Eszopiclone preparation method

Abstract

The invention relates to an eszopiclone preparation method comprising main steps that: zopiclone is subjected to a reaction with D-dibenzoyltartaric acid or a hydrate thereof, such that dextral zopiclone-D-dibenzoyltartrate is produced; and the salt is dissociated, such that eszopiclone is obtained. According to the method, D-dibenzoyltartaric acid with a substance amount of a quarter to a half of that of zopiclone is adopted. The reaction conditions are mild, operation is convenient, product yield is high, and product purity is high. The method is suitable for large-scale industrialized productions.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical synthesis, in particular to a preparation method of eszopiclone. Background technique [0002] Zopiclone is a pyrrolidone compound with hypnotic, sedative, muscle relaxant, anxiolytic and anticonvulsant effects. It was developed by the French company Rhone-poulenc Rorer in 1987 and is marketed as a racemate. Zopiclone is a non-benzodiazepine compound that selectively acts on GABA (γ-aminobutyric acid)-benzodiazepine receptors to produce a central inhibitory effect and exert a sedative and hypnotic effect. It is a fast-acting hypnotic. [0003] Eszopiclone is the right-handed isomer of zopiclone, the chemical name is (+)-6-(5-chloropyridin-2-yl)-7(S)-(4-methylpiperazine-1- (yl)carbonyloxy)-6,7-dihydro-5-hydro-pyrrole[3,4-b]pyrazin-5-one. It was developed and produced by Sepracor Pharmaceuticals in Massachusetts, USA. It was approved for clinical use by the FDA on December 16, 2004, and it ...

AI Technical Summary

Problems solved by technology

[0004] There are many reports in the literature about the synthesis of eszopiclone using D-dibenzoyl tartaric acid or D-dibenzoyl tartaric acid monohydrate to resolve zopiclone, but there is a large amount of resolving agent and the operation Disadvantages such as relatively complex, high energy consumption or insufficient reaction conditions

For example, EP0495717, US2002 / 0193378, US2005 / 0043311, US2006 / 0194806, US2008 / 014680, and US2009 / 019805 all use a resolving agent whose molar ratio with zopiclone is 1:1, and it is necessary to obtain the intermediate Zopiclone-D-dibenzoyl tartrate is refined many times and then deacidified to obtain the crude product of eszopiclone. The crude product needs to be refined many times to obtain the high-quality product. The whole process is complicated and requires a large amount of organic solvents. lead to high production costs

US2010 / 0056785 also uses D-dibenzoyltartaric acid monohydrate with a molar ratio of 1:1 to zopiclone for resolution, using a mixed solvent (water / water-miscible organic solvent) during the reaction, Although the method omits the recrystallization procedure of eszopiclone D-dibenzoyl tartrate, the method needs to be heated at 75-80°C when preparing eszopiclone D-dibenzoyl tartrate reaction, and in the reaction of adding alkali in the second step, it is necessary to use activated carbon to purify or use specially treated water (D.M.Water), the operating conditions are harsh and the process is still relatively complicated

[0005] Under the situation that the effect of using D-dibenzoyltartaric acid as a resolving agent has been unsatisfactory, US2007 / 0203145 discloses a method for a new resolving agent, and this patent also clearly points out that as a resolving agent D- Dibenzoyltartaric acid ((+)-dibenzoyltartaric acid) is not ideal, especially its resolution is far inferior to D-p-methyldibenzoyltartaric acid ((+)-ditoluoyltartaric acid), so the patented invention technology Scheme selects to use tartaric acid and p-methyldibenzoyl tartaric acid as resolving agent, but as known from the patent disclosure specification utilizes tartaric acid as resolving agent, although try to change the consumption of resolving agent, reaction temperature is high during this method resolution ( about 100°C), and it is necessary to add seed crystals to induce crystallization during the splitting process, because the effect of adding seed crystals is related to factors such as seed crystal purity, size, dosage, adding time, stirring rate and other factors [Zhang Gang et al., Precipitation Adding seed crystal technology in the crystallization process, Chemical World, 2002, No. 6, 326-328], so it is necessary to strictly control various factors induced by the seed crystal, which undoubtedly increases the difficulty of the process for large-scale industrial production , reducing the controllability of the process

In addition, this method requires the use of acetonitrile / ethanol / dichloromethane mixed solvents during resolution, and the use of mixed solvents in industrialized large-scale production is very unfavorable for the recovery and reuse of solvents, and the production cost is relatively high

Subsequently, Charyulu et al. reported in 2008 ["An improved process for eszopiclone: ​​Anti-insomnia agent" (Org.Commun.2008, 1:233-38)], using the reported better resolution agent D-p-methyldiphenyl Formyl tartaric acid monohydrate is carried out resolution and prepares the method for eszopiclone; Although use D-p-methyldibenzoyl tartaric acid resolution to have the advantage that resolution effect is good, but this resolving agent price is more expensive (US2007 / 0203145 also pointed out that D-p-methyldibenzoyl tartaric acid is expensive), and its production cost is also high