Synthesis of SARS-COV-2 Mpro inhibitor 2-(2-chlorophenyl)-7-(isoquinolin-4-yl)-5,7-diazaspiro[3.4]octane-6,8-dione
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.
severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)main proteaseinhibitorsynthetic process
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