The synthesis of a selective PDE4/TNFα inhibitor

Two syntheses of cis-4-cyano-4-(1-cyclohexyl-3-ethyl-1H-indazol-6-yl)cyclohexanecarboxylic acid (1), a selective PDE4/TNF alpha inhibitor are described. The first synthesis relied on a solvolysis of a tertiary benzylic alcohol to the nitrile using TMSCN and on the epimerization of an ester to its thermodynamically favored position prior to its hydrolysis. It was demonstrated that the selectivity was controlled by the rate of hydrolysis of the two diastereomeric esters. The second synthesis proved to be more efficient and used a novel nucleophilic aromatic substitution of a fluoroindazole with the anion of a tertiary nitrile. Another key element of the route was a selective Pinner reaction of a secondary nitrile in the presence of a tertiary nitrile.