Principles and Practices of Green Chemistry

Prepared by:Milton Perez, P.E.Associate Director,Env. AffairsPfizer 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 UniversityPress: New York, 1998, p.30. By permission of Oxford University Press)

 1. PreventionIt is better to prevent waste than to treat or clean up waste after it has been created. 2. Atom EconomySynthetic methods should be designed to maximize the incorporation of all materials used in the process into the final product. 3. Less Hazardous Chemical SynthesesWherever 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 ChemicalsChemical products should be designed to effect their desired function while minimizing their toxicity.

5. Safer Solvents and AuxiliariesThe use of auxiliary substances (e.g., solvents, separation agents, etc.) should be made unnecessary wherever possible and innocuous when used. 6. Design for Energy EfficiencyEnergy requirements of chemical processes should be recognized for theirenvironmental and economic impacts and should be minimized. If possible, synthetic methods should be conducted at ambient temperature and pressure. 7. Use of Renewable FeedstocksA raw material or feedstock should be renewable rather than depleting whenever technically and economically practicable. 8. Reduce DerivativesUnnecessary 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.

9. CatalysisCatalytic reagents (as selective as possible) are superior to stoichiometric reagents. 10. Design for DegradationChemical 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 PreventionAnalytical 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 PreventionSubstances 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.

12 Principles of Green Chemistry

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

1300 L/kgMedicinal Chemistry

1990

100 L/kgOptimised

Med. Chemistry1994

22 L/kgCommercial Route

(1997)

7 L/kgCommercial Routefollowing solvent

recovery

CH2CL2

Acetone

Ethanol

Methanol

Ether

Ethyl Acetate

2-Butanone

Toluene

Pyridine

t-Butanol

4 L/kgFuture Target

New solvent

Green Chemistry and the Synthesis of Viagra (Sildenafil)

Safety Aspects of Green Chemistry

1) PreventionLess 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 EfficiencyThe 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) Heptane

Di-isopropyl ether or ether 2-MeTHF or t-Butyl methyl ether

Dioxane or dimethoxyethane 2-MeTHF or t-Butyl methyl ether

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 ComparisonsMeCl / 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

MethyleneChloride

EthylAcetate

Side by Side Comparisons2-Methyl THF / THF

•Extraction solvent

•Reaction solvent

•Green solvent 2 Me THF THF

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 ComparisonsHexane / 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?