采用2-(4-甲基苯基)丙酸、对肼基苯甲酸为起始原料,分别经甲酯化、甲基化、溴代以及Fischer吲哚合成、苄酯化制备2-(4-(溴甲基)苯基)-2-甲基丙酸甲酯(中间体1)和2,3-二甲基-1H-吲哚-5-甲酸苄酯(中间体2),然后通过N-烷基化、催化氢化、酰化、Suzuki偶联以及水解反应首次合成SR11023对映异构体,总收率达16.5％.该合成路线为首次报道,方法简单,反应条件温和,中间体与目标化合物均通过1 H NMR、13C NMR以及ESI-HRMS进行结构确证.通过GAL-4 PPARγ萤光素酶报告基因及TR-FRET PPARγ竞争性结合分析确证了 SR11023对映异构体为高亲和性PPARγ拮抗剂,并阐明α-甲基对活性的影响.
Abstract
Using 2-(4-methylphenyl)propionic acid and p-hydrazine benzoic acid as starting materials,methyl 2-(4-(bromomethyl)phenyl)-2-methylpropanoate benzyl(intermediate 1)and 2,3-dimethyl-lH-indole-5-carboxylate(intermediate 2)were synthesized via methylation,methylation,bromination,Fischer indole synthesis,and benzylation,respectively.Then,SR11023 enantiomer was synthesized through N-alkylation,catalytic hydrogenation,acylation,Suzuki coupling,and hydrolysis reactions with an overall yield of 16.5％.The synthesis route was reported for the first time,with a simple method and mild reaction conditions.The structure of the intermediate and target compound were confirmed by1H NMR,13C NMR and ESI-HRMS.The SR11023 enantiomer was confirmed as a high affinity PPARγ antagonist by GAL-4 PPARγ luciferase reporter and TR-FRET PPARγ competitive binding analysis,and elucidated the influence of α-methyl in SR11023 enantiomers on PPARγ affinity and agonistic activity.
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