title: Synthesis of two potent glucocorticoid receptor agonists labeled with carbon-14 and stable isotopes.
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.
authors.affiliation: Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT, USA.
authors.forename: Bachir
authors.initials: B
authors.lastname: Latli
authors.affiliation: Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT, USA.
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: Reeves
authors.affiliation: Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT, USA.
authors.forename: Zhulin
authors.initials: Z
authors.lastname: Tan
authors.affiliation: Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Hrapchak
authors.affiliation: Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT, USA.
authors.forename: Jinhua J
authors.initials: JJ
authors.lastname: Song
authors.affiliation: Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT, USA.
authors.forename: Carl B
authors.initials: CB
authors.lastname: Busacca
authors.affiliation: Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT, USA.
authors.forename: Chris H
authors.initials: CH
authors.lastname: Senanayake
mesh_terms: D002250:Carbon Radioisotopes / Q000737:chemistry*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis*; D011965:Receptors, Glucocorticoid / Q000819:agonists*
chemical_list: D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; D011965:Receptors, Glucocorticoid
keywords: carbon-13; carbon-14; deuterium; glucocorticoid mimics; radiosynthesis