Synthesis of a peroxime proliferator activated receptor (PPAR) alpha/gamma agonist via stereocontrolled Williamson ether synthesis and stereospecific SN2 reaction of S-2-chloro propionic acid with phenoxides.
The stereospecific synthesis of the PPAR alpha/gamma 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 degrees 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.
Aikins
James A
JA
Chemical Product Research and Development, Lilly Development Centre, rue Granbonpre 11, B-1348 Mont-St-Guibert, Belgium.
Haurez
Michael
M
Rizzo
John R
JR
Van Hoeck
Jean-Pierre
JP
Brione
Willy
W
Kestemont
Jean-Paul
JP
Stevens
Christophe
C
Lemair
Xavier
X
Stephenson
Gregory A
GA
Marlot
Eric
E
Forst
Mindy
M
Houpis
Ioannis N
IN
D020650:Combinatorial Chemistry Techniques; D015394:Molecular Structure; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D011422:Propionates / Q000138:chemical synthesis*; D013237:Stereoisomerism; D013696:Temperature
D047493:PPAR alpha; D047495:PPAR gamma; D011422:Propionates; C501950:S-2-ethoxy-3-(4-(R-1-(2-(4-ethyl-phenyl)-ethylcarbamoyl)-ethoxy)-phenyl)- propionic Acid