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Synthesis of [ 3 H], [ 13 C 3 , 15 N], and [ 14 C]SCH 900567: an inhibitor of TNF‐ α (tumor necrosis factor alpha) converting enzyme (TACE)
Author(s) -
Ren Sumei,
Hesk David,
McNamara Paul,
Koharski David,
Borges Scott
Publication year - 2014
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/jlcr.3229
Subject(s) - chemistry , hydantoin , moiety , racemization , derivatization , stereochemistry , high performance liquid chromatography , chromatography , organic chemistry
SCH 900567 is a specific inhibitor of tumor necrosis factor‐alpha converting enzyme and is a potential candidate for the treatment of rheumatoid arthritis. [ 3 H]SCH 900567 was synthesized to support the initial drug metabolism and pharmacokinetics studies. Stable isotope‐labeled [ 13 C 3 , 15 N]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. [ 13 C 3 , 15 N]SCH 900567 is synthesized via a linear sequence of seven steps from commercially available materials in 2.6% overall yield. [ 14 C]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 [ 14 C]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.