噻唑乙酸及其酯衍生物的合成及生物活性研究

Studies of Synthesis and Biological Activity of Thiazole Acetic Acid and its Ester Derivatives

以乙酰丙酸乙酯为原料,经氯代、缩合得2-氨基-4-甲基噻唑-5-乙酸乙酯3,再经酰氯的氨解、酯的水解等反应分别合成了新型2-芳基甲酰胺-4-甲基噻唑-5-乙酸及其酯衍生物4 (收率为51%~63%)和5 (收率为40%~50%),其结构均经1 H NMR,13 C NMR,HRMS表征.并对3的合成工艺进行优化和目标化合物4与5清除DPPH自由基和黄嘌呤氧化酶抑制活性进行检测.3的最佳合成工艺条件是:乙酰丙酸乙酯、磺酰氯和硫脲的物质的量比1∶1.2∶1,氯化反应以二氯甲烷作溶剂回流反应1h,缩合反应以无水乙醇作溶剂回流反应3h,浓盐酸5mL,总收率达到82.5%.该合成工艺过程简单、生产安全、反应条件温和、环境友好、产品收率高.活性检测结果显示:酯类化合物4和乙酸类化合物5均具有一定的清除DPPH自由基的能力,且5的活性优于4;但对黄嘌呤氧化酶均无抑制作用.

2-amino-4-methylthiazole-5-ethyl 3 acetate was synthesized from ethyl levulinate by chlorination and condensation reaction,and then novel 2-primary aryl amides-4-methylthiazole-5-acetic acid and its ester derivatives 4(the yield of 51%-63%)and 5(the yield of 40%-50%)were synthesized via ammonolysis of acyl chloride and hydrolysis of ester reaction.The target compounds were confirmed by 1 HNMR,13 C NMR and HRMS.The synthesis process of 3 was optimized and the DPPH free radical scavenging activity and xanthine oxidase inhibitory activity of target compounds 4 and 5 were detected.The optimum synthetic conditions of 3 were as follows:molar ratio of ethyl levulinate,sulfonyl chloride and thiourea was 1∶1.2∶1.Dichloromethane was used as the solvent in the reaction of chlorination and refluxed of 1 h and absolute ethyl alcohol was used as the solvent in the reaction of concentration and refluxed of 3 h.5.0 mL hydrochloric acid was needed,and the total yield was 82.5%.The synthetic process are simple,safe,mild reaction conditions,environmentally friendly and high yield.The test of biological activity shows that:Esters 4 and Acetic acids 5 have certain ability to scavenge DPPH free radicals,and the activity of 5 is better than 4;but it has no inhibitory effect on xanthine oxidase.