盐酸特比萘芬的合成工艺优化

Improved Synthetic Process of Terbinafine Hydrochloride

以4-甲基苯磺酰氯代替三溴化磷,与6,6-二甲基-3-羟基-4-炔-1-庚烯(2)在二氯甲烷和三乙胺中反应得(E)-6,6-二甲基-2-庚烯-4-炔-1-(4-甲基苯磺酸酯)(3),然后3与N-甲基-1-萘甲胺(4)发生缩合得盐酸特比萘芬(1),纯度99.6%。由于4-甲基苯磺酸酯基的立体效应,中间体3的E/Z比例可从原工艺的3∶1提高到40∶1,总收率(以2计)从43%提高到59%。

4-Methylbenzenesulfonyl chloride instead of phosphorus tribromide reacted with 6,6-dimethyl-3-hydroxy-4-yne-1-heptene(2)in DCM and trimethylamine to give(E)-6,6-dimethyl-2-heptene-4-yne-1-(4-methylbenzenesulfonate)(3).Then compound 3 was condensed with N-methyl-1-naphthylamine(4)to obtain terbinafine hydrochloride(1)with a purity of 99.6%.Due to the steric effect of the 4-methylbenzenesulfonate group,the ratio of E/Z for compound 3 was increased from 3∶1 to 40∶1,and the total yield was increased from 43%to 59%(based on 2).