| Summary: | Thesis: Ph. D., Massachusetts Institute of Technology, Department of Chemistry, May, 2019 Cataloged from the PDF of thesis. Includes bibliographical references. In this thesis, I have optimized a synthesis of rufinamide an important epilepsy medication. This convergent synthesis generates two reactive intermediates in situ (aryl azide and propiolamide) and then combines them in a regioselective click reaction utilizing copper tubing as the catalyst. Next, I have optimized a synthesis of nicardipine which is prescribed to treat high blood pressure. The nature of the project required that the final product be relatively pure (>90 %) so that the final product could be crystallized from the reaction mixture. Nicardipine was synthesized in three steps, but in two flow reactors where one of the reactors induced two steps. The reaction mixture was then purified using two in-line aqueous extrations. First, the reaction stream was washed with HCl to produce the salt of nicardipine and wash away polar compounds. Then, the product is extracted into the aqueous layer by using a 1:1 water DMSO mixture. Finally, the synthesis's scale was increased and run in the system that was created in collaboration with the Jensen lab and Myerson lab. Next, a fully continuous synthesis of linezolid was optimized and run. The synthesis targeted the challenging intermediate amide epoxide that rapidly cyclizes into unwanted oxazolines. We were able to circumvent this side reactivity by masking the nucleophilic amide N-H by quenching the resulting nitrillium after Ritter type reaction with 2-propanol to produce the imidate. After accessing the masked amide epoxide, linezolid was produced by nucleophilic addition to the epoxide with the aniline made from a nucleophilic aromatic substitution (SNAr) reduction sequence. Finally, late stage oxazolidinone formation produces linezolid in a 73% yield in 27 minutes longest linear sequence. Next, I contributed to a system that automatically optimized and analyzed organic reactions in continuous flow. This system in collaboration with the Jensen lab fully integrated software, hardware that controlled the continuous platform, and in-line analytics. This system, after the chemist had provided the desired chemical space, could optimize a reaction without any manual intervention. Finally, I developed a monolithic cellular solid made of functionalized silica for catalyst support. This system could solve some of the problems associated with packed bed reactors including catalyst deactivation due to channeling or clogging of the reactor. This type of catalyst support could be applicable to a large number of catalysts by attaching the catalyst to silane side chains with appended functionality. Portions of this thesis have been published in the following articles co-written by the author and have been reprinted and/or adapted with permission from their respective publishers.Zhang, P.; Russell, M.G.; Jamison, T.F. "Continuous Flow Total Synthesis of Rufinamide" Org. Proc. Res. Dev. 2014, 15671570. © 2014 American Chemical Society. MGR ran the optimization of the synthesis as well as isolation and characterization of the final product. PZ wrote the manuscript and validated the results under TFJ's guidance. Zhang, P.; Weeranoppanant, N.; Thomas, D. A.; Tahara, K.; Stelzer, T.; Russell, M. G.; OMahony, M.; Myerson, A. S.; Lin, H.; Kelly, L. P.; Jensen, K. F.; Jamison, T. F.; Dai, C.; Cui, Y.; Briggs, N.; Beingessner, R. L.; Adamo, A. Advaced Continuous Flow Platform for On-Demand Pharmaceutical Manufacturing, Chem. Eur. J. 2018, 24, 2776-2784. DOI:10.1002/chem.201706004. © 2018 John Wiley & Sons, Inc. MGR optimized the synthesis of nicardipine as well as ran the synthesis in the synthesis frame. PZ, HL, LPK, CD, RLB all woked to develop chemistry for the syntheses of the different drug targets. NW, DAT, and AA worked to develop the up-steam synthesis unit as well as necessary undeveloped components. KT, TS, MM, YC, and NB woked to deleop the continuous recrystalization unit and purified the drug targets. TFJ, KFJ, and ASM provided instrumental guidance to the teams. Russell, M. G.; Jamison, T. F. "Seven-Step Continuous Flow Synthesis of Linezolid Without Intermediate Purification," Angew. Chem Int. Ed. 2019, 58, 7678-7681. DOI:10.1002/anie.201901814. © 2019 John Wiley & Sons, Inc. All synthetic work was carried out by MGR under TFJ's guidance. B6dard, A.-C.; Adamo, A.; Aroh, K. C.; Russell, M. G.; Bedermann, A. A.; Torosian, J.; Yue, B.; Jensen, K. F.; Jamison, T. F. Reconfigurable System for Automated Optimization of Diverse Chemical Reactions, Science 2018, 361, 1220-1225. © 2018 American Association for the Advancement of Sciences. Reprinted with permission from AAAS. MGR and ACB worked together to run the various optimizations as well as substrate scopes. AAB developed initial conditions for several of the reactions. AA developed the system with JT and BJ's assistance. KCA integrated the system with the software as well as modeled the optimization protocols. KFJ and TFJ provided instrumental guidance to the teams. Leibfarth, F. A.; Russell, M. G.; Langley, D. M.; Seo, H.; Kelly, L. P.; Carney, D. W.; Sello, J. K.; Jamison, T. F. Continuous-Flow Chemistry in Undergraduate Education: Sustainable Conversion of Reclaimed Vegetable Oil into Biodiesel, J. Chem. Ed. 2018, 95, 1371-1375. DOI:10.1021/acs.jchemed.7b00719. © 2018 American Chemical Society. MGR and DML developed and optimized the chemistry. FAL wrote the manuscript and the laboratory experiment. MGR, HS, and LPK, taught the experiment. DWC provided assistance. JKS and TFJ provided guidance. by Mary Grace Russell. Ph. D. Ph.D. Massachusetts Institute of Technology, Department of Chemistry
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