A Novel, Practical Synthesis of Estra-1,3,5(10)-triene-3,17β-dicarboxylic Acid 17-tert-Butylamide (SK&F 105656) from Estrone, via a Palladium-Catalyzed Methoxycarbonylation of a 3-Fluorosulfonate

Article abstract of DOI:10.1021/jo00101a028

The title compound was prepared in nine steps from estrone in 22percent overall yield.Each step was performed on a 50-150 gal scale and 3.5 kg of the title compound was prepared.Estrone was converted to its 3-methanesulfonate with methanesulfonyl chloride.The 17-cyanohydrin was prepared using trimethylsilyl cyanide.Dehydration with phosphorus oxychloride/pyridine followed by Pd/C-catalyzed hydrogenation gave the 17β-cyano-3-hydroxyestra-1,3,5(10),16-tetraen-3-yl methanesulfonate derivative stereoselectively.Hydrolysis with sodium hydroxide in ethylene glycol gave a 3/1 β/α mixture of 17-carboxylic acid isomers.Reaction with Vilsmeier reagent and quenching into tert-butylamine, followed by selective crystallization, yielded the desired 3-hydroxyestra-1,3,5(10)-triene-17β-carboxylic acid tert-butylamide.Reaction with fluorosulfonic anhydride yielded the 3-fluorosulfonate.Palladium-catalyzed carbonylation in the presence of methanol gave the 3-carboxylic acid methyl ester, which was saponified to yield SK&F 105656.