(642c) Development of a Sustainable Phase Transfer Catalysed Continuous Process for a Pharmaceutical Intermediate

Three of the major environmental problems in the pharmaceutical industry are solvent-laden waste, catalyst-containing waste and waste produced from side or by reactions. Batch processing dominates pharmaceutical and fine chemical manufacturing. Compared to continuous processing, batch processing is inherently less mass and energy efficient. Continuous flow also provides the possibility of continuous solvent recovery even if a more dilute reaction be required to maintain mobility.

Phase Transfer Catalysis (PTC) is a long established procedure for the facilitation of reactions between two immiscible phases using quaternary ammonium salts. From the perspective of green chemistry, 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 conversion and/or selectivity, and hence reduce waste produced. We evaluate the synergetic environmental advantages of operating PTC in a continuous flow system.

The model chemical system used in our investigation is the heteroatom O-allylation of 3-phenyl-1-propanol with allyl bromide. A typical chemical system reported in the literature using 2-phenylethanol was conducted in plant scale batch wise at a reaction temperature of 65-75°C using NaOH micropearls, toluene (solvent) and tetrabutylammonium hydrogen sulfate (TBAH) reacted for at least 16 hours to give the product as a toluene concentrate (approximately 95 mol% product by GC). From our batch process development on 3-phenyl-1-propanol system, 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. It was found that the model reaction could be operated at room temperature with a 0.028 mol eq. of Tetra-n-butylammonium bromide (TBAB). 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 toluene and this also facilitates flow processing.

The model 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. Sustainability metrics such as the efficiency of using chemical reagents/solvent/energy, the extent of aqueous/solids waste generation, E factor, equipment efficiency, and cost efficiency will be discussed.