Presentation on theme: "Green Chemistry at Pfizer Peter Dunn Pfizer Green Chemistry Lead."— Presentation transcript:
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.
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)
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!