Pharmacologist collaborators at Mayo Clinic have found antipyrine 3 (R1, R5=CH3, R4 = H) to be a lead drug for treatment of pulmonary fibrosis. We have developed several modular approaches to the synthesis of antipyrine analogs (see equations 1, 2, and 3), allowing for variation at the N1-position (equation 3), the N2-position (equation 2), and the N4 or N5 positions (equation 1). N1-alkylation on pyrazolidinone 7 (eqn 3) is easier than on pyrazolone 2 (eqn 1), which is largely limited to methylation. The use of crotonic acid to produce pyrazolidinones 5 and 7 is highly effective. The use of phenylhydrazine is completely regioselective for the N2-phenyl isomer (eqn 3); conversely methylhydrazine is regioselective for the N1-methyl isomer, with 8:1 regioselectivity (eqn 2). N-Acylation of N2-H pyrazolodinone 5 using carboxylic acids is possible using our Mukayama’s Reagent procedure. Both pyrazolidinones 6 and 8 as well as the various pyrazolones 3 will be assayed at the mayo clinic as potential drug candidates for pulmonary fibrosis.

Synthetic methedologies for pyrazolones analogues as potential drug candidates for pulmonary fibrosis

253rd National Meeting (2017)

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