Gram-scale Synthesis of a Novel Core Building Block for the New GPR40 Agonist Design

Background: 3-[4-(Benzyloxy)phenyl]propanoic acid moiety is central to many advanced agonists of free fatty acid receptor 1 (FFA1 or GPR40) which are a new, promising class of antidiabetic drugs. An aldehydo carboxylic acid tert-butyl ester building block is required for speedy SAR exploration of analogs of Eli Lilly’s GPR40 agonist LY2881835 which was in phase I clinical trials. Methods: The aldehyde functionality of the target building block was masked as methyl carboxylate. The phenylpropionic acid tert-butyl ester portion was constructed using Horner-Wadsworth-Emmons chemistry followed by olefin hydrogenation. The aldehyde function was unmasked via methyl ester hydrolysis, mixed anhydride reduction to alcohol and back-oxidation with manganese (IV) dioxide. Results: The synthesis of the target building block was realized in 7 chemical steps (the final three of which were conducted in succession not requiring interim purifications) involving isolation and characterization of four hitherto undescribed intermediates. Conclusion: The method described is suitable for production of the target alehydo carboxylic acid tertbutyl ester building block on a multigram scale, which will facilitate the parallel synthesis of LY2881835 analogs and expedite the respective SAR exploration.