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

Author(s): Alexey Lukin , Daria Bagnyukova , Nikolay Zhurilo , Mikhail Krasavin .

Journal Name: Letters in Organic Chemistry

Volume 13 , Issue 7 , 2016

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Graphical Abstract:


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.

Keywords: 3-[4-(benzyloxy)phenyl]propanoic acid core, Horner-Wadsworth-Emmons olefination, mixed anhydride reduction, GPR40 agonists, structure-activity relationships, free fatty acid ligands, reductive amination, tert-butyl ester.

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Article Details

Year: 2016
Page: [491 - 495]
Pages: 5
DOI: 10.2174/1570178613666160805115331
Price: $58

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