American Chemical Society
jo050268e_si_002.cif (18.14 kB)

Synthesis of a Peroxime Proliferator Activated Receptor (PPAR) α/γ Agonist via Stereocontrolled Williamson Ether Synthesis and Stereospecific SN2 Reaction of S-2-Chloro Propionic Acid with Phenoxides

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posted on 2005-06-10, 00:00 authored by James A. Aikins, Michael Haurez, John R. Rizzo, Jean-Pierre Van Hoeck, Willy Brione, Jean-Paul Kestemont, Christophe Stevens, Xavier Lemair, Gregory A. Stephenson, Eric Marlot, Mindy Forst, Ioannis N. Houpis
The stereospecific synthesis of the PPAR α/γ agonist 1 was accomplished via ethylation of the optically pure trihydroxy derivative 6, itself derived via an enzymatic resolution. The ethylation can be accomplished without epimerization only under strict control of the reaction conditions and the choice of base (sodium tert-amylate), temperature (−30 °C), order of addition, and solvent (DMF). The key diastereospecific SN2 reaction of the phenol 4 with S-2-chloropropionic acid is best achieved via the sodium phenoxide of 4 derived from Na0 as the reagent of choice. The structure elucidation and key purification protocols to achieve pharmaceutical purity will also be described