CN-120192321-B - Synthesis method of N-acetyl zopiclone

Abstract

The invention relates to a method for preparing zopiclone related substance N-acetyl zopiclone, which takes N-demethyl zopiclone or salt thereof as raw material, disperses or dissolves in solvent, and adds acetylation reagent to carry out reflux reaction in the presence of alkaline catalyst. The synthesis method of the invention realizes the aims of judging the reaction end point, high crude product purity, high yield, mild reaction condition and low impurity content of the product by visual inspection of solution clarification, and is applicable to production amplification and the product is applicable to being used as zopiclone impurity standard.

Inventors

• HUANG JINBIAO
• WANG JUN
• You Zefang
• CHEN JIEWEN
• HONG SHUHUA
• LIAO ZHIGANG
• PAN HONGJU

Assignees

• 广东华润顺峰药业有限公司

Dates

Publication Date

20260508

Application Date

20231221

Claims (2)

1. 1. The preparation method of the N-acetyl zopiclone is characterized in that N-demethyl zopiclone or a salt thereof is dispersed or dissolved in a solvent, an acetylating reagent acetic anhydride is added to react in the presence of an alkaline catalyst, the alkaline catalyst is selected from one or more of 4-dimethylaminopyridine, triethylamine and pyridine, the solvent is acetonitrile, the reaction is carried out under a heating reflux state, and when a reaction solution becomes clear, the reaction is complete; the dosage of the alkaline catalyst is 0.2-0.5 times of the mass of the raw material N-desmethylzopiclone; The dosage of the acetylating reagent is 0.3-1 times of the mass of the N-demethyl zopiclone; the volume of the solvent is 15-30 times of the mass of the N-desmethylzopiclone.
2. 2. The preparation method according to claim 1, wherein after the reaction is completed, the solvent is evaporated to dryness under reduced pressure, filtered by adding water, and the filter residue is washed with water to be neutral and dried.

Description

Synthesis method of N-acetyl zopiclone Technical Field The invention belongs to the field of organic synthesis, and in particular relates to a preparation method of zopiclone related substance N-acetyl zopiclone. Background Abnormal sleep volume and abnormal behavior during sleep are manifestations of normal rhythmic alternating sleep and wakefulness, which can be caused by various factors and are often associated with somatic diseases. Studies on sleep and sleep disorders dates back to the 19 th century, and show that the blue spot and the interstitial nuclei in the bridle are associated with the occurrence of REM (rapid eye movement sleep), whereas the interstitial nuclei in the midbrain may be associated with NREM (non rapid eye movement sleep), the interstitial nuclei contain 5-hydroxytryptamine neurons, the blue spot contains noradrenergic neurons, and the increase or decrease of 5-hydroxytryptamine chemically can predispose or inhibit NREM and REM, and thus, the 5-hydroxytryptamine neuronal central pathways may be associated with the maintenance of NREM and the excitation of REM, while the noradrenergic neuronal central pathways may be associated with the maintenance of REM and arousal. The cyclic pyrrolidone class of compounds which have been newly discovered in recent years to have sedative hypnotic activity is represented by the compound zopiclone (Zopiclone, chemical name 6- (5-chloropyridin-2-yl) -7- [ (4-methylpiperazin-1-yl) formyloxy ] -5, 6-dihydropyrrolo [3,4-b ] pyrazin-5-one) developed by ronan planckian, france and marketed in france in 1988 (now a product under the minofenamic flag). The compounds are inhibitory neurotransmitter gamma-aminobutyric acid (GABA) receptor agonists and have been marketed as representative sedative-hypnotics in this class of compounds in more than 80 countries and regions of the world. Zopiclone has the structure shown below: Although the zopiclone structure and benzodiazepine are different, it can bind to benzodiazepine receptor and has the same pharmacological action as benzodiazepine drug, and is the first non-benzodiazepine sedative hypnotic drug. Zopiclone is a GABAA receptor agonist, can strengthen the inhibition effect of GABA, has the effects of sedation, hypnosis, muscle relaxation, palpitation resistance, scorch resistance and the like, has an in vivo half-life of only 5 hours, effectively shortens the sleep latency period after taking, increases the total sleep time, reduces the night awakening times, does not produce side effects such as memory damage and the like after awakening, has no dependence effect, has adverse reactions such as sequelae and the like caused, and is much weaker than benzodiazepine drugs. Clinically used in the treatment of severe sleep disorders, including transient insomnia and short-term insomnia, are therefore referred to as representatives of third-generation sedative hypnotics. Zopiclone is a quick-acting hypnotic with higher safety because of quick absorption, quick effect taking and no influence of medicine taking time, repeated dose and sex, is marketed in China in 1989, belongs to a national medical insurance product, enters a national basic medicine catalogue variety, and currently, domestic zopiclone has already occupied the main share of the domestic market. Zopiclone can produce a variety of impurities during production and storage. According to domestic and foreign reports, the related substances of the zopiclone which are found at present are about nine. These impurities are brought in by the synthesis process of zopiclone or are generated by the degradation of zopiclone, and have important influence on the safety and effectiveness of medicines, and the chemical structures of the impurities are respectively as follows: In the long term synthesis and study of zopiclone, the applicant found and isolated identified an impurity which was present in the drug substance and which was not previously contemplated by the person skilled in the art, 6- (5-chloropyridin-2-yl) -7- [ (4-acetylpiperazin-1-yl) carbonyloxy ] -5, 6-dihydropyrrol [3.4-b ] pyrazin-5-one, hereinafter referred to as N-acetylzopiclone, having the following structure: n-acetyl zopiclone At present, no detailed related studies on the impurity have been reported. In 2007, U.S. patent No. 7456173B2 (Compositions comprising zopiclone DERIVATIVES AND methods of MAKING AND using the same), when a series of zopiclone analogs are listed, two corresponding isomers of N-acetyl zopiclone are described, the structure is as follows. The specification of US7456173B2 does not address both materials in detail, but gives a synthetic route to compounds of the above structure or similar structures. The applicant has found, in practice, repeated operations on routes in the literature, the synthetic routes described in the prior art having unsatisfactory problems: Route 1. Route of condensation reaction of hydroxyl and 4-acetylpiperazine-1-formyl chloride under alkaline co