Synthesis of two potent glucocorticoid receptor agonists labeled with carbon‐14 and stable isotopes. (22nd September 2015)

• Record Type: Journal Article
• Authors: Latli, Bachir; Reeves, Jonathan T.; Tan, Zhulin; Hrapchak, Matt; Song, Jinhua J.; Busacca, Carl B.; Senanayake, Chris H.
• Is Part Of: Journal of labelled compounds & radiopharmaceuticals. Volume 58:Number 11/12(2015)
• Page Start: 445
• Page End: 452
• Publication Date: 2015-09-22
• Subjects: glucocorticoid mimics -- radiosynthesis -- carbon‐14 -- carbon‐13 -- deuterium; Tracers (Chemistry) -- Periodicals; Radiopharmaceuticals -- Periodicals; 615.8424
• DOI: 10.1002/jlcr.3349
• Languages: English
• ISSNs: 0362-4803

Abstract

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‐ 14 C]pyrimidine [ 14 C]‐(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 [ 14 C]‐(13), which was synthesized in one pot from enolization of trifluoromethylketone (12), followed by bromine–magnesium exchange and then electrophile trapping reaction with [ 14 C]‐carbon dioxide. A chiral auxiliary ( S )‐1‐(4‐methoxyphenyl)ethylamine was then coupled to this acid to give [ 14 C]‐(15). Propargylation and separation of diastereoisomers by crystallizations gave the desired diastereomer [ 14 C]‐(17) in 34% yield. Sonogashira coupling to iodopyridine (10) followed by cyclization to the azaindole [ 14 C]‐(18) and finally removal of the chiral auxiliary gave [ 14 C]‐(2) in 7% overall yield. For stable isotope syntheses, [ 13 C6 ]‐(1) was obtained in three steps using [ 13 C4 ]‐(6) and trimethylsilylacetylene‐[ 13 C2 ] in 26% yield, while [ 2 H5 ]‐(2) was obtained by first preparing the iodopyridine [ 2 H5 ]‐(10) in five steps. Then, Sonogashira coupling to chiral alkyne (24) and cyclization gave [ 2 H5 ]‐(2) in 42% overall yield. Abstract : The detailed descriptions of the syntheses of two potent glucocorticoid mimics (1 ) and (2 ) labeled with carbon‐14, carbon‐13, and deuterium are presented.