title: 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.
abstract: 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.
authors.affiliation: Chemical Product Research and Development, Lilly Development Centre, rue Granbonpre 11, B-1348 Mont-St-Guibert, Belgium.
authors.forename: James A
authors.initials: JA
authors.lastname: Aikins
authors.forename: Michael
authors.initials: M
authors.lastname: Haurez
authors.forename: John R
authors.initials: JR
authors.lastname: Rizzo
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Van Hoeck
authors.forename: Willy
authors.initials: W
authors.lastname: Brione
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Kestemont
authors.forename: Christophe
authors.initials: C
authors.lastname: Stevens
authors.forename: Xavier
authors.initials: X
authors.lastname: Lemair
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Stephenson
authors.forename: Eric
authors.initials: E
authors.lastname: Marlot
authors.forename: Mindy
authors.initials: M
authors.lastname: Forst
authors.forename: Ioannis N
authors.initials: IN
authors.lastname: Houpis
mesh_terms: 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
chemical_list: 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