Chiral alpha-halo ketones derived from N-protected amino acids are key building blocks for the synthesis of HIV protease inhibitors such as atazanavir used in HAART combination therapy.
Kappe and De Souza have reported a continuous flow through route to these intermediates which utilises a tube-in-tube reactor to introduce diazomethane generated on demand into the reaction stream containing mixed anhydride derivatives of N-protected amino acids. The resulting alpha-diazo ketones are then decomposed with HCl or HBr to afford the corresponding alpha-halo ketones.
This process allows the safe generation, separation and use of diazomethane in a continuous integrated multi-step synthesis of important API intermediates.
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).