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Title: Control tools for flow chemistry processing and their application to the synthesis of bromodomain inhibitors
Author: Ingham, Richard Jeremy
ISNI:       0000 0004 5346 3527
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2014
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Flow chemistry and continuous processing techniques are now frequently used in synthetic laboratories, taking advantage of the ability to contain reactive or hazardous intermediates and to perform moderate scale-up processes for important compounds. However, only a limited number of methods and tools for connecting flow synthesis steps into a single protocol have been described, and as a result manual interventions are frequently required between consecutive stages. There are two main challenges to overcome. Work-up operations such as solvent extractions and filtrations are invariably needed to ensure high purity of the intermediates. Solutions for achieving this are well established within industrial facilities for continuous production, but adapting such machinery for laboratory use is rarely straightforward. Secondly, the combination of multiple steps tends to result in a more elaborate reactor configuration. The control procedures required to achieve optimum performance may then be beyond the capabilities of a single researcher. Computer control and remote monitoring can help to make such experiments more practical; but commercially-available systems are often highly specialised, and purpose-built at high cost for a particular system, and so are not suitable for laboratory scientists to use routinely. This work describes the development of software tools to enable rapid prototyping of control systems that can integrate multiple instruments and devices (in Chapter 2). These are applied to three multi-step synthesis projects, which also make use of enabling technologies such as heterogeneous reagents and in-line work-up techniques so that material can be passed directly from one stage to the next: In Chapter 1, a series of analogues of a precursor to imatinib, a tyrosine kinase inhibitor used for the treatment of chronic myeloid leukaemia, are prepared. A “catch-react-release” technique for solid-phase synthesis is used, with computer-controlled operation of the reactors. In Chapter 3, a two-step procedure for the synthesis of piperazine-2-carboxamide, a valuable 3D building block, is developed. A computer control system enabled extended running and the integration of several machines to perform optimisation experiments. In Chapter 4, improvements to the continuous synthesis of 2-aminoadamantane-2-carboxylic acid are discussed. This includes an integrated sequence of three reactions and three workup operations. The final chapter describes a project to evaluate the application of control techniques to a medicinal chemistry project. New ligands for BRD9 and CECR2, proteins involved in the recognition of acetylated histone proteins, are produced. A number of triazolopyridazine compounds were synthesised and tested using a number of assay techniques, including a frontal-affinity chromatography system under development within our group. Pleasingly, the qualitative FAC data showed a good correlation with biological assessments made using established assay techniques. Further work using the FAC method is ongoing.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Laboratory automation ; Flow chemistry ; Synthetic chemistry