Self-Optimising Multiphasic Flow Reactor & Work-up Processing

Three key elements, each with its own significant academic research challenges & questions to be answered: i) Evaluate systems for continuous separation of liquid from immiscible liquids & solids to allow the reactor to be coupled with at-line HPLC & benchtop MS & NMR, whose use might also allow real-time spectroscopic calibration with IR & UV-Vis. The separation methods will be developed to allow sequential at-line measurement (ie through semi-continuous or automated preparation of samples). This will build on existing & proven physical principles for separation including the use of extended surfaces of differing surface energies to promote separation [6]. The development of appropriate separation systems for in-line & at-line monitoring will depend on the reaction system (see iii) & will be carried out in parallel with these developments ii) Establish thermal & barometric control of the multiphasic flow reactor to allow a wider range of chemistries. This will be carried out in close collaboration with the planned PhD student to start in Jan 2016 iii) Exemplar reaction systems are highlighted below & through discussion with AZ a feasible work programme will be established to develop a hierarchical approach to developing multiphasic flow systems. There are a wide range of conditions that can be evaluated, both in terms of the chemical reactions, but also the physical forms (multiphasic) that such reactions require a) Optimisation of a variety of liquid-liquid reactions will be demonstrated. This could include exemplar reactions such as oxidation with liquid oxidants, nitration of organic molecules & biphasic cyclopropanation reactions. Rapid experimentation using automated systems will enable development of mechanistic & statistical models for facile & scalable process development. Characterisation of mass transfer coefficients will be performed for a variety of reactor configurations including both plug flow & CSTR & combinations of active & static mixers. b) A variety of exemplar liquid-liquid work-up separation systems will be evaluated, though a common aspect each requires reliable separation & sampling from both phases. This could be achieved using stacked hydrophilic/hydrophobic plates to drive separation - by using stacks of alternating laser cut components it may be able to make units that have a similar footprint to the freactor & avoid the cost associated with machining channels into layers. In addition, such devices would also allow for counter-current liquid-liquid extraction at a small scale. Excitingly, optimisation will be targeted to deliver high quality product subsequent to biphasic reaction systems. Systems will be critically evaluated & benchmarked for their operability & scalability. c) Liquid-solid systems are perhaps most common & an exemplar is the continuous crystallisation currently being evaluated in an existing AZ supported project. This has already been tested successfully in the iPRD Freactor & involves co-feeding a racemic acid & chiral base to give diastereomeric solid. In this case we would self-optimise the yield by varying solvent, stoichiometry, concentration & residence time by separating the solid with an in-line filter, monitoring first the enantiomer concentrations in the mother liquors, then by diverting a solvent flow dissolve the crystals off the filter & then to the HPLC, MS or ORD detector. The system would require flexibly programmed diversions of solvent flow for sequences of sampling & washing. An ambitious extension of this might be analysis & optimisation of particle size. Cooling crystallisations could also be evaluated. For insoluble solids, designs that can be tested are reverse washing or flows directed through exchangeable multi-parallel filters. Exemplars could include hydrogen transfer with Pd/C, Suzuki cross-coupling or Grignard reactions. d) Exemplar tri-phasic systems

Activities (i)-(iii) will be carried out over years 1-3 as appropriate.