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

J. Org. Chem., 70 (12), 4695 -4705, 2005. 10.1021/jo050268e S0022-3263(05)00268-9
Web Release Date: May 5, 2005

Synthesis of a Peroxime Proliferator Activated Receptor (PPAR) / Agonist via Stereocontrolled Williamson Ether Synthesis and Stereospecific S_N2 Reaction of S-2-Chloro Propionic Acid with Phenoxides

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, and Ioannis N. Houpis*

Chemical Product Research and Development, Lilly Development Centre, rue Granbonpre 11, B-1348 Mont-St-Guibert, Belgium, and Lilly Technology Center, B-110, Indianapolis, Indiana 46285

houpis_ioannis@yahoo.com

Received February 10, 2005

Abstract:

The stereospecific synthesis of the PPAR

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 S_N2 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

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