Green Chemistry at Pfizer Peter Dunn Pfizer Green Chemistry Lead

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

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

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.

Use of Internal Tools – Med. Chem. Solvent Selection Guide 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 Undesirable Pentane Hexane(s) Di-isopropyl ether Diethyl ether Dichloromethane Dichloroethane Chloroform NMP DMF Pyridine DMAc Dioxane Dimethoxyethane Benzene Carbon tetrachloride

Solvent Replacement Table Red SolventsAlternative PentaneHeptane Hexane(s)Heptane Di-isopropyl ether or ether2-MeTHF or t-Butyl methyl ether Dioxane or dimethoxyethane2-MeTHF or t-Butyl methyl ether Chloroform, dichloroethane or carbon tetrachloride DCM DMF NMP or DMAcAcetonitrile PyridineEt 3 N (if pyridine used as base) DCM (extractions)EtOAc, MTBE, toluene, 2-MeTHF DCM (chromatography)EtOAc / Heptanes BenzeneToluene

DCM use per year in tonnes Year Combined Groton, Sandwich and La Jolla DCM use Pfizer Green Chemistry Results – Some Examples

Pfizer Solvent Switching Program Isopropylether (IPE) Use/lbs/year Year PGRD Global Diisopropylether Use

Reagent Selection Guide

Example: Oxidation of Primary Alcohol to Aldehyde PCC PDC Me 2 S/Cl 2 (Corey- Kim) PIPO/NaOCl DMSO/SO 3 -py DMSO/DCC (Pfitzner-Moffatt) Dess-Martin periodinane DMSO/oxalyl chloride (Swern) TPAP/NMO NiO 2 BaMnO 4 MnO 2 TEMPO/NaOCl Air/metal(cat) CrO 3 DMSO/TFAA Cl 2 /py TEMPO/tcca Air/TEMPO/water Air/TEMPO/metal(cat) NaOCl/RuO 2 Green Criteria for this Transformation References for Reagents without links  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 Chemistry - Pfizer’s 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, )  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

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:

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)

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)

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).

 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) Pregabalin (Lyrica ® ) Launch Process

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) (S)-[Rh-Trichickenfootphos]

Enzymatic Resolution of CNDE  Enzymatic hydrolysis of Cyano diester enabled early resolution of chiral center  Enzyme screen revealed 2 (S)-selective hits with E>200:  Thermomyces lanuginosus lipase (Novozymes)  Rhizopus delemar lipase (Amano)

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

Comparison of Pregabalin Processes  Chemoenzymatic route uses >5x less inputs than 1 st generation route

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 %

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.

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

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 <24 hours with a relatively simple work-up.  Quality: Enzymes are highly selective, giving improved cis: trans ratio.  Triethyl Borane: pyrophoric and toxic  NaBH 4 : Safety hazard. H 2 source.  Multiple solvents and low temperature requirement eliminated

Co-factor Recycling Systems

High Levels of Aqueous Waste

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

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. Environmental Benefits

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.

Thanks and Acknowledgment  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, O’Shaughnessy, 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 – today’s audience!