抗病毒药letermovir的合成工艺改进

Improved Synthetic Process of Antiviral Drug Letermovir

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-（trifluoromethyl）aniline （2） reacted with bis（trichloromethyl）carbonate to give 2-methoxy-5-（trifluoromethyl）phenyl isocyanate, which reacted with 2-bromo-6-fluoroaniline to afford N-（2-bromo-6-fluorophenyl）-N＇-[2-methoxy-5-（trifluoromethyl）phenyl]urea（5）. Then methyl [8-fluoro-3-[2-methoxy-5-（trifluoromethyl）phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl]acetate（7） was synthesized from methyl acrylate and 5 via an “one pot” method of Heck coupling and Michael addition. In this step, dioxane and N,N-diisopropylethylamine were used instead of isobutyronitrile and triethylamine so that the reaction time was shortened from 16 h to 9 h, and the yield was increased from 68.5% to 79.4%. Then compound 7 was chlorinated with phosphoryl chloride to prepare methyl [2-chloro-8-fluoro-3-[2-methoxy-5-（trifluoromethyl）phenyl]-3,4-dihydroquinazolin-4-yl]acetate（8）. Meanwhile, 1-（3-methoxyphenyl）piperazine（9） was prepared from diethanol amine via chlorination and N-alkylation. Finally, the antiviral drug letermovir（1） was obtained via condensation of 8 and 9, followed by the chiral separation and hydrolysis with an overall yield of 12.7% （based on 2） and a purity of 99.7% .