Metrics. Yield. Atom Economy (AE) Reaction Mass Efficiency (RME) E-factor. Mass Intensity (MI)/Process Mass Intensity (PMI)

Transcription

1 Metrics Atom Economy, Reaction Mass Efficiency, E-factor, Process Mass Intensity, Life Cycle Analysis, Carbon Footprinting and measuring changes in behaviour Helen Sneddon Head of Green chemistry, GSK 5 th October 2017

2 Metrics Yield Atom Economy (AE) Reaction Mass Efficiency (RME) E-factor Industry Output (tonnes) E-factor Oil <0.1 Bulk Chemicals <5 Fine Chemicals Pharmaceuticals Mass Intensity (MI)/Process Mass Intensity (PMI)

3 E-factor comparison Example reductive amination E-factor = Environmental (E)-factor = [total waste (kg) / product (kg)] * Aldehyde, 0.45 mmol = g Chloroform, 7 ml = g Amine, 0.9 mmol = g AcOH in CHCl 3, 0.9 mmol = 1.8 ml = g NaBH(OAc) 3, 1.35 mmol = 0.286g Aq NaHCO 3, 15 g Chloroform, 15 ml = g MgSO 4 ~ 5 g Typical yield = 53% = mmol = g E factor = (55.58/0.118)-1 = 470

4 E-factor comparison Example reductive amination E-factor = Environmental (E)-factor = [total waste (kg) / product (kg)] * Aldehyde, mmol = g Amine, mmol = g 10:1 MeOH: AcOH, 5.1 ml = g Picoline borane, mmol = g Aq NaHCO 3, 10 g 2-MeTHF, 15 ml = g MgSO 4 ~ 5 g Typical yield = 75% = g E factor = (31.89/0.114)-1 = 278 (N.B. E-factor normally calculated for a whole route, not just one step)

5 5

6 6

7 7

8 8

9 9

10 10

11 11

12 Metrics: GSK chlorinated solvent usage Green & Sustainable Chemistry in Industry a Pharmaceutical Case Study 12

13 Increased adoption of the circular economy... Encouraging recycling of precious metal catalysts Green & Sustainable Chemistry in Industry a Pharmaceutical Case Study 13

14 Increased adoption of the circular economy... Encouraging recycling of inhalers 14

15 Conclusions Green & Sustainable Chemistry in Industry a Pharmaceutical Case Study 15

16 Future research opportunities Reactions that GCI companies use now but would strongly prefer better reagents Amide formation avoiding poor atom economy reagents: OH activation for nucleophilic substitution Reduction of amides without hydride reagents Oxidation/Epoxidation methods without the use of chlorinated solvents Safer and environmentally friendly Mitsunobu reaction Friedel-Crafts reaction on inactivated systems Nitrations More Aspirational reactions* Others C-H activation of aromatics (cross-couplings avoiding the preparation of haloaromatics) Aldehyde or ketone + NH 3 + X to give chiral amine Asymmetric hydrogenation of unfunctionalised olefins/enamines/imines New green fluorination methods under mild conditions N-centered chemistry avoiding azides, hydrazine etc. Asymmetric hydroamination Green sources of electrophilic nitrogen (not TosN 3, nitroso or diimide) Asymmetric hydrocyanation Replacement for dipolar aprotic solvents *Chem 21 Vision 2020

17 Acknowledgements - All involved in Green Chemistry at GSK - Catherine Alder - Richard Henderson - Ann Bullion - Catriona Oare - Mike Darcy - Giulia Paggiola -John Hayler - Israil Pendrak - Anikó Redman - Lena Shukla - Leanna Shuster - Lee Thorp Amoxicillin - Roger Barrett - Andrew Dominey - Doug Hayes - Simon Hayes - Mark Hughes - Matt John - Peter Sutton - Charles Wade and many others Green & Sustainable Chemistry in Industry a Pharmaceutical Case Study 17

18 Back up slides Green & Sustainable Chemistry in Industry a Pharmaceutical Case Study 18

19 Why Do We Need a Next Generation? Add More Solvents: Many literature sources in recent years have highlighted new potentially greener solvents, with particular emphasis on bioderived solvents. Some of these publications focus solely on derivatization or on a narrow range of property data. We wish to provide a more holistic view, examining a wide range of properties and studies. Guide scope updated from 110 to 150 solvents. Verify & Update Data: Much of the data underlining the GSK Solvent Guide was sourced 10+ years ago. Review databases and literature for more recent, relevant data. Ensure references are well documented for future users. Reassess Methodology: Incorporate new data and understandings of chemical risk. Analyze methods to ensure that they accurately reflect these risks for full dataset. Green & Sustainable Chemistry in Industry a Pharmaceutical Case Study 43

20 Methodology: Changes from Previous Generation Life Cycle Analysis (LCA): Due to lack of complete data on the majority of solvents within the dataset, LCA is no longer included in calculation of the composite score. Data available will still be retained and displayed. Health Score: Change from EU Risk Phrases to GHS Hazard Phrases. Update methods to prioritize regulatory TLVs, except where GHS phrases suggest serious risk of CMR hazards. Environment Scores (Aquatic & Air): Include 400 series GHS phrases as part of scoring methods. Definition of Scoring Areas: Summary Areas Category Areas Waste Biotreatment Solvent Recycling Incineration VOC Emissions* Environment Air Quality Impact Aquatic Impact Human Health Health Hazards* Exposure Potential Safety Flammability & Explosion Risk* Reactivity* *Priority Scoring Category Green & Sustainable Chemistry in Industry a Pharmaceutical Case Study 44

21 Solvent Composite Scoring The 10 category scores are combined to give summary scores for each of: Waste, Environment, Health, and Safety. These are then combined to give a composite score: Composite Score 4 Waste Environment Health Safety A solvent is classified as Red if any one of the following criteria are true: Any one of the VOC Emissions, Health Hazard, Flammability & Explosion, or Reactivity category scores are 2.0 or any two are 3.5. Three or more of the 10 total category scores are 3.5. If a solvent is not already classified as Red above, then: Any solvent with 4 or more data gaps is assigned as Amber. Any other solvent with composite score 6.4 is Amber. Any other solvent with composite score > 6.4 is Green. This method tries to give a holistic definition of Green solvents. Green & Sustainable Chemistry in Industry a Pharmaceutical Case Study 45

22 Methodology: A Map of the Data Involved NO x /SO x /Acid Emissions Enthalpy of Combustion Auto Ignition Temperature Electrical Conductivity* Flash Point Boiling Point Azeotrope with H 2 O? Melting Point NFPA Fire Rating Acidity Peroxide Formation Self-Reactivity Key: Waste: Incineration Recycling Biotreatment VOC Emissions Water Solubility Theoretical Oxygen Demand (ThOD) Vapor Pressure Environment: Aquatic Impact Air Impact Health: Health Hazards Exposure Safety: Flammability & Explosion Reactivity *This data point includes a particularly large number of data gaps. Green & Sustainable Chemistry in Industry a Pharmaceutical Case Study 46

23 Methodology: A Map of the Data Involved NO x /SO x /Acid Emissions Enthalpy of Combustion Auto Ignition Temperature Electrical Conductivity* Flash Point Boiling Point Azeotrope with H 2 O? Melting Point NFPA Fire Rating Acidity Peroxide Formation Self-Reactivity Key: Waste: Incineration Recycling Biotreatment VOC Emissions Water Solubility Theoretical Oxygen Demand (ThOD) Vapor Pressure Photochemical Ozone Creation Potential* (POCP) Odor Threshold* Environment: Aquatic Impact Air Impact Health: Health Hazards Exposure GHS Hazard Phrases Safety: Flammability & Explosion Reactivity Aquatic Toxicity *This data point includes a particularly large number of data gaps. Log K OW Biodegradability Green & Sustainable Chemistry in Industry a Pharmaceutical Case Study 47

24 Methodology: A Map of the Data Involved NO x /SO x /Acid Emissions Enthalpy of Combustion Auto Ignition Temperature Electrical Conductivity* Flash Point Boiling Point Azeotrope with H 2 O? Melting Point NFPA Fire Rating Acidity Peroxide Formation Self-Reactivity Key: Waste: Incineration Recycling Biotreatment VOC Emissions Water Solubility Theoretical Oxygen Demand (ThOD) Vapor Pressure Photochemical Ozone Creation Potential* (POCP) Odor Threshold* Environment: Aquatic Impact Air Impact Health: Health Hazards Exposure Regulatory Limit Values Occupational Exposure Limit (OEL)* GHS Hazard Phrases Safety: Flammability & Explosion Reactivity Aquatic Toxicity *This data point includes a particularly large number of data gaps. Log K OW Biodegradability Green & Sustainable Chemistry in Industry a Pharmaceutical Case Study 48

25 The First Generation: History of GSK s Solvent Guide 1999: SB scientists created the company s first sustainability-based solvent guide, including categories on Waste Disposal, Environmental, Human Health, and Safety concerns : Scope expanded from 47 to 110 solvents. A single page guide was developed for most commonly used solvents : Life Cycle Assessment added as additional data category : GSK publishes Green Reagent Guides covering 15 synthetic transformations. 4 1 D. Curzons, D. J. C. Constable and V. L. Cunningham, Clean Technol. Environ. Policy, 1999, 1, C. Jimenez-Gonzalez, A. D. Curzons, D. J. C. Constable and V. L. Cunningham, Clean Technol. Environ. Policy, 2005, 7, R. K. Henderson, C. Jimenez-Gonzalez, D. J. C. Constable, S. R. Alston, G. G. A. Inglis, G. Fisher, J. Sherwood, S. P. Binks, A. D. Curzons, Green Chem., 2011, 13, Sneddon, H. F., et al., Green Chemistry, 2013, 15, Green & Sustainable Chemistry in Industry a Pharmaceutical Case Study 49

26 Other Pharma Solvent Guide Efforts 2007: Pfizer publishes their Medicinal Chemistry solvent guide : IMI:CHEM21 EU public-private collaboration, including work package on training and sustainability tools : Sanofi publishes their solvent guide, sorted by chemical class : ACS GCI PR begins collaborative solvent guide efforts. 2 solvent guide 5 Other pharma companies also have internal green solvent guides which have not been fully published, but are directly contributing to ACS GCI PR efforts (e.g. Merck, BMS). 1 K. Alfonsi, J. Colberg, P. J. Dunn, T. Fevig, S. Jennings, T. A. Johnson, H. P. Kleine, C. Knight, M. A. Nagy, D. A. Perry and M. Stefaniak, Green Chem., 2008, 10, D. Prat, et al., Org. Proc. Res. Dev., 2013, 17, L. J. Diorazio, D. R. J. Hose, and N. K. Adlington, Org. Proc. Res. Dev. DOI: /acs.oprd.6b : AstraZeneca publish their Green & Sustainable Chemistry in Industry a Pharmaceutical Case Study 50