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.

Call number: LD2668 .T4 1985 C348 / Master of Science

Submitted to the faculty of the School of Informatics in partial fulfillment of the requirements for the degree Master of Science in Chemical Informatics (Laboratory Informatics Specialization), Indiana University, June 2006 / Industry and academic laboratories have long resisted conversion to electronic laboratory notebooks (ELN) while at the same time integrating many other kinds of information systems, most notably laboratory information management systems (LIMS), chromatography data systems (CDS), and scientific data management systems (SDMS), within laboratory operations. Scientists in both academia and industry stand to gain important functionality unavailable with paper notebooks with the adoption of ELNs such as comprehensive searching of notebooks (keyword, result, and molecular structure/substructure searching, for example); distributed availability; and long term access to data. Currently, most laboratory information systems operate independently, requiring manual data entry by users into each individual system. This process creates data and information disparities as well as creating poor referential integrity within experimental metadata. Electronic laboratory notebooks would provide a logical point around which experiment details and observations could be centered electronically. Through an ELN, experimental documentation or metadata could be communicated automatically with a LIMS, SDMS, or CDS without analyst involvement. This “electronically connected” system would allow analysts to perform their responsibilities without the interruption of independent information systems thus increasing analyst productivity and reducing user entry errors into data management systems. The thesis project consisted of two phases: the first phase was the implementation of an ELN and the second phase was the development of a software developer kit (SDK) for LABTrack based on Web Services. In the first phase of the project the adoption of an ELN, was studied within a classroom laboratory (G823 Introduction to Cell Biology) over the course of one academic semester. In the second phase of the project an SDK for LABTrack was developed to allow the importation of information from custom developed applications into LABTrack. Finally, a web portal integrating LABTrack and NuGenesis was developed to demonstrate the capabilities of the LABTrack SDK and existing capabilities of the NuGenesis SDK.