Risk Assessment and Safety Evaluation Study for Ozonolysis of β-Pinene: Raw Material of a Novel Prostaglandin D₂ Receptor Antagonist S-5751

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.

A New Paradigm in Oxidative Cleavage Reaction: The Use of Continuous Reactors To Enable Safe Scale Up of Ozonolysis

“…During the ozone addition reaction in the RC1 (Figure 5), the observed total heat evolution was -381 kJ/mol with adiabatic temperature rise of 187°C in excellent agreement with previous studies that measured adiabatic temperature (186°C and 170°C) (18,20) for the similar molecules β-pinene 1 and allylic 7 alcohol ozonolysis addition, respectively. Furthermore, the results are also in agreement with the heat predicted by computational modeling carried out by the author (-445 kJ/mol).…”

“…The latter results from computational chemistry are also in good agreement with the experimental calorimetric results from Pfizer (Scheme 3) where the measured heat of reaction of ozone addition was 535 kJ/mol (18). These predictions are also in good agreement with the calorimetric measurement of β-pinene ozonolysis (Scheme 1) where the heat of ozone addition is 499 kJ/mol (20).…”

“…Indeed, a safety evaluation (20) of the β-pinene ozonide reaction mixture (Scheme 1) showed a severe and fast self-decomposition with an onset temperature 48°C. In another safety evaluation of the ozonolysis of a terminal alkene substrate similar to β-pinene 1, the DSC of an ozonized reaction mixture of tertiary allylic alcohol 7 to form hydroperoxide 8 by Ragan and co-workers (Scheme 3) showed an exothermic event at 45°C (18).…”

A Mild One-Pot Conversion of Alkenes into Amines through Tandem Ozonolysis and Reductive Amination

“…10 H) (d,J = 6.3 Hz,3 H). 13 C NMR: δ = 142.3,140.1,128.7,128.5,128.4,128.3,126.2,125.7,55.4,48.5,38.7,36.6,32.3,20.3.…”

“…6, 128.4, 128.3, 125.7, 67.5, 58.4, 48.7, 35.3, 32.8, 13.9. (d,J = 6.3 Hz,3 H). 13 C NMR: δ = 147.6,142.0,129.3,128.5,128.4,125.9,116.9,113.2,47.9,38.8,32.5,20.9.…”