A Practical Synthesis of the Dual Matrix Metalloprotease/Tumor Necrosis Factor Inhibitor MMP090

Abstract

A practical 9-step synthesis of the dual matrix metalloprotease/tumor necrosis factor inhibitor MMP090, trans-(R)-[[N-(4-ethoxyphenylsulfonyl)-N-(4-pyridinylmethyl)]amino]-N-hydroxy-4-propoxy cyclohexaneacetamide 10, was accomplished in 12% overall yield from d-4-hydroxyphenylglycine. Highlights include: (1) selective hydrogenation of d-hydroxyphenylglycine to afford predominantly the trans isomer without racemization; (2) virtually complete removal of the undesired cis diastereoisomer by fractional recrystallization of a TBS ether derivative of the functionalized cyclohexylglycine; (3) direct conversion of the TBS ether into the n-propyl ether in the presence of a catalytic amount of bismuth bromide in high yield; and (4) conversion of the carboxylic acid into the hydroxamic acid using an aqueous solution of hydroxylamine.