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Piperylene Sulfone: Fully Recyclable Diprotic Apolar Solvent for Benign Pharmaceutical Processes

Charles A. Eckert1, Charles L LIotta1, and Douglas P. Kjell2. (1) School of Chemical & Biomolecular Engineering and Specialty Separations Center, Georgia Institute of Technology, 311 Ferst Drive, NW, Atlanta, GA 30332-0100, (2) Chemical Process Research & Development, Lilly, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285

Many pharmaceutical intermediates require polar aprotic solvents for dissolution, but solvent removal and product purification can yield undesirable environmental effects. Typical reactions in polar aprotics include nucleophilic displacements, amide formation, and metal mediated couplings, and it is not unusual to need large amounts of water to isolate product from the polar aprotic either by precipitation or extraction. We have excerpted 19 patents from Organic Process Research & Development, 2008(1) and found that six of these explicitly mention a polar aprotic solvent: Four are nucleophilic displacements (one each ether formation, fluorination, alklyation, thioether formation), and two are amide formations. Of these six, two cite as solvent DMSO and four DMF.

In fact, dipolar, aprotic solvents such as DMSO and DMF are excellent for organic reactions with inorganic salts because they are inexpensive and dissolve disparate materials. But their high boiling points preclude benign separation and recycle. We report piperylene sulfone, a labile DMSO substitute, which undergoes a retro-cheletropic reaction into volatile species under modest conditions, and which can easily be collected and converted back into piperylene sulfone via a concerted reaction for re-use. This provides the opportunity for facilitating recovery and recycling of both catalyst as well as the solvent itself.

We have already investigated the use of piperylene sulfone to couple separation and solvent and catalyst recycle with many reactions. In nucleophilic substitution reactions it gives rates comparable to those in DMSO. We show TEMPO oxidations of alcohols in piperylene sulfone with higher turn over frequency than DMSO and multiple recyles. Other examples include asymmetric transfer hydrogenation in piperylene sulfone and sulfone induced in situ acid catalysis. Here we show new opportunities for this solvent in the pharmaceutical industry.