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Synthesis of [H-3], [C-13(3), N-15], and [C-14]SCH 900567
An inhibitor of TNF-alpha (tumor necrosis factor alpha) converting enzyme (TACE)
Ren, S., Hesk, D., McNamara, P., Koharski, D., & Borges, S. (2014). Synthesis of [H-3], [C-13(3), N-15], and [C-14]SCH 900567: An inhibitor of TNF-alpha (tumor necrosis factor alpha) converting enzyme (TACE). Journal of Labelled Compounds and Radiopharmaceuticals, 57(11), 632-636. https://doi.org/10.1002/jlcr.3229
SCH 900567 is a specific inhibitor of tumor necrosis factor-alpha converting enzyme and is a potential candidate for the treatment of rheumatoid arthritis. [H-3]SCH 900567 was synthesized to support the initial drug metabolism and pharmacokinetics studies. Stable isotope-labeled [C-13(3), N-15]SCH 900567 was requested by the bioanalytical group as an internal standard for Liquid chromatography-tandem mass spectrometry (LC-MS/MS) method development as well as by the drug metabolism and pharmacokinetics group for a potential microdose study. [C-13(3), N-15]SCH 900567 is synthesized via a linear sequence of seven steps from commercially available materials in 2.6% overall yield. [C-14]SCH 900567 was needed for a quantitative whole body autoradiography studies and was prepared from unlabeled Active Pharmaceutical Ingredient (API) via hydrolysis of the hydantoin moiety followed by rebuilding the hydantoin ring using potassium [C-14]cyanate to give the desired product in 42.8% overall yield. Activation of the hydantoin moiety of SCH 900567 to achieve hydrolysis followed by derivatization of the resulting amino acid to avoid decarboxylation during cyclization is also discussed.
