title: 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.
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.
authors.affiliation: Product Development and ‡HCV Discovery Performance Unit, GlaxoSmithKline , 5 Moore Drive, Research Triangle Park, North Carolina 27709, United States.
authors.forename: Roy K
authors.initials: RK
authors.lastname: Bowman
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Brown
authors.forename: Jannine H
authors.initials: JH
authors.lastname: Cobb
authors.forename: John F
authors.initials: JF
authors.lastname: Eaddy
authors.forename: Mark A
authors.initials: MA
authors.lastname: Hatcher
authors.forename: Martin R
authors.initials: MR
authors.lastname: Leivers
authors.forename: John F
authors.initials: JF
authors.lastname: Miller
authors.forename: Mark B
authors.initials: MB
authors.lastname: Mitchell
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Patterson
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Toczko
authors.forename: Shiping
authors.initials: S
authors.lastname: Xie
mesh_terms: D000447:Aldehydes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001729:Bismuth / Q000737:chemistry; D002244:Carbon / Q000737:chemistry; D002384:Catalysis; D004305:Dose-Response Relationship, Drug; D004952:Esters / Q000737:chemistry*; D016174:Hepacivirus / Q000187:drug effects*; D006878:Hydroxides / Q000737:chemistry; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016651:Lithium Carbonate / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010984:Platinum / Q000737:chemistry; D017680:Potassium Compounds / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000447:Aldehydes; D000998:Antiviral Agents; D004952:Esters; D006878:Hydroxides; D007093:Imidazoles; D017680:Potassium Compounds; D011355:Prodrugs; C000592218:imidazole-4,5-dicarbaldehyde; D016651:Lithium Carbonate; D010984:Platinum; D002244:Carbon; D001729:Bismuth; C029943:potassium hydroxide