Trk激酶抑制剂关键中间体的合成工艺改进

An improved synthesis of key intermediate of Trk kinase inhibitor

目的开发Trk激酶抑制剂关键中间体—3,5-二氨基-4-氰基-1 H-吡唑的合成新路线。方法以丙二腈为原料,在NaOH的乙腈溶液中与氯甲酸氯乙酯反应,生成2-(1,3-二氧戊环-2-烯)-丙二腈,溶于乙醇,控制反应液温度下滴加浓氨水,反应完成后旋干乙醇,得到的残留物再与水合肼反应,得到目标产物3,5-二氨基-4-氰基-1 H-吡唑。结果与结论与原有的制备方法相比,新路线的合成原料更低廉易得,合成反应也更简单且易控制,无需使用剧毒的氰化物,总收率较高(约18.9%),具有较好的应用前景。

Objective To develop a new synthetic route of 3,5-diamino-4-cyano-1 H-pyrazole-key intermediate of Trk kinase inhibitor.Methods Based on the commercially available malononitrile as raw material,the sodium hydroxide and ethyl chloride formic acid chloride were added in acetonitrile,generating 2-(1,3-dioxolane-2-ene)-malononitrile,which was dissolved in ethanol,and ammonia was added when the temperature of reaction was controlled.After ethanol was evaporated,the residue treated with hydrazine hydrate to obtain the target product.Results and Conclusion Compared with the original preparation method,the raw materials of the new route are cheaper and easier to obtain,and the synthesis reaction is simpler and easier to control,without the use of highly toxic cyanide.The total yield of 18.9%is higher,which has good application prospects.