1. 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

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

3. 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

4. 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

5. 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.

6. 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.

7. 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.

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

9. 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

10. 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.

11. 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.

12. 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.

13. 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?

14. 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

15. 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.

16. 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.

17. 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

18. 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

19. 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

20. 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)? ppm ppm
Carcinogen**? Anticipated Not Anticipated
Flammable? No Yes
Estimated Disposal Cost $ /liter $ /liter

21. Side by Side Comparisons 2-Methyl THF / THF
2 Me THF
THF
Extraction solvent
Reaction solvent
Green solvent
Purchase Cost $ / L $ / 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 ppm
Carcinogen? Not established No
Flammable? Yes Yes
Boiling Point oC oC

22. 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)? ppm (n-hexane) ppm
Carcinogen**? Not Anticipated Not Anticipated
Boiling Point oC oC
Flash Point
Hazardous waste cost??? oC oC

23. Green Chemistry Screening Tools: Solvent Selection Spreadsheet

24. Questions?