目的 设计并合成罗氟司特中3,5-二氯-4-氨基吡啶引入的两个杂质3-(环丙甲氧基)-N-(3-氯-5-溴-4-吡啶基)-4-(二氟甲氧基)苯甲酰胺和3-(环丙甲氧基)-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-羟基苯甲醛为起始原料经过亲核取代、氧化、酰氯化和酰胺化合成了目标化合物。结果 合成了目标化合物,并利用¹H-NMR、¹³C-NMR和MS确证了结构;HPLC归一化法测得样品质量分数分别为98.8%、99.8%。并证明这两个杂质存在于罗氟司特中。结论 这两种杂质的合成为罗氟司特中杂质的研究提供了依据。

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.