论文部分内容阅读
2-甲氧基-5-三氟甲基苯胺(2)与固体光气反应得2-甲氧基-5-(三氟甲基)苯基异氰酸酯,不经处理直接与2-溴-6-氟苯胺缩合得Ⅳ-(2-溴-6-氟苯基)-N-[2-甲氧基-5-(三氟甲基)苯基]脲(5)。5与丙烯酸甲酯在二噁烷中以N,N-二异丙基乙胺为缚酸剂,经Heck偶联和Michael加成“一锅法”合成[8-氟-3-[2-甲氧基-5-(三氟甲基)苯基]-2-氧代-1,2,3,4-四氢喹唑啉-4-基]乙酸甲酯(7),反应时间由16 h缩短至9 h,收率由68.5%提高至79.4%。7经三氯氧磷氯代得[2-氯-8-氟-3-[2-甲氧基-5-(三氟甲基)苯基]-3,4-二氢喹唑啉-4-基]乙酸甲酯(8)。此外,二乙醇胺经氯代、Ⅳ-烃化反应得3-甲氧基苯基哌嗪(9)。8与9反应后经(2S,3S)-2,3-双(4-甲基苯甲酰基)酒石酸手性拆分、水解得抗病毒药letermovir(1)。改进后的工艺总收率12.7%(以2计),纯度99.7%。
2-Methoxy-5-trifluoromethylaniline (2) was reacted with solid phosgene to obtain 2-methoxy-5- (trifluoromethyl) phenylisocyanate, which was directly reacted with 2-bromo- - fluoroaniline to give IV- (2-bromo-6-fluorophenyl) -N- [2-methoxy-5- (trifluoromethyl) phenyl] urea (5). 5 and methyl acrylate in dioxane with N, N-diisopropylethylamine as an acid-binding reagent via Heck coupling and Michael addition “one-pot synthesis” [8-fluoro-3- [ Methyl 2-methoxy-5- (trifluoromethyl) phenyl] -2-oxo-1,2,3,4- tetrahydroquinazolin-4-yl] acetate (7), reaction time From 16 h to 9 h, the yield increased from 68.5% to 79.4%. 7 Phosphorus oxychloride gave [2-chloro-8-fluoro-3- [2-methoxy-5- (trifluoromethyl) phenyl] -3,4-dihydroquinazolin-4 - yl] acetate (8). In addition, diethanolamine is chlorinated and IV-alkylated to give 3-methoxyphenylpiperazine (9). After 8 and 9 reaction, the antiviral letermovir (1) was hydrolyzed by (2S, 3S) -2,3-bis (4-methylbenzoyl) tartaric acid. The total process yield improved 12.7% (2), purity of 99.7%.