Design and scale-up of an alkylated Minisci reaction to produce ethionamide with 4-cyanopyridine as raw materials

Tuberculosis is a serious bacterial infection in developing countries, especially in areas with drug resistance. The development of the anti-tuberculosis drug ethionamide (ETA) is therefore particularly important. We have designed a new route for ETA synthesis and considered the drug's amenability to large-scale manufacture. We evaluated different routes for the synthesis of ETA and selected the most suitable process for the industrial production of this material, which involved the Minisci reaction of 4-cyanopyridine with propionic acid using a AgNO 3 /(NH 4 ) 2 S 2 O 8 catalyst system under acidic conditions. The effects of different parameters on the reaction were studied, and the production of the intermediate of 2-ethyl-4-cyanopyridine was twice recrystallized from methanol to obtain pure ETA. In the Minisci reaction, the system was stirred for an additional 20 min at 80 °C after the addition of ammonium persulphate solution. The subsequent formation of thioamide was conducted at 40 °C to 60 °C for 1.5 h with a 1:5:2 molar ratio of 4-cyanopyridine, propionic acid, and ammonium sulphide. The purity of the crude ETA reached 98.77  % after two recrystallization steps. This process could be scaled up on a much larger scale (1 kg), leading to the yield of alkylation reaction and overall yield of the production process as 44.06 % and 31.26 %, respectively.