Continuous Consecutive Reactions with Inter‐Reaction Solvent Exchange by Membrane Separation

Abstract Pharmaceutical production typically involves multiple reaction steps with separations between successive reactions. Two processes which complicate the transition from batch to continuous operation in multistep synthesis are solvent exchange (especially high‐boiling‐ to low‐boiling‐point solvent), and catalyst separation. Demonstrated here is membrane separation as an enabling platform for undertaking these processes during continuous operation. Two consecutive reactions are performed in different solvents, with catalyst separation and inter‐reaction solvent exchange achieved by continuous flow membrane units. A Heck coupling reaction is performed in N,N‐dimethylformamide (DMF) in a continuous membrane reactor which retains the catalyst. The Heck reaction product undergoes solvent exchange in a counter‐current membrane system where DMF is continuously replaced by ethanol. After exchange the product dissolved in ethanol passes through a column packed with an iron catalyst, and undergoes reduction (>99 % yield).

[1]  Steven V. Ley,et al.  Multi-step organic synthesis using solid-supported reagents and scavengers: a new paradigm in chemical library generation , 2000 .

[2]  Richard J Ingham,et al.  Organic synthesis: march of the machines. , 2015, Angewandte Chemie.

[3]  The Journal of Catalysis , 1962, Nature.

[4]  Andrew G. Livingston,et al.  Nanofiltration membrane cascade for continuous solvent exchange , 2007 .

[5]  J. Wegner,et al.  Flow Chemistry – A Key Enabling Technology for (Multistep) Organic Synthesis , 2012 .

[6]  Ryan L Hartman,et al.  Multistep microchemical synthesis enabled by microfluidic distillation. , 2010, Angewandte Chemie.

[7]  James M. B. Evans,et al.  End-to-end continuous manufacturing of pharmaceuticals: integrated synthesis, purification, and final dosage formation. , 2013, Angewandte Chemie.

[8]  David Cantillo,et al.  Continuous-flow technology—a tool for the safe manufacturing of active pharmaceutical ingredients. , 2015, Angewandte Chemie.

[9]  A. Livingston,et al.  Experimental strategies for increasing the catalyst turnover number in a continuous Heck coupling reaction , 2013 .

[10]  S. Caron,et al.  Efficient synthesis of [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]-acetic acid, a novel COX-2 inhibitor. , 2003, The Journal of organic chemistry.

[11]  Volker Hessel,et al.  Separation/recycling methods for homogeneous transition metal catalysts in continuous flow , 2015 .

[12]  Norman N. Li.  Separation and Purification Technology , 1992 .

[13]  Martin D. Johnson,et al.  Development and Scale-Up of a Continuous, High-Pressure, Asymmetric Hydrogenation Reaction, Workup, and Isolation , 2012 .

[14]  ANDREW LIVINGSTON,et al.  Membrane Separation in Green Chemical Processing , 2003 .

[15]  B. Gutmann,et al.  Kontinuierliche Durchflussverfahren: ein Werkzeug für die sichere Synthese von pharmazeutischen Wirkstoffen , 2015 .

[16]  城塚 正,et al.  Chemical Engineering Scienceについて , 1962 .

[17]  Kamalesh K. Sirkar,et al.  Nanofiltration-based diafiltration process for solvent exchange in pharmaceutical manufacturing , 2003 .

[18]  Andreas Kirschning,et al.  Applications of immobilized catalysts in continuous flow processes. , 2004, Topics in current chemistry.

[19]  S. Y. Wong,et al.  On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system , 2016, Science.

[20]  Matthew J. Rosseinsky,et al.  Crystal Growth & Design , 2011 .

[21]  Timothy Noël,et al.  Suzuki-Miyaura cross-coupling reactions in flow: multistep synthesis enabled by a microfluidic extraction. , 2011, Angewandte Chemie.

[22]  Steven V. Ley,et al.  Organische Synthese: Vormarsch der Maschinen , 2015 .

[23]  O. Repič,et al.  A Practical and Chemoselective Reduction of Nitroarenes to Anilines Using Activated Iron , 2005 .