Green Chemistry at Pfizer

Peter DunnPfizer Green Chemistry Lead

Agenda

Introduction to Green Chemistry at PfizerWhat it is, what it encompasses

Making a Difference through Green ChemistryEngagement and alignment across the companyInternal tools – helping chemists “go green”Education Supporting and influencing academic researchResults

Solvent Reduction Program ResearchPregabalin (Lyrica®) Process Development Program

Future Directions

Pfizer Green Chemistry MissionTo 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 SheldonGreen Chem 2005, 7, 267-278

Pfizer Green Chemistry - What Does it Encompass?

Spans R&D and ManufacturingResearch 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 chemistryIncludes 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 companySchools - 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 responsibilityA 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

WaterAcetone Ethanol 2-Propanol 1-Propanol Ethyl Acetate Isopropyl acetate Methanol MEK 1-Butanol t-Butanol

Usable

CyclohexaneHeptaneToluene Methylcyclohexane TBME IsooctaneAcetonitrile 2-MeTHF THF Xylenes DMSO Acetic Acid Ethylene Glycol

Undesirable

Pentane Hexane(s)Di-isopropyl ether Diethyl ether Dichloromethane Dichloroethane ChloroformNMPDMF PyridineDMAc Dioxane DimethoxyethaneBenzeneCarbon tetrachloride

Pfizer Solvent Replacement Table

EtOAc / HeptanesDCM (chromatography)

TolueneBenzene

EtOAc, MTBE, toluene, 2-MeTHFDCM (extractions)

Et3N (if pyridine used as base)Pyridine

AcetonitrileDMF NMP or DMAc

DCMChloroform, dichloroethane or carbon tetrachloride

2-MeTHF or t-Butyl methyl etherDioxane or dimethoxyethane

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

HeptaneHexane(s)

HeptanePentane

AlternativeRed Solvents

0

20

40

60

80

100

120

140

2004 2005 2006 2007

DC

M u

se p

er y

ear i

n to

nnes

Year

Combined Groton, Sandwich and La Jolla DCM use 2004 - 2007

120.4

93.5

58.051.7

Pfizer Green Chemistry Results –Some Examples

Pfizer Solvent Switching Program

0

5000

10000

15000

20000

25000

2004 2005 2006 2007

Isop

ropy

leth

er(IP

E) U

se/lb

s/ye

ar

Year

20771

6243

666 108

PGRD Global Diisopropylether Use

Wide Utility Scalability

"Greenness"

The ability of a reagent to work On a wide variety of drug likeMolecules. As judged by experienced Discovery Scientists

Availability, Lack of MajorThermal or Tox Hazards. AsJudged by API-Supply Chain

Criteria clearly laid outFor each transformation

Pfizer Green Chemistry –Reagent Selection Guide

Wide Utility Scalability

"Greenness"

The ability of a reagent to work On a wide variety of drug likeMolecules. As judged by experienced Discovery Scientists

Availability, Lack of MajorThermal or Tox Hazards. AsJudged by API-Supply Chain

Criteria clearly laid outFor each transformation

Pfizer Green Chemistry –Reagent Selection Guide

Wide Utility Scalability

"Greeness"

Example: Oxidation of Primary Alcohol to AldehydePCCPDC

Me2S/Cl2(Corey-

Kim)

PIPO/NaOCl

DMSO/SO3-py

DMSO/DCC(Pfitzner-Moffatt)

Dess-Martin periodane

DMSO/oxalyl chloride(Swern)

TPAP/NMO

NiO2BaMnO4MnO2

TEMPO/NaOCl

Air/metal(cat)

IBX

DMSO/TFAA

Cl2/py

TEMPO/tcca

Air/TEMPO/water

Air/TEMPO/metal(cat)

NaOCl/RuO2

Green Criteria forthis Transformation

References for Reagentswithout links

An excellent review covering the Green aspects of alcohol oxidations can be found in 2006 Ang Chem Int3206

In addition 2005JOC729 pulls together a well organised collection of key references for various air oxidation of alcohols

CrO3

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 basedShare 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. ProgramPregabalin (Lyrica®) is a Drug for the treatment of NeuropathicPainLaunched in the US in September 2005Sales $1.16 billion (2006), $1.8 billion (2007)

Medicinal ChemistryPregabalin Synthesis

10 steps, 33% overall yieldCost was 6x target

CO2H

NH2

Pregabalin

N

O

O

O

H3C Ph

1) LDA, THF

2) BrCH2CO2R ON

O

O

O

H3C PhOR

Efficient synthesis of racemic PregabalinFinal Step Classical ResolutionWrong enantiomer difficult to recycleE-Factor 86Chemistry Published (Org. Process R and D, 1997, 1, 26)

CHO

CN

CO2EtEtO2C

NH2

CO2H

NH2

CO2H

(S)-Mandelicacid

25-29 % overall> 99.5 % ee

Pregabalin (Lyrica®) LaunchProcess

Enzymatic Resolution of CNDE

Enzymatic hydrolysis of Cyano diester enabled early resolution of chiral centerHydrolase screen revealed 2 (S)-selective hits with E>200:

Thermomyces lanuginosus lipase (Novozymes)

Rhizopus delemar lipase (Amano)

(CH3)2CHCH2 CN

CO2EtEtO2C

(CH3)2CHCH2

CO2EtO2C

CN(CH3)2CHCH2

CO2EtEtO2C

CNEnzymeWater

pH = 7

R-Diester

25oC

_

S-MonoesterOrganic Soluble

+

Water SolubleRacemicDiester

Biocatalytic Kinetic Resolution Route

EtO2C CO2Et

CN

H2O

EtO2C CO2Et

CN

R-1, 85 % ee

-O2C

CN

CO2Et

H2O CN

CO2Et

H2, Ni

H2O CO2H

NH2

Lipolase

+

racemic CNDE 1

NaOEt, 100%

>98 % ee @ 45% conversion

Step 1

765g/L of total volume

recycling of R-1

(S)- CNDE acid (S)- CNEStep 285-90%

PregabalinStep 390-95%

99% purity, >99.7% eeoverall 40-45% yields after one recycling

(3.25 Kg/L of H2O)

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

(R) Diester

(S) Diester

Water

Enzyme

(R) Diester

(S) Monoester

Water

Enzyme

Enzymatic

Resolution

RacemisedRecovered

(S) Monoester

Water

Enzyme

Water

Enzyme

-CO2

(CH3)2CHCH2

CO2Et

CN

Pregabalin

Biotreatment Plant

The Pregabalin Process

Comparison of Pregabalin Processes

Chemoenzymatic route uses >5x less inputs than 1st generation route

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

Pregabalin Synthetic Improvements

By replacing all reaction solvents with water, bringing the Resolution to the beginning, and the Raney nickel reduction to the end, theproposed 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 2005Treatment of Neuropathic painSales in 2006 $ 1.16 billionSales in 2007 $ 1.8 billionNew enzymatic chemistry successfullyscaled 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

PregabalinEnzyme Chemistry –C. Martinez, S. Hu, J, Tao, P. KellerherEnergy Calculations – Kevin Hettenbach

60 members of the Pfizer Green Chemistry teamsTo our partners in education and researchTo 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.