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Synthesis of two potent glucocorticoid receptor agonists labeled with carbon‐14 and stable isotopes
Author(s) -
Latli Bachir,
Reeves Jonathan T.,
Tan Zhulin,
Hrapchak Matt,
Song Jinhua J.,
Busacca Carl B.,
Senanayake Chris H.
Publication year - 2015
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.3349
Subject(s) - chemistry , sonogashira coupling , diastereomer , alkyne , yield (engineering) , carbon 14 , medicinal chemistry , stereochemistry , organic chemistry , combinatorial chemistry , palladium , catalysis , materials science , physics , quantum mechanics , metallurgy
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 C 6 ]‐(1) was obtained in three steps using [ 13 C 4 ]‐(6) and trimethylsilylacetylene‐[ 13 C 2 ] in 26% yield, while [ 2 H 5 ]‐(2) was obtained by first preparing the iodopyridine [ 2 H 5 ]‐(10) in five steps. Then, Sonogashira coupling to chiral alkyne (24) and cyclization gave [ 2 H 5 ]‐(2) in 42% overall yield.