Principles and Practices of Green Chemistry Prepared by: Milton Perez, P.E. Associate Director,Env. Affairs Pfizer La Jolla Laboratories IEA Biotech Committee April 19, 2006

Agenda Introduction to Green Chemistry Safety Aspects of Green Chemistry Some Practical Considerations Example of Green Chemistry Screening Tools

What is green chemistry? “…the utilization of a set of principles that reduces or eliminates the use or generation of hazardous substances in the design, manufacture and application of chemical products.” *Source: Paul T. Anastas and John C. Warner, Green Chemistry: Theory and Practice (New York, NY: Oxford University Press Inc., 1998). ISBN 0 19 850698 8

Why Green Chemistry? Green Chemistry Describes Technologies, Techniques, and Philosophies, that Enable Efficient Discovery, Development and Manufacturing of new Pharmaceuticals. As our Industry Becomes Increasingly Competitive, It is Incumbent that We Incorporate the Most Efficient, Economical, and Environmentally Sound Practices Possible in Our Daily Operations

12 Principles of Green Chemistry   (Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice, Oxford University Press: New York, 1998, p.30. By permission of Oxford University Press) 1. Prevention It is better to prevent waste than to treat or clean up waste after it has been created. 2. Atom Economy Synthetic methods should be designed to maximize the incorporation of all materials used in the process into the final product. 3. Less Hazardous Chemical Syntheses Wherever practicable, synthetic methods should be designed to use and generate substances that possess little or no toxicity to human health and the environment. 4. Designing Safer Chemicals Chemical products should be designed to effect their desired function while minimizing their toxicity.

5. Safer Solvents and Auxiliaries The use of auxiliary substances (e.g., solvents, separation agents, etc.) should be made unnecessary wherever possible and innocuous when used.   6. Design for Energy Efficiency Energy requirements of chemical processes should be recognized for their environmental and economic impacts and should be minimized. If possible, synthetic methods should be conducted at ambient temperature and pressure. 7. Use of Renewable Feedstocks A raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable. 8. Reduce Derivatives Unnecessary derivatization (use of blocking groups, protection/ deprotection, temporary modification of physical/chemical processes) should be minimized or avoided if possible, because such steps require additional reagents and can generate waste.

12 Principles of Green Chemistry 9. Catalysis Catalytic reagents (as selective as possible) are superior to stoichiometric reagents.   10. Design for Degradation Chemical products should be designed so that at the end of their function they break down into innocuous degradation products and do not persist in the environment. 11. Real-time analysis for Pollution Prevention Analytical methodologies need to be further developed to allow for real-time, in-process monitoring and control prior to the formation of hazardous substances. 12. Inherently Safer Chemistry for Accident Prevention Substances and the form of a substance used in a chemical process should be chosen to minimize the potential for chemical accidents, including releases, explosions, and fires.

Sildenafil (Viagra) Case Study Early Development Route Final Process Route

Green Chemistry and the Synthesis of Viagra (Sildenafil) 1300 L/kg Medicinal Chemistry 1990 100 L/kg Optimised Med. Chemistry 1994 22 L/kg Commercial Route (1997) 7 L/kg following solvent recovery CH2CL2 Acetone Ethanol Methanol Ether Ethyl Acetate 2-Butanone Toluene Pyridine t-Butanol 4 L/kg Future Target New solvent

Safety Aspects of Green Chemistry 1) Prevention Less volume >>> less chance for unplanned events. If hazardous waste is not generated, the infrastructure to manage it will not be required, or if required, to a lesser degree. Fewer hazardous waste storage areas, or smaller ones, means less time spent on weekly inspections and therefore less time in direct contact with containers.

Safety Aspects of Green Chemistry 2) Atom Efficiency The more efficient the transformation of raw materials into product, the fewer waste streams that will be generated and the less risk of hazardous substances being generated and therefore handled.

Safety Aspects of Green Chemistry 3) Less Hazardous Chemical Synthesis With less hazardous chemical processes, the result will be less risk of unplanned events. Process safety requirements will decrease. Less risk related to storage of hazardous materials due to decreased raw material needs; therefore potentially less need for fire/life safety infrastructure, segregated storage areas.

Safety Aspects of Green Chemistry 4) Design Safer Chemicals The more inherently safer a product is, the safer they will be to manufacture. Pesticides are a good example. 5) Safer Solvents and Auxiliaries How much time and resources are spent assessing and managing solvent exposures? Many halogenated solvents >>> suspected carcinogens. Spark hazards?

Safety Aspects of Green Chemistry 6) Design for Energy Efficiency With less heat and pressure, there is less risk of injury due to unplanned release or venting. Cryogenic systems can also cause injury due to extreme cold. 7) Use Renewable Feedstocks Sustainability aspect of Green Chemistry

Safety Aspects of Green Chemistry 8) Reduce Derivatives Fewer steps >>> fewer hazardous materials >>> less risk of exposure to employees. 10) Design For Degradation Another principle relating sustainability to green chemistry. 11) Real Time Analysis for Pollution Prevention Real-time monitoring allows for assurance of proper reaction conditions which leads to a more controlled situation. More control >>> less risk of generating unwanted products and less risk of upsets. If sampling is done manually, this method would avoid potential employee exposures and the need for personal protective equipment.

Safety Aspects of Green Chemistry 12) Inherently Safer Chemistry for Accident Prevention Industry has experienced many notable chemical accidents; some through carelessness, others accidental, even others unpredictable, and few intentional. On the whole, if you minimized the amount of chemicals used, and select less hazardous materials, the risk decreases. Be careful not to increase accident potential inadvertently while minimizing waste generation; need to consider the whole situation.

Some Practical Considerations: Reducing MeCl Usage Extractions If you need to use MeCl measure it, don’t just fill up the separating funnel ? Can Ethyl acetate, t-butyl methyl ether or toluene be used instead ? Chromatography Can Ethyl Acetate : Heptane mixtures be used (similar polarity) ? EtOH/EtOAc mixtures are an alternative to MeCl/MeOH Can Reverse Phase Chromatography be used ? Reactions Can you reduce the concentration, CRD suggest 1g in 5ml. Evaporation When stripping down MeCl on a rotary evaporator. Transfer the evaporated solvent to the waste container periodically

Some Practical Considerations: Reducing MeCl Usage Consider using 2-MeTHF as a replacement for DCM in extractions 2-MeTHF avoids the emulsions associated with DCM and has low water solubility making it excellent for extractions. Consider using isopropyl acetate for extractions More stable to base than EtOAc and has lower water solubility. Trifluorotoluene (benzotrifluoride) is heavier than water and immiscible with water. A potential bottom level replacement for DCM though significantly more expensive. Note multiple extractions are often not required All of the product is often in the first extraction (especially when extraction solvents with low water solubility are used

Green Chemistry Screening Tools: Solvent Replacement Table Non-Green Solvents Alternative Pentane Heptane Hexane(s) Di-isopropyl ether or ether 2-MeTHF or t-Butyl methyl ether Dioxane or dimethoxyethane Chloroform, dichloroethane or carbon tetrachloride DCM DMF or DMAc Acetonitrile or NMP Pyridine Et3N (if pyridine used as base) DCM (extractions) EtAc, MTBE, toluene, 2-MeTHF DCM (chromatography) EtAc / Heptanes Benzene Toluene

Side by Side Comparisons MeCl / Ethyl Acetate Methylene Chloride Ethyl Acetate Extraction solvent Reaction solvent Chromatography eluant Purchase Cost (4L ACS) $ 3.03 / L $ 3.52 / L Hazardous Air Pollutant*? Yes No Ozone Depleting Compound*? No No Occupational Exposure Limit (PEL)? 25 ppm 400 ppm Carcinogen**? Anticipated Not Anticipated Flammable? No Yes Estimated Disposal Cost $0.48-1.04/liter $0.22-0.28/liter

Side by Side Comparisons 2-Methyl THF / THF 2 Me THF THF Extraction solvent Reaction solvent Green solvent Purchase Cost $ 54.46 / L $ 24.70 / L Source Corn starch Oil “Peroxide forming Potential” Lower than THF Present. Miscibility with H2O No Yes Global warming Potential No No Occupational Exposure Limit (PEL) Not established 200 ppm Carcinogen? Not established No Flammable? Yes Yes Boiling Point 78-80oC 66oC

Side by Side Comparisons Hexane / Heptane Hexanes Heptane Chromatography eluant Purchase Cost (HPLC Grade) $2.20/liter $5.25/liter Hazardous Air Pollutant*? Yes No VOC*? Yes Yes Ozone Depleting Compound*? No No Occupational Exposure Limit(TLV)? 50 ppm (n-hexane) 400 ppm Carcinogen**? Not Anticipated Not Anticipated Boiling Point 68-70oC 98oC Flash Point Hazardous waste cost??? -22oC -4oC

Green Chemistry Screening Tools: Solvent Selection Spreadsheet

Questions?