A Convergent Kilogram-Scale Synthesis of the PPARα Agonist LY518674:  Discovery of a Novel Acid-Mediated Triazolone Synthesis

Abstract

The first kilogram-scale synthesis of the PPARr 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 acidmediated 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.

The Role of New Technologies in Defining a Manufacturing Process for PPARα Agonist LY518674

“…A one-pot preparation and purification of semicarbazide 16 (Scheme ) was developed to replace the three-step sequence outlined in Scheme . An earlier attempt to develop a one-pot process starting with 4-methylbenzylhydrazine ( 15 ) was unsuccessful due to an inability to separate 16 from its regioisomer 17 . Direct recrystallization from either IPA or EtOH gave no significant enrichment, and the mesylate salt of 16 was found to be unstable in alcoholic solvents at elevated temperatures.…”

“…The alkylation reaction was conducted as described by Schmid and co-workers . This process gave a reaction profile consisting of the desired acid 5 and 1−2% each of 10 and 4 , as well as excess alkylating agent and ethyl methacrylate from the dehydrobromination of EBIB.…”

“…The starting point for our research was the route selected for further development by Dr. Christopher Schmid and his colleagues (Scheme ) . The convergent synthesis involves the coupling of semicarbazide 3 and carboxylic acid 5 to give acylsemicarbazide 7 .…”

N2-Alkylation of semicarbazones. A general and efficient protocol for the synthesis of 2-alkylsemicarbazides from semicarbazide

“…20 Synthesis of the hydromethanesulfonate salt of 2-(4methylbenzyl)semicarbazide involved reaction of tert-butoxycarbonyl hydrazine with 4-methylbenzaldehyde to give the corresponding Boc-protected hydrazone which was reduced with H2/Pd into 1,2-disubstituted hydrazine followed by treatment with trimethylsilyl isocyanate, and then with MeSO2OH. 21 All the above approaches to 2-alkylsemicarbazides are based on construction of semicarbazide fragment by N-N or С-N bond formation and have such drawbacks as multistep procedures, laborious isolation of products, low yields, use of highly toxic reagents, poor scalability, etc.…”

A New Efficient Route to 2-Alkylsemicarbazides

“…A derivative of 2-benzylsemicarbazide was synthesized by N-alkylation of tert-butoxycarbonyl hydrazine, followed by successive reactions with triphosgene, NH3, HCl in MeOH, and aqueous NaHCO3 [20]. Synthesis of the hydromethanesulfonate salt of 2-(4-methylbenzyl) semicarbazide involved reaction of tert-butoxycarbonyl hydrazine with 4-methylbenzaldehyde to give the corresponding Boc-protected hydrazine, which was reduced with H2/Pd into 1,2-disubstituted hydrazine, followed by treatment with trimethylsilyl isocyanate, and then with MeSO2OH [21].…”