Practical Synthesis of Valbenazine via 1,3-Dipolar Cycloaddition  

作　　者：Yalan Peng Zuming Lin Lili Zhu Shiqing Han Sha-Hua Huang Ran Hong 

机构地区：[1]College of Biotechnology and Pharmaceutical Engineering,Nanjing Tech University,Nanjing,Jiangsu,211816 China [2]School of Environmental and Chemical Engineering,Shanghai Institute of Technology,Shanghai,201418 China [3]State Key Laboratory of Chemical Biology,Shanghai Institute of Organic Chemistry,Chinese Academy of Sciences,Shanghai,200032 China [4]Innovation Research Institute of Traditional Chinese Medicine(IRI),Shanghai University of Traditional Chinese Medicine,1200 Cailun Road,Shanghai,201203 China

出　　处：《Chinese Journal of Chemistry》2024年第8期841-845,共5页中国化学（英文版）

基　　金：the National Natural Science Foundation of China(22271194 and 22371295);the Jiangsu Synergetic Innovation Center for Advanced Bio-Manufacture(Grant No.XTD 2210);the Science and Technology Commission of Shanghai Municipality(20XD1404700)is greatly appreciated.

摘　　要：Comprehensive Summary,Valbenazine(Ingrezza),a potent and highly selective inhibitor of vesicular monoamine transporter type 2(VMAT2)through the active metabolite hydrotetrabenazine(HTBZ),has been approved for the treatment of tardive dyskinesia and,very recently,for chorea,which is associated with Huntington's disease.Despite numerous synthetic efforts dedicated to the synthesis of HTBZ,the industrial preparation of valbenazine uses dihydroisoquinoline as a starting material and the chiral resolution of racemic HTBZ derived from ketone reduction.Herein,we present a practical synthesis of HTBZ and valbenazine featuring a highly stereoselective 1,3-dipolar cycloaddition and enzymatic kinetic resolution.The cascade process includes cycloaddition,N—O bond cleavage,and lactamization,which proved to be operationally simple.The allure of the enzymatic resolution developed in this work offers a rapid access toward affording tetrahydroisoquinoline(THIQ)-fused piperidine in the production of medically significant compounds,such as yohimbine and reserpine.

关 键 词：CYCLOADDITION CHEMOENZYMATIC Kinetic resolution PRODRUGS VMAT2 inhibitor 

分 类 号：O62[理学—有机化学]