Download - Semi-Synthetic artemisinin progress report
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Semi-synthetic artemisinin project progress report
Dirk Pohlmann
project management MPIKG and CEO ArtemiFlow GmbH
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SINGLET OXYGEN GENERATION
Photochemical generation via photosensitizers
green reagent, high atom economy
S0
S1
T1
photosensitizer
3O2
1O2
oxygen
hn 1260 nm
http://spie.org/x16290.xml l=660 nm l=560 nm
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SCALE-UP OF PHOTOCHEMICAL REACTIONS
Light intensity diminishes rapidly with path depth
e = 50000 M-1 cm-1
𝐴 = 𝜀 ∙ 𝑐 ∙ 𝑑
www.uv-consulting.de/deutsch/produkte/produktuebersicht.html
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SCALE-UP OF PHOTOCHEMICAL REACTIONS
Decreasing path length: high irradiation intensity
Continuous removal of product: prevention of side reactions
Batch Falling film Channel
L A
M P
l
I/I0
L A
M P
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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
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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
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BIPHASIC REACTIONS
Flow pattern change with gas/liquid flow rate:
Specific interfacial area in batch : 100 m2m-3 to 2000 m2m-3
Plug flow
Slug flow Liquid phase Gas phase
Thin film of liquid Annular flow
Specific interfacial area
(a)
18700 m2m-3
23500 m2m-3
3500 m2m-3
Ehrfeld, W.; Hessel, V.; Löwe, H. Microreactors: New Technology for Modern Chemistry, Wiley-VCH, 2000
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BIPHASIC REACTIONS
Chen, L., Tian, Y. S., Karayiannis, T. G. Int. J. Heat Mass Transfer, 2006, 49, 4220-4230
increasing gas flow rate 1.1 mm tube
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SEMI-SYNTHESIS
Singlet oxygen reacts with dihydroartemisinic acid, further reactions
mediated by acid
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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, 13, 5008 –5011
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INITIAL REACTOR
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ENERGY REQUIREMENTS
Mercury lamp 450 W + chiller: 1700 W
200 g/d artemisinin: 200 kWh per kg artemisinin!
improvement in energy efficiency required
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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
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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
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CONTINUOUS ONE-POT PROCESS
Simple setup, small footprint of system
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YIELD
Yield of 65% can be achieved, simplifying purification
NMR of crude: • mainly artemisinin • main side products
known:
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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
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CONTINUOUS PURIFICATION
Continuous purification benefical
single continuous process yielding pure product
Evaluation of two processes:
continuous crystallization
Simulated Moving Bed (SMB) chromatography
http://www.nitechsolutions.co.uk/
Juza, M., Mazzotti, M., Morbidelli, M., Trends Biotechnol. 2000, 18, 108–118
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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
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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
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DHAA
Artesunate Artemether
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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