活性酯法合成一种新型头孢菌素及抗菌活性研究  

Synthesis and Antimicrobial Study of a New Type of Cephalosporin by an Active Ester Method

作　　者：陈昆南 傅红燕 王长军 Chen Kun-nan;Fu Hong-yan;Wang Chang-jun(Guangzhou Baiyunshan Tianxin Pharmaceutical Co.,LTD,Guangdong 510300)

机构地区：[1]广州白云山天心制药股份有限公司,广州510300

出　　处：《国外医药（抗生素分册）》2020年第6期486-490,共5页World Notes on Antibiotics

摘　　要：目的利用具有环保优势的活性酯法工艺合成新的头孢菌素。方法以7-氨基头孢烷酸(7-ACA)为起始原料,与2-巯基苯并噻唑(M)反应得到三位取代中间体(1),再与(Z)-2-(2-氨基噻唑-4-基)-2-甲氧羰基甲氧亚氨基硫代乙酸 (S)-2-苯并噻唑酯(MICA ester)在水和乙腈的溶剂中用Na2CO3做催化剂经亲核取代反应得到一种新的头孢菌素钠盐(2),最后在0.01mol/L盐酸的乙腈-水的溶剂体系下得到一种新型头孢菌素(3)。通过琼脂扩散法初步筛选该化合物对肺炎球菌、化脓性链球菌和金黄色葡萄球菌3种常见菌株的抗菌活性,并通过微量稀释法进一步测定它们的最小抑菌浓度(MIC值)。结果合成了1个新的头孢菌素类化合物(3),其结构经1H-NMR、13C-NMR、MS和HRMS确证。该化合物具有一定的抑菌能力,其MIC测试结果表明,化合物(3)对所测菌株的MIC值在22~50μg/mL范围内,抑菌活性与对照药物头孢丙烯相当。结论活性酯法工艺合成新的头孢菌素在头孢菌素类抗生素制药工业中具有积极现实意义。Objective To synthesize a new type of cephalosporin by utilizing the active ester method with environmental advantages.Methods The reaction was carried out,starting materials,7-Amino cephalosporin acid (7-ACA) reacted with 2-mercaptobenzothiazole (M) to get 3-substituted intermediates,which underwent nucleophilic substitution with MICA ester in water and THF in the presence of Na2CO3 as catalyst to get a new cephalosporin sodium salt (2).Finally,a new type of cephalosporin (3) was obtained under the acetonitrile-water solvent system of 0.01mol/L hydrochloric acid.The antimicrobial activity against Pneumococcus,Streptococcus pyogenes and Staphylococcus aureus were determined by the microdilution method.Results 1H-NMR,13C-NMR,MS and HRMS spectra data of the compounds indicated that the new cephalosporin compound (3) was structurally correct.The MIC values of the above compound was further tested,and the results showed that compound (3) of MIC value were in the range of 22~96μg/mL,and the antibacterial activity was comparable to that of the control drug Cefprozil.Conclusion the synthesis of new cephalosporins by active ester method has practical significance in the pharmaceutical industry of cephalosporins antibiotics.

关 键 词：活性酯 7-ACA 头孢菌素 合成 

分 类 号：R978.1[医药卫生—药品]