Polymer-based Solvents for Minimizing Pollution during the Synthesis of Fine Chemicals

Most processes used in the pharmaceutical industry are, by necessity, carried out in organic solvents. In many cases these solvents are volatile and sufficiently water-soluble to contaminate air emission and aqueous discharge streams, adding to the environmental burden and the cost of downstream processing and recovery operations. One example is the use of tetrahydrofuran (THF) as the solvent for Grignard reactions which must be carried out under anhydrous conditions. The desired product is often obtained by aqueous precipitation. Since THF is soluble in the water phase it must be recovered by distillation which is a very energy-intensive process. We feel that solvent replacements combined with recovery and recycling will be important in the development of benign chemical processes. For this approach to be successful it is crucial that appropriate solvation properties be attained in the replacement solvent while ensuring that the potential for environmental contaminations be minimized. Furthermore, difficult separation problems must be avoided so that more efficient recovery of solvents is facilitated. Facile synthetic methods have been developed for both low molecular weight and polymerbound derivatives of THF for use as replacement solvents for THF. We have identified one step in the synthesis of the orally active HIV-1 protease inhibitor L-735,524 as a suitable model reaction to use in the evaluation of these novel solvents. This reaction is known to be very sensitive to the solvent medium and therefore represents a critical test of our replacement solvents. Reaction kinetics, as well as possible separation schemes necessary for regeneration of the low molecular weight and polymer-bound solvents have been investigated. Both types of solvent replacement have been very successful in the replacement of THF. The low molecular weight derivatives can be carried through several reaction steps thereby avoiding costly solvent switches because of their minimal water solubility and volatility. The polymer-bound solvents, which are dissolved in a relatively benign continuous phase, can be recovered form the process stream by microfiltration and regenerated for re-use. Thus, it is envisioned that our replacement solvents can be part of an intelligent reaction/separation sequence that improves upon currently used sequences in terms of both environmental impact and productivity. Thesis Supervisors: T. Alan Hatton, Ralph Landau Professor of Chemical Engineering Practice Stephen L. Buchwald, Professor of Chemistry