SARS-COV-2 M^(pro)抑制剂2-(2-氯苯基)-7-(异喹啉-4-基)-5,7-二氮杂螺[3.4]辛-6,8-二酮的合成  

Synthesis of SARS-COV-2 M^(pro)inhibitor 2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione

作　　者：闫翱翔 臧瑞涵 李华[1] 陈丽霞[1] 李行舟 YAN Aoxiang;ZANG Ruihan;LI Hua;CHEN Lixia;LI Xingzhou(Wuya College of Innovation,Shenyang Pharmaceutical University,Shenyang 110016,China;National Key Laboratory of National Security Essential Drugs at the Academy of Military Medicine,Beijing 100850,China)

机构地区：[1]沈阳药科大学无涯创新学院,辽宁沈阳110016 [2]军事医学研究院国家安全特需药品全国重点实验室,北京100850

出　　处：《沈阳药科大学学报》2024年第9期1198-1204,共7页Journal of Shenyang Pharmaceutical University

基　　金：国家自然科学基金资助项目(82141216)。

摘　　要：目的研究SARS-COV-2 M^(pro)抑制剂2-(2-氯苯基)-7-(异喹啉-4-基)-5,7-二氮杂螺[3.4]辛-6,8-二酮(1)的合成方法,为其深入研究和其衍生物的合成提供借鉴方法。方法以(2-氯苯基)乙酸甲酯为起始原料,经亲电取代、还原、磺酰化、环化、选择性水解得到3-(2-氯苯基)-1-乙氧羰基环丁烷-1-甲酸(6),在三乙胺存在下,化合物6与叠氮磷酸二苯酯反应,生成的酰基叠氮化合物经Curtius重排生成相应的异氰酸酯;再与4-氨基异喹啉反应,并在碳酸钠的作用下进一步环合生成目标化合物。结果中间体及目标化合物的化学结构经^(1)H-NMR、^(13)C-NMR、ESI-MS确证。结论对化合物6的合成路线进行了优化;通过化合物6获得了一条更精简的化合物1的合成路线,该路线既避免了有毒的三光气的使用,也避免了副反应的发生;通过制备型HPLC得到化合物1的两个顺反异构体,并使用NOESY确定了化合物的构型。Objective To study the synthetic process of 2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione(1)as the SARS-COV-2^(pro)inhibitor,and provide a reference method for the synthesis of its derivatives.Methods With 2-(2-chlorophenyl)methyl acetate as the starting material,the 3-(2-chlorophenyl)-1-(ethoxycarbonyl)cyclobutane-1-carboxylic acid(6)was obtained by electrophilic substitution,reduction,sulfonylation,cyclization and selective hydrolysis.In the presence of triethylamine,the compound 6 reacted with diphenylphosphoryl azide,and the acyl azide generated was rearranged by Curtius rearrangement to generate the corresponding isocyanate,and then reacted with 4-aminonenenebc isoquinoline,and further cyclization under the action of sodium carbonate generates target compound 1.Results The chemical structures of the intermediate and target compound were confirmed by^(1)H-NMR and ESI-MS.Conclusion The synthetic route of compound 6 has been optimized;A more streamlined synthetic route for compound 1 is obtained through compound 6,which not only avoids the use of toxic triphosgene but also avoids the occurrence of side reactions;Two cis-trans isomers of compound 1 are obtained by preparative HPLC,and the configurations of the two isomers are determined by NOESY.

关 键 词：严重急性呼吸窘迫综合征冠状病毒2型 主蛋白酶 抑制剂 合成方法 

分 类 号：R914[医药卫生—药物化学]