Aikins James A, Haurez Michael, Rizzo John R, Van Hoeck Jean-Pierre, Brione Willy, Kestemont Jean-Paul, Stevens Christophe, Lemair Xavier, Stephenson Gregory A, Marlot Eric, Forst Mindy, Houpis Ioannis N
Chemical Product Research and Development, Lilly Development Centre, rue Granbonpre 11, B-1348 Mont-St-Guibert, Belgium.
J Org Chem. 2005 Jun 10;70(12):4695-705. doi: 10.1021/jo050268e.
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.
过光学纯三羟基衍生物6的乙基化反应完成了PPARα/γ激动剂1的立体定向合成，该衍生物6本身是通过酶促拆分得到的。只有在严格控制反应条件、碱（叔戊醇钠）的选择、温度（-30℃）、加料顺序和溶剂（DMF）的情况下，乙基化反应才能在不发生差向异构化的情况下完成。苯酚4与S-2-氯丙酸的关键非对映选择性SN2反应，最好通过以Na0为首选试剂得到的4的苯酚钠来实现。还将描述结构解析和达到药物纯度的关键纯化方案。
