Preparation technology for 5-(2-cyano4-pyridyl)-3-(4-pyridyl)-1,2,4-troazole

Abstract

The invention belongs to the field of medicine and chemical engineering, and particularly discloses a preparation technology for 5-(2-cyano4-pyridyl)-3-(4-pyridyl)-1,2,4-troazole (topiroxostat). The preparation technology is characterized in that methyl isonicotinate serving as a compound II is used as a starting raw material, the compound II, phosphorus oxychloride, N,N-dimethyl formamide, iodine and 28% ammonium hydroxide form a compound III which is 2-cyano methyl isonicotinate in a one-pot synthesis mode, then a compound IV which is 2-cyano isonicotinyi hydrazine is formed through synthesis, a topiroxostat crude product Ia is prepared through condensing the compound IV which is 2-cyano isonicotinyi hydrazine and 4-cyanopyridine, salifying is performed on the crude product Ia and para-toluenesulfonic acid to form topiroxostat tosilate Ib, and finally the topiroxostat finished product I is obtained through desalting in a refined mode. The number of reactions steps is reduced, the yield of the finished product is increased, the reaction process is low in toxin and has small influences on environment, the reaction route is short, the cost is greatly lowered, the product purity is larger than 99.7%, the net contamination is smaller than 0.1%, and standard requirements are met.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, in particular to a preparation process of 5-(2-cyano4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole (topinostat) . technical background [0002] Topiroxostat (Topiroxostat, CAS: 577778-58-6), chemical name: 5-(2-cyano4-pyridyl)-3-(4-pyridyl)-1,2,4-triazole, English name: 4-[5-(Pyridin-4-yl)-1H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile, its chemical structure is as follows: [0003] [0004] The drug was developed by Fuji Pharmaceutical Industry Co., Ltd. of Japan. It selectively and reversibly inhibits xanthine oxidoreductase. It is a selective inhibitor of non-purine xanthine oxidase and can reduce serum uric acid levels; the drug started in 2004 Clinical trials were carried out. Phase I and Phase II clinical trials were conducted by Japan Fuji Pharmaceutical Co., Ltd., and Phase III clinical trials were jointly conducted by Japan Sanwa Chemical Industry Co., Ltd. and Fuji Pharmaceuti...

AI Technical Summary

Problems solved by technology

[0017] In summary, there are two main methods for introducing cyano groups in topilastat compounds at this stage: one is to use pyridine nitrogen oxide as the reaction substrate and use cyanide reagents to introduce cyano groups. This method is relatively simple but requires The use of highly toxic cyanide has high requirements for production operations and waste liquid post-treatment, and there are relatively large safety hazards; second, the use of amide method to add cyano groups has high safety, but this method is cumbersome to operate, and it needs to be used during the experiment. A large amount of formamide and concentrated sulfuric acid have high requirements on equipment, and the post-treatment process is relatively cumbersome; in addition, the yield is low, and the yield of the target compound 2-cyanoisonicotinic acid methyl ester is only 30%.

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