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Synthesis of deleobuvir, a potent hepatitis C virus polymerase inhibitor, and its major metabolites labeled with carbon‐13 and carbon‐14
Author(s) -
Latli Bachir,
Hrapchak Matt,
Chevliakov Maxim,
Li Guisheng,
Campbell Scot,
Busacca Carl A.,
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.3294
Subject(s) - chemistry , stereochemistry , indole test , aniline , organic chemistry
Deleobuvir, (2 E )‐3‐(2‐{1‐[2‐(5‐bromopyrimidin‐2‐yl)‐3‐cyclopentyl‐1‐methyl‐1 H ‐indole‐6‐carboxamido]cyclobutyl}‐1‐methyl‐1 H ‐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 C 6 was the starting material to prepare butyl ( E )‐3‐(3‐methylamino‐4‐nitrophenyl‐ 13 C 6 )acrylate [ 13 C 6 ]‐(11) in six steps. This intermediate was then used to obtain [ 13 C 6 ]‐(1) and [ 13 C 6 ]‐(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 C 6 ]‐(3), [ 13 C 6 ]‐(4) and [ 14 C]‐(3) were synthesized in three steps from the acids [ 13 C 6 ]‐(1), [ 13 C 6 ]‐(2) and [ 14 C]‐(1) using known procedures.