2-甲基-3-氟-5-二苄基氨基-6-苄氧基苯甲酸苯酯的合成

Synthesis of Phenyl 2-Methyl-3-fluoro-5-dibenzylamino-6-benzyloxybenzoate

2-甲氧基-5-氟苯甲酸(2)经甲基化得2-甲基-3-氟-6-甲氧基苯甲酸(3)和2的混合物,不经分离直接酯化和定向水解后分离纯化得2和2-甲基-3-氟-6-甲氧基苯甲酸苯酯(4),4经脱甲基、邻位硝化及氢化还原得2-甲基-3-氟-5-氨基-6-羟基苯甲酸苯酯(8),8的羟基和氨基同时经苄基保护,反应结束后通过缓慢降温便可析出eravacycline的关键中间体2-甲基-3-氟-5-二苄基氨基-6-苄氧基苯甲酸苯酯(1),避免使用柱色谱纯化。总收率52.8%(以2计)。

2-Methoxy-5-fluorobenzoic acid （2） was subjected to methylation to afford a mixture of 2-methyl-3- fluoro-6-methoxybenzoic acid （3） and the unreacted 2. Then the mixture were subjected to esterification and directional hydrolysis directly without any further purification to give phenyl 2-methyl-3-fluoro-6-methoxybenzoate （4） and retrieve 2. Compound 4 reacted with BBr3 to remove methyl group followed by nitration and hydrogenation reduction to give phenyl 2-methyl-3-fluoro-5-amino-6-hydroxybenzoate （8）, which was subjected to benzyl protection to protect both hydroxyl and amino groups. Then the key intermediate of eravacycline, phenyl 2-methyl-3-fluoro-5-dibenzylamino-6- benzyloxybenzoate （1）, was separated out from the solvent by lowering the temperature slowly, this method could avoid the chromatographic purification successfully. This improved synthetic route was simple and the overall yield was 52.8 % （based on 2）.