甲磺酸加贝酯的合成及工艺研究

Synthesis and process of gabexate mesylate

甲磺酸加贝酯是一种小分子非肽类蛋白抑制剂,能够进入胰管降低胰液中酶的活性.本研究以己内酰胺为原料,在氢氧化钠的作用下水解为氨基己酸,己内酰胺与氢氧化钠比例为1∶1.2,反应时间1.5 h.然后氨基己酸与S-甲基异硫脲硫酸盐在氢氧化钠条件下先在10℃下反应30 min,然后常温反应6 h,胍基化为6-胍基己酸.6-胍基己酸制为盐酸盐后与对羟基苯甲酸乙酯在三氟甲磺酸存在的条件下,吡啶为缚酸剂,经过两步酸化形成甲磺酸加贝酯.本研究以“一锅法”为参考,不使用污染性、腐蚀性更大的氯化亚砜,改用三氟甲磺酸,通过正交设计实验,得出最适合的条件.本方法操作更为简便,反应更为绿色,符合工业生产的要求.

Gabexate mesylate is a small molecule non-peptide protein inhibitor that can enter the pancreatic duct and reduce the activity of enzymes in pancreatic juice.In this paper,caprolactam was used as raw material,and it was hydrolyzed into aminocaproic acid under the action of sodium hydroxide.The ratio of caprolactam to sodium hydroxide was 1∶1.2,and the reaction time was 1.5 h.Then,aminocaproic acid and S-methylisothiourea sulfate were reacted at 10℃ for 30 min under the condition of sodium hydroxide,and then reacted at room temperature for 6 h,and guanidinium was converted to 6-guanidinohexanoic acid.6-guanidinohexanoic acid was prepared as hydrochloride with ethyl p-hydroxybenzoate in the presence of trifluoromethanesulfonic acid,and pyridine was used as an acid binding agent,and two-step acidification was performed to form gabexate mesylate.In this paper,the“one-pot method”was used as a reference,instead of using thionyl chloride which was more polluting and corrosive,trifluoromethanesulfonic acid was used instead,and the most suitable conditions were obtained through orthogonal design experiments.The method is simpler to operate,and the reaction is greener,and meets the requirements of industrial production.