Naar een Groene

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Naar een Groene Duurzame Productie van
Farmaceutica
Roger A.Sheldon Biocatalysis
Organic Chemistry Delft University of
Technology r.a.sheldon_at_tnw.tudelft.nl
Minisymposium Groene Gezondheid
Stichting Huize Aarde Enschede,15
februari,2006
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Sustainability Meeting the needs of the present
generation without compromising the needs of
future generations to meet their own needs
is the goal
Green Chemistry Technologies that are energy
efficient,minimise or preferably eliminate the
formation of waste,avoid the use of toxic and/or
hazardous solventsand reagents and, where
possible,utilise renewable raw materials.
is the means
Primary Pollution Prevention not Remediation
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Do Politicians Understand the Issues?
Its not pollution that is the problem its the
impurities in our air and water.
Dan Quayle
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• E Factor amount of waste/kg product
• 
  Tonnage E Factor
• Bulk Chemicals 104-106 lt1 - 5
• Fine chemical Industry 102-104 5 - gt50
• Pharmaceutical Industry 10-103 25 - gt100

R.A. Sheldon, Chem Ind, 1992,903 1997,12
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The E Factor

• Is the actual amount of waste formed in
• the process, including solvent losses, acids
• and bases used in work-up,process aids,
• and,in principle,waste from energy production
• (c.f. atom efficiency is a theoretical nr.)
• Can be derived from amount of raw materials
• purchased /amount of product sold,i.e., from
  the
• mass balance E raw materials-product/produc
  t
• A good way to quickly show (e.g.,to students)the
  
• enormity of the waste problem

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Where does all this Waste come from?
Processes are not Atom Efficient Stoichiomet
ric Reagents -Acids Bases,Oxidants
Reductants -Halogenation Halogen
Substitution Solvent Losses - air
emissions aqueous effluent
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Atom EfficiciencyStoichiometric vs Catalytic
Oxidation
Stoichiometric The Jones Reagent (Sir Ewart
Jones)
3 PhCH(OH)CH
2 CrO
3 H
SO
3 PhCOCH
Cr
(SO
)
6 H
O


3
3
2
4
3
2
4
3
2
Atom efficiency 360 / 860 42 Byproducts
Cr2(SO4)3 , Na2SO4 , H2O
Etheor ca. 1.5
Catalytic
Atom efficiency 120/138 87 Byproduct H2O
Etheor ca. 0.1(0)
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Cr(VI) The Organic Chemists Favorite Oxidant
1856 Attempted synthesis of quinine
(W.H.Perkin)
K
C
r
O
2
2
7

H
O
C
H
N
3 O
C
H
N
O
2
2
1
0
1
3
2
0
2
4
2
2
allyltoluidine
quinine
? Led to the serendipitous synthesis of the first
synthetic dyestuff mauveine (aniline purple)
N
H
O
M
e
O
N
quinine
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Cr(VI) The Organic Chemists Favorite Oxidant
2000 Julia Roberts in Erin Brokovich
Its hexavalent chromium, highly toxic, highly
carcinogenic. Gets into your DNA, so you pass the
trouble along to your kids.
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The Environmental Impact EQ

• EQ
  E(kg waste) Q (Unfriendliness
  )
• e.g. NaCl1 ( arbitrary)
• Cr salts 1000?

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The Question of Solvents
The Problem ? Toxicity / atmospheric
emissions of volatile solvent (e.g.
chlorinated hydrocarbons ) ? Toxicity /
ground water contamination by
non-volatile, polar solvents

• Solvents contribute ca.85 of non-aqueous
• mass in processes in the pharma industry.
• Current recovery efficiencies typically 50-80.
• (Alan
  Curzons,GSK)

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FDA Guidelines on Solvent Use in Pharma Industry

• Should never be used benzene,tetrachlorocarbon
  ,1,2 dichloroethane, 1,1-dichloroethane,etc
• Can be used if unavoidable (residues in the
  product subject to regulations) hexane, toluene,
  dichloromethane, dioxane, pyridine, methanol,
• Preferred solventsH2O,scCO2 ethanol ,tert-butyl
  alcohol,tert-butyl methyl ether, ethyl acetate,etc

www.fda.gov/cder/guidance/index.htm)
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Properties of Green Solvents

• Low reactivity toxicity
• Easy recyclability (no disposal)
• Easy removal from the product
• (and the catalyst)

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New Route for Pfizers Sertraline(Zoloft) is
Greener
J.C.Colberg et al,OPRD,8,385,2004
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The Twelve Principles of Green Chemistry

• 7. Renewable raw materials
• 8. Shorter syntheses
• 9. Catalytic methodologies
• 10. Design for Degradation
• Analysis for Pollution
• prevention
• 12. Inherently Safer Chemistry

1. Prevention instead of remediation 2.
Atom efficiency 3. Less hazardous chemicals 4.
Design safer chemical products 5. Safer
solvents auxiliaries 6. Energy efficient by
design
P.T.Anastas J.C.Warner,Green Chemistry Theory
Practice ,Oxford Univ. Press,New York,1998
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Why Biocatalysis?

• Mild conditions ambient temperature
• /pressure and physiological pH
• Fewer steps ( avoidsprotection/
• deprotection steps )
• Largely avoids toxic/hazardous
• reagents solvents
• High chemo-,regio- and stereoselectivities

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Production of Lipitor Intermediates
Lipitor (Pfizer) Sales in 2005 12 bio
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Enzymatic Synthesis of Lipitor Intermediate
KRED keto reductase GDH glucose
dehydrogenase HHDH halohydrin dehalogenase
(non-natural nucleophile)
S.C.Davies,J.H.Grate,D.R.Gray,J.M.Gruber,G.W.Huism
an,S.K.Ma, L.M.Newman,R.A.Sheldon, and
L.A.Wang,WO 2004/015132 to Codexis
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Enantioselective Ketone Reduction

• high enantioselectivity
• mild (ambient) conditions
• no metal catalysts required
• no need for dedicated equipment
• low productivities

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DNA Shuffling Evolution in the Fast Lane
Genes From Nature
HTP Screening
Novel Genes
W.P.C.Stemmer,Nature,370,389-391,1994
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Ketone Reduction with Shuffled KREDs Codexis
KRED
NAD(P)H NAD(P)
Na-gluconate
Glucose NaOH
GDH
Wild type enzymes
Shuffled enzymes
10 g/L KRED/GDH 80 g/L Substrate Reaction time
24 hrs Phase separation gt1 hour Isolated yield
80 / ee 99.8
lt1 g/L KRED/GDH 160 g/L Substrate Reaction time
10 hrs. Phase separation 1 minute Isolated yield
gt95 / ee gt99.9
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Van een geneesmiddel wordt altijd iemand beter