首页|Practical Synthesis of Valbenazine via 1,3-Dipolar Cycloaddition

Practical Synthesis of Valbenazine via 1,3-Dipolar Cycloaddition

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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 ke-tone reduction.Herein,we present a practical synthesis of HTBZ and valbenazine featuring a highly stereoselective 1,3-dipolar cy-cloaddition 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.

CycloadditionChemoenzymaticKinetic resolutionProdrugsVMAT2 inhibitor

Yalan Peng、Zuming Lin、Lili Zhu、Shiqing Han、Sha-Hua Huang、Ran Hong

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College of Biotechnology and Pharmaceutical Engineering,Nanjing Tech University,Nanjing,Jiangsu 211816,China

School of Environmental and Chemical Engineering,Shanghai Institute of Technology,Shanghai 201418,China

State Key Laboratory of Chemical Biology,Shanghai Institute of Organic Chemistry,Chinese Academy of Sciences,Shanghai 200032,China

Innovation Research Institute of Traditional Chinese Medicine(IRI),Shanghai University of Traditional Chinese Medicine,1200 Cailun Road,Shanghai 201203,China

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国家自然科学基金国家自然科学基金Jiangsu Synergetic Innovation Center for Advanced Bio-Manufacture上海市科委项目

2227119422371295XTD221020XD1404700

2024

10.1002/cjoc.202300618

中国化学(英文版)
中国化学会 上海有机化学研究所

中国化学(英文版)

CSTPCD
影响因子：0.848
ISSN：1001-604X
年,卷(期)：2024.42(8)
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