Synthetic method of 2-cyano-3-methylpyridine

Abstract

The invention discloses a synthetic method of 2-cyano-3-methylpyridine. The synthetic method comprises the following steps: adding 3-methylpyridine to a reaction kettle, slowly adding phosphorus pentoxide under a stirring condition time and time again, and stirring for 30 minutes; cooling a solution to 5-10 DEG C, slowly and dropwise adding concentrated nitric acid while controlling dropwise addition speed and controlling the temperature of reaction liquid not to exceed 10 DEG C in the whole dropwise addition process, and after ending dropwise addition, reacting for 3 hours; slowly pumping the reaction liquid into the reaction kettle filled with a mixed solution of sodium cyanide and caustic soda liquid while controlling pumping speed so as to avoid generation of white smoke, and after ending dropwise addition, reacting for 8 hours; adding dichloromethane to the solution, extracting an organic phase, and removing dichloromethane by distillation, thus obtaining the 2-cyano-3-methylpyridine crystal. According to the synthetic method, the activation of pyridine rings is realized by using phosphorus pentoxide and concentrated nitric acid. Compared with a conventional technology, the synthetic method has the advantages that the raw materials are low in cost and small in toxicity, reaction production processes are few, the energy consumption is low, little waste liquid is discharged, the industrial production is easy, and the production cost and the environmental cost are reduced.

Description

technical field [0001] The invention relates to a method for synthesizing a pharmaceutical intermediate 2-cyano-3-picoline, which belongs to the field of organic synthesis. Background technique [0002] 2-cyano-3-methylpyridine is an important intermediate in organic synthesis, commonly used in the synthesis of antiallergic drug rupatadine, antihistamine drug loratadine, omeprazole, buprodil and other drugs Starting materials, with the advancement of science and technology, new uses of this compound are being continuously developed and applied. [0003] 2-cyano-3-methylpyridine is usually obtained by direct cyanation of 3-methylpyridine. There are many synthetic routes in the laboratory, but relatively few can achieve industrial application. Currently, 2-cyano- 3-picoline synthesis methods mainly contain the following three categories: [0004] The first type is the ammonia oxidation method (relevant documents include: former East German patent: DD241903; Tetrabutylammonin...

AI Technical Summary

Problems solved by technology

This type of method is widely used in industrialization, but its oxidation selectivity is poor, and usually directly obtains 2-, 5-, 4-cyanopyridines substituted in multiple positions, which is difficult to separate

[0005] The second type of method is to use cyanide ions to directly react with activated pyridine groups (N-oxidized 3-picoline, N-alkyl or acyl pyridinium salts) to react to obtain the target product, (relevant documents include: World Intellectual Property Organization patents: WO20011017970, 2001; 1-Acyloxypyridinium Ion: The Reactive Intermediate in a Modified Reissert-Henze Reaction, Fife, et al., Heterocycles, 1984; Preparation of cyanopyridines by direct cyanation, Katritzky, et al. Synthesis, 2005), this method The steps are cumbersome, and the comprehensive yield is generally lower than 55%.

This process has many steps, the yield is generally lower than 55%, and the application site requirements of dimethyl sulfate are relatively high

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