Aaron Beeler September 27, 2016 How Chemistry is Changing Small Molecule Manufacturing by Expanding the Reaction Toolbox 2nd International Symposium on Continuous Manufacturing of Pharmaceuticals http://www.beelerlab.com/
Introduction chemistry opens reaction space for process chemists. Improved safety for hazardous reagents, hazardous intermediates, and hazardous conditions. Improved efficiency of challenging reactions Minimization of undesired side reactions Process and medicinal chemists can design synthetic routes through the lens of flow chemistry. More direct synthesis routes Fewer unit operations Access to underutilized or avoided chemotypes
Synthesis of Tetrazoles Excess azide required Potential buildup/release of HN 3 which is highly toxic and explosive SnBu 3 (a toxic reagent) is often utilized to generate the tributyl tin azide Stoichiometric azide Minimal HN 3 generated No heaspace for buildup Faster reaction Less side products No unreacted azide Angewandte Chemie International Edition Volume 50, Issue 15, pages 3525-3528, 8 MAR 2011 DOI: 10.1002/anie.201006272 http://onlinelibrary.wiley.com/doi/10.1002/anie.201006272/full#fig1 Jamison, T. F. Angew. Chem. Int. Ed. 2011, 50, 3525-3528
Synthesis of Triazoles Buildup and/or isolation of organic azide intermediates can be prohibitive Azide is generated in situ and does not require isolation Short reaction time improves efficiency and minimizes lifetime of the azide Demonstrated Productivity Utilizing a hood scale setup with 1/16 OD tubing, Bogdan and Sach demonstrated a the potential to reach 13.8g/8h Bogdan, A. R.; Sach, N. W. Adv. Synth. Catal. 2009, 351, 849 854
A Telescoped Continuous Synthesis of Rufinamide Figure published in: Riccardo Porta; Maurizio Benaglia; Alessandra Puglisi; Org. Process Res. Dev. 2016, 20, 2-25. DOI: 10.1021/acs.oprd.5b00325 Copyright 2015 American Chemical Society T. F. Jamison; Org. Proc. Res. Dev. 2014, 18, 1567-1570
Continuous Generation of Diazomethane Diazomethane is highly explosive and toxic Specialized equipment is required Considered dangerous at any scale Only small amounts of CH 2 N 2 generated Potential to continuously monitor consumption No possibility for exposure Demonstrated Productivity Utilizing the small CSTR they demonstrated the potential for generating 42.6 mmol (1.8 g) CH 2 N 2 /h, corresponding to 70 g /8 h Kappe, C. O. J. Org. Chem., 2016, 81, 5814 5823
Continuous Generation of Diazomethane Methylation of sensitive substrates Homologation of acid chlorides Cyclopropanation of alkenes Cycloaddition with alkynes Kappe, C. O. J. Org. Chem., 2016, 81, 5814 5823
Reactive Organo-Li Intermediates Virtually impossible to avoid cross reactivity Requires protecting group strategy (two addition reactions) Reactive intermediates are generated and reacted with electrophiles rapidly and do not have opportunity for cross-reactivity Reactions are complete in < 1 second Demonstrated Productivity Yoshida and coworkers demonstrated this reaction at 1.05g/5 minutes Yoshida, J. Chem. Commun. 2013, 49, 9896-9904
Photochemistry In Poor UV penetration Long diffusion lengths Potential degradation of product Poor control of temperature Difficult control wavelength Controlled UV penetration/high photon flux Accelerated reactions and short residence time of product, i.e., reduced chance for degradation Good control of temperature and wavelength Noel, T. Chem. Rev. 2016, ASAP
A Challenging Photochemical Cycloaddition Lumb, J. Angew. Chem. Int. Ed. 2015, 43, 7503-7513 In solution the reaction results in only E/Z isomerization The reactions are traditionally run in the solid state to facilitate dimerization Overcome poor reaction efficiency with high photo flux Platform for reaction development and optimization. Beeler, A. B. Angew. Chem. Int. Ed. 2015, 54, 11521-11525 Noel, T. Chem. Rev. 2016, ASAP
Technologies for Process Scale Photochemistry are Catching Up Published in: Luke D. Elliott; Malcolm Berry; Bashir Harji; David Klauber; John Leonard; Kevin I. Booker-Milburn; Org. Process Res. Dev. 2016, 20, 1806-1811.DOI: 10.1021/acs.oprd.6b00277 Copyright 2016 American Chemical Society UV- Reactor Parallel flow reactor design High pressure mercury lamp Demonstrated 8 kg/24 hr Booker-Milburn, K. Org. React. Proc. Dev. 2016, ASAP Visible Light Reactor Traditional wrapped tubing Swimming pool lights Demonstrated 1.2 kg/24 hr Stephenson, C. R. J. Chem 2016, 1, 456-472
Synthesis of Artmesinin in A feat of engineering Required additional step to mitigate safety concerns of intermediate peroxide Demonstrated 360kg batches Burgard, A.; Org. Proc. Res. Dehv. 2014, 18, 417-422 Minimizes safety concerns of O 2 Eliminates the need to generate the mixed-anhydride Utilizing a second generation hood scale LED based system Seeberger demonstrated the potential for continuous production of 165 g/24 h Seeberger, P. H. Angew. Chem. Int. Ed., 2012, 51, 1706 1709. Seeberger, P. H. Chem. Eur. J., 2013, 19, 5450 5456
High Pressure Biphasic Hydrogenation High pressure and high temperature hydrogenations are challenging/dangerous in a laboratory environment. Scale is highly apparatus limited. Safety concerns require specialized containment Published in: Takashi Ouchi; Claudio Battilocchio; Joel M. Hawkins; Steven V. Ley; Org. Process Res. Dev. 2014, 18, 1560-1566. DOI: 10.1021/op500208j Copyright 2014 American Chemical Society Minimization of reaction volume mitigates safety concerns Packed bed reactors reduce unit operations (ie no filtration of catalyst) Reactions can be exceptionally efficient and scaleable Demonstrated Productivity Utilizing the H.E.L trickle bed system Ley and Hawkins demonstrated continuous production of 81.6 g/h Ley, S. V. Org. Proc. Res. Dev. 2014, 18, 1560-1566
Summary A selection of reaction that are defining the the lens of flow chemistry Rendering reactions more efficient and safer (azides) Utilizing reagents that would never be considered (diazomethane) Controlling highly reaction intermediates (aryl lithiums) Accessing chemotypes that have been avoided (cyclobutanes) Integrating challenging reactions into scalable multistep processes (photochemistry) Rendering reactions safer, more efficient, and more scalable (hydrogenation)