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Selection of Green Solvents

Denis PRAT, Process Safety & Environment Chemistry & Biochemistry
Sanofi Chimie, Gentilly (France)

4th Industrial Green Chemistry World Conference, Mumbai,
05 December 2015

Green Solvents | 1

AGENDA

● Sanofi Social Responsibility
● What is a green solvent
● Published solvent selection guides
● Including Sanofi’s !!
● The CHEM21 European project
● Comparison of solvent guides
● Elaboration of CHEM21 solvent guide
● How to rank bio-derived solvents?

Green Solvents | 2

SANOFI CORPORATE SOCIAL
RESPONSIBILITY: 4 PILLARS

• Access to Healthcare
PATIENT • Patient Safety
• Innovation for the Patient

• Ethics in R&D
ETHICS • Business Ethics
• Human Rights

• Health & Safety
PEOPLE • Diversity
• Workforce Development

• CO2 reduction
PLANET • Water
• Green chemistry

Green Solvents | 3

SANOFI’S INDUSTRIAL PRODUCTION OF
SEMISYNTHETIC ARTEMISININ IN YEAST
S. cerevisiae
Synthetic Biology
Mevalonate pathway Hydroxyase
Mevalonate pathway Synthase
(BOTTOM) Unit
(TOP)
Artemisinic
Acetyl- atoB HMGS tHMGRMevalonate ADS Amorphadiene CPR p450 Acid
MK PMK MPD idi ispA FPP
CoA H
H
O
CH3 OH
HO 2C OPP
H3C SCoA OH H
HO
H
J. D. Keasling et al., Nature, 2006, 440, 940-943 O

Green Chemistry Photo oxidation Purification
Cyclisation
H H
H Réduction H
O Dérivatisation
H H
O O
HOO
H H H H
O HO RO HO

O
O O O

Artemisinin J. Turconi et al., OPRD, 2014, 18, 417 Artemisinic Acid

Green Solvents | 4

912. 2011. Jimenez-Gonzalez et al. Green Solvents | 5 . OPRD. 15.IMPACT OF SOLVENTS IN THE PROCESS GREENNESS ● 1 kg of API necessitates more than 100 kg of material ● PMI ● Solvents and water represent >80% of these ● Reduce the impact by reduction of solvent & water amount ● Use the “greenest” solvents 7% 5% 56% 32% C.

SOLVENTS IMPACT IN THE PROCESS GREENNESS ● Whatever the metrics considered. the yield (process efficiency) has a direct impact on the synthesis greenness ● But solvents are most often the main contributors PMI CO2 Impact Cumulated Energy Demand Life Cycle Assessment Global Warming Potential Green Solvents | 6 .

Green Chem. 13.WHAT IS A GREEN SOLVENT? ● Criteria for a green solvent ● From renewable feedstock ● Low energy demand ● Biodegradable ● Not soluble in water ● No VOCs (BP not too low) ● Easy to recycle: BP not too high ● Criteria for a safe solvent P. G. ● Stability 2011. ● Low flammability (high FP) ● Moderate toxicity Green Solvents | 7 . Jessop. 1391.

SOLVENT SELECTION GUIDES ● The definition of a green solvent is not straightforward ● Some criteria are contradictory ● There is no universal metrics set to compare the greenness criteria Green Solvents | 8 .

SOLVENT SELECTION GUIDES ● The definition of a green solvent is not straightforward ● Some criteria are contradictory ● There is no universal metrics set to compare the greenness criteria ● Some companies/ institutions have edited solvent selection guides in order to help chemists in their choice ● Occupational health ● Safety (Flash point. resistivity.…) ● Environment ● Industrial & regulation issues ● These guides reflect their policy and culture ● Local constraints ● Accidents ● Habits Green Solvents | 9 . peroxides.

PFIZER’S SOLVENT GUIDE Green Chem. 2008. 31 Green Solvents | 10 . 10.

854 Green Solvents | 11 .GSK SOLVENT GUIDE Green Chem. 2011. 13.

GCI-PR GUIDE Green Solvents | 12 .

but with supporting data ● To make proposals for substitution of undesirable solvents (e. regulatory & industrial issues. g. CMR) ● To offer useful data and advice Green Solvents | 13 . ● To promote renewable solvents ● To give clear recommendations.GENESIS OF SANOFI’S SOLVENT GUIDE ● We did not have a common vision of the preferred solvents ● Sanofi-Synthelabo-Hoechst-Marion-Roussel-Rhone-Poulenc-Rorer ● Research vs Production ● Working group created in 2009 ● Reshaping of former HSE guide ● Integration of industrial constraints ● Integration of GHS/ CLP ● Constraints: ● Increasing difficulties to change the solvents during development ● Purposes: ● To educate chemists to SH&E.

bifunctional. aprotic polar. halogenated. hydrocarbons. one paragraph per solvent Green Solvents | 14 . miscellaneous. esters. ethers.STRUCTURE OF SANOFI’S SOLVENTS GUIDE ● One chapter per solvent family ● Alcohols. ketones. ● In these chapters.

2013. 1517 Green Solvents | 15 . with clear recommendations • Which is the most advisable aprotic polar solvent? OPRD.SANOFI’S SOLVENTS GUIDE ● First level of lecture ● Overview per family of solvents. 17.

SANOFI’S SOLVENTS GUIDE ● Second level of lecture ● One ID card for each solvent ● Third level ● One paragraph per solvent Green Solvents | 16 .

17. 2013. 1517 Green Solvents | 17 .SANOFI’S SOLVENTS GUIDE ● Four levels of ranking OPRD.

THE IMI-CHEM21 PROJECT ● IMI-CHEM21 project: ● Created in 2012 ● 4-year project ● Six pharmaceutical companies from the European Foundation of Pharmaceutical Industries and Associations (EFPIA) ● Ten Universities ● Five small to medium companies ● Funded by EFPIA and the European Union ● Develops sustainable biological and chemical methodologies ● Supports research projects • Catalytic chemistry • Enzymatic chemistry • Synthetic biology ● Provides training packages • Education of the future chemists Green Solvents | 18 .

THE IMI-CHEM21 PROJECT ● Benchmark and gap analysis (WP1) ● Portfolio review: the most used reactions in Pharmaceutical Industry ● Catalysts to be replaced (critical elements) ● Chemicals of concern & regulatory issues ● Survey of solvent selection guides ● Education and Training Package (WP5) ● Green metrics ● Renewable resources • York University ● New transformations ● CHEM21 solvent selection guide • Including bio-derived solvents Green Solvents | 19 .

Banned Green Solvents | 20 . advisable. requested. Undesirable ● Sanofi: 4 levels of ranking ● Recommended. Usable. Subst. Subst.SOLVENT GUIDES COMPARISON ● Pfizer: 3 levels of ranking ● Preferred.

Undesirable ● Sanofi: 4 levels of ranking ● Recommended. 3 environment ● Criteria scored from 1 (best) to 10 (worse) ● GSK: similar ● Plus legislation flags and EHS flags ● But scored from 10 (best) to 1 (worse)! Green Solvents | 21 . Subst. Usable. advisable. Banned ● Astra Zeneca: no clear ranking ● 2 Safety criteria. but simpler ● 1 safety criterion.SOLVENT GUIDES COMPARISON ● Pfizer: 3 levels of ranking ● Preferred. 7 environment ● Criteria scored from 1 (best) to 10 (worse) ● GCI-PR: similar. Subst. 1 health. requested. 1 health.

SOLVENT GUIDES COMPARISON ● What is the level of convergence of these guides? ● Survey based on 51 solvents ● Some manipulation was needed to establish a solvent ranking from AZ. Environment • Select the most stringent one in each category ● Ex: GCI-PR guide Green Solvents | 22 . GSK and GCI-PR guides ● Limit the number of criteria • One of each: Health. Safety.

E scores ● Arithmetical mean of this sum ● 3 groups of similar sizes centred on this mean ● 3-color code Green Solvents | 23 .SOLVENT GUIDES COMPARISON ● transformation of AZ. GSK and GCI-PR guides ● Sum of H. S.

SOLVENT GUIDES SURVEY ● Based on qualitative rankings (51 solvents) ● If large majority. easy conclusion ● Other cases: to be confirmed (TBC) Green Solvents | 24 .

COMPARISON OF THE DIFFERENT GUIDES Ranking Solvents Recommended Water. DMPU. Ac2O Problematic Me-THF.. toluene. DCM. 4546 Green Solvents | 25 . chloroform. EtOH. methoxyethanol Highly hazardous Et2O. Me-cyclohexane. Green Chem. DCE. xylene. 2014. cyclohexanone. AcOnBu. formic acid. Prat. DMSO Problematic or THF. DMA. hexane. NMP. J. 16. AcOMe. MTBE. Wells. CCl4. PhOMe. sulfolane Recommended or MeOH. Hayler. acetone. MEK. Benzene. iPrOH. nBuOH. DMF. dioxane. pyridine Hazardous ? Hazardous iPr2O. nitromethane ● Aligned with regulations ● 67% convergence ● The divergences reflect the different weighing of criteria D. tBuOH. TEA. heptane. ethylene glycol. A. chlorobenzene. cyclohexane. AcOiPr. pentane. acetonitrile. AcOEt. DME. BnOH. MIBK. Problematic ? AcOH.

AcOnBu. cyclohexanone. pyridine Hazardous ? Hazardous iPr2O. toluene. iPrOH. acetone. nitromethane ● CHEM21 solvent guide based on this survey ● A simple ranking methodology was needed ● Based on HSE criteria ● To rank the intermediate solvents ● To rank newer/ bio-derived solvents Green Solvents | 26 . Ac2O Problematic Me-THF. heptane. DMA. Me-cyclohexane. NMP. cyclohexane. AcOiPr. nBuOH. hexane. DME. AcOMe. tBuOH. DCM. chloroform. formic acid. chlorobenzene. PhOMe. ethylene glycol. CCl4. MTBE. DMSO Problematic or THF. xylene. BnOH. DMPU. AcOEt. benzene. DMF. dioxane.CHEM21 SOLVENT GUIDE Ranking Solvents Recommended Water. MEK. methoxyethanol Highly hazardous Et2O. DCE. pentane. acetonitrile. sulfolane Recommended or MeOH. TEA. Problematic ? AcOH. EtOH. MIBK.

CHEM21 SOLVENT GUIDE ● Ranking methodology 1) Collect physical data and GHS statements from the Safety Data Sheets Family Solvent BP FP AIT Worst H4xx (°C) (°C) (°C) H3xx Water Water 100 na na none none Alcohols EtOH 78 13 423 H319 none i-PrOH 82 12 456 H319 none n-BuOH 118 29 367 H318 none Esters Ethyl acetate 77 -4 484 H319 none i-PrOAc 89 2 460 H319 none n-BuOAc 126 22 421 H336 none Ethers Diethyl ether 34 -45 160 H302 none Diisopropyl ether 69 -28 405 H336 none Me-THF 80 -11 270 H318 none 1.4-Dioxane 101 12 180 H351 none Anisole 154 52 475 none none DME 85 -6 200 H360 none Hydrocarbons Pentane 36 -40 285 H304 H411 Hexane 69 -22 225 H361 H411 Heptane 98 -4 215 H304 H410 Me-Cyclohexane 101 -4 258 H304 H411 Benzene 80 -11 562 H350 none Toluene 111 4 480 H351 none Xylenes 140 27 480 H312 none Green Solvents | 27 .

AIT < 200°C Hydrocarbons Pentane -40 285 8 . the AIT. the resistivity.Ability to form peroxides (EUH019) Heptane -4 215 6 Me-Cyclohexane -4 258 6 Benzene -11 562 6 Toluene 4 480 5 Xylenes 27 480 4 Green Solvents | 28 .4-Dioxane 12 180 7 Anisole 52 475 4 1 is added to the safety score for each of the following properties: DME -6 200 7 .Resistivity > 108 W. etc Family Solvent FP AIT Safety (°C) (°C) score Water Water na na 1 Alcohols EtOH 13 423 4 i-PrOH 12 456 4 Basic 1 3 4 5 7 n-BuOH 29 367 3 Safety Esters Ethyl acetate -4 484 5 score Flash Point > 60 23 to 60 22 to 0 -1 to -20 < -20 i-PrOAc 2 460 4 (°C) n-BuOAc 22 421 4 GHS .CHEM21 SOLVENT GUIDE ● Ranking methodology 2) The safety score is calculated from the FP. H226 H225 or H224 Ethers Diethyl ether -45 160 10 Diisopropyl ether -28 405 9 Me-THF -11 270 6 1.m Hexane -22 225 8 .

2) (cat. CHEM21 SOLVENT GUIDE ● Ranking methodology 3) The health score derives from the most stringent H3xx statement + 1 if BP < 85°C Family Solvent BP Worst Health Health score 2 4 6 7 9 (°C) H3xx score Water Water 100 none 1 CMR H341 H351 H340 H350 Alcohols EtOH 78 H319 3 H361 H360 i-PrOH 82 H319 3 (cat. 1) n-BuOH 118 H318 4 Esters Ethyl acetate 77 H319 3 STOT H371 H373 H334 H370 H372 i-PrOAc 89 H319 2 n-BuOAc 126 H336 2 Ethers Diethyl ether 34 H302 3 Diisopropyl ether 69 H336 3 H302 H312 H301 H311 H300 H310 Me-THF 80 H318 5 Acute toxicity H332 H336 H331 H330 1.4-Dioxane 101 H351 6 Anisole 154 none 1 DME 85 H360 9 Hydrocarbons Pentane 36 H304 3 H315 H317 H318 H314 (skin) Hexane 69 H361 7 Irritation H319 H335 (eyes) Heptane 98 H304 2 Me-Cyclohexane 101 H304 2 Benzene 80 H350 10 Toluene 111 H351 6 Xylenes 140 H312 2 Green Solvents | 29 .

CHEM21 SOLVENT GUIDE ● Ranking methodology 4) The Environment score depends on the BP and on the H4xx statement Family Solvent BP H4xx Env. (°C) score Water Water 100 none 1 Alcohols EtOH 78 none 3 i-PrOH 82 none 3 Environment 3 5 7 n-BuOH 118 none 3 score Esters Ethyl acetate 77 none 3 BP (°C) 70-139 50-69 <50 i-PrOAc 89 none 3 140-200 >200 n-BuOAc 126 none 3 GHS No H4xx after full H412 H413 H400 H410 H411 Ethers Diethyl ether 34 none 7 REACh registration Diisopropyl ether 69 none 5 Me-THF 80 none 3 1.4-Dioxane 101 none 3 Anisole 154 none 5 Other No. or partial REACh DME 85 none 3 registration Hydrocarbons Pentane 36 H411 7 Hexane 69 H411 7 Heptane 98 H410 7 Water: score= 1 Me-Cyclohexane 101 H411 7 H420 (ozone layer hazard): score = 10 Benzene 80 none 3 Toluene 111 none 3 Xylenes 140 none 5 Green Solvents | 30 .

4-Dioxane 7 6 3 Problematic One score = 7 Problematic Anisole 4 1 5 Problematic DME 7 9 3 Hazardous (red) Hydrocarbons Pentane 8 3 7 Hazardous 4 < Two scores < 6 Problematic Hexane 8 7 7 Hazardous Heptane 6 2 7 Problematic (yellow) Me-Cyclohexane 6 2 7 Problematic Other Recommended Benzene 6 10 3 Hazardous Toluene 5 6 3 Problematic Xylenes 4 2 5 Problematic Green Solvents | 31 .CHEM21 SOLVENT GUIDE ● Ranking methodology 5) The ranking by default is given by the combination of HS&E scores Family Solvent Safety Health Env. Ranking by score score score default Water Water 1 1 1 Recommended Alcohols EtOH 4 3 3 Recommended Combination of Solvent ranking by i-PrOH 4 3 3 Recommended SH&E scores default n-BuOH 3 4 3 Recommended Esters Ethyl acetate 5 3 3 Recommended One score > 8 Hazardous i-PrOAc 4 2 3 Recommended (red) n-BuOAc 4 2 3 Recommended Ethers Diethyl ether 10 3 7 Hazardous Two scores > 7 Hazardous Diisopropyl ether 9 3 5 Hazardous (red) Me-THF 6 5 3 Problematic 1.

4-Dioxane 101 12 H351 none 7 6 3 Problematic Hazardous Anisole 154 52 none none 4 1 5 Problematic Recommended DME 85 -6 H360 none 7 9 3 Hazardous Hazardous Hydrocarbons Pentane 36 -40 H304 H411 8 3 7 Hazardous Hazardous Hexane 69 -22 H361 H411 8 7 7 Hazardous Hazardous Heptane 98 -4 H304 H410 6 2 7 Problematic Problematic Me-Cyclohexane 101 -4 H304 H411 6 2 7 Problematic Problematic Benzene 80 -11 H350 none 6 10 3 Hazardous HH Toluene 111 4 H351 none 5 6 3 Problematic Problematic Xylenes 140 27 H312 none 4 2 5 Problematic Problematic Green Solvents | 32 . Ranking by Ranking from (°C) (°C) H3xx score score score default the survey Water Water 100 na none none 1 1 1 Recommended Recommended Alcohols EtOH 78 13 H319 none 4 3 3 Recommended Recommended i-PrOH 82 12 H319 none 4 3 3 Recommended Recommended n-BuOH 118 29 H318 none 3 4 3 Recommended Recommended Esters Ethyl acetate 77 -4 H319 none 5 3 3 Recommended Recommended i-PrOAc 89 2 H319 none 4 2 3 Recommended Recommended n-BuOAc 126 22 H336 none 4 2 3 Recommended Recommended Ethers Diethyl ether 34 -45 H302 none 10 3 7 Hazardous HH Diisopropyl ether 69 -28 H336 none 9 3 5 Hazardous Hazardous Me-THF 80 -11 H318 none 6 5 3 Problematic Problematic 1.CHEM21 SOLVENT GUIDE ● The ranking thus obtained is consistent with the ranking based on the survey of classical solvents (81% agreement) Family Solvent BP FP Worst H4xx Safety Health Env.

MTBE.CHEM21 SOLVENT GUIDE ● As the model is valid. BnOH. AcOH. it can be used to assign a preliminary greenness assessment of any solvent ● Intermediate solvents ● Bio-derived solvents ● Newer solvents Ranking Solvents Recommended MeOH. MEK. MIBK. or Problematic acetone. formic Hazardous ? acid. Ac2O Problematic or THF. cyclohexane. tBuOH. ethylene glycol. pyridine Green Solvents | 33 . ? AcOMe. DCM. cyclohexanone.

CHEM21 SOLVENT GUIDE ● Ranking of intermediate solvents ● A debate is needed (chemists + occupational hygienists) Family Solvent Safety Health Env. score Ranking by default score score Alcohols MeOH 4 7 5 Problematic t-BuOH 4 3 3 Recommended Benzyl alcohol 1 2 7 Problematic Ethylene glycol 1 2 5 Recommended Ketones Acetone 5 3 5 Problematic MEK 5 3 3 Recommended MIBK 4 2 3 Recommended Cyclohexanone 3 2 5 Recommended Esters Methyl acetate 5 3 5 Problematic Ethers MTBE 8 3 5 Hazardous THF 6 7 5 Problematic Hydrocarbons Cyclohexane 6 3 7 Problematic Halogenated DCM 1 7 7 Hazardous Amines Pyridine 4 2 3 Recommended Acids Formic acid 3 7 3 Problematic Acetic acid 3 7 3 Problematic Ac2O 3 7 3 Problematic Green Solvents | 34 .

score Ranking by default Ranking after score score discussion Alcohols MeOH 4 7 5 Problematic Recommended t-BuOH 4 3 3 Recommended Recommended Benzyl alcohol 1 2 7 Problematic Problematic Ethylene glycol 1 2 5 Recommended Recommended Ketones Acetone 5 3 5 Problematic Recommended MEK 5 3 3 Recommended Recommended MIBK 4 2 3 Recommended Recommended Cyclohexanone 3 2 5 Recommended Problematic Esters Methyl acetate 5 3 5 Problematic Problematic Ethers MTBE 8 3 5 Hazardous Hazardous THF 6 7 5 Problematic Problematic Hydrocarbons Cyclohexane 6 3 7 Problematic Problematic Halogenated DCM 1 7 7 Hazardous Hazardous Amines Pyridine 4 2 3 Recommended Hazardous Acids Formic acid 3 7 3 Problematic Problematic Acetic acid 3 7 3 Problematic Problematic Ac2O 3 7 3 Problematic Problematic Green Solvents | 35 .CHEM21 SOLVENT GUIDE ● Ranking of intermediate solvents ● A debate is needed (chemists + occupational hygienists) Family Solvent Safety Health Env.

a. 3-Propane diol 214 >100 none none 1 1 7 Problematic Glycerol 290 177 none none 1 1 7 Problematic Esters i-Butyl acetate 115 22 H336 none 4 2 3 Recommended i-Amyl acetate 142 25 none none 3 1 5 Recommended Glycol diacetate 186 82 none none 1 1 5 Recommended g-Valerolactone 207 100 n.a.a. 1 5 7 Problematic Diethyl succinate 218 91 n. 1 2 7 Problematic Miscellaneous Ethyl lactate 155 47 H318 none 3 4 5 Problematic Lactic acid 230 113 H318 none 1 4 7 Problematic TH-Furfuryl alcohol 178 75 H360 none 1 9 5 Hazardous Green Solvents | 36 .CHEM21 SOLVENT GUIDE ● Ranking of bio-derived solvents Family Solvent BP (°C) FP (°C) Worst H4xx Safety Health Env. n.a.a. Ranking by H3xx score# score score default Alcohols i-Butanol 107 28 H318 none 3 4 3 Recommended i-Amyl alcohol 131 43 H315 none 3 2 3 Recommended 1.a.a. n. 1 5 7 Problematic Hydrocarbons D-Limonene 175 49 H304 H400 4 2 7 Problematic Turpentine 166 38 H302 H411 4 2 7 Problematic p-Cymene 177 27 n. n. 4 5 5 Problematic Aprotic polar Dimethyl carbonate 90 16 none none 4 1 3 Recommended Ethylene carbonate 248 143 H302 none 1 2 7 Problematic Propylene carbonate 242 132 H319 none 1 2 7 Problematic Cyrene 203 61 H319 n.

CHEM21 SOLVENT GUIDE ● Ranking of ethers Solvent BP (°C) FP (°C) Worst H4xx Safety Health Env. Ranking by H3xx score# score score default MTBE 55 -28 H315 none 8 3 5 Hazardous ETBE 72 -19 H336 none 7 3 3 Problematic CPME 106 -1 H302 H412 7 2 5 Problematic TAME 86 -7 H302 none 6 2 3 Recommended THF 66 -14 H351 none 6 7 5 Problematic Me-THF 80 -11 H318 none 6 5 3 Problematic Green Solvents | 37 .

C. and the University of York. a discussion is needed in each institution to challenge the ranking ● The environment criterion should include the CO2 synthesis impact D. Abou- Shehada. P. GSK. Sneddon. Wells. Prat.. J. Pfizer.CHEM21 SOLVENT GUIDE ● Gives a preliminary desirability of any solvents for fine chemistry scale- up purposes ● Classical solvents ● Bio-derived solvents ● Newer solvents ● Is the fruit of a successful collaboration between (inter alia) Sanofi. ● The methodology is not perfect ● The health criterion should be based on OEL ● It only gives a preliminary assessment. Green Chem. Hayler. A. advance article Green Solvents | 38 . Dunn. H. S. McElroy. Orion. R. J. J&J.

inspired by each others ● Regulations are the same for everyone. like Sanofi’s. will continue to exist and evolve ● Solvents guide have been elaborated for pharma of fine chemical industries ● This does not favor bio-sourced solvents (high BP) ● The field of green chemistry is wider ● Solvents guide are needed for other applications ● The methodology of CHEM21 guide can be adapted to these applications • Different weighing of criteria Green Solvents | 39 . and restrain the solvent choice ● CHEM21 solvent guide is very useful for a preliminary ranking ● Especially when little data are available ● But a discussion between experts will always be necessary to give a final ranking ● Companies guide.CONCLUSIONS ● There is no universal solvent guide but: ● Guides tend to homogenize.

Isnard. Ducandas. Green Solvents | 40 . Cruciani and P. S. T. Main contributors: Sanofi: O.R. Sneddon (GSK) . S. Dunn (Pfizer). Hosek. P. CHEM21: A. resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007- 2013) and EFPIA companies in kind contribution. The research for this work has received funding from the Innovative Medicines Initiative joint undertaking project CHEM21 grant agreement n°115360. J. Abou-Shehada (York). Wells (Charnwood Consulting). Ruisseau. McElroy & S. Senac. E. Flemming. P. official policy of any individual company or institution. Hayler & H. Guntrum. Letestu. C. V. The conclusions reached in this presentation are the collective opinion of the authors who contribute to the CHEM21 consortium and do not reflect. Pardigon. at this time. P. H. J.

HEMI-SYNTHESIS OF ARTEMISININE Green Solvents | 41 .

HEMI-SYNTHESIS OF ARTEMISININE Green Solvents | 42 .

Bayer. ● CatSci Ltc. Sanofi (co-coordinator). Pfizer ● Universities ● University of Manchester (Managing Entity) ● Austrian Center of Industrial Biotechnology ● University of Stuttgart (Institute for Technical Biochemistry) ● University of Leeds ● University of Antwerp ● University of Durham ● Leibniz Institute for Catalysis (LIKAT) ● University of York ● Small and medium companies ● Charnwood Technical Consulting ● Evolva Biotec ● Reaxa Ltd. CHEM21. ● VU Amsterdam Green Solvents | 43 . Orion.Who We Are ● EFPIA ● GSK (coordinator). J & J.