氘代Voxelotor-D_(2)的合成研究  

Synthesis of Voxelotor-D_(2)

作　　者：唐文强 仝红娟 徐小娜 张怡天 刘斌[1,2] TANG Wen-qiang;TONG Hong-juan;XU Xiao-na;ZHANG Yi-tian;LIU Bin(School of Pharmacy,Shaanxi Institute of International Trade&Commerce,Xianyang 712046,China;Xianyang Key Laboratory of Molecular Imaging and Drug Synthesis,Xianyang 712046,China;School of pharmaceutical&Chemical Engineering,Xianyang Vocational Technical College,Xianyang 712000,China)

机构地区：[1]陕西国际商贸学院医药学院,陕西咸阳712046 [2]咸阳市分子影像与药物合成重点实验室,陕西咸阳712046 [3]咸阳职业技术学院医药化工学院,陕西咸阳712000

出　　处：《化学研究与应用》2024年第9期2190-2196,共7页Chemical Research and Application

基　　金：陕西省自然科学基础研究计划项目(2021JQ-883,2021JM-540)资助;陕西省教育厅一般专项科研计划项目(23JK0328)资助;陕西高校青年科技创新团队项目(陕教[2019]90号)资助;咸阳市分子影像与药物合成重点实验室资助项目(2021QXNL-PT-0008)资助。

摘　　要：本文报道一种结构新颖的Voxelotor-D_(2)(1)的合成方法。以2-(1-异丙基-1H-吡唑-5-基)烟酸乙酯的合成(2)为原料,首先经水解反应得到2-(1-异丙基-1H-吡唑-5-基)烟酸(3),然后,化合物(3)经四氘铝酸锂还原得到[2-(1-异丙基-1H-吡唑-5-基)吡啶-3-基]甲醇-D_(2)(4),最后,中间体(4)与2,6-二羟基苯甲醛(5)发生Mitsunobu反应,得到目标化合物(1),产物结构经1HNMR、^(13)CNMR及LC-MS表征。随后,分别考察并确定还原反应的适宜条件为:还原剂LiAlD_(4)的用量为n(LiAlD_(4))∶n(3)=0.6∶1、反应温度为70℃,反应时间8h,该条件下中间体4的收率为47%。确定Mitsunobu反应的适宜条件为:物料比n(5)∶n(4)=1.2∶1,反应溶剂为二氯甲烷,该条件下产物1收率达到59%。The synthetic method for a novel Voxelotor-D,(1)was reported.2-(1-Isopropyl-1H-pyrazol-5-yl)nicotinic acid(3)was synthesized through hydrolysis reaction by using ethyl 2-(1-isopropyl-1H-pyrazol-5-yl)nicotinate(2)as raw material.Then,compound(3)was reduced by lithium tetradeuterioaluminate to obtain(2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methan-D_(2)-ol(4).Finally,the intermediate(4)underwent a Mitsunobu reaction with 2,6-dihydroxybenzaldehyde(5)to obtain the target compound(1).The product structure was characterized by 1H NMR,^(13)C NMR and LC-MS.Subsequently,the suitable conditions for the reduction reaction were investigated and determined as follows:the dosage of the reducing agent LiAID_(4)was n(LiAID_(4)):n(3)=0.6:1,the reaction temperature was 70℃,the reaction time was 8 hours.The optimum conditions for Mitsunobu reaction were as follows:material ratio was n(5):n(4)=1.2:1,the reaction solvent was dichloromethane and the yield of product 1 was up to 59%.

关 键 词：氘代药物 沃塞洛托 还原反应 MITSUNOBU反应 

分 类 号：O625.6[理学—有机化学]