Continuous synthesis of artemisinin-derived medicines.

Described is a continuous, divergent synthesis system which is coupled to continuous purification and is capable of producing four anti-malarial APIs. The system is comprised of three linked reaction modules for photooxidation/cyclization, reduction, and derivatization. A fourth module couples the crude reaction stream with continuous purification to yield pure API.

[1]  Brahim Benyahia,et al.  Development of a Multi-Step Synthesis and Workup Sequence for an Integrated, Continuous Manufacturing Process of a Pharmaceutical , 2014 .

[2]  Edward L. Williams,et al.  3 A.M. , 1971 .

[3]  Richard Van Noorden Demand for malaria drug soars , 2010, Nature.

[4]  A. Palmieri,et al.  Flow Synthesis of Substituted γ‐Lactones by Consecutive Photocatalytic/Reductive Reactions , 2014 .

[5]  Steven V Ley,et al.  KMnO(4)-Mediated oxidation as a continuous flow process. , 2010, Organic letters.

[6]  Jun-ichi Yoshida,et al.  Flash chemistry: flow chemistry that cannot be done in batch. , 2013, Chemical communications.

[7]  Steven V Ley,et al.  An expeditious synthesis of imatinib and analogues utilising flow chemistry methods. , 2013, Organic & biomolecular chemistry.

[8]  Jonathan P. McMullen,et al.  Palladium-catalyzed amination reactions in flow: overcoming the challenges of clogging via acoustic irradiation , 2011 .

[9]  J. Burrows,et al.  The global pipeline of new medicines for the control and elimination of malaria , 2012, Malaria Journal.

[10]  Peter H Seeberger,et al.  A continuous-flow process for the synthesis of artemisinin. , 2013, Chemistry.

[11]  Timothy F. Jamison,et al.  End-to-end continuous flow synthesis and purification of diphenhydramine hydrochloride featuring atom economy, in-line separation, and flow of molten ammonium salts , 2013 .

[12]  R. Reynolds,et al.  Methods for the isolation and characterization of constituents of natural products XIX. Use of a Celite-sodium borohydride column for reduction of carbonyl compounds at the micro level , 1975 .

[13]  Steven J. Broadwater,et al.  The continuous-flow synthesis of Ibuprofen. , 2009, Angewandte Chemie.

[14]  Steven V Ley,et al.  A flow-based synthesis of imatinib: the API of Gleevec. , 2010, Chemical communications.

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

[16]  P. Tiwari,et al.  A one-pot conversion of artemisinin to its ether derivatives☆ , 2002 .

[17]  K. Jensen,et al.  Integrated continuous microfluidic liquid-liquid extraction. , 2007, Lab on a chip.

[18]  S. Ley,et al.  Continuous Preparation of Arylmagnesium Reagents in Flow with Inline IR Monitoring , 2012 .

[19]  A. Kirschning,et al.  Multiple Organolithium Generation in the Continuous Flow Synthesis of Amitriptyline , 2013 .

[20]  R. Rosenfeld Nature , 2009, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[21]  K. Jensen,et al.  Multistep synthesis of amides from alcohols and amines in continuous flow microreactor systems using oxygen and urea hydrogen peroxide as oxidants , 2013 .

[22]  Ian W Davies,et al.  Looking Forward in Pharmaceutical Process Chemistry , 2009, Science.

[23]  C. Oliver Kappe,et al.  A Scalable Two-Step Continuous Flow Synthesis of Nabumetone and Related 4-Aryl-2-butanones , 2011 .

[24]  Andreas Kirschning,et al.  Heating under high-frequency inductive conditions: application to the continuous synthesis of the neurolepticum olanzapine (Zyprexa). , 2013, Angewandte Chemie.

[25]  Xiaolei Fan,et al.  Facile stoichiometric reductions in flow: An example of artemisinin , 2012 .

[26]  David S. Teager,et al.  Streamlined Process for the Conversion of Artemisinin to Artemether , 2012 .

[27]  Peter H Seeberger,et al.  Continuous-flow synthesis of the anti-malaria drug artemisinin. , 2012, Angewandte Chemie.

[28]  Steven V Ley,et al.  Flow chemistry syntheses of natural products. , 2013, Chemical Society reviews.