Synthesis of Felbinac acid and Felbinac ester via PEPPSI palladium N-heterocyclic carbene catalytic system

Abstract

Ethyl-4-biphenylacetate (Felbinac ester) and 4-biphenylacetic acid (Felbinac acid) are common active metabolites of non-steroidal anti-inflammatory drugs (NSAIDs) and are frequently used in the treatment of muscle inflammation and arthritis. The current studies synthesized Felbinacs via a Suzuki-Miyaura cross-coupling reaction mediated through PEPPSI-palladium N-heterocyclic carbene as a catalyst. The catalyst was synthesized through N-benzylation of benzimidazole followed by N-butylation of the resulting N-benzylbenzimidazole to yield the N-benzyl-N-butylbenzimidazolium bromide (the pre-carbene). The pre-carbene was then reacted with palladium bromide (PdBr₂) in 3-methylpyridine, to produce the pre-catalyst (Pd-NHC-Py-Br₂). The intermediates and the pre-catalyst were characterized using ¹H and ¹³C NMR, FT-IR, and elemental analyses. The pre-catalyst was used to mediate the synthesis of 4-biphenylacetic acid (Felbinac acid) and 4-biphenylacetate (Felbinac ester) from the coupling reaction of Ethyl-4-bromophenyl acetate with phenylboronic acid. The Pd-NHC-Py-Br2 pre-catalyst demonstrated excellent air and moisture stability.