A new synthesis of allosteric HIV-1 integrase inhibitor GSK3839919A is described. Key to the efficiency was the synthesis of (S)-2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2-methylpyridin-3-yl)-2-(tert-butoxy)acetate in only 5 steps compared to 13 steps in the original synthesis. This advanced building block has been used in the syntheses of many drug candidates targeting allosteric HIV integrases. Process development leading to the efficient multi-kilogram synthesis of GSK3839919A is also described, including the optimization of two Pd-catalyzed reactions and isolation of the active pharmaceutical ingredient without salt formation and use of lyophilization and gentisic acid as in the original synthesis.

中文翻译：

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高效变构 HIV-1 整合酶抑制剂 GSK3839919A 的快速合成

描述了变构 HIV-1 整合酶抑制剂 GSK3839919A 的新合成。效率的关键是 ( S )-2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2-methylpyridin-3-yl)-2-( tert -butoxy)acetate的合成与原始合成中的 13 个步骤相比，仅需 5 个步骤。这种先进的构建模块已被用于合成许多针对变构 HIV 整合酶的候选药物。还描述了导致 GSK3839919A 高效合成多千克的工艺开发，包括两个 Pd 催化反应的优化和活性药物成分的分离而不形成盐，以及在原始合成中使用冻干和龙胆酸。