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- Title
Synthesis of two potent glucocorticoid receptor agonists labeled with carbon-14 and stable isotopes.
- Authors
Latli, Bachir; Reeves, Jonathan T.; Tan, Zhulin; Hrapchak, Matt; Song, Jinhua J.; Busacca, Carl B.; Senanayake, Chris H.
- Abstract
Two potent glucocorticoid receptor agonists were prepared labeled with carbon-14 and with stable isotopes to perform drug metabolism, pharmacokinetics, and bioanalytical studies. Carbon-14 labeled (1) was obtained from an enantiopure alkyne (5) via a Sonogashira coupling to a previously reported 5-amino-4-iodo-[2-14C]pyrimidine [14C]-(6), followed by a base-mediated cyclization (1) in 72% overall radiochemical yield. Carbon-14 labeled (2) was prepared in five steps employing a key benzoic acid intermediate [14C]-(13), which was synthesized in one pot from enolization of trifluoromethylketone (12), followed by bromine-magnesium exchange and then electrophile trapping reaction with [14C]-carbon dioxide. A chiral auxiliary ( S)-1-(4-methoxyphenyl)ethylamine was then coupled to this acid to give [14C]-(15). Propargylation and separation of diastereoisomers by crystallizations gave the desired diastereomer [14C]-(17) in 34% yield. Sonogashira coupling to iodopyridine (10) followed by cyclization to the azaindole [14C]-(18) and finally removal of the chiral auxiliary gave [14C]-(2) in 7% overall yield. For stable isotope syntheses, [13C6]-(1) was obtained in three steps using [13C4]-(6) and trimethylsilylacetylene-[13C2] in 26% yield, while [2H5]-(2) was obtained by first preparing the iodopyridine [2H5]-(10) in five steps. Then, Sonogashira coupling to chiral alkyne (24) and cyclization gave [2H5]-(2) in 42% overall yield.
- Subjects
GLUCOCORTICOID receptors; CARBON; ISOTOPES; BENZOIC acid; SONOGASHIRA reaction
- Publication
Journal of Labelled Compounds & Radiopharmaceuticals, 2015, Vol 58, Issue 11/12, p445
- ISSN
0362-4803
- Publication type
Article
- DOI
10.1002/jlcr.3349