Continuous-Flow Synthesis of syn-2-Amino-1,3-diol via Catalytic Hydrogenation: A Vital Intermediate of (+)-Thiamphenicol and (+)-Florfenicol

In this paper, an expeditious and efficient continuous-flow process is reported for the synthesis of syn-2-amino-1,3-diol. The starting material syn-2-nitro-1,3-diol reacts with hydrogen gas in a micro fixed-bed reactor packed with a Raney Ni catalyst to provide syn-2-amino-1,3-diol in 93% isolated yield. The reaction time in the flow system was markedly reduced (from 36 h in batch to 5 min in flow) due to enhanced mass transfer. The effects of the catalyst, solvent, reaction temperature, reaction time, pressure, and H2 flow rate have been investigated successively. The optimum conditions for the continuous-flow reaction are described as follows when using Raney Ni as a catalyst at a reaction temperature of 25 °C, a reaction pressure of 10 bar, a reaction solvent of 3% AcOH in methanol, an H2 flow rate of 25 sccm, and a liquid flow rate of 0.6 mL/min. The reaction kinetics in the temperature range of 10–40 °C were investigated. The reaction rate constants and activation energy were determined. The continuous flow system allows for an efficient hydrogenation of syn-2-nitro-1,3-diol on the hectogram scale, corresponding to an overall productivity of 73.6 g/d after continuous operation for over 240 h.