S1P3受体拮抗剂TY-52156的合成工艺优化

Optimization of synthesis process of S1P3 receptor antagonist TY-52156

以3,3-二甲基-2-丁酮、乙酸乙酯和对氯苯胺为起始原料,经Claisen缩合、氯代、重氮化、亲核取代等五步反应生成目标产物TY-52156,总收率为42.4%。目标化合物结构经1H-NMR、13 C-NMR和HRMS确证。通过优化Claisen缩合(t-BuOK/MTBE)及亲核取代(AcONa/EtOH)两步的反应条件,使其总收率比原有路线提高了1.36倍,更适合较大规模制备TY-52156。

Target product TY-52156 was obtained by classical Claisen condensation,chlorination,diazotization and nucleophilic substitution from starting materials 3,3-dimethyl-2-butanone,ethyl acetate and p-chloroaniline,and gave total yield in 42.4%.The structure of the target compound was confirmed by 1H-NMR,^(13)C-NMR and HRMS.By optimizing the reaction conditions of Claisen condensation(t-BuOK/MTBE)and nucleophilic substitution(AcONa/EtOH),the total yield was increased 1.36 folds compared with the traditional process,which was more suitable for large-scale preparation of TY-52156.