Synthesis Of GW501516, An Agonist Of PPAR

The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor gene family. Three closely related isoforms, PPARa, -γ, and -δ( or -β), have been identified in organisms. In contrast to PPARa and -γ, there are no marketed drugs that target PPARS due to the lack of selective ligands as chemical tools to study its pharmacology. GW501516 (1), which was discovered by combinatorial chemistry and structure-based drug design, was shown to be the most potent and selective PPARδagonist known with an EC₅₀ of 1.1 nM against PPARδand 1000-fold selectivity over the other human subtypes, PPARa, and -y. Thus, it could be used as ideal chemical tools to study the function of the ubiquitously expressed PPARδand as potential therapeutic agents for the treatment of diseases associated with raised serum triglycerides and low levels of HDL-C.Based upon the synthetic routes reported in literatures, we selected a route starting from 4-(trifloromethyl) benzonitrile (5) for the synthesis of GW501516 in this thesis. The target compound was prepared in an 8-step sequence. Chloromethylthiazole (10) was obtained by preparation of benzthioamide, thioazolecarboxylate synthesis, reduction and chlorination. 2-methyl-4-thiocyanatophenol (3), prepared with o-cresol and sodium thiocyanate, was reduced to afford 2-methyl-4-mercaptophenol (4). 4 was first etherized with 10 and then with methyl bromoacetate via Williamson reaction to give ethyl ester of 1 which was easily converted to GW501516.The total yield reached up to 29.2% based on 5, and the structure of target compound was confirmed by ¹H NMR, ¹³C NMR, ESI-MS.The synthetic process was greatly improved in this thesis. Two work-up procedures of 3 and 1 were simplified without using column chromatography. The amount of LiAlH₄ for the reduction of ethyl thioazolecarboxylate was cut from 1.0 to 0.5 mole equivilence. 12 was obtained from 4 via one-pot, regioncontrolled dietherifications with 10 and then-with methyl bromoacetate. And this one-pot reaction was cost-effective due to the use of K₂CO₃ instead of expensive Cs₂CO₃. Our improved approach has an economic advantage for further scale-up purpose.