Title of Invention	AN IMPROVED PROCESS FOR THE PREPARATION OF N,N-DIMETHYL-3-(4-METHYL-BENZOYL)-PROPIONAMIDE
Abstract	The invention disclosed in this apposition relates to an improved process for the preparation of N,N-dimethyl-3-(4-methyl-benzoyl)-propanolamine from the free acid via its halide by using N,N-dimethylammonium – N<SUP>1</SUP> N<SUP>1</SUP> -dimethyl carbonates, both as a solvent and reagent. The said propionamide is a key intermediate in the preparation of Zolpidem.

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Field of Invention The present invention relates to an improved process for the preparation of N,N- dimethyl-3-(4-methyl-benzoyl)-propionamide. N5N-dimethyl-3-(4-methyl-benzoyl)- Propionamide having the formula I prepared by the process of the present invention is useful for the preparation of Zolpidem. An important route for the synthesis of Zolpidem is based on the general method for preparing 2-phenylimidazo[l52-a]pyridine derivatives, described in J. Med. Chem., 40, 3109-3118 (1997). In this method 2-aminopyridine is reacted with a bromo keto ester of formula II, which is obtained from 3-(4-methyl-benzoyl)-propionic acid formula IV via 3-(4-methyl-benzoyl)- propionamides of the formula III. The authors have not reported the preparation of the compound of the formula III in which R = R = CH3, useful as intermediate of Zolpidem. The process comprises of converting the acid of formula IV to a mixed anhydride with either ethylchloroformate or pivaloyloxy chloride and then reacting the anhydride with dimethylamine. This process mentioned in the prior art for the preparation of the intermediate of Zolpidem suffers from the following limitations: Dimethylamine used in the process is an odorous gas, exposure to which causes irritation of nose and throat, conjunctivitis, dermatitis, dyspnea, pulmonary edema, frost bite etc. (Merck Index, pg.569,13^*' End., 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 and its key intermediate 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 N,N-dimethyl-3-(4-methyl-benzoyl)"propionamide of the formula I which is an important intermediate 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 N,N-dimethyl-3-(4-methyl-benzoyl)-propionamide of the formula I which is an important intermediate for the preparation of Zolpidem , by avoiding the use of dimethylamine gas. Summary of the Invention According to the present invention there is provided an improved process for the preparation of N,N-dimethyl-3-(4-methylbenzoyl)-propionamide of formula-I with an alkyl chloroformate in the presence of a base and a solvent at a temperature in the range of-10 to + 30^C and carrying out the reaction for a period of 15 to 60 minutes to obtain the mixed anhydride (ii) reacting the mixed anhydride with N,N-dimethylammonium N\N -dimethyl carbonate (DMADMC) ofthe formula-V at a temperature in the range of 0 to 60^C for a period of 15 to 60 minutes to obtain the amide ofthe formula-I. DMADMC (CAS Registry No. 4137-10-4) is an adduct of dimethylamine and carbon dioxide. It is a liquid at ambient temperature with sufficient polarity and is miscible with most organic solvents. At 60^C, it disassociates into dimethylamine and carbon dioxide which can be resuscitated and condensed on cooling. Thus it can be distilled and recovered [Chem. ZtgA13 (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 solvent which may be employed in step (i) may be selected from aliphatic or aromatic hydrocarbons, chlorinated solvents, ethers, esters and aprotic polar solvents. The base employed in the step (i) may be selected from the group trimethylamine, triethylamine, tributylamine, pyridine and the like. The intermediate amide of formula I may then be transformed to Zolpidem by the Scheme shown below: The compound formula I is brominated in a halohydrocarbon solvent resulting in compound of formula VI which is then condensed with a compound of formula VII to obtain Zolpidem of formula VIII, as per general procedure described in J.Med.Chem. 40, 3109 - 3118 (1997) for analogs of Zolpidem and adopted as an alternative route of synthesis of Zolpidem in patent US 2002 / 0183522. 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. Exampie-1 Preparation of N,N-dimethyl-3-(4-methyl-beiizoyl)- propionamide of the formula I To a suspension of 10 g (52 mmol) 3-(4-methyl-benzoyl)-propionic acid in 125 ml ethyl acetate at 0*^C is added 5.7 g (55 mmol) triethylamine, followed by 5.6g (63 mmol) ethyl chloroformate . The reaction mixture is stirred for 30 minutes at 0 to 5*^C and 8 g (59 mmol)) DMADMC is added over a period of 15 minutes and stirred for another 30 minutes. The reaction mixture is washed with water (100 ml x 2). The organic layer is dried over anhydrous sodium sulphate and concentrated milder reduced pressure. The residue obtained is stirred with heptane (100 ml), filtered and dried to obtain 8.4g (73%) of the N,N-dimethyl-3-(4-methyl-benzoyl)" propionamide (purity by HPLC: 98.3%). Example-2 Preparation of N,N-dimethyl-3-(4-methyl-benzoyl)- propionamide of the formula I To a suspension of 10 g (52 mmol) 3-(4-methyl-benzoyl)-propionic acid in 100 ml ethyl acetate at O^C is added 5.7g (55 mmol) triethylamine, followed by 5.6 g (63 mmol) ethylchloroformate . The reaction mixture is stirred for 30 minutes at 0 to 5*^C. To it is added a solution of 17.45 g (131 m mol) DMADMC in 30 ml ethyl acetate over a period of 15 minutes and stirred for another 30 minutes. The reaction mixture is washed with water (100 ml x 2). The organic layer is dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue obtained is stirred with heptane (100 ml), filtered and dried to obtain 9.1g (80 %) of N,N-dimethyl-3-(4-methyl-benzoyl)-propionamide (purity by HPLC: 99.4 %). • 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. 3. The invention provides a process for the preparation of a key intermediate namely N,N-dimethyl-3-(4-methyl-benzoyl)-propionamide, useful for the preparation of Zolpidem, using the safe DMADMC reagent. WE CLAIM: 1. An improved process for the preparation of N,N-dimethyl-3-(4-methyl-benzoyl)-propionamideof the formula-I, an important intermediate for the preparation of Zolpidem, which comprises (i) reacting 3-(4-methyl-benzoyl) propionic acid of the formula-IV with an alkyl chloroformate in the presence of a base and a solvent at a temperature in the range of-10 to + 30^C and carrying out the reaction for a period of 15 to 60 minutes to obtain the mixed anhydride (ii) reacting the mixed anhydride with N,N-dimethylammonium dimethyl carbonate (DMADMC)ofthe formula-V. at a temperature in the range of 0 to 60°C for a period of 15 to 60 minutes to obtain the amide of the formula-I. 2. A process as claimed in claim 1 wherein the alkyl chloroformate used in step (i) is ethyl chloroformate. 3. A process as claimed in claim 1 wherein the solvent employed in step (i) is selected from aliphatic or aromatic hydrocarbons, chlorinated solvents, ethers, esters and aprotic polar solvents. 4. A process as claimed in claims 1 and 2 wherein the base employed in step (i) is selected from trimethylamine, triethylamine, tributylamine, pyridine and the like. 5. An improved process for the preparation of N,N-dimethyl-3-(4-methyl-benzoyl) propanolamine of the formula-I a key intermediate of Zolpidem, substantially as herein described with reference to the Examples 1 & 2 .

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