ABSTRACT
ABBV-168 is a dihalogenated nucleotide under investigation for the treatment of hepatitis C virus. Three synthetic routes aimed at achieving the stereoselective installation of the C2' gem-Br,F substitution and subsequent Vorbruggen glycosylation were explored to prepare the penultimate nucleoside intermediate. Development culminated in a route to ABBV-168 featuring a de novo chromatography-free furanose synthesis, protecting group-directed Vorbruggen glycosylation, and highly selective phosphoramidation to furnish the API.
Subject(s)
Antiviral Agents/pharmacology , Hepacivirus/drug effects , Hepatitis C/drug therapy , Nucleotides/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Humans , Microbial Sensitivity Tests , Molecular Conformation , Nucleotides/chemical synthesis , Nucleotides/chemistryABSTRACT
A five-step synthesis of a TRPV1 receptor antagonist 1 is described. The key step involves a novel palladium-catalyzed amidation reaction of 4-chloro-1-methylindazole 8 with the benzyl urea 9 to form the unsymmetrically substituted urea 1.
Subject(s)
Analgesics/chemical synthesis , Palladium/chemistry , TRPV Cation Channels/antagonists & inhibitors , Urea/chemical synthesis , Amides/chemistry , Analgesics/chemistry , Analgesics/pharmacology , Benzyl Compounds/chemistry , Catalysis , Indazoles/chemistry , Magnetic Resonance Spectroscopy , Urea/analogs & derivatives , Urea/chemistry , Urea/pharmacologyABSTRACT
A general and practical method for the preparation of unsymmetrically substituted ureas has been developed utilizing palladium-catalyzed amidation. Both aryl bromides and chlorides, as well as heteroaryl chlorides, have been coupled to aryl, benzyl, and aliphatic ureas by using a novel nonproprietary bipyrazole ligand (bippyphos).
Subject(s)
Palladium/chemistry , Urea/analogs & derivatives , Urea/chemical synthesis , Catalysis , Combinatorial Chemistry Techniques , Molecular Structure , Urea/chemistryABSTRACT
A new practical method for the asymmetric Michael addition of arylboronic acids to alpha,beta-unsaturated carbonyl compounds utilizing in situ generated chiral rhodium-binap-based catalyst has been developed to address the unavailability of the preformed catalysts. While maintaining high levels of enantioselectivity reported for the preformed catalysts, the new method provides a convenient access to either enantiomeric form of the product and allows for a substantial reductions in both the boronic acid and the catalyst loads.
Subject(s)
Boronic Acids/chemistry , Ketones/chemistry , Rhodium/chemistry , CatalysisABSTRACT
The reaction of o-fluorobenzaldehydes and their O-methyloximes with hydrazine has been developed as a new practical synthesis of indazoles. Utilization of the methyloxime derivatives of benzaldehydes (in the form of the major E-isomers) in this condensation effectively eliminated a competitive Wolf-Kishner reduction to fluorotoluenes, which was observed in the direct preparations of indazoles from aldehydes. Reaction of Z-isomers of methyloximes with hydrazine resulted in the formation of 3-aminoindazoles via a benzonitrile intermediate.
Subject(s)
Indazoles/chemical synthesisABSTRACT
Trialkyltin and trialkyllead amides react directly and remarkably easily with 1,3,5,7-tetranitrocubane to form mono- to tetrakis(trialkyltin)- and -(trialkyllead) tetranitrocubanes. These are all stable compounds. The X-ray crystallographic properties of some are given. The (trialkylstannyl)cubanes react with electrophiles such as bromine with unexpected cleavage of alkyltin bonds rather than cubyl-tin bonds. On the other hand, the (trialkylplumbyl)cubanes do ultimately undergo cubyl-lead bond cleavage. This provides a useful way to achieve substitution on the cubane nucleus and provides access to compounds such as 1,3,5,7-tetrabromo-2,4,6,8-tetranitrocubane. The lead derivatives of tetranitrocubane are also useful for making 1,2,3,5,7-pentanitrocubane and 1,2,3,4,5,7-hexanitrocubane.
