头霉素关键中间体7-MAC的合成方法改进  

Improved synthesis of the key intermediate of cephamycin 7-MAC

作　　者：陈兴贺[1] 蔡娟娟[1] 王博[1] 付德才[1] 

机构地区：[1]河北科技大学化学与制药工程学院,河北石家庄050018

出　　处：《中国药物化学杂志》2013年第1期32-35,共4页Chinese Journal of Medicinal Chemistry

摘　　要：目的改进头霉素关键中间体7α-甲氧基-7β-氨基-3-[(1-甲基-1H-四氮唑-5-基)硫甲基]头孢-3-烯-4-羧酸二苯甲酯(7-MAC)的合成方法。方法以7-氨基-3-乙酰氧甲基头孢烯酸(7-ACA)为原料,经亲核取代反应合成3-(1-甲基-1H-四氮唑-5-基)硫甲基-7-氨基头孢烯酸(2),2经取代-消除反应、酯化反应制得7-甲硫亚胺-3-[(1-甲基-1H-四氮唑-5-基)硫甲基]头孢-3-烯-4-羧酸二苯甲酯(5),在中间体5的7α位引入甲氧基制得目标化合物7-MAC。结果与结论目标化合物的结构经质谱、核磁共振氢谱确证,总收率为60%以上,纯度为99.1%,透光率高于75%。该方法反应条件温和,得到的产品质量好,有利于工业化生产。7α-Methoxy-7β-amino-3-[ （ 1-methyl-lH-tetrazo-5-yl ） thiomethyl ]-3-cephem4-carboxylic acid diphenylmethyl ester（7-MAC, 1 ） was the key intermediate for the preparation of cephamycin antibiotics. The synthetic method of 7-MAC was optimized and improved and its structure was confirmed by MS and 1H-NMR in this paper. Reaction of 7-aminocephalosporanic acid （7-ACA） with 5-mercapto-1-methyl-1H-tet- razole gave 7-amino-3- [ （ 1 -methyl-1H-tetrazo-5 -yl ） thiomethyl ] -3-cephem-4-carboxylic acid （ 2 ） with a high yield in the presence of boron trifluoride and acetonitrile mixture. 7-Methylsulfeninmine-3-[ （1-methyl-lH- tetrazo-5-yl） thiomethyl]-3-cephem-4-carboxylic acid diphenylmethyl ester（5） was prepared by the reaction of methylsulfenyl bromide and 7-trimethylsilylamino-3- E （ 1 -methyl- 1H-tetrazo -5-yl ） thiomethyl ] -3-cephem- 4-carboxylic acid trimethylsilyl ester（3）, and esterification with diphenyldiazomethane. 7-MAC was obtained by reaction of compound 5 with methanol solution of aluminum trimethoxide in the presence of tripheny- lphosphine ,in a total yield of more than 60% with the good quality and high transmittance.

关 键 词：头霉素 7-MAC 合成 改进 

分 类 号：R914.5[医药卫生—药物化学]