抗精神分裂症候选药物盐酸ulotaront的拆分工艺改进  

Improvement of Resolution Process for Schizophrenia Candidate Drug Ulotaront Hydrochloride

作　　者：薛云林 钱坤 王真 姚星宇 陈寅 XUE Yunlin;QIAN Kun;WANG Zhen;YAO Xingyu;CHEN Yin(School of Pharmacy,Jiangsu Ocean University,Lianyungang 222005)

机构地区：[1]江苏海洋大学药学院,江苏连云港222005

出　　处：《中国医药工业杂志》2024年第7期928-931,共4页Chinese Journal of Pharmaceuticals

基　　金：连云港市高新区重点研发计划项目(ZD201916);江苏省研究生创新实践项目(SJCX22-1651)。

摘　　要：改进抗精神分裂症候选药物盐酸ulotaront(SEP-363856,1)的拆分工艺。筛选5种常用的拆分剂L-苹果酸、L-乳酸、L-酒石酸、L-樟脑磺酸和L-樟脑酸,确定最佳拆分剂为L-酒石酸,用量为0.3当量。并对重结晶溶剂及其用量也进行了优化,最终确定用25倍体积无水乙醇重结晶,得(S)-(5,7-二氢-4H-噻吩并[2,3-c]吡喃-7-基)-N-甲基甲胺L-酒石酸盐(8),8依次经氢氧化钾游离、成盐酸盐,得目标产物1,ee值为99.0%。优化后的工艺拆分收率由27%(原研工艺)提高至38%,总收率由14%(原研工艺)提高至21%。The resolution process for schizophrenia candidate drug ulotaront hydrochloride(SEP-363856,1)had been optimized in this study.By screening five common resolving agents,namely L-malic acid,L-lactic acid,L-tartaric acid,L-camphorsulfonic acid,and L-camphoric acid,the best one was determined to be L-tartaric acid,and the optimal equivalent was found to be 0.3.The recrystallization solvent and its amount were also optimized,and 25 volumes of anhydrous ethanol was used to obtain(S)-(5,7-dihydro-4H-thieno[2,3-c]pyran-7-yl)-N-methylmethylamine L-tartrate(8).Compound 8 was treated with aqueous potassium hydroxide and subsequent salt formation with HCl in ethyl acetate,then 1 was obtained with ee value of 99.0%.The optimized resolution yield increased from 27%(original research process)to 38%,and the total yield increased from 14%(original research process)to 21%.

关 键 词：盐酸ulotaront(SEP-363856) 手性拆分 L-酒石酸 

分 类 号：R971[医药卫生—药品] TQ460.6[医药卫生—药学]