依那度他的合成工艺研究  

Study on the synthetic process of enarodustat

作　　者：宁新平 袁瑜 黄波 潘滢浩 鲁晓莉 李元波 孟广鹏 NING Xin-ping;YUAN Yu;HUANG Bo;PAN Ying-hao;LU Xiao-li;LI Yuan-bo;MENG Guang-peng(Chengdu Sintanovo Biotechnology Co.,Ltd.,Chengdu 610000,China;College of Pharmacy,Chengdu University of Traditional Chinese Medicine,Chengdu 610000,China)

机构地区：[1]成都诺和晟泰生物科技有限公司,四川成都610000 [2]成都中医药大学药学院,四川成都610000

出　　处：《中国药物化学杂志》2023年第1期25-29,共5页Chinese Journal of Medicinal Chemistry

摘　　要：目的优化依那度他的合成工艺。方法以2,4-二氯烟酸为起始原料,经叔丁基三氯乙酰亚胺酯保护羧基、苄氧基取代反应、肼基取代反应、关环反应、三唑互变异构、碘代反应、Sonogashira反应、酯基酸解后酰胺化,再经钯炭催化还原、脱叔丁基和水解等一系列反应得到依那度他。结果与结论目标化合物依那度他及部分中间体的化学结构经^(1)H-NMR和LC-MS谱确证,目标化合物纯度大于99%(HPLC法),总收率为25.75%(以2,4-二氯烟酸计),高于文献报道收率(22.66%)。本工艺成本较低,减少了有毒有害物质的使用,对环境污染小,更适合工业化生产。Enarodustat is a HIF prolyl hydroxylase inhibitor used in the treatment of renal anemia.With 2,4-dichloronicotinic acid as the starting material,enarodustat was obtained with protection of carboxyl group by tert-butyl 2,2,2-trichloroacetimidate,followed by a series of reactions including benzyloxy and diazanyl substitution,ring closure,triazole tautomerism,iodine substitution,Sonogashira reaction,ester hydrolysis and amidation,palladium-carbon catalyzed reduction,de-tert-butylation and hydrolysis.The chemical structures of the target product enarodustat and some intermediates were confirmed by ^(1)H-NMR and LC-MS,and the total yield was 25.75%.The improved synthetic route has the advantages of easy availability in solvent,low cost,high yield and purity,high solvent recovery and environmentally friendly,which would provide new perspective for industrial application.

关 键 词：HIF-PHD抑制剂 依那度他 SONOGASHIRA反应 

分 类 号：R914[医药卫生—药物化学]