Semi-synthetic artemisinin project progress report Dirk Pohlmann project management MPIKG and CEO ArtemiFlow GmbH 15.1.2013, Nairobi, 1
SINGLET OXYGEN GENERATION Photochemical generation via photosensitizers green reagent, high atom economy photosensitizer oxygen S 1 T 1 1 O 2 hn 1260 nm 3 O 2 S 0 l=660 nm l=560 nm http://spie.org/x16290.xml 15.1.2013, Nairobi, 2
SCALE-UP OF PHOTOCHEMICAL REACTIONS Light intensity diminishes rapidly with path depth A = ε c d e = 50000 M -1 cm -1 www.uv-consulting.de/deutsch/produkte/produktuebersicht.html 15.1.2013, Nairobi, 3
L A M P L A M P SCALE-UP OF PHOTOCHEMICAL REACTIONS Decreasing path length: high irradiation intensity Continuous removal of product: prevention of side reactions I/I 0 l Batch Falling film Channel 15.1.2013, Nairobi, 4
BENEFITS OF FLOW CHEMISTRY Small tubing: high irradiation intensity Excellent control over reaction parameters (time, temperature, mixing, pressure etc.) High surface / volume ratio control exothermic reactions Lower operating volumes safety and reagent consumption In-line analysis Ready scale-up by number-up Easy automation 15.1.2013, Nairobi, 5
BIPHASIC REACTIONS High gas-liquid interfacial area: enhanced rate of mass transfer Extended pressure increases oxygen solubility Gases: Hydrogen Fluorine Carbon dioxide Carbon monoxide Singlet oxygen Triplet oxygen Ozone www.imm-mainz.de 15.1.2013, Nairobi, 6
BIPHASIC REACTIONS Flow pattern change with gas/liquid flow rate: Plug flow Specific interfacial area (a) 3500 m 2 m -3 Slug flow Liquid phase Gas phase 18700 m 2 m -3 Annular flow Thin film of liquid 23500 m 2 m -3 Specific interfacial area in batch : 100 m 2 m -3 to 2000 m 2 m -3 Ehrfeld, W.; Hessel, V.; Löwe, H. Microreactors: New Technology for Modern Chemistry, Wiley-VCH, 2000 15.1.2013, Nairobi, 7
BIPHASIC REACTIONS increasing gas flow rate 1.1 mm tube Chen, L., Tian, Y. S., Karayiannis, T. G. Int. J. Heat Mass Transfer, 2006, 49, 4220-4230 15.1.2013, Nairobi, 8
SEMI-SYNTHESIS Singlet oxygen reacts with dihydroartemisinic acid, further reactions mediated by acid 15.1.2013, Nairobi, 9
INITIAL REACTOR 2 Pumps required: delivery of substrate solution, addition of acid 450 W medium pressure mercury lamp for photochemical step Artemisinin yield: 40%, productivity: 200 g/d High energy consumption and low yield Lèvesque, F., Seeberger, P.H. Angew. Chem. Int. Ed., 2012, 51, 1706 1709 Lèvesque, F., Seeberger, P.H. Org. Lett., 2011, 15.1.2013, 13, 5008 5011 Nairobi, 10
INITIAL REACTOR 15.1.2013, Nairobi, 11
ENERGY REQUIREMENTS Mercury lamp 450 W + chiller: 1700 W 200 g/d artemisinin: 200 kwh per kg artemisinin! improvement in energy efficiency required 15.1.2013, Nairobi, 12
NEW GENERATION PHOTOREACTOR Improved setup: LED lamp matches spectrum of photosensitizer High energy efficiency Less energy required for cooling small footprint 1to per year for industry version Artemisinin yield up to 65% Larger reactor possible 15.1.2013, Nairobi, 13
NEW GENERATION PHOTOREACTOR Photoreactor: cheap FEP-tubing wrapped around glass/pc plate 7.5 ml volume high transmission of light chemically resistant can be immersed in cooling liquid for thermosetting 15.1.2013, Nairobi, 14
CONTINUOUS ONE-POT PROCESS Simple setup, small footprint of system 15.1.2013, Nairobi, 15
YIELD Yield of 65% can be achieved, simplifying purification NMR of crude: mainly artemisinin main side products known: 15.1.2013, Nairobi, 16
PURIFICATION Recrystallization yields artemisinin of high purity No impurities detected by NMR and HPLC with MS/ELSD detector Minor impurity peaks with UV detection (210 nm) HPLC - UV detection NMR 15.1.2013, Nairobi, 17
CONTINUOUS PURIFICATION Continuous purification benefical single continuous process yielding pure product Evaluation of two processes: continuous crystallization Simulated Moving Bed (SMB) chromatography Juza, M., Mazzotti, M., Morbidelli, M., Trends Biotechnol. 2000, 18, 108 118 http://www.nitechsolutions.co.uk/ 15.1.2013, Nairobi, 18
STARTING MATERIAL Dihydroartemisinic acid present in plant Unused waste compound from extraction process Mother liquor remaining from artemisinin extraction: ~ 8% DHAA (results provided by AnalytiCon) Basic extract: 42% DHAA, can be converted to artemisinin without purification 15.1.2013, Nairobi, 19
COMPANY ArtemiFlow GmbH, founded in November 2012 Personnel: 3 Prof. Peter Seeberger CSO: Dr. Daniel Kopetzki (Junior Scientist of the Year, Brandenburg 2012) CEO: Dirk Pohlmann Milestones for ArtemiFlow GmbH: funding defined business plan written (waiting for more lab data) clients identified Development company for industry prototype indentified cost estimates known 15.1.2013, Nairobi, 20
DHAA Artesunate Artemether 15.1.2013, Nairobi, 21
PLANTS Which plants do we need? First answers: no turbos? young plants up to 3 months fresh dried cheap seeds? Or new seeds=combined ART and DHAA content? max combination of Artimisinin +DHAA after 3 months 3 harvests per year = breaking the pork cycle 15.1.2013, Nairobi, 22