Scalable Synthesis of TRPV1 Antagonist Bipyridinyl Benzimidazole Derivative via the Suzuki-Miyaura Reaction and Selective SeO2 Oxidation

In this study, a kilogram-scale synthesis of a potent TRPV1 antagonist, 1, is described. To synthesize bipyridinyl benzimidazole derivative 1, we have developed a scalable Suzuki-Miyaura reaction capable of providing a key intermediate, 6 '-methyl-3-(trifluoromethyl)-2,3 '-bipyridine 4, on a kilogram scale. Then, unlike the existing oxidation reaction pathway, two synthetic routes that can be applied to mass production of bipyridinyl carboxylic acid intermediate 5 or aldehyde intermediate 6 were developed by appropriately controlling the oxidation reaction using a selenium dioxide oxidizing agent. Using our developed synthetic procedure, which includes Suzuki-Miyaura coupling, selective selenium dioxide oxidation, and benzimidazole formation, multi-kilogram-scale bi-pyridinyl benzimidazole derivative 1 can be synthesized.

Automated summary

In this study, a kilogram-scale synthesis of a potent TRPV1 antagonist, 1, is described. A scalable Suzuki-Miyaura reaction was developed to obtain a key intermediate, 6'-methyl-3-(trifluoromethyl)-2,3'-bipyridine 4, on a kilogram scale. Two synthetic routes for mass production of bipyridinyl carboxylic acid intermediate 5 or aldehyde intermediate 6 were developed using controlled oxidation reactions. With the developed synthetic procedure, a multi-kilogram-scale bi-pyridinyl benzimidazole derivative 1 can be synthesized.