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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

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.
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
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
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
Pfizer Green Chemistry Results –
Some Examples
Combined Groton, Sandwich and La Jolla DCM use 2004 - 2007
140
120.4
DCM use per year in tonnes
120
93.5
100
80
58.0
60
51.7
40
20
0
2004
2005
2006
Year
2007
Pfizer Solvent Switching Program
PGRD Global Diisopropylether Use
Isopropylether (IPE) Use/lbs/year
25000
20771
20000
15000
10000
6243
5000
666
108
0
2004
2005
2006
Year
2007
Reagent Selection Guide
Scalability
Wide Utility
Availability, Lack of Major
Thermal or Tox Hazards. As
Judged by API-Supply Chain
The ability of a reagent to work
On a wide variety of drug like
Molecules. As judged by
experienced medicinal
chemists
"Greenness"
Criteria clearly laid out
For each transformation
Reagent Selection Guide
Scalability
Wide Utility
Availability, Lack of Major
Thermal or Tox Hazards. As
Judged by API-Supply Chain
The ability of a reagent to work
On a wide variety of drug like
Molecules. As judged by
experienced medicinal
chemists
"Greenness"
Criteria clearly laid out
For each transformation
Example: Oxidation of Primary Alcohol to Aldehyde
Wide Utility
Scalability
PCC
PDC
References for Reagents
without links
CrO3
DMSO/oxalyl chloride
(Swern)
DMSO/TFAA
Dess-Martin
periodinane
DMSO/SO3-py
Me2S/Cl2
(CoreyKim)
NiO2
BaMnO4
MnO2
TEMPO/tcca
TPAP/NMO
PIPO/NaOCl
DMSO/DCC
(Pfitzner-Moffatt)
TEMPO/NaOCl
Cl2/py
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
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, 411420)
 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:
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.
 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).
Pregabalin (Lyrica®) Launch
Process
CN
NH2
CHO
EtO2C
CO2Et
CO2H
(S)-Mandelic
acid
NH2
 Efficient synthesis of racemic Pregabalin
 Final Step Classical Resolution
CO2H
25-29 % overall
 Wrong enantiomer difficult to recycle
 E-Factor 86
 Chemistry Published (Org. Process R and D, 1997, 1, 26)
> 99.5 % ee
Asymmetric Hydrogenation Route
OCO2Et
CN Pd(OAc)2, PPh3
CN
CHO +
CN
CO2t-BuNH3
CN
CO (300psi)
1%
(Me-DuPHOS)-Rh
0.05% mol
45 psi, 18h
CO2Et
CN
NH2
CO2-t-BuNH3+
97.7% ee

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)
CO2H
61% (42% overall)
99.8%
BF4Rh
P
P
(S)-[Rh-Trichickenfootphos]
Enzymatic Resolution of CNDE
(CH3)2CHCH2
EtO2C
CN
Enzyme
Water
pH = 7
CO2Et 25oC
(CH3)2CHCH2
CN
(CH3)2CHCH2
+
EtO2C
Racemic
Diester
CO2Et
R-Diester
Organic Soluble
_
O2C
CO2Et
S-Monoester
Water Soluble
 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)
CN
Biocatalytic Kinetic Resolution Route
CN
recycling of R-1
NaOEt, 100%
EtO2C
R-1, 85 % ee
CN
EtO2C
+
CO2Et
racemic CNDE 1
765g/L of total volume
(3.25 Kg/L of H2O)
CO2Et
CN
H2O
Lipolase
-
O2C
CO2Et
(S)- CNDE acid
Step 1
CN
H2O
CO2Et
Step 2
>98 % ee
@ 45% conversion
(S)- CNE
85-90%
 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
H2, Ni
H2O
Step 3
NH2
CO2H
Pregabalin
90-95%
99% purity, >99.7% ee
overall 40-45% yields
after one recycling
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
80
Solvents
Total
50042
57920
6230
11682
 Chemoenzymatic route uses >5x less inputs than 1st 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®)
OH
O
OH
O
O
OH
NC
OH
O
NC
O
O
NC
O
hydroxyketone
hydroxynitrile
cis diol
O
N
H
OH
N
O
O
O
OH
O
NC
O
OH
TBIN
F
Atorvastatin
 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
OH
NC
O
Chemical Route
NaBH4
Et3B
THF/MeOH/HOAc
cryogenic temp
O
O
OH
NC
Biocatalytic Route
enzyme
aqueous buffer
ambient temperature
OH
O
O
 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
 NaBH4: Safety hazard. H2 source.
 Multiple solvents and low temperature requirement eliminated
Co-factor Recycling Systems
Substrate Coupled Co-factor Regeneration
OH O
O
NC
OH OH O
NC
O
O
ketoester
cis diol
NADH
alcohol
+
dehydrogenase NAD
isopropanol
acetone
Enzyme Coupled Co-factor Regeneration
OH O
O
NC
OH OH O
alcohol
dehydrogenase
O
NC
O
ketoester
cis diol
NADPH
NADP+
glucose
gluconic acid
glucose
dehydrogenase
Co-factor Recycling Systems
Substrate Coupled Co-factor Regeneration
OH O
O
NC
OH OH O
NC
O
O
ketoester
cis diol
NADH
alcohol
+
dehydrogenase NAD
isopropanol
acetone
Enzyme Coupled Co-factor Regeneration
OH O
O
NC
OH OH O
alcohol
dehydrogenase
O
NC
O
ketoester
cis diol
NADPH
NADP+
glucose
gluconic acid
glucose
dehydrogenase
High Levels of
Aqueous Waste
Co-factor Recycling Systems
Substrate Coupled Co-factor Regeneration
OH O
O
NC
OH OH O
NC
O
O
ketoester
cis diol
NADH
alcohol
+
dehydrogenase NAD
Greener Option
isopropanol
acetone
Enzyme Coupled Co-factor Regeneration
OH O
O
NC
OH OH O
alcohol
dehydrogenase
O
NC
O
ketoester
cis diol
NADPH
NADP+
glucose
gluconic acid
glucose
dehydrogenase
High Levels of
Aqueous Waste
Environmental Benefits
Chemical
6000000
5000000
Lt/ year
4000000
Enzymatic
3000000
Chemical
Enzymatic
2000000
1000000
0
Aqueous Waste
Organic Waste
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.
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!