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 Education Supporting and influencing academic research Results Solvent Reduction Program Research Pregabalin (Lyrica ) Process Development Program Future Directions
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.
Green Chemistry What is it? Green Chemistry efficiently utilizes (preferably renewable) raw materials, eliminates waste and avoids the use of toxic and/or hazardous reagents and solvents in the manufacture and application of chemical products. Roger Sheldon Green Chem 2005, 7, 267-278
Pfizer Green Chemistry - What Does it Encompass? Spans R&D and Manufacturing Research scale synthesis of small molecules to make potential new medicines (lab scale) Scale up synthesis to make supplies of pre-clinical and clinical study materials (kilo & pilot plant scale) Manufacturing of new medicines (batch production or continuous) Includes and goes beyond synthetic chemistry Includes engineering (e.g. process technology innovation continuous processing, PAT, biocatalysts etc) Includes other sciences [e.g. Biology - substitution of radio-labeled assays, analytical chemistry, large molecule chemistry (Biologics)] Reaches outside the company Schools - influence the next generation of science and engineering students. Academia to positively shape today's chemistry research to solve industry (and society s) needs. Much of our chemistry is based on chemical reactions established 50-100 years ago!
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 Chemistry 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 a Manufacturing GC Award.
Use of Internal Tools Pfizer Solvent Selection Guide Use of Preferred Usable Undesirable Water Acetone Ethanol 2-Propanol 1-Propanol Ethyl Acetate Isopropyl acetate Methanol MEK 1-Butanol t-butanol Cyclohexane Heptane Toluene Methylcyclohexane TBME Isooctane Acetonitrile 2-MeTHF THF Xylenes DMSO Acetic Acid Ethylene Glycol Pentane Hexane(s) Di-isopropyl ether Diethyl ether Dichloromethane Dichloroethane Chloroform NMP DMF Pyridine DMAc Dioxane Dimethoxyethane Benzene Carbon tetrachloride
Pfizer Solvent Replacement Table Red Solvents Pentane Hexane(s) Di-isopropyl ether or ether Dioxane or dimethoxyethane Chloroform, dichloroethane or carbon tetrachloride DMF NMP or DMAc Pyridine DCM (extractions) DCM (chromatography) Benzene Alternative Heptane Heptane 2-MeTHF or t-butyl methyl ether 2-MeTHF or t-butyl methyl ether DCM Acetonitrile Et 3 N (if pyridine used as base) EtOAc, MTBE, toluene, 2-MeTHF EtOAc / Heptanes Toluene
Pfizer Green Chemistry Results Some Examples Combined Groton, Sandwich and La Jolla DCM use 2004-2007 140 120 120.4 DCM use per year in tonnes 100 80 60 40 93.5 58.0 51.7 20 0 2004 2005 2006 2007 Year
Pfizer Solvent Switching Program PGRD Global Diisopropylether Use 25000 Isopropylether (IPE) Use/lbs/year 20000 15000 10000 5000 20771 6243 0 2004 2005 2006 2007 Year 666 108
Pfizer Green Chemistry Reagent Selection Guide Wide Utility The ability of a reagent to work On a wide variety of drug like Molecules. As judged by experienced Discovery Scientists Scalability Availability, Lack of Major Thermal or Tox Hazards. As Judged by API-Supply Chain "Greenness" Criteria clearly laid out For each transformation
Pfizer Green Chemistry Reagent Selection Guide Wide Utility The ability of a reagent to work On a wide variety of drug like Molecules. As judged by experienced Discovery Scientists Scalability Availability, Lack of Major Thermal or Tox Hazards. As Judged by API-Supply Chain "Greenness" Criteria clearly laid out For each transformation
Example: Oxidation of Primary Alcohol to Aldehyde Wide Utility PCC PDC Scalability References for Reagents without links IBX Dess-Martin periodane TPAP/NMO CrO 3 DMSO/TFAA DMSO/DCC (Pfitzner-Moffatt) Me 2 S/Cl 2 (Corey- Kim) DMSO/oxalyl chloride (Swern) DMSO/SO 3 -py TEMPO/tcca PIPO/NaOCl TEMPO/NaOCl NiO 2 BaMnO 4 MnO 2 NaOCl/RuO 2 Cl 2 /py 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 Green Criteria for this Transformation In addition 2005JOC729 pulls together a well organised collection of key references for various air oxidation of alcohols "Greeness"
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, 411-420) Identify commonly used reactions in Pharmaceutical Manufacturing. 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 (including CA, UK, PR, CT, MI). Hold GC workshops for university students in the areas where Pfizer is based Share success internally and promote externally, (e.g. Presidential Award Winning Green Chemistry) Have worked with educational partners to develop a middle school green chemistry (sustainability) curriculum: http://grogrdapp66.pfizer.com:8080/ram/temp_files/2007/greenchemistry_6-12-07.asx
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. Exemplified by the Pregabalin Process Dev. Program 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 O O 1) LDA, THF O O N O N O NH 2 H 3 C Ph 2) BrCH 2 CO 2 R O OR H 3 C Ph CO 2 H Pregabalin 10 steps, 33% overall yield Cost was 6x target
Pregabalin (Lyrica ) Launch Process CN CHO NH 2 EtO 2 C CO 2 Et CO 2 H (S)-Mandelic acid NH 2 Efficient synthesis of racemic Pregabalin Final Step Classical Resolution Wrong enantiomer difficult to recycle CO 2 H 25-29 % overall > 99.5 % ee E-Factor 86 Chemistry Published (Org. Process R and D, 1997, 1, 26)
Enzymatic Resolution of CNDE (CH 3 ) 2 CHCH 2 EtO 2 C CN CO 2 Et Enzyme Water ph = 7 25 o C (CH 3 ) 2 CHCH 2 EtO 2 C CN (CH 3 ) 2 CHCH 2 + _ CO O 2 C 2 Et CN CO 2 Et Racemic Diester R-Diester Organic Soluble S-Monoester Water Soluble Enzymatic hydrolysis of Cyano diester enabled early resolution of chiral center Hydrolase screen revealed 2 (S)-selective hits with E>200: Thermomyces lanuginosus lipase (Novozymes) Rhizopus delemar lipase (Amano)
Biocatalytic Kinetic Resolution Route EtO 2 C CN CO 2 Et racemic CNDE 1 765g/L of total volume (3.25 Kg/L of H 2 O) recycling of R-1 NaOEt, 100% H 2 O Lipolase Step 1 EtO 2 C CN CO 2 Et R-1, 85 % ee - O 2 C + CN CO 2 Et (S)- CNDE acid >98 % ee @ 45% conversion H 2 O Step 2 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 CN (S)- CNE 85-90% CO 2 Et H 2, Ni H 2 O NH 2 CO 2 H Step 3 Pregabalin 90-95% 99% purity, >99.7% ee overall 40-45% yields after one recycling
The Pregabalin Process (CH 3 ) 2 CHCH 2 CN Racemised CO 2 Et Pregabalin Recovered (R) Diester (S) Diester Water Enzyme Enzymatic Resolution (R) Diester (S) Monoester Water Enzyme (S) Monoester Water Enzyme -CO 2 Water Enzyme Biotreatment Plant
Comparison of Pregabalin Processes Table 1. Inputs for 1000 kg Pregabalin via 1st Generation and New Routes Kilograms Inputs 1st Generation Route New Route CNDE 6212 4798 Enzyme 0 574 (S)-Mandelic acid 1135 0 Raney nickel 531 79.5 Solvents 50042 6230 Total 57920 11681.5 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 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 by Martinez et al. (OPRD, 2008, 11, on the web). In 2006 Pfizer received the AstraZeneca Award for Excellence in Green Chemistry and Engineering for its work on Pregabalin.
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 Energy Calculations Kevin Hettenbach 60 members of the Pfizer Green Chemistry teams To our partners in education and research To YOU today s audience! Pfizer GC Solvent Guide Reagent Guide has been published P.J. Dunn and D.A. Perry et al. Green Chemistry, 2008, 9, 31-36.