A simple, efficient and scalable synthesis of hypnotic agent, zolpidem
Yasareni Sumalatha, Tamma Ranga Reddy, Padi Pratap Reddy and
Bollikonda Satyanarayana *
Dr Reddy’s Laboratories Limited, Bachupalli, Qutubullapur, Rangareddy District-72, Andhra Pradesh, India. Fax: 91 40 4434 6285,
E-mail:
[email protected];
[email protected]
Abstract
A simple, efficient, scalable and cost effective synthesis of zolpidem is discussed. In the present article, the reported seven stage process modified in to four stages, overall yield was improved from 40% to 66% and more than 99.9% HPLC purity has been achieved with free of its process related impurities.
Keywords: Zolpidem, Hypnotic, Insomnia, Related substances
Introduction
Zolpidem (1) is a short acting nonbenzodiazepine imidazopyridine hypnotic drug, used for the treatment of insomnia and in the market it is available as its tartrate salt. It potentiates gamma- aminobutyric acid (GABA), an inhibitory neurotransmitter, by binding to benzodiazepine receptors located on the gamma-aminobutyric acid receptors1. Additionally zolpidem also possesses anxiolytic and anticonvulsant properties, thus useful for the treatment of anxiety, sleep disorders and other neurological and psychiatric complaints2. Our present work reports a scalable process for the preparation of N, N-dimethyl-2-(6-methyl-2-p-tolyl-imidazo[1,2- a]pyridin-3-yl)-acetamide (1), commonly known as zolpidem.
The reported synthesis (Scheme-1) of zolpidem involved the bromination of 4-methyl acetophenone (2) followed by condensation of resultant bromo derivative (3) with 2-amino 5- methyl pyridine3 to give an imidazo pyridine intermediate compound 4, which upon Mannich reaction4 gave N, N-dimethyl amino imidazopyridine derivative 5. Compound 5 was further converted into its cyano methyl imidazo pyridine derivative 7 through a methyl iodide quaternary salt 6. The cyano compound 7 on alkaline hydrolysis yielded a pyridine acetic acid compound 85. Finally, the key intermediate 8 reacted with carbonyl diimidazole6 and followed by amidation with anhydrous dimethyl amine yielded zolpidem (1).
