No abstract

Safety evaluation for ozonolysis of β-pinene was conducted using DSC, ARC, and RC1e. ARC measurement showed that the concentration of the ozonized mixture affects its thermal stability. The sample at a high concentration of 1.83 mol/L was very unstable even at room temperature and decomposed rapidly. ADT24 of the diluted sample of 0.73 mol/L was 28.2 °C. Although reductive decomposition of the ozonized mixture at extremely low temperature is very dangerous because of accumulation of the heat of reaction, its process temperature was validated to not exceed the ADT24. As a result, pilot manufacturing on a 300-L reactor scale could be achieved.

Novel alcohol oxidation using a Na2WO4−H2O2 system was applied to manufacture 12α-hydroxy-3-oxooleanano-28,13-lactone which is a key intermediate of S-0139. Oxidation of the hydroxyl group of oleanolic acid was optimized based on the design of experiment (DoE) approach. Statistical analysis was used to maximize the yield of the corresponding ketone and minimize the generation of byproducts. The safety evaluation of this oxidation was also conducted in detail, and pilot manufacturing was achieved.