425675-44-1Relevant articles and documents
The role of new technologies in defining a manufacturing process for ppara agonist ly518674
Argentine, Mark D.,Braden, Timothy M.,Czarnik, Jeffrey,Conder, Edward W.,Dunlap, Steven E.,Fennell, Jared W.,LaPack, Mark A.,Rothhaar, Roger R.,Scherer, R. Brian,Schmid, Christopher R.,Vicenzi, Jeffrey T.,Wei, Jeffrey G.,Werner, John A.,Roginski, Robert T.
experimental part, p. 131 - 143 (2010/04/22)
The impact of several new technologies on the development of a manufacturing process for LY518674 is described. Extensive use of process analytical technology (PAT) throughout development, both at laboratory and pilot-plant scale, enabled data-rich experi
A convergent kilogram-scale synthesis of the PPARα Agonist LY518674: Discovery of a novel acid-mediated triazolone synthesis
Braden, Timothy M.,Coffey, D. Scott,Doecke, Christopher W.,LeTourneau, Michael E.,Martinelli, Michael J.,Meyer, Christopher L.,Miller, Richard D.,Pawlak, Joseph M.,Pedersen, Steven W.,Schmid, Christopher R.,Shaw, Bruce W.,Staszak, Michael A.,Vicenzi, Jeffrey T.
, p. 431 - 440 (2012/12/31)
The first kilogram-scale synthesis of the PPARα agonist LY518674 (1) is described. The de novo convergent synthetic approach involved coupling of two rapidly assembled components, triazolone formation via a novel acid-promoted cyclization reaction, and final step saponification, delivering the compound in 32.5% overall yield via eight total steps with a six-step longest linear sequence. A regioselective alkylation on the dianion of 4-hydroxyphenylbutyric acid allowed the direct preparation of one of the convergent coupling partners, carboxylic acid 12, and an unusual solvent effect enabled the installation of a urea group on a protected hydrazine, permitting the regiospecific preparation of the other coupling partner, semicarbazide mesylate 17. Sulfonic acids were found to effect the desired triazolone ring formation, affording 25 from the coupled precursor acyl semicarbazide 23. Following saponification of 25 to 1, a wide solubility differential between ethyl acetate extracts of 1 and solutions of 1 in anhydrous ethyl acetate was harnessed in the final crystallization step to deliver the final compound in high yield and purity. The novel acid-mediated triazolone formation was further evaluated on a range of additional substrates, showing the new methodology to be largely complementary to existing base-mediated triazolone syntheses.
