaric acid, is marketed as a non-benzodiazepine hypnotic for the treatment of sleep disorders. The process for the preparation of Zolpidem freebase was disclosed in EP No 50563 and U.S. Patent No. 4382938 of Synthelabo. The process comprises of reacting zolpidic acid of the formula-II with dimethylamine of the formula-Ill in the presence of carbonyldiimidazole. The dimethylamine was added as a solution in tetrahydrofuran. This process suffers from the use of expensive reagent and solvent besides handling of toxic hazardous dimethyl amine. It is also reported to give low yields and form impurities, as per PCT Patent WO-0180857, P.l 1. An alternative process of preparing Zolpidem is described in WO-0180857. The process comprises of converting zolpidic acid to its chloride of the formula-IV using thionyl chloride, and further reacting the chloride with dimethylamine. This process also suffers from use of gaseous hazardous dimethylamine. Dimethylamine used in these processes is an odorous gas, exposure to which causes irritation of nose and throat, conjunctivitis, dermatitis, dispend, pulmonary edema, frost bite etc. (Merck Index, pg.569,13' ., entry 3255). Commercially dimethylamine is also available as 30-40 % aqueous solution. However, aqueous solution is not suitable because the reactive intermediates such as acid chloride and anhydride are not stable in aqueous conditions. Due to the commercial importance gained for the use of Zolpidem, there is a need to develop an improved process for the preparation of Zolpidem free from the drawbacks mentioned above. Objectives of the invention Therefore , the main objective of the present invention is to provide an improved process for the preparation of Zolpidem which is simple and safe . Another objective of the present invention is to provide an improved process for the preparation of Zolpidem by avoiding the use of dimethylamine gas. Still another objective of the present invention is to provide an improved process for the preparation of Zolpidem by the conversion of the zolpidic acid halide to Zolpidem base. Yet another objective of the present invention is to provide an improved process for the preparation of Zolpidem by avoiding the formation of any impurities . Summary of the Invention Accordingly, the present invention provides an improved process for the preparation of Zolpidem of the formula-I (ii) removing the excess halogenating agent and the solvent by distillation at reduced pressure and, (iii) reacting the residue with N,N-dimethyl ammonium –N N'-dimethylcarbamate (DMADMC) in the presence or absence of a solvent, at a temperature in the range of 0 to 60°C to obtain Zolpidem of the formula-I. DMADMC (CAS Registry No. 4137-10-4) of formula V is an adduct of dimethylamine and carbondioxide. It is a liquid at ambient temperature with sufficient polarity and is miscible with most organic solvents. At 60^C5 it disassociates into dimethylamine and carbon dioxide which can be reassociated and condensed on cooling. Thus it can be distilled and recovered [Chem. Zts.113 (1989) pg.261-271]. Due to relatively weak bond between the components, DMADMC serves as an active carrier of dimethylamine [EP 62161; Chemist. 98 (1983) 88842]. DMADMC acts both as a reagent and as a solvent. The halogenating agent used in step (i) may be either oxalyl chloride or thionyl chloride. Solvents such as aliphatic or aromatic hydrocarbons, chlorinated solvents, ethers, esters and aprotic polar solvents may be used in the step (i), preferably heptane. The solvent which can be used in step (iii) may be selected from aliphatic or aromatic hydrocarbons, chlorinated solvents, ethers, esters and aprotic polar solvents. The details of the present invention are given in the following examples, which are provided only to illustrate the invention and should not be construed in any way to limit the scope of the present invention. Example-1 Preparation of Zolpidem To a suspension of 5g (17.7mmol) zolpidic acid in 30ml heptane , cooled to 0*^C, is added 3.9ml ( 44.7mmol) oxalyl chloride slowly. The resulting reaction mixture is stirred for 3 hours. The solvent and the excess oxalyl chloride are removed under reduced pressure and the residue washed with 25ml heptane. To the residue is added slowly 15g DMADMC to obtain a clear solution, and stirring continued for another 30 minutes. To the reaction mixture is added 20ml water and stirred for 15 minutes to dissolve the excess DMADMC and the dimethylammonium chloride salt formed in the reaction. The solid separated is filtered and dried at 40^C under vacuum for 4 hours to obtain 4.2 gm (76% ) of Zolpidem (purity by HPLC:98.3%) Example-2 Preparation of Zolpidem To a suspension of 5g (17.7mmol) zolpidic acid in 30 mL heptane , cooled to 0*^C, is added 3.9ml ( 44.7mmol) oxalyl chloride slowly. The resulting reaction mixture is stirred for 3 hours. The solvent and the excess oxalyl chloride are removed under reduced pressure and the residue washed with 25 ml heptane. To this is added a solution of 7.1 Ig (53.1mmol) DMADMC in ethyl acetate (15ml) slowly over a period of 15minutes and stirred for 30 minutes. Excess DMADMC and solvent are removed by distillation. Water (50ml) is added to the residue, the slurry stirred for 5 minutes and filtered. The solid is dried at 40*^C under vacuum for 4 hours to obtain 4.6gm (83%) of Zolpidem (purity by HPLC:98.1%) Exainple-3 Preparation of Zolpidem To a suspension of 5g (17.7mmol) zolpidic acid in 30ml heptane , cooled to O^C, is added 2.5g (34.3 mmol) thionyl chloride slowly. The reaction mixture is refluxed for 5 hours. The solvent and excess thionyl chloride are removed minder reduced pressure and the residue washed with heptane (25ml). To this is added a solution of 7.11g (53.1 mmol) DMADMC in 15ml ethylacetate slowly over a period of 15 minutes and stirred for 30 minutes. Excess DMADMC and solvent are removed by distillation. To the residue is added 50ml water and the slurry stirred for 15minutes. The solids are filtered and dried at 40 for 4 hours under vacuum to obtain 3.9gm (71%) of Zolpidem (purity by HPLC: 95.2 %). ExampIe-4 Preparation of Zolpidem To a suspension of 5g (17.7mmol) zolpidic acid in 30ml ethylacetate, is added 3.96g (39.2mmol) triethylamine and stirred at O for lOminutes. To the reaction mixture is added 4.89g (35.1mmol) ethylchloroformate slowly. After stirring for 45 minutes, lOg (74.6mmol) DMADMC in 20ml ethylacetate was added slowly during 15 minutes. Stirring is continued for 1 hour, 30 ml water is added and stirred for another 15 minutes. The layers are separated. The organic layer is dried over sodium sulphate and concentrated under reduced pressure. The residue obtained is stirred with 25 ml heptane for 1 hour and filtered to obtain 4.4g (80.3%) of Zolpidem (purity by HPLC: 97.7%) • Advantages of the invention 1. The process avoids the use of hazardous reagent, namely dimethyl amine gas or its concentrated aqueous solutions thereby making the process safe . 2. The process employs safe reagent, N,N-dimethyl ammonium- N\N dimethyl carbonate (DMADMC), which is a liquid at ambient temperatures due to which the process can be carried out without using any additional solvent which makes the process economical and safer. WE CLAIM: 1. A process for the preparation of Zolpidem of the formula-I which comprises; i) Reacting zolpidic acid with a halogen ting agent to get zolpidic acid chloride of the formula IV . ii) Reacting the resulting zolpidic acid chloride ofthe formula IV within-dimethyl ammonium - N\N'.dimethylcarbamate (DMADMC) of formula in the presence or absence of solvent, at a temperature in a range of 0^ to below 60^ C to obtain Zolpidem ofthe formula I. iii) Removing the solvent, if present, by heating milder reduced pressure, cooling and adding water to precipitate Zolpidem and iv) filtering and drying to get Zolpidem ofthe formula-l 2. A process as in claim 1 wherein the solvent when used in step (ii) is selected from aliphatic or aromatic hydrocarbons, chlorinated solvents, ethers, esters and aprotic polar solvents. 3. A process for the preparation of Zolpidem of the formula-I substantially as herein described with reference to the Examples 1 to 4.

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