2-巯基-4-(4-吡啶基)噻唑的合成及其与头孢母环对接工艺优化

Synthesis of(2)-mercapto-4-(4-pyridyl)thiazole and its optimization of docking process with cephalosporin ring

以4-乙酰吡啶为主要原料,经过溴化、硫化、环合、碱性水解、脱酸等一系列反应,制得头孢洛林酯三位侧链2-巯基-4-(4-吡啶基)噻唑,总收率37.47%。以碱活化巯基生成4-(4-吡啶基)-1,3-噻唑-2-硫醇钠,并与3位完成活化的3-羟基头孢对接,制得7β-苯乙酰氨基-3-(4-吡啶基-2-噻唑巯基)-3-头孢烯-4-羧酸二苯甲基酯(BPMCC)。通过MS和1H NMR对目标产物及各步反应中间体的结构进行了表征。结果表明,加入洗气装置可将二硫代氨基甲酸铵的产率提升到89.2%;改进了2-巯基-4-(4-吡啶基)噻唑氢溴酸盐环合工艺,确定最佳反应温度为0℃,最佳溶剂为无水乙醇、乙腈混合溶液,最佳投料比n(4-溴乙酰吡啶氢溴酸盐)∶n(二硫代氨基甲酸)=1∶1.1;确定了2-巯基-4-(4-吡啶基)噻唑从反应体系中析出的最佳pH为6.8;确定了宜采用分步法生产7β-苯乙酰氨基-3-(4-吡啶基-2-噻唑巯基)-3-头孢烯-4-羧酸二苯甲基酯。

The main chain of 4-acetylpyridine was subjected to a series of reactions such as bromination,sulfurization,cyclization,alkaline hydrolysis and deacidification to obtain the three-position side chain of ceftarolinepozhe-(2)-mercapto-4-(4-pyridyl)thiazole,the total yield was 37.47%.The base was activated to form a 4-(4-pyridyl)-1,3-thiazole-2-thiolate sodium,and was docked with the 3-activated 3-hydroxycephalosporin to obtain 7β-phenylacetamido-3-(4-pyridinyl-2-thiazolyl)-3-cephem-4-carboxylic acid benzhydryl ester(BPMCC).The structure of the target product and the reaction intermediate of each step was characterized by MS and 1 H NMR.The results were as follows:the addition of a scrubber increased the yield of ammonium dithiocarbamate to 89.2%;improved the(2)-mercapto-4-(4-pyridyl)thiazole hydrobromide ring closure process to determine the best reaction temperature was 0℃,the optimum solvent was the mixed solution of anhydrous ethanol and acetonitrile;the optimal raw material ratio were determined:n(4-bromoacetylpyridine hydrobromide)∶n(dithiocarbamic acid)=1∶1.1;The optimum pH of 2-mercapto-4-(4-pyridyl)thiazole precipitated from the reaction system was 6.8;The 7β-phenylacetamido-3-(4-pyridyl-2-thiazolyl)-3-cephem-4-carboxylic acid benzhydryl ester was produced by a stepwise method.