Continuous flow synthesis of α-halo ketones: essential building blocks of antiretroviral agents.
The development of a continuous flow process for the multistep synthesis of α-halo ketones starting from N-protected amino acids is described. The obtained α-halo ketones are chiral building blocks for the synthesis of HIV protease inhibitors, such as atazanavir and darunavir. The synthesis starts with the formation of a mixed anhydride in a first tubular reactor. The anhydride is subsequently combined with anhydrous diazomethane in a tube-in-tube reactor. The tube-in-tube reactor consists of an inner tube, made from a gas-permeable, hydrophobic material, enclosed in a thick-walled, impermeable outer tube. Diazomethane is generated in the inner tube in an aqueous medium, and anhydrous diazomethane subsequently diffuses through the permeable membrane into the outer chamber. The α-diazo ketone is produced from the mixed anhydride and diazomethane in the outer chamber, and the resulting diazo ketone is finally converted to the halo ketone with anhydrous ethereal hydrogen halide. This method eliminates the need to store, transport, or handle diazomethane and produces α-halo ketone building blocks in a multistep system without racemization in excellent yields. A fully continuous process allowed the synthesis of 1.84 g of α-chloro ketone from the respective N-protected amino acid within ~4.5 h (87% yield).
Institute of Chemistry, University of Graz , Heinrichstrasse 28, A-8010 Graz, Austria.
Vagner D
VD
Pinho
Bernhard
B
Gutmann
Leandro S M
LS
Miranda
Rodrigo O M A
RO
de Souza
C Oliver
CO
Kappe
D000596:Amino Acids / Q000737:chemistry*; D000812:Anhydrides / Q000737:chemistry*; D044966:Anti-Retroviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D003978:Diazomethane / Q000138:chemical synthesis* / Q000737:chemistry; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006846:Hydrocarbons, Halogenated / Q000138:chemical synthesis* / Q000737:chemistry; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure
D000596:Amino Acids; D000812:Anhydrides; D044966:Anti-Retroviral Agents; D017320:HIV Protease Inhibitors; D006846:Hydrocarbons, Halogenated; D007659:Ketones; D003978:Diazomethane