来曲唑杂质A合成工艺研究

Study on the Synthesis Process of Letrozole's Related Compound A

杂质A是来曲唑的同分异构体,是来曲唑最重要的杂质之一。从来曲唑的合成路径着手对杂质A的合成工艺进行了研究。从来曲唑的合成工艺来看,对氰基氯苄和三氮唑进行反应除生成中间体1-(4-腈基苄基)-1H-1,2,4-三氮唑外,还合成了中间体的N-烃基化物异构体。从结构上可反推测出杂质A和N-烃基化物异构体有很大的关系。为此,设计出一条合成杂质A的工艺路线,以对氟苯甲腈和N-烃化产物异构体为原料,在叔丁醇钾的催化作用下反应,产物经乙酸乙酯提纯后得到杂质A纯品,产品纯度达99.8%,收率为40.9%。

Related compound A is letrozole＇s isomer and one of the most important impurities. In order to explore that how related compound A has been created, the synthetic method of letrozole is studied carefully. Our study turns out that 4-（chloromethyl） benzonitrile reacts with triazole to form N-hydroxyl iodide isomer in addition to the intermediate which is 4-[1-（1,2,4-triazolyl）methyl]-benzontrile. To sum up, the generation of related compound A should be related with N-hydroxyl iodide isomer which is the product of isomerization reaction from 4-（Chloromethyl）benzonitrile and triazole. From the structure of the similarity on consideration, we think that the 4-[1-（1,2,4-triazolyl）methyl]-benzontrile reacts with 4-fluorobenzonitrile to form letrozole, and at the same time the isomer should react with 4-fluorobenzonitrile too. So, a feasible process route has been designed. That is, in the presence of potassium tert-butoxide, the target compound was synthesized from 4-fluorobenzonitrile and isomer of 4-[1-（1,2,4-triazolyl） methyl]-benzontrile via one step. The product is refined by ethyl acetate to obtain the related compound A. The purity of related compound A is 99.8 % and its yield coefficient is 40.9 %.