阿伐那非中间体N-1的合成及其相关杂质研究

Synthesis of Avanafil Intermediate N-1 and Its Related Impurities

为加强对阿伐那非原料药的质量控制,研究了阿伐那非中间体N-1的合成及其工艺杂质A、B和C引入的原因,并合成了阿伐那非中间体N-1杂质A、B和C。以4-氯-2-甲硫基嘧啶-5-羧酸乙酯(1)为起始原料,经过取代和氧化等反应得到阿伐那非中间体N-1,氧化物继续与3-氯-4-甲氧基苄胺(2)反应得到杂质B,氧化物在碱性条件下水解得到杂质C,4-氯-2-甲硫基嘧啶-5-羧酸乙酯(1)与4-甲氧基苄胺经过取代和氧化等反应得到杂质A,目标化合物的结构经过NMR与MS确证,纯度达97.5%以上(HPLC),可作为阿伐那非中间体N-1质量控制的杂质对照品。

In order to strengthen the quality control of avanafil API,study on synthesis of avanafil intermediate N-1 and the reason of its A,B and C impurities that are introduced,and the synthesis of intermediate N-1 avanafil impurities A,B and C.Using ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate(1)as the starting material,avanafil intermediate N-1 was obtained through substitution,oxidation reaction,the oxide continued to react with 3-chloro-4-methoxybenzylamine(2)to obtain impurity B,the oxide is hydrolyzed under alkaline conditions to obtain impurity C,Ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate(1)reacted with 4-methoxybenzylamine to obtain impurity A,the structure of the target compound by NMR and MS spectra,HPLC detection of purity was more than 99.5%,can be used as intermediate avanafil N-1 quality control of impurity reference.