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.

Recent developments in heterocycle labeling with carbon isotopes

“…For its labeled version, Latli and coworkers decided to insert the radiocarbon tag on the SCHEME 14 General approach to the synthesis of carbon-14 AZD5122 SCHEME 15 Synthesis of carbon-14labeled α7 receptor agonist SCHEME 16 Synthesis of carbon-14labeled Traut's reagent benzoimidazole moiety. 54 The t-butyl cinnamate derivative 44 was reacted in the presence of acid chloride In 2015, the same authors described the carbon-14 radio synthesis of compound [ 14 C]-55, a potent IκB kinase-β (IKK-β) inhibitor. Interestingly, the thienopyridine heterocycle is largely present in different classed of compounds, with a broad recognized activity as hepatitis C virus inhibitors, allosteric modulator of M4 muscarinic receptor, and inhibitors of NMDA receptors.…”

“…Its structure features 2 bicyclic heterocycles: a benzo‐imidazole and an indole, connected to each other by a peculiar methylen‐cyclobutan amide spacer. For its labeled version, Latli and coworkers decided to insert the radiocarbon tag on the benzoimidazole moiety . The t ‐butyl cinnamate derivative 44 was reacted in the presence of acid chloride [ 14 C]‐ 49 affording the key labeled intermediate [ 14 C]‐ 45 , a benzo [d] imidazolone which was readily coupled with the other portion of the scaffold bearing the indole derivative ( 46 ).…”