Synthesis of HCV replicase inhibitors: base-catalyzed synthesis of protected α-hydrazino esters and selective aerobic oxidation with catalytic Pt/Bi/C for synthesis of imidazole-4,5-dicarbaldehyde

Roy K Bowman; Andrew D Brown; Jannine H Cobb; John F Eaddy; Mark A Hatcher; Martin R Leivers; John F Miller; Mark B Mitchell; Daniel E Patterson; Matthew A Toczko; Shiping Xie

doi:10.1021/jo4014595

Synthesis of HCV replicase inhibitors: base-catalyzed synthesis of protected α-hydrazino esters and selective aerobic oxidation with catalytic Pt/Bi/C for synthesis of imidazole-4,5-dicarbaldehyde

J Org Chem. 2013 Dec 6;78(23):11680-90. doi: 10.1021/jo4014595. Epub 2013 Nov 13.

Authors

Roy K Bowman¹, Andrew D Brown, Jannine H Cobb, John F Eaddy, Mark A Hatcher, Martin R Leivers, John F Miller, Mark B Mitchell, Daniel E Patterson, Matthew A Toczko, Shiping Xie

Affiliation

¹ Product Development and ‡HCV Discovery Performance Unit, GlaxoSmithKline , 5 Moore Drive, Research Triangle Park, North Carolina 27709, United States.

PMID: 24171666
DOI: 10.1021/jo4014595

Abstract

A robust convergent synthesis of the prodrugs of HCV replicase inhibitors 1-5 is described. The central 5H-imidazo[4,5-d]pyridazine core was formed from acid-catalyzed cyclocondensation of an imidazole-4,5-dicarbaldehyde (20) and a α-hydrazino ester, generated in situ from the bis-BOC-protected precursors 25 and 33. The acidic conditions not only released the otherwise unstable α-hydrazino esters but also were the key to avoid facile decarboxylation to the parent drugs from the carboxylic ester prodrugs 1-5. The bis-BOC α-hydrazino esters 25 and 33 were prepared by addition of ester enolates (from 23 and 32) to di-tert-butyl azodicarboxylate via catalysis with mild inorganic bases, such as Li2CO3. A selective aerobic oxidation with catalytic 5% Pt-Bi/C in aqueous KOH was developed to provide the dicarbaldehyde 20 from the diol 27.

MeSH terms

Aldehydes / chemical synthesis
Aldehydes / chemistry
Aldehydes / pharmacology*
Antiviral Agents / chemical synthesis
Antiviral Agents / chemistry
Antiviral Agents / pharmacology*
Bismuth / chemistry
Carbon / chemistry
Catalysis
Dose-Response Relationship, Drug
Esters / chemistry*
Hepacivirus / drug effects*
Hydroxides / chemistry
Imidazoles / chemical synthesis
Imidazoles / chemistry
Imidazoles / pharmacology*
Lithium Carbonate / chemistry
Microbial Sensitivity Tests
Molecular Structure
Oxidation-Reduction
Platinum / chemistry
Potassium Compounds / chemistry
Prodrugs / chemical synthesis
Prodrugs / chemistry
Prodrugs / pharmacology*
Structure-Activity Relationship
Virus Replication / drug effects*

Substances

Aldehydes
Antiviral Agents
Esters
Hydroxides
Imidazoles
Potassium Compounds
Prodrugs
imidazole-4,5-dicarbaldehyde
Lithium Carbonate
Platinum
Carbon
Bismuth
potassium hydroxide