Abstract
Hazards evaluation of chemical reaction processes plays an important role in the prevention of serious incidents during scale-up. In this study, a hazards evaluation of the synthetic process for 6-benzyloxyindole is described.
First the synthesis of 4-benzyloxy-2-nitropyrrolidinostyrene intermediate, which has a potential exothermic decomposition hazard, was evaluated. Using the results of the reaction calorimetry data, the details of a reaction mechanism were clarified. The issue of a safety temperature margin was solved by the extension of the reaction time and elimination of the concentration.
Secondly, the synthesis of 6-benzyloxyindole was evaluated. The original procedure was a reduction process using hydrazine and Raney Ni. The result of a reaction calorimetry study indicated that the reaction was very exothermic, with significant heat accumulation after the addition of hydrazine. This procedure had a potential hazard of exceeding the boiling point of the solvent resulting in a runaway reaction. Therefore, an alternative procedure was employed using hydrogen gas under catalytic conditions. The results of the reaction calorimetry study, indicated that the heat flow of the alternative procedure could be controlled by the addition rate of hydrogen gas and agitation speed. For the kinetic evaluation, on-line spectroscopic FT-IR monitoring of both chemical processes was also demonstrated and compared with the two procedures. Both the formation of intermediates and overall reaction behavior were detected through the FT-IR. The two reaction procedures mentioned above showed different kinetic profile of these intermediates formation. The exothermic behavior of both procedures could be attributed to the different rates of formation of these intermediates during the course of reactions.
