ABSTRACT
The development of an improved short and efficient commercial synthesis of the JAK2 inhibitor, a complex pyrrolopyridine, BMS-911543, is described. During the discovery and development of this synthesis, a Pd-catalyzed C-H functionalization was invented which enabled the rapid union of the key pyrrole and imidazole fragments. The synthesis of this complex, nitrogen-rich heterocycle was accomplished in only six steps (longest linear sequence) from readily available materials.
Subject(s)
Heterocyclic Compounds, 3-Ring/pharmacology , Protein Kinase Inhibitors/pharmacology , Catalysis , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemistry , Humans , Janus Kinase 2/antagonists & inhibitors , Janus Kinase 2/metabolism , Ligands , Molecular Structure , Palladium/chemistry , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistryABSTRACT
The development of a short and efficient synthesis of a complex 6-azaindole, BMS-663068, is described. Construction of the 6-azaindole core is quickly accomplished starting from a simple pyrrole, via a regioselective Friedel-Crafts acylation, Pictet-Spengler cyclization, and a radical-mediated aromatization. The synthesis leverages an unusual heterocyclic N-oxide α-bromination to functionalize a critical C-H bond, enabling a highly regioselective copper-mediated Ullmann-Goldberg-Buchwald coupling to install a challenging triazole substituent. This strategy resulted in an efficient 11 step linear synthesis of this complex clinical candidate.
Subject(s)
Anti-HIV Agents/chemical synthesis , Anti-HIV Agents/pharmacology , Aza Compounds/chemical synthesis , Aza Compounds/pharmacology , Indoles/chemical synthesis , Indoles/pharmacology , Organophosphates/chemical synthesis , Organophosphates/pharmacology , Piperazines/chemical synthesis , Piperazines/pharmacology , Virus Attachment/drug effects , Aza Compounds/chemistry , Cyclic N-Oxides/chemistry , HIV-1/drug effects , Halogenation , Humans , Indoles/chemistry , Molecular Structure , Organophosphates/chemistry , Piperazines/chemistry , Prodrugs , Pyrroles/chemistry , StereoisomerismABSTRACT
Here we report the solution-liquid-solid (SLS) synthesis of silicon (Si) nanowires. Nanowires are grown by trisilane (Si3H8) decomposition in a high boiling solvent, octacosane (C28H58) or squalane (C30H62), in the presence of either Au or Bi nanocrystals. To our knowledge, this is the first report of a colloidal synthetic route carried out in a solvent at atmospheric pressure that provides crystalline Si nanowires in large quantities.
ABSTRACT
High yields of crystalline Ge nanowires were synthesized for the first time in a conventional solvent of trioctylphosphine by disproportionating GeI2 in the presence of Bi nanoparticle growth seeds at 350 degrees C and atmospheric pressure.
