Transition-metal catalyzed synthesis of ketoprofen

Transition metal-catalyzed reactions including carbonylations, hydrovinylat ions and hydrogenations have been applied in the synthesis of alpha-(3-benz oylphenyl)propanoic acid (Ketoprofen). 3-Vinylbenzophenone was obtained fro m 3-bromobenzophenone by a Pd-catalyzed Heck coupling reaction. Pd-catalyze d carbonylation of this olefin gave the isopropyl alpha-(3-benzoylphenyl) p ropionate in high yield (95%) and with high regioselectivity (>99.5%). Keto profen was obtained in 90% yield by hydrolysis of the isopropyl ester. It w as also obtained in two steps from 3-vinylbenzophenone by a Ni-catalyzed hy drovinylation selectively affording 3-(3'-benzoylphenyl)-1-butene, followed by an oxidation. 3-Ethynylbenzophenone was obtained from 3-bromobenzopheno ne by Pd-catalyzed coupling reaction. By means of a Pd-catalyzed carbonylat ion, this alkyne was converted regioselectively (97%) into methyl alpha-(3- benzoylphenyl) acrylate (93% yield). Hydrolysis of the ester afforded the a lpha-(3-benzoylphenyl)acrylic acid. Asymmetric hydrogenation of this acid t o give (S)-ketoprofen in 95% optical yield was achieved using a chiral Ru-( S)-BINAP catalyst.