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.
We
report a large-scale carboxylation of N-Boc-4,4-difluoropiperidine
(1) enabled by a continuous flow process. The flow process
involved N-Boc-directed α-deprotonation using s-BuLi in THF and subsequent trapping with CO2 gas. Flow chemistry enabled the safe and scalable preparation of
400 g of carboxylic acid 2 over the course of a day to
support our medicinal chemistry research program.
Pyridine derivatives
Pyridine derivatives R 0380New Stereoselective Syntheses of cis-and trans-2-Methyl-4-arylpiperidines. -The reaction conditions for the stereoselective reduction of readily prepared piperidinols (III) to trans-and cis-2-methyl-4-arylpiperidines (IV) and (V) are carefully optimized. Ni-Catalysts in unpolar solvent give the trans-products preferentially, whereas palladium on carbon in ethanol results in moderate cis-selectivity. -(MERSCHAERT*, A.; DELHAYE, L.; KESTEMONT, J.-P.; BRIONE, W.; DELBEKE, P.; MANCUSO, V.; NAPORA, F.; DIKER, K.; GIRAUD, D.; VANMARSENILLE, M.; Tetrahedron Lett. 44 (2003) 24, 4531-4534; Lilly Res. Lab., Chem. Proc. R&D, Lilly Dev. Cent. S. A., B-1348 Mont St. Guibert, Belg.; Eng.) -Mais 38-116
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