Abstract

Development of a Sustainable Phase Transfer Catalysed Continuous Process for a Pharmaceutical Intermediate

Soo Khean Teoh, Team Leader, Scientist II, Institute of Chemical and Engineering Sciences (ICES)

Phase Transfer Catalysis (PTC) is a long established procedure for the facilitation of reactions between two immiscible phases using quaternary ammonium salts. PTC provides environmental benefits in eliminating, reducing or replacement of environmentally incompatible dipolar aprotic solvent such as DMF, DMSO and THF. It could replace/eliminate stronger and/or highly toxic bases (NaH, organic base), increase yield/selectivity/conversion and hence reduce waste produced. We evaluate the synergetic environmental advantages of operating PTC in a continuous flow system.From batch process development of O-allylation of 3-phenyl-1-propanol with allyl bromide, an effective amount of PTC accelerates the reaction by about 8 fold at room temperature. In the absence of PTC, the reaction temperature has to be elevated to achieve the required reaction rate and conversion. Using NaOH solution (50% w/w) instead of NaOH pellets, the reaction could perform as well (95% conversion in 1 hour with 97% product purity by GC) without the need of solvent and this also facilitates flow processing. The reaction has been demonstrated at scale both batch wise (˜ 2 liter) and continuously (˜ 3 liter/hour). In the continuous process, the reaction is operated counter-currently in a liquid-liquid extractor. The reaction is robust and takes about 100 mins to reach its steady state with a comparable reaction conversion to the batch process. The synergetic sustainability benefits of operating phase transfer catalyzed process in a continuous flow system are being compared to the traditional batch process from reaction to work-up.