普克鲁胺中间体3-氟-4-异硫氰酸根-2-三氟甲基苯甲腈的合成

Synthesis of Proxalutamide Intermediate 3-Fluoro-4-isothiocyanato-2-trifluoromethylbenzonitrile

普克鲁胺是新一代雄激素受体拮抗剂,3-氟-4-异硫氰酸根-2-三氟甲基苯甲腈作为药物普克鲁胺的重要中间体片段,对普克鲁胺的合成具有重要意义。以2-氟三氟甲苯为原料,经羧基化、酰胺化和Hofmann重排反应得到关键前体化合物2-氟-3-三氟甲基苯胺(11),11再经溴代、氰基取代、水解和氨基氧化得到普克鲁胺中间体3-氟-4-异硫氰酸根-2-三氟甲基苯甲腈,其结构经^(1)H NMR和^(13)C NMR确证。该合成路线总收率为36%,实现了原料廉价易得、操作简便、反应条件温和、后处理简便和收率较高等优点,具有较好的工业化前景。

Proxalutamide is a new generation of androgen receptor antagonist.3-fluoro-4-isothiocyanate-2-trifluoromethylbenzonitrile,as an important intermediate fragment of the drug,is of great significance for the synthesis of proxalutamide.Using 2-fluorotrifluorotoluene as raw material,the key precursor compound 2-fluoro-3-trifluoromethylaniline(11)was obtained through the reaction of carboxylation,amidation,and Hofmann rearrangement,and then bromo-substituted,cyano-substituted,hydrolyzed and amino oxidation to obtain the intermediate 3-fluoro-4-isothiocyanato-2-trifluoromethylbenzonitrile of proxalutamide Its structure was confirmed by^(1)H NMR and^(13)C NMR.The total yield of the synthesis route is 36%,which has the advantages of cheap and easily available raw materials,simple operation,mild reaction conditions,simple post-treatment and high yield,and has a good industrial prospect.