替诺昔康的中间体合成研究  

Synthesis of the Intermediates for Tinoxicam

作　　者：刘伟[1] 李茂林[1] 刘金强[1] 程任兵 陈新志[1] 

机构地区：[1]浙江大学材料与化学工程学院,浙江杭州310027

出　　处：《精细与专用化学品》2005年第19期16-17,23,共3页Fine and Specialty Chemicals

基　　金：浙江大学SRTP项目

摘　　要：以3-氨基-2-噻吩甲酸甲酯为原料,经氯磺化、甲胺化、N-烷基化、环合等反应合成了替诺昔康的中间体4-羟基-3-甲基-2H-噻吩并[2,3-e]-1,2-噻嗪-2-羧酸甲酯-1,1-二氧化物(MHTTCD)。氯磺化时在大大减少溶剂(醋酸)用量的条件下,收率为78%,甲胺化收率为81.6%。环合反应在甲醇钠的甲醇溶液中进行,合适的甲醇钠浓度为1mol/L。回流反应1h,该步收率达55.5%。合成路线反应总收率为11.11%。通过GC-MS确认了各中间体的结构。由于N-烷基化时以氯乙酸乙酯代替肌氨酸乙酯盐酸盐以及收率的提高,降低了合成成本。The intermediate of Tinoxicam ,4-hydroxy-3-methyl-2H-thieno[ 2,3-e] -1,2-thiazine -2-（methyl） carboxylate-1,1-dioxide （MHTTCD） was synthesized from methyl 3-amino-2-thiophene methyl carboxylate through four steps： chlorosulfonylation, methylamination, N-alkylation, and cyclization. The solvent, acetic acid was greatly reduced in the chlorosulfonylation step, and the yield of 78% was obtained. The yield for methylamination was 81.6% with the aqueous methylamine as the reagent. The cyclization was carried out in the methanol solution of sodium methylate with the appropriate concentration of 1mol/L, and the yield of 55.5% was obtained after reacting for 1 hour. The total yield was 11. 11%. The structures of the intermediates were confirmed by MS. The production cost was lowed on account of the replacement of ethyl sarcosinate hydrochloride by ethyl chloroacetate in the process of N-alkylation and the increase of yield.

关 键 词：替诺昔康 磺酰氯化 甲胺化 N-烷基化 环合反应 合成研究 中间体 N-烷基化 氯乙酸乙酯 反应合成 环合反应 GC-MS 甲酸甲酯 羧酸甲酯 

分 类 号：TQ460.4[化学工程—制药化工]