目的 設(shè)計(jì)并合成羅氟司特中3,5-二氯-4-氨基吡啶引入的兩個雜質(zhì)3-(環(huán)丙甲氧基)-N-(3-氯-5-溴-4-吡啶基)-4-(二氟甲氧基)苯甲酰胺和3-(環(huán)丙甲氧基)-N-(3-氯-4-吡啶基)-4-(二氟甲氧基)苯甲酰胺。方法 以4-二氟甲氧基-3-羥基苯甲醛為起始原料經(jīng)過親核取代、氧化、酰氯化和酰胺化合成了目標(biāo)化合物。結(jié)果 合成了目標(biāo)化合物,并利用¹H-NMR、¹³C-NMR和MS確證了結(jié)構(gòu);HPLC歸一化法測得樣品質(zhì)量分?jǐn)?shù)分別為98.8%、99.8%。并證明這兩個雜質(zhì)存在于羅氟司特中。結(jié)論 這兩種雜質(zhì)的合成為羅氟司特中雜質(zhì)的研究提供了依據(jù)。

Objective To design and synthesize impurities introduced by 4-amine-3,5-dichloropyridine in roflumilast: 3-(cyclopropylmethoxyl)-N-(3-chloro-5-bromo-4-pyridyl)-4-(difluoromethoxyl)benzamide and 3-(cyclopropylmethoxyl)-N-(3-chloro- 4-pyridyl)-4-(difluoromethoxyl)benzamide. Methods 4-Difluoromethoxyl-3-hydroxybenzaldehyde was used as starting material to synthesize the target compound by nucleophilic substitution, oxidation, acylation and amidation reactions. Results The target compounds were synthesize and characterized by ¹H-NMR, ¹³C-NMR and MS. And the purities detected by HPLC were 98.8% and 99.8%. The two impurities were proved to exist in roflumilast. Conclusion The synthesis of two impurities provides reference for the study of impurities in roflumilast.