title: Synthesis of deleobuvir, a potent hepatitis C virus polymerase inhibitor, and its major metabolites labeled with carbon-13 and carbon-14.
abstract: Deleobuvir, (2E)-3-(2-{1-[2-(5-bromopyrimidin-2-yl)-3-cyclopentyl-1-methyl-1H-indole-6-carboxamido]cyclobutyl}-1-methyl-1H-benzimidazol-6-yl)prop-2-enoic acid (1), is a non-nucleoside, potent, and selective inhibitor of hepatitis C virus NS5B polymerase. Herein, we describe the detailed synthesis of this compound labeled with carbon-13 and carbon-14. The synthesis of its three major metabolites, namely, the reduced double bond metabolite (2) and the acyl glucuronide derivatives of (1) and (2), is also reported. Aniline-(13) C6 was the starting material to prepare butyl (E)-3-(3-methylamino-4-nitrophenyl-(13) C6 )acrylate [(13) C6 ]-(11) in six steps. This intermediate was then used to obtain [(13) C6 ]-(1) and [(13) C6 ]-(2) in five and four more steps, respectively. For the radioactive synthesis, potassium cyanide-(14) C was used to prepare 1-cylobutylaminoacid [(14) C]-(23) via Buchrer-Bergs reaction. The carbonyl chloride of this acid was then used to access both [(14) C]-(1) and [(14) C]-(2) in four steps. The acyl glucuronide derivatives [(13) C6 ]-(3), [(13) C6 ]-(4) and [(14) C]-(3) were synthesized in three steps from the acids [(13) C6 ]-(1), [(13) C6 ]-(2) and [(14) C]-(1) using known procedures.
authors.affiliation: Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT, 06877-0368, USA.
authors.forename: Bachir
authors.initials: B
authors.lastname: Latli
authors.affiliation: Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT, 06877-0368, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Hrapchak
authors.affiliation: Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT, 06877-0368, USA.
authors.forename: Maxim
authors.initials: M
authors.lastname: Chevliakov
authors.affiliation: Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT, 06877-0368, USA.
authors.forename: Guisheng
authors.initials: G
authors.lastname: Li
authors.affiliation: Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT, 06877-0368, USA.
authors.forename: Scot
authors.initials: S
authors.lastname: Campbell
authors.affiliation: Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT, 06877-0368, USA.
authors.forename: Carl A
authors.initials: CA
authors.lastname: Busacca
authors.affiliation: Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT, 06877-0368, USA.
authors.forename: Chris H
authors.initials: CH
authors.lastname: Senanayake
mesh_terms: D000179:Acrylates / Q000138:chemical synthesis*; D000998:Antiviral Agents / Q000138:chemical synthesis*; D001562:Benzimidazoles / Q000138:chemical synthesis*; D002250:Carbon Radioisotopes / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis*
chemical_list: D000179:Acrylates; D000998:Antiviral Agents; D001562:Benzimidazoles; D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D019275:Radiopharmaceuticals; C000592437:deleobuvir
keywords: NS5B polymerase; acyl glucoronide; carbon-13; carbon-14; deleobuvir; metabolites