Continuous Flow Total Synthesis of Rufinamide

Small molecules bearing 1,2,3-triazole functionalities are important intermediates and pharmaceuticals. Common methods to access the triazole moiety generally require the generation and isolation of organic azide intermediates. Continuous flow synthesis provides the opportunity to synthesize and consume the energetic organoazides, without accumulation thereof. In this report, we described a continuous synthesis of the antiseizure medication rufinamide. This route is convergent and features copper tubing reactor-catalyzed cycloaddition reaction. Each of the three chemical steps enjoys significant benefits and has several advantages by being conducted in flow. The total average residence time of the synthesis is approximately 11 min, and rufinamide is obtained in 92% overall yield.

[1]  Christian Spiteri,et al.  Copper-catalyzed azide-alkyne cycloaddition: regioselective synthesis of 1,4,5-trisubstituted 1,2,3-triazoles. , 2010, Angewandte Chemie.

[2]  O. Henriksen,et al.  Rufinamide: a double-blind, placebo-controlled proof of principle trial in patients with epilepsy , 2001, Epilepsy Research.

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

[4]  B. J. Macnulty.  Some polymers of substituted acetylenes , 1966 .

[5]  Sejal M. Patel,et al.  Continuous flow coupling and decarboxylation reactions promoted by copper tubing. , 2010, Organic letters.

[6]  Whitney H. Mudd,et al.  An efficient synthesis of rufinamide, an antiepileptic drug , 2010 .

[7]  T. Endo,et al.  A novel phosphine-catalysed polyaddition of terminal acetylenes bearing electron-withdrawing groups with dithiols. Synthesis of polymers having dithioacetal moieties in the main chain , 1997 .

[8]  Volker Hessel,et al.  Solvent- and catalyst-free huisgen cycloaddition to rufinamide in flow with a greener, less expensive dipolarophile. , 2013, ChemSusChem.

[9]  E. De Clercq,et al.  Regiospecific Synthesis and Anti-Human Immunodeficiency Virus Activity of Novel 5-Substituted N-Alkylcarbamoyl and N,N-Dialkyl Carbamoyl 1,2,3-Triazole-TSAO Analogues , 1998, Antiviral chemistry & chemotherapy.

[10]  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 .

[11]  D. Bonner,et al.  In Vitro Activity of a New Oral Triazole, BMS-207147 (ER-30346) , 1998, Antimicrobial Agents and Chemotherapy.

[12]  T. Koenig,et al.  Palladium-Catalyzed Hydroarylation of Propiolamides. A Regio- and Stereocontrolled Method for Preparing 3,3-Diarylacrylamides , 1998 .

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

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

[15]  Andrew R. Bogdan,et al.  The Use of Copper Flow Reactor Technology for the Continuous Synthesis of 1,4‐Disubstituted 1,2,3‐Triazoles , 2009 .

[16]  Morten Meldal,et al.  Peptidotriazoles on solid phase: [1,2,3]-triazoles by regiospecific copper(i)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides. , 2002, The Journal of organic chemistry.

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

[18]  Fahmi Himo,et al.  Copper(I)-catalyzed synthesis of azoles. DFT study predicts unprecedented reactivity and intermediates. , 2005, Journal of the American Chemical Society.

[19]  Steven V Ley,et al.  Accelerating spirocyclic polyketide synthesis using flow chemistry. , 2014, Angewandte Chemie.

[20]  E. De Clercq,et al.  1,2,3-Triazole-[2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D- ribofuranosyl]-3'-spiro-5"-(4"-amino-1",2"-oxathiole 2",2"-dioxide) (TSAO) analogues: synthesis and anti-HIV-1 activity. , 1994, Journal of medicinal chemistry.

[21]  Joel Morris,et al.  Substituent effects on the antibacterial activity of nitrogen-carbon-linked (azolylphenyl)oxazolidinones with expanded activity against the fastidious gram-negative organisms Haemophilus influenzae and Moraxella catarrhalis. , 2000, Journal of medicinal chemistry.

[22]  D. Buckle,et al.  Studies on 1,2,3-triazoles. 13. (Piperazinylalkoxy) [1]benzopyrano[2,3-d]-1,2,3-triazol-9(1H)-ones with combined H1-antihistamine and mast cell stabilizing properties. , 1986, Journal of medicinal chemistry.

[23]  Luke G Green,et al.  A stepwise huisgen cycloaddition process: copper(I)-catalyzed regioselective "ligation" of azides and terminal alkynes. , 2002, Angewandte Chemie.

[24]  V. Brandolini,et al.  Pyrazolo[3,4-d][1,2,3]triazole-1-carboxamides and 5-alkylaminopyrazolo[3,4-d]oxazoles: synthesis and evaluation of the in vitro antifungal activity. , 1992, Farmaco.

[25]  E. Scriven,et al.  Azides: their preparation and synthetic uses , 1988 .

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