Preparing method for N-substituted pyrrolo [3,4-B] pyrazine-5,7(6H)-diketone

Abstract

The invention relates to a preparing method for a dexzopiclone intermediate N-substituted pyrrolo [3,4-B] pyrazine-5,7(6H)-diketone, in particular to preparation of 6-(5-chloropyridine-2-yl)-5H-pyrrolo [3,4-B] pyrazine-5,7(6H)-diketone. According to the preparation method, N-substituted pyrrolo [3,4-B] pyrazine-5,7(6H)-diketone is prepared with triphosgene / triphenylphosphine oxide serving as a reaction reagent, as the product is a crystalline solid and is slightly soluble in an organic solvent while a catalyst is soluble in the organic solvent, the product can be obtained through direct suction filtration, and posttreatment is convenient; besides, a mother solution can be directly and consecutively reused, cyclic use of aryl oxide phosphate and the solvent is achieved, and the preparing method has the advantages that operation is simple, the reaction conditions are mild, the yield is high, and the quantity of three wastes is small; use of highly-corrosive toxic reagents such as thionyl chloride and chloroformate is avoided from the source, and high implementation value and social and economic benefits are achieved.

Description

technical field [0001] The present invention relates to a preparation method of N-substituted pyrrolo[3,4-B]pyrazine-5,7(6H)-dione, an intermediate of eszopiclone, especially 6-(5-chloropyridine-2 The invention relates to the preparation of -5H-pyrrolo[3,4-B]pyrazine-5,7(6H)-dione, which belongs to the technical field of medicine. Background technique [0002] Eszopiclone is a fast and short-acting non-benzodiazepine sedative and hypnotics developed by Sepracor Corporation of the United States. It is the D-single isomer of zopiclone. Preclinical and clinical studies have shown that the affinity of this product to benzodiazepine receptors is 50 times that of eszopiclone, and eszopiclone has the advantages of stronger curative effect and lower toxicity than zopiclone. [0003] 6-(5-Chloropyridin-2-yl)-5H-pyrrolo[3,4-B]pyrazine-5,7(6H)-dione is a key intermediate in the synthesis of zopiclone and eszopiclone , There are three main methods for the synthesis of 6-(5-chloropyrid...

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Problems solved by technology

[0004] The first kind, US3862149 has reported 3-((5-chloropyridin-2-yl) carbamoyl) pyrazine-2-carboxylic acid is refluxed in sulfur oxychloride, and yield is 77%, used strong in the reaction Corrosive thionyl chloride is used as both a solvent and a reaction reagent. After the reaction, thionyl chloride needs to be evaporated to dryness under reduced pressure. This process is highly corrosive to equipment and is not suitable for industrial production.

[0005] The second method reported by Zuo Daizhu et al. in Chinese Journal of Medicinal Chemistry, 1996, 6, 25~30 is to use 3-((5-chloropyridin-2-yl)carbamoyl)pyrazine-2-carboxylic acid The cyclization method heated to 120~130°C in 3 times the amount of acetic anhydride has a yield of 77%. The solvent used is acetic anhydride. Because acetic anhydride is easy to produce poison, the purchase and use are greatly restricted, and the process Acetic anhydride cannot be recycled and used mechanically, and the amount of waste water is relatively large

[0006] The third one is the eszopiclone intermediate 6-(5-chloropyridin-2-yl)-5H-pyrrolo[3,4-B]pyrazine-5,7(6H)- disclosed in Chinese patent application 200610013491.9 The preparation method of diketone is to mix 3-((5-chloropyridin-2-yl)carbamoyl)pyrazine-2-carboxylic acid and organic base in an organic solvent, cool to -20°C, and at this temperature Chloroformate was added dropwise, the reaction was completed, pickled, washed with water, and the solvent was evaporated to dryness under reduced pressure to obtain the product with a yield of more than 85%. This reaction needs to be carried out at low temperature, and highly toxic chloroformate was used. The processing is cumbersome, and the amount of "three wastes" is relatively large

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