- 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
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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.
- McGuire, Michael A.,Sorenson, Edmund,Owings, Franklin W.,Resnick, Theodore M.,Fox, Margaret,Baine, Neil H.
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- 3-Carboxy-20-keto steroids are dual uncompetitive inhibitors of human steroid 5α-reductase types 1 and 2
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Steroidal 3-carboxy-20-ketones have been prepared within two structural series, the androsta-3,5-dienes and the estra 1,3,5-trienes, as potential inhibitors of types 1 and 2 steroid 5α-reductase, the enzyme activity responsible for the final step in biosynthesis of dihydrotestosterone. These compounds are shown to be potent uncompetitive inhibitors of both human recombinant enzyme activities, defining a novel class of dual steroid 5α-reductase inhibitors.
- Yamashita, Dennis S.,Holt, Dennis A.,Oh, Hye-Ja,Shah, Dinu,Yen, Hwa-Kwo,Brandt, Martin,Levy, Mark A.
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p. 1481 - 1485
(2007/10/03)
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- Steroidal A ring aryl carboxylic acids: A new class of steroid 5α-reductase inhibitors
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A series of 17β-carbamoyl-1,3,5(10)-estratriene-3-carboxylic acids has been prepared and evaluated in vitro as inhibitors of human and rat prostatic steroid 5α-reductase (EC 1.3.1.30). Potent inhibition of the human enzyme, in particular, was observed and preliminary studies using rat enzyme suggest that the inhibition results from the formation of an enzyme-NADP+-inhibitor complex. The compounds were synthesized from estrone, generally employing a differentiated bis-triflate carbonylation strategy.
- Holt,Levy,Ladd,Oh,Erb,Heaslip,Brandt,Metcalf
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p. 937 - 942
(2007/10/02)
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