Chemische Fertigungssysteme: Kontrolle auf mehreren Ebenen für die divergente, kontinuierliche und vielstufige Synthese von pharmazeutisch aktiven Wirkstoffen

Wahrend kontinuierliche chemische Prozesse in der akademischen Forschung und der Industrie untersucht werden, werden nach wie vor praktisch alle pharmazeutisch aktiven Wirkstoffe (APIs; active pharmaceutical ingredients) uber eine Abfolge einzelner Batchprozesse hergestellt. Methoden fur die divergente, mehrstufige kontinuierliche Produktion von niedermolekularen Verbindungen sind bislang nicht verfugbar. Wir beschreiben hier die Entwicklung eines chemischen Fertigungssystems bestehend aus austauschbaren Durchflussreaktionsmodulen, das einen grosen chemischen Strukturraum zuganglich macht. Die Steuerung des Gesamtprozesses auf drei Ebenen – durch die Wahl des Ausgangsmaterials, der Reagentien oder der Reihenfolge der Module – ermoglichte die Synthese von funf APIs als Vertreter dreier unterschiedlicher Strukturklassen (γ-Aminosauren, γ-Lactame, β-Aminosauren), einschlieslich der Bestseller-Medikamente Lyrica und Gabapentin, in guten Gesamtausbeuten (49–75 %).

[1]  K. Goa,et al.  Gabapentin. A review of its pharmacological properties and clinical potential in epilepsy. , 1993, Drugs.

[2]  R. Turner,et al.  A self-organizing chemical assembly line. , 2013, Journal of the American Chemical Society.

[3]  J. S. Carey,et al.  Analysis of the reactions used for the preparation of drug candidate molecules. , 2006, Organic & biomolecular chemistry.

[4]  A. Lajtha,et al.  Neurochemical basis of the therapeutic effect of γ-aminobutyric acid and its derivatives , 1978, Progress in Neurobiology.

[5]  J. R. White,et al.  Effect of selective phosphodiesterase type IV inhibitor, rolipram, on fluid and cellular phases of inflammatory response , 1993, Inflammation.

[6]  Andreas Seidel-Morgenstern,et al.  Continuous synthesis of artemisinin-derived medicines. , 2014, Chemical communications.

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

[8]  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 .

[9]  Mathias Christmann,et al.  One-pot reactions accelerate the synthesis of active pharmaceutical ingredients. , 2011, Angewandte Chemie.

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

[11]  M. Finn,et al.  Click Chemistry: Diverse Chemical Function from a Few Good Reactions. , 2001 .

[12]  P. Anelli,et al.  Fast and selective oxidation of primary alcohols to aldehydes or to carboxylic acids and of secondary alcohols to ketones mediated by oxoammonium salts under two-phase conditions , 1987 .

[13]  P. Seeberger,et al.  Consecutive oxygen-based oxidations convert amines to α-cyanoepoxides. , 2014, Chemical communications.

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

[15]  Mark Tarleton,et al.  A flow chemistry route to 2-phenyl-3-(1H-pyrrol-2-yl)propan-1-amines , 2011 .

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

[17]  J. Hartwig.  Raising the Bar for the "Perfect Reaction" , 2002, Science.

[18]  Kerry Gilmore,et al.  Kontinuierliche oxidative Cyanierung primärer und sekundärer Amine mit Singulettsauerstoff , 2014 .

[19]  Flavien Susanne,et al.  Continuous flow synthesis. A pharma perspective. , 2012, Journal of medicinal chemistry.

[20]  John D. Hayler,et al.  Key green chemistry research areas—a perspective from pharmaceutical manufacturers , 2007 .

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

[22]  Steven V Ley,et al.  Multistep synthesis using modular flow reactors: Bestmann-Ohira reagent for the formation of alkynes and triazoles. , 2009, Angewandte Chemie.

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

[24]  P. Seeberger,et al.  Kontinuierliche Synthese des Malariawirkstoffs Artemisinin , 2012 .

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

[26]  Matthew Burns,et al.  Assembly-line synthesis of organic molecules with tailored shapes , 2014, Nature.

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

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

[29]  M. Cates,et al.  Pregabalin for the Treatment of Generalized Anxiety Disorder , 2012, The Annals of pharmacotherapy.

[30]  Andreas Kirschning,et al.  Induktives Heizen unter Hochfrequenzbedingungen: Anwendung in der kontinuierlichen Synthese des Neuroleptikums Olanzapin (Zyprexa) , 2013 .

[31]  J. Yoshida,et al.  "Cation flow" method: a new approach to conventional and combinatorial organic syntheses using electrochemical microflow systems. , 2001, Journal of the American Chemical Society.

[32]  Timothy F. Jamison,et al.  Continuous flow multi-step organic synthesis , 2010 .

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

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

[36]  M. Christmann,et al.  Eintopfreaktionen beschleunigen die Synthese pharmazeutischer Wirkstoffe , 2011 .

[37]  C. Wermuth,et al.  Synthesis and biochemical evaluation of baclofen analogues locked in the baclofen solid-state conformation. , 1991, Journal of medicinal chemistry.

[38]  T. Jamison,et al.  Continuous-flow synthesis of functionalized phenols by aerobic oxidation of Grignard reagents. , 2014, Angewandte Chemie.

[39]  P. Seeberger,et al.  Continuous-flow oxidative cyanation of primary and secondary amines using singlet oxygen. , 2014, Angewandte Chemie.

[40]  T. Nurmikko,et al.  EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision , 2010, European journal of neurology.

[41]  K. Jensen,et al.  Multistep continuous-flow microchemical synthesis involving multiple reactions and separations. , 2007, Angewandte Chemie.

[42]  K. Sharpless,et al.  Click-Chemie: diverse chemische Funktionalität mit einer Handvoll guter Reaktionen , 2001 .

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

[44]  Peter H Seeberger,et al.  Highly efficient continuous flow reactions using singlet oxygen as a "green" reagent. , 2011, Organic letters.