Synthesis of deleobuvir, a potent hepatitis C virus polymerase inhibitor, and its major metabolites labeled with carbon-13 and carbon-14
| Autor: | Chris H. Senanayake, Carl A. Busacca, Scot Campbell, Bachir Latli, Matt Hrapchak, Maxim Chevliakov, Guisheng Li |
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| Rok vydání: | 2015 |
| Předmět: |
chemistry.chemical_classification
Acrylate Double bond Chemistry Stereochemistry Hepatitis C virus Metabolite Organic Chemistry Carbon-13 Deleobuvir medicine.disease_cause Biochemistry Ns5b polymerase Analytical Chemistry chemistry.chemical_compound Drug Discovery medicine Radiology Nuclear Medicine and imaging Carbon-14 Spectroscopy |
| Zdroj: | Journal of Labelled Compounds and Radiopharmaceuticals. 58:250-260 |
| ISSN: | 0362-4803 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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