Expeditious Synthesis of a Potent Allosteric HIV-1 Integrase Inhibitor GSK3839919A

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.

Automated summary

A new synthesis of allosteric HIV-1 integrase inhibitor GSK3839919A is reported, with a key advance in the synthesis of a crucial building block. The process development for the efficient multi-kilogram synthesis of GSK3839919A is also described, including optimization of Pd-catalyzed reactions and the use of lyophilization and gentisic acid.