Continuous Flow Synthesis of α-Halo Ketones: Essential Building Blocks of Antiretroviral Agents

Abstract

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).

Chemical reaction engineering, process design and scale-up issues at the frontier of synthesis: Flow chemistry

“…Diazomethane has been produced in situ in the inner tube and progressively dosed in the shell thanks to a semipermeable membrane [43].…”

The route from problem to solution in multistep continuous flow synthesis of pharmaceutical compounds

“…Any excess reagent was destroyed before leaving the closed system to prevent human exposure. 49 Owing to scalability issues, photochemical and electrochemical transformations are rarely encountered in pharmaceutical manufacturing. However, miniaturization in continuous flow systems makes photo- [50][51][52][53] and electrochemical 54 reactors feasible.…”

Taming tosyl azide: the development of a scalable continuous diazo transfer process

“…The high surface-area-to-volume ratios of tubular reactors also ensures efficient removal of heat, thereby reducing the risk of reaction runaway. [45][46][47] A number of hazardous intermediates including azides, 48-53 diazonium salts, [54][55][56][57][58][59] and diazo compounds, [60][61][62][63][64][65][66][67][68][69][70][71][72] to name but a few, have all been accessed using continuous processing techniques. [45][46][47] There have been few reports of the diazo transfer process in flow, and to date these have all employed sulfonyl azides directly as reagents.…”