Chimie verte (CHM–7013)
Prof. Thierry Ollevier
Stratégies vertes en synthèse
• Choix de plusieurs voies synthétiques pour une même molécule
• Réactions en cascade
 Réactions en un seul pot
 Réactions tandem (domino)
• Synthèse convergente plutôt que linéaire
 Réactions multi-composantes
• Réactions de condensation
 Économie d’atomes
• Procédés catalytiques plutôt que stœchiométriques
 Organocatalyses plutôt que catalyse avec métaux lourds
• Éviter groupes protecteurs
• Réacteurs en boucle fermée (“Closed-loop systems”)
Chimie verte (CHM–7013)
Prof. Thierry Ollevier
Chimie verte et pharma
Reaction companies use now but would strongly use better reagents
Research Area
Amide formation avoiding poor atom economy
•reagents
• OH activation for nucleophilic substitution
• Reduction of a mides without hydride reagents
• Oxidation/Epoxidation methods without the use of
chlorinated solvents
• Safer and more environmentally Mitsunobu reactions
• Friedel-Crafts reaction on unactivated systems
• Nitrations
Number of Roundtable companies voting for this
research area as a priority research area
6 votes
5 votes
4 votes
4 votes
3 votes
2 votes
2 votes
More apirational reactions
Research Area
• C-H activation of aromatics (X-couplings avoiding the
preparation of haloaromatics)
• Aldehyde or ketone + NH3+ “X” to give chiral amine
• Asymetric hydrogenation of unfunctionalised olefins /
enamines / imines
• New greener fluorination methods
• N-Centred chemistry avoiding azides, hydrazine etc.
• Asymetric hydramination
• Green sources of electrophilic nitrogen (not TsN3, nitroso or
diimine
• Asymetric hydrocyanation
Number of Roundtable companies voting for this
research area as a priority research area
6 votes
4 votes
4 votes
4 votes
3 votes
2 votes
2 votes
2 votes
“Key Green Chemistry Research Areas – A Perspective from Pharmaceutical Manufacturers”
Constable, D. J. C. et al., Green Chem. 2007, 9, 411–420
Chimie verte (CHM–7013)
Prof. Thierry Ollevier
Réactions en un seul pot
• Révision d’une voie réactionnelle originelle d’un médicament
Route comparison between the old and new commercial synthesis of Zoloft
NMe
+ TiO2
+ MeNH4Cl
TiCl4 / MeNH2
Toluene / hexane
THF
O
Pd/C, H2
(D)-mandelic acid
THF
EtOH
Cl
Cl
Cl
Cl
racemic mixture
cis and trans isomers
6 / 1 ratio
(isolated as hydrochloric salt
Cl
Cl
Cl
(isolated)
Sertraline Mandelate
(isolated)
NHMe
NMe
Cl
NHMe
NHMe
NHMe
Cl
MeNH2
EtOH
+ H2O
(D)-mandelic acid
Pd / CaCO3, H2
EtOH
EtOH
Cl
Cl
Cl
(not isolated)
Cl
Cl
Cl
racemic mixture
cis and trans isomers
20 / 1 ratio
( not isolated )
Sertraline Mandelate
(isolated)
“A New and Simplified Process for Preparing Two Key Intermediates in the Synthesis
of Sertraline Hydrochloride”
Taber, G. P.; Pfisterer, D. M.; Colberg, J. C., Org. Proc. Res. Dev. 2004, 8, 385–388
Chimie verte (CHM–7013)
Prof. Thierry Ollevier
Réactions en un seul pot
• Impact de l’utilisation de solvants
Sertraline Hydrochloride First
Commercial Route
Sertraline Hydrochloride New
Route
EtOH
EtOH
EtAc
THF
Toluene
Hexane
Total
34 000 L
28 000 L
19 000 L
8 000 L
12 000 L
EtAc
EtOH
THF
toluene
hexane
EtAc
EtOH
EtAc
15 000 L
9 000 L
Total
24 000 L
101 400 L
Comparison of solvent utilization (solvents L/1000 kg of sertaline hydrochloride) between the first
commercial route and the new route for Zoloft
“A New and Simplified Process for Preparing Two Key Intermediates in the Synthesis
of Sertraline Hydrochloride”
Taber, G. P.; Pfisterer, D. M.; Colberg, J. C., Org. Proc. Res. Dev. 2004, 8, 385–388
Chimie verte (CHM–7013)
Prof. Thierry Ollevier
Économie d’atomes
• Original article: “The Atom Economy – A Search for Synthetic Efficiency”
Trost, B. M. Science 1991, 1471–1477
Hydrogenation:
OH
O
CH3O
+
CH3O
CHO
H
CH3
H
ether, rt
O
catalyst
CHO
3.0 LiClO4
+
H2
O
H
CH3
100 % atom efficient
CO2H
Carbonylation:
COOH
OH
+
CO
catalyst
72 %
HO
CO2H
+
N
O
TBDMS
CH3CHO
LiN(i-C3H7)2
THF, 0 oC
100 % atom efficient
Hydroformylation:
H
CO2H
CHO
N
O
+ CO/H2
TBDMS
catalyst
100 % atom efficient
90 %
Oxidation:
O
OH
catalyst
+
O2
“A New and Simplified Process for Preparing Two Key Intermediates in the Synthesis
of Sertraline Hydrochloride”
Taber, G. P.; Pfisterer, D. M.; Colberg, J. C., Org. Proc. Res. Dev. 2004, 8, 385–388
+
H2O
87 % atom efficient
Chimie verte (CHM–7013)
Prof. Thierry Ollevier
Économie d’atomes
• Synthèse de l’Ibuprofène (Procédé Boots)
O
CH3
H
H3C
O
O
CH3
AlCl3
H3C
H
O
CH3
Cl
CH3
H3C
H
OH
CH3
H3C
CH3
O
H3O+
CH3
CH3
N
H3C
NaOC2H5
H3C
CH3
CH3
COOC2H5
C N
CO2C2H5
H3C
H3C
CH3
H
O H
H
O H
CH3
H3C
ibuprofen
“Origins, Current Status, and Future Challenges of Green Chemistry”
Anastas, P. T.; Kirchhoff, M. M., Acc. Chem. Res. 2002, 35, 686–694
CH3
COOH
O
NH2OH
Chimie verte (CHM–7013)
Prof. Thierry Ollevier
Économie d’atomes
O
H
O
O
O
EAt = 0.75
AlCl3
Chemical Formula: C10H14
Molecular Weight: 134
Chemical Formula: C4H6O3
Molecular Weight: 102.09
Chemical Formula: C4H7ClO2
Molecular Weight: 123
O
Cl
CO2CH2CH3
Chemical Formula: C2H5NaO
Molecular Weight: 68
O
O
CO2Et
NaOEt
H
EAt = 0.71
Chemical Formula: C16H22O3
Molecular Weight: 262
H
H3O+
CO2Et
O
Chemical Formula: C12H16O
Molecular Weight: 176
O+
Chemical Formula: H3
Molecular Weight: 19
Chemical Formula: C13H18O
Molecular Weight: 190
H
NH2OH
Chemical Formula: H3NO
Molecular Weight: 33
EAt = 0.68
O
N
OH
Chemical Formula: C13H19NO
Molecular Weight: 205
EAt = 0.92
Chimie verte (CHM–7013)
Prof. Thierry Ollevier
Économie d’atomes
H
N
cat.
N
OH
EAt = 0.91
Chemical Formula: C13H17N
Molecular Weight: 187
OH
2 équiv. H2O
N
EAt = 0.92
O
Chemical Formula: C13H18O2
Molecular Weight: 206
Globalement :
H
Chemical Formula: C10H14
Molecular Weight: 134
CO2H
Chemical Formula: C13H18O2
Molecular Weight: 206
EAt = 206/(134+102+123+68+19+33+36) = 0.40
EAt = 0.40
Chimie verte (CHM–7013)
Prof. Thierry Ollevier
Économie d’atomes
• Synthèse “verte” de l’Ibuprofène (Procédé BHC)
H
CH3
H3C
CH3
O
O
HF
O
CH3
O
CH3
CH3
H3C
Raney nickel H2
CH3
CH3
CH3
H3C
CO Pd
CH3
CH3
H3C
Ibuprofen
COOH
Chimie verte (CHM–7013)
Prof. Thierry Ollevier
Économie d’atomes
O
H
O
O
O
EAt = 0.75
HF
Chemical Formula: C10H14
Molecular Weight: 134
Chemical Formula: C12H16O
Molecular Weight: 176
O
OH
Ra Nickel
EAt = 1
H2
Chemical Formula: C12H18O
Molecular Weight: 178
Chemical Formula: C12H16O
Molecular Weight: 176
OH
CO2H
CO
EAt = 1
Pd
Chemical Formula: C12H18O
Molecular Weight: 178
Chemical Formula: C13H18O2
Molecular Weight: 206
Globalement :
H
CO2H
Chemical Formula: C13H18O2
Molecular Weight: 206
Chemical Formula: C10H14
Molecular Weight: 134
EAt = 206/(134+102+2+28) = 0.78
EAt = 0.78
Chimie verte (CHM–7013)
Prof. Thierry Ollevier
Économie d’étapes
• Nombre d’étapes
O
H
13 steps
N
Ni (0) cat
1-2 %
70 %
H
COT
• Synthèses orientées vers la fonction (“FOS”)
 Synthèse d’analogues à fonctionnalités simplifiées
 Intérêt : s’orienter vers la fonction plus que vers la cible
 Activité biologique obtenue par remplacement par un squelette
plus simple
 Squelette plus simple qui incorpore caractéristiques structurales
nécessaires à l’acitivité
“Function-Oriented Synthesis, Step Economy, and Drug Design”
Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H., Acc. Chem. Res. 2008, 41, 40–49
Chimie verte (CHM–7013)
Prof. Thierry Ollevier
Économie d’étapes
• Exemples de synthèses orientées vers la fonction (“FOS”)
O
OH
O
HN
O
OH
O
OMe
OH
O
Function
Oriented
Synthesis
RO
N
O
OH
OH
H
O
O
O
H
O
Function
Oriented
Synthesis
H
O
Artemisinin
IC50 = 9.2 nM
H
Ar
O
O
O
OCH3
Simplified analog
IC50 = 15 nM
“Function-Oriented Synthesis, Step Economy, and Drug Design”
Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H., Acc. Chem. Res. 2008, 41, 40–49
Chimie verte (CHM–7013)
Prof. Thierry Ollevier
Synthèse sans groupes protecteurs
• Différentes approches de synthèse chimique. Synthèse de l’ambiguine H
Proposed origin:
Me
Example:
Me
Me
OH
N C
Me
NR
• function oriented
• no protecting groups
• enzyme needed to
promote/control reactivity
(PP = pyrophoshate)
N
H
Me
O
N
Me
OPP
Me
PG
Me
H
H
Ambiguine H
• target-oriented
• protecting groups
H
Me
N
H
(PG needed)
• reactivity is “caged”
until appropriate time
N
C
Me
Me
• target-oriented
• no protecting groups
• no enzyme
• natural reactivity of
O
Me
N
H
PG
PG
Me
X
functionnal groups is used
constructively
“Total Synthesis of Marine Natural Products without using Protecting Groups”
Baran, P. S.; Maimone, T. J.; Richter, J. M., Nature 2007, 446, 404–408