Green Chemistry at Pfizer

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Green Chemistry at Pfizer
Peter Dunn Pfizer Green Chemistry Lead
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Agenda

• Introduction to Green Chemistry at Pfizer
• What it is, what it encompasses
• Making a Difference through Green Chemistry
• Engagement and alignment across the company
• Internal tools helping chemists go green --
  solvent guides, reagent guide, acid/base guide,
  metrics tool.
• Education
• Supporting and influencing academic research
• Results
• Solvent reduction program across our Research
  Division
• Pregabalin (Lyrica) Process Development Program
• Atorvastatin (Lipitor) Process Development
  Program
• Future Directions

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Pfizer Green Chemistry Mission

• To introduce, educate and promote application
  of Green Chemistry across Pfizer.
• Key Philosophy Voluntary restraint is better
  than enforced constraint.
• Green Chemistry includes protection of the
  environment and worker safety.
• Informing and influencing the Green
  Chemistry research agenda.

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Pfizer Green Chemistry Engagement
Alignment

• Success required attention to Green Chemistry
  across all our locations research, scale-up, and
  manufacturing facilities.
• We have
• A full-time GC leader with a company-wide
  responsibility
• A company GC Policy and Steering Committee
  (responsible for the strategic plan,
  communications plans, key policy decisions, and
  monitoring of performance).
• Research site GC teams Medicinal Chemists,
  Process Chemists and EHS colleagues, set annual
  objectives, manage site-based awards programs,
  raise awareness, and drive behavior change.
• Integrated GC into our co-development process
  with manufacturing and initiated Manufacturing GC
  Awards.

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Use of Internal Tools Med. Chem. Solvent
Selection Guide
Undesirable Pentane Hexane(s) Di-isopropyl
ether Diethyl ether Dichloromethane
Dichloroethane Chloroform NMP DMF
Pyridine DMAc Dioxane Dimethoxyethane Benzene C
arbon tetrachloride
Preferred Water Acetone Ethanol 2-Propanol
1-Propanol Ethyl Acetate Isopropyl acetate
Methanol MEK 1-Butanol t-Butanol
Usable Cyclohexane Heptane Toluene
Methylcyclohexane TBME Isooctane Acetonitrile
2-MeTHF THF Xylenes DMSO Acetic Acid
Ethylene Glycol
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Solvent Replacement Table
Red 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 NMP or DMAc Acetonitrile
Pyridine Et3N (if pyridine used as base)
DCM (extractions) EtOAc, MTBE, toluene, 2-MeTHF
DCM (chromatography) EtOAc / Heptanes
Benzene Toluene
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Pfizer Green Chemistry Results
Some Examples
Combined Groton, Sandwich and La Jolla DCM use
2004 - 2007
120.4
93.5
DCM use per year in tonnes
58.0
51.7
Year
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Pfizer Solvent Switching Program

• PGRD Global Diisopropylether Use

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Reagent Selection Guide

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Reagent Selection Guide

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Example Oxidation of Primary Alcohol to Aldehyde
PCC PDC
CrO3
References for Reagents without links
DMSO/oxalyl chloride (Swern)
DMSO/TFAA
DMSO/SO3-py
Dess-Martin periodinane
NiO2 BaMnO4 MnO2
Me2S/Cl2 (Corey-Kim)
TEMPO/tcca
TPAP/NMO
PIPO/NaOCl
Cl2/py
DMSO/DCC (Pfitzner-Moffatt)
TEMPO/NaOCl
NaOCl/RuO2
Air/TEMPO/water
Air/metal(cat)
Air/TEMPO/metal(cat)

• An excellent review covering the Green aspects of
  alcohol oxidations can be found in 2006 Ang Chem
  Int 3206
• In addition 2005JOC729 pulls together a well
  organised collection of key references for
  various air oxidation of alcohols

Green Criteria for this Transformation
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Green Chemistry - Pfizers Support and Influence
on Academic Research

• Membership in the ACS GCI Pharmaceutical
  Roundtable
• Let Academics and Govt agencies know of some of
  the key challenges in Pharmaceutical
  Manufacturing so they can be addressed (see P.J.
  Dunn et al., Green Chemistry, 2007, 9, 411-420)
• Inform research community, encourage funding
  agencies.
• Selectively fund key research areas (examples
  include)
• Amide formation with high economy
• Amide reduction (through the Roundtable)
• Oxidations without chlorinated solvents
• Suzuki reactions without halogenation (through
  the Roundtable)
• Solvent recovery using membrane technology

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Pfizer Green Chemistry - Education

• Pfizer believes education is a key to changing
  behaviors of present colleagues and future
  scientists
• We
• Hold GC seminars at all our research sites - by
  chemists for chemists with prominent chemistry
  speakers
• Hold GC workshops for university students (St
  Louis, Connecticut, Puerto-Rico, Ireland, UK)
• Have worked with educational partners to develop
  a middle school green chemistry (sustainability)
  curriculum
• http//grogrdapp66.pfizer.com8080/ram/temp_files/
  2007/GreenChemistry_6-12-07.asx

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Pfizer Green Chemistry Results External
Recognition

• Institute of Chemical Engineers (IChemE)-
  AstraZeneca Award
• Excellence in Green Chemistry and Engineering
  Award (2006)
• For Lyrica revised synthesis significant
  reductions in waste by using a enzymatic process,
  and performing all reaction steps in water
• UK Institute of Chemical Engineers (IChemE)
• Crystal Faraday Award for Green Chemical
  Technology" (2003)
• For process redesign of Viagra (sildenafil
  citrate) Sets a new benchmark standard for
  minimising solvent use in Pharmaceutical
  Manufacturing
• U.S. Environmental Protection Agency (EPA)
• Presidential Green Chemistry Award
  (2002)
• Revised manufacturing process for Zoloft
  (sertraline hydrochloride) - doubled product
  yield, and significantly reduced environmental
  impacts (use of resources, waste minimization)

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Green Chemistry in Process Dev.

• Pregabalin (Lyrica) is a Drug for the treatment
  of Neuropathic Pain
• Launched in the US in September 2005
• Sales 1.16 billion (2006), 1.8 billion (2007)

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Medicinal Chemistry Pregabalin Synthesis

• 10 steps, 33 overall yield
• Cost was 6x target
• Silverman et al. Synthesis, 1989, 953. (racemic
  synthesis)
• Yuan et al., Biorg. Med. Chem. Lett., 1991, 34,
  2295 (chiral synthesis shown on slide).

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Pregabalin (Lyrica) Launch Process

• Efficient synthesis of racemic Pregabalin
• Final Step Classical Resolution
• Wrong enantiomer difficult to recycle
• E-Factor 86
• Chemistry Published (Org. Process R and D, 1997,
  1, 26)

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Asymmetric Hydrogenation Route

• Higher yield (42 overall)
• Original Catalyst (Me-DuPHOS-Rh, S/C ratio 2700)
• Licensed chiral ligand expensive
• In-house chiral ligand developed to give lower
  costs
• Much improved environmental profile but similar
  cost to resolution route.
• Chemistry Published (2004JACS5966) (2003JOC5731)

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Enzymatic Resolution of CNDE

• Enzymatic hydrolysis of Cyano diester enabled
  early resolution of chiral center
• Enzyme screen revealed 2 (S)-selective hits with
  Egt200
• Thermomyces lanuginosus lipase (Novozymes)

• Rhizopus delemar lipase (Amano)

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Biocatalytic Kinetic Resolution Route

• Biocatalytic with low (0.8) protein loading
• Resolution at first step (wrong enantiomer
  can be recycled)
• High throughput simple operations
• All 4 reactions conducted in water
• Enzymatic Step scaled up to 10, 000 Kg scale
• E-Factor improved from 86 to 17

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Comparison of Pregabalin Processes

• Chemoenzymatic route uses gt5x less inputs than
  1st generation route

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Pregabalin Synthetic Improvements

• By replacing all reaction solvents with water,
  bringing the Resolution to the beginning, and the
  Raney nickel reduction to the end, the proposed
  improvements will yield annual improvements of
• Starting material usage reduction of 800 tons
• Solvent reductions
• Methanol 1 million gallons
• Ethanol 0.4 million gallons
• Tetrahydrofuran 2.2 million gallons
• Isopropanol 2 million gallons
• Mandelic Acid usage eliminated 500 tons
• Energy use reduced by 83

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Pregabalin Summary

• Launched in the US in September 2005
• Treatment of Neuropathic pain
• Sales in 2006 1.16 billion
• Sales in 2007 1.8 billion
• New enzymatic chemistry successfully scaled up
  to 10 tonnes scale.
• Process was switched to the enzymatic
• route in 3Q2006
• By making the switch to optimal route very early
  in the product lifetime, Pfizer ensures close to
  maximum benefits to the environment.
• Chemistry has been published Martinez et al.
  (OPRD, 2008, 11, 392).
• In 2006 Pfizer received the AstraZeneca Award for
  Excellence in Green Chemistry and Engineering for
  its work on Pregabalin.

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New Process for Atorvastatin (Lipitor)

• The reduction of hydroxyketone to cis diol is a
  key step that sets the stereochemistry for
  atorvastatin. This step has now been converted
  from a chemical reduction to a biocatalytic
  reduction

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Comparison of Chemical and Biocatalytic Reactions

• Chemical process is slow 80 hours for 6 x
  methanol distillations to remove the boron
  based waste. Enzymatic reaction takes lt24 hours
  with a relatively simple work-up.
• Quality Enzymes are highly selective, giving
  improved cis trans ratio.
• Triethyl Borane pyrophoric and toxic
• NaBH4 Safety hazard. H2 source.
• Multiple solvents and low temperature
  requirement eliminated

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Co-factor Recycling Systems

• NAD 1500/kg
• NADP 8000/kg

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Co-factor Recycling Systems

• NAD 1500/kg
• NADP 8000/kg

High Levels of Aqueous Waste
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Co-factor Recycling Systems
Co-factor Recycling Systems
Greener Option

• NAD 1500/kg
• NADP 8000/kg

• NAD 1500/kg
• NADP 8000/kg

High Levels of Aqueous Waste
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Environmental Benefits

• The total organic waste for the reduction step
  will be reduced by 3.4 million L / annum (65
  reduction)
• Liquid Nitrogen usage of 3 million L / annum
  is eliminated
• Large Savings in energy use and processing
  time.

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Where do we go from here ?

• Aggressively pursue ultra low E-Factors for our
  high volume products (especially Celebrex,
  Lyrica, Atorvastatin).
• Use a Metrics based system so that all new
  commercial products meet a good dignity level
  of environmental performance.
• Continue our successful work in minimising the
  environmental footprint to discover drugs.
• Continue with our external education work
  promoting Green Chemistry.

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Thanks and Acknowledgment

• Thank You!

• Pregabalin
• Enzyme Chemistry C. Martinez, S. Hu, J, Tao, P.
  Kellerher
• Asymmetric Hydrogenation G. Hoge, W. Kissel
• Energy Calculations Kevin Hettenbach
• Lipitor
• D. Bauer, M. Burns, A. Denhole, A. Fahy, C.
  Healy,
• OShaughnessy, E, Maitiu, F. Stomeo, G. Wittaker,
  J. Wong
• IEP, (Wiesbarden, Germany)
• 60 members of the Pfizer Green Chemistry teams
• To our partners in education and research
• To YOU todays audience!