Green Chemistry for Healthy Pharma - Bioeconomy Dialogues: la Chimica Verde in Lombardia 7 marzo 2018
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Bioeconomy Dialogues: la Chimica Verde in Lombardia
7 marzo 2018
Green Chemistry for Healthy Pharma
GLOBAL INNOVATION & TECHNICAL OPERATIONS
fulvio.uggeri@bracco.com
Vision and Mission
VISION
Developing innovative solutions
for the prevention, early
identification and treatment of disease
to improve the quality of life
MISSION
To operate on a global scale thanks
to the direct presence of collaborators
all over the world and
a vanguard know-how
To constantly innovate our products,
services and professional expertise of
collaborators so as to offer customers
an ever increasing added value
3 Business Units Bracco is an Italian multinational headquartered in Milan with 3 Business Units: BRACCO IMAGING International leader in diagnostic imaging ACIST MEDICAL SYSTEMS Leading company in systems for the administration of contrast media and advanced medical devices for cardiology CDI – ITALIAN DIAGNOSTICS CENTRE Polyclinic facility in the sectors of prevention, diagnosis and rehabilitation
A Global Presence
The Bracco Group operates all over the world,
either directly or through joint ventures, partnerships,
or distribution and agency agreements
Sales
in more
than100
Countries
Commitment
to Research and Innovation
Investment of 9% of reference turnover in R&D
for diagnostic imaging and advanced medical devices,
with a portfolio comprising over 1,800 patents
and 7 R&D centres in the world
7 R&D CENTRES
ITALY
Colleretto Giacosa - Ivrea
SWITZERLAND
Geneva
Lausanne
USA
Freemont - Silicon Valley
Princeton (New Jersey)
Minneapolis (Minnesota)
Maple Grove (Minnesota)
Environmentally
friendly Production
The Group has 9 production units in Italy, Germany,
Switzerland, China, Japan, the USA and Canada
All the Bracco plants pay special attention
to their environmental impact
ITALY GERMANY CHINA USA
Manufacturing Ceriano Laghetto Singen Shanghai Minneapolis
Plants Colleretto Giacosa SWITZERLAND JAPAN CANADA
Torviscosa Geneva Saitama Montréal
Bracco Imaging
Bracco Imaging is a worldwide leader in the market of contrast
agents for diagnostic imaging
Computed tomography (X-rays)
Magnetic resonance imaging
Ultrasounds
Scintigraphy (radionuclides)
1
Bracco’s contrast agents
Non ionic X-ray contrast agents
HO OH
OH
CONH CONH
I I OH I I HO OH
OH
CONH CONH HO CON CONH
I OH Me I
OH
Iopamidol (1974) Iomeprol (1979)
MRI contrast agents
- - -
- COO OOC COO
COO 2 Meg+ N N
3+
Ph O N - Gd
N N COO N N OH
-
3+ OOC
-
COO Gd COO
-
Multihance Prohance
2
Green Chemistry
Prof. Paul Anastas
The father of green chemistry
P. T. Anastas, J. C. Warner, Green Chemistry: Theory and Practice
Oxford University Press, Oxford, 1998
3
Iomeprol: old process
COOH COOH COCl
1) H2, Pd/C I I SOCl2 I I AcO COCl
2) ICl H 2N COOH H 2N COCl DMAC
O2N COOH
I I
5-nitroisophthalic acid
1 2
OH
COCl COCl CONH OH
I I CH3I I I 1) isoserinol I I
OH
-
AcO CONH COCl DMAC AcO CON COCl 2) OH HO CON CONH OH
I CH3 I CH3 I
3 4 Iomeprol
4Iomeprol: Smiles process
H OH
O N OH
COOH
+
1) n-BuOH/H 1) ICl
H OH
N OH 2) ClCH2CONHCH3
HO COOH 2) isoserinol HO
base
O
(1)
(2)
H OH H OH
O N OH O N OH
I I - I I
H H OH OH
O H OH
N N OH HO N OH
CH3 O Smiles N
O I O rearrangement CH3 I O
(3) Iomeprol
5Iomeprol: Smiles process
Smiles Process: Environmental Evaluation
Water and alcohols as main solvents
Elimination of toxic and/or dangerous reagents/solvents:
- thionyl chloride
- methyl iodide
- dimethylacetamide and chlorinated solvents
- hydrogen
- aromatic amines (intermediates)
Reduction of waste
Reduction of energy and water consumption
6Iopamidol: current process
COOH COOH COOH
H2 ICl/ HCl I I
O2N COOH Pd/C H 2N COOH H 2N COOH
1 I
5-nitroisophthalic acid 2
COCl COCl COCl
I I I I
SOCl2 4 O
OAc
n-dodecane H 2N COCl NH COCl
DMAC
diglyme I OAc I
3 5
OH
O NH
OH
OH
1) H2N I I
OH O OH
NH
2) NaOH NH
OH
OH I O
Iopamidol
7Iopamidol: new process
COOH COOBu COOBu
HO OH
n-BuOH H2
NH2
O2N COOH O2N COOBu Pd/C H 2N COOBu
1 2
5-nitroisophthalic acid
OH OH
O NH O NH
OH OH
ICl I I PhB(OH)2
OH OH
NH NH
H 2N H 2N
OH OH
O I O
3
4
O OH
O NH B Ph O NH
COCl OH
O
I I 1) I I
OAc O
O OH
NH B Ph NH
H 2N 2) NaOH NH
O OH
I O OH I O
Iopamidol
5
8Iopamidol: new process
Environmental Evaluation
Elimination of toxic and/or dangerous reagents/solvents:
- thionyl chloride
- diglyme
Dimethylacetamide reduced by 50%
Overall yield increased by 10%
Reduction of energy
9Iodine chloride
manufacturing process
HCl conc. Yield: 100%
I2 + Cl2 2 ICl Atom economy: 100%
Drawbacks related to production and use of chlorine
CHLORINE HAZARD IDENTIFICATION (GHS classification):
H270 May cause or intensify fire; oxidizer
H280 Contains gas under pressure;
may explode if heated
H331 Toxic if inhaled
H400 Very toxic to aquatic life
H315 Causes skin irritation
H319 Causes serious eye irritation
H335 May cause respiratory irritation
10Green iodination with iodine
and iodic acid
COOH COOH
I I
5 + 6 I2 + 3 HIO3 5 + 9 H 2O
H 2N COOH H 2N COOH
I
Green alternative to ICl iodination
All the iodine employed goes in the final molecule
Water is the only by-product!
Waste reduction COOH COOH
I I I Cl
Elimination of chlorinated impurities H 2N COOH H 2N COOH
Cl I
11Current process for
Gadoteridol
OEt +- - +
H H EtO H Na OOC COO Na
N N 1 N N N N
OEt BrCH2COOH
N N N N NaOH N N
OH +-
H H pH 12.5 Na OOC CHO
Cyclen 2 3
+- - + +- - +
Na OOC COO Na Na OOC COO Na
NaOH N N O N N
pH 12.5 N N N N OH
+- pH 12.5 +-
70°C Na OOC H Na OOC
4 5
- -
OOC COO
GdCl3 N N Propylene oxide
3+
Gd
N N OH
-
OOC
Gadoteridol
12Propylene oxide on demand
from propylene carbonate
cat.
O O + CO2
200°C O
O
O O + CO2
O NaOH
O
Propylene carbonate
Eye irritation
Gadoteridol reactor
13Dimethylacetamide
replacement/elimination
OH
COCl OH CONH
I I I I OH
OH
H 2N
OH
CONH COCl CONH CONH
I I OH
OOCCH3 OOCCH3
6 7
Mechanochemistry
The best solvent is no solvent!
14Safer processes taking
advantage of flow chemistry
Serinol synthesis from nitromethane
NaOH NO2
MeNO2 + CH2O HO OH
H2 NH2
HO OH
Rh/C
Acetoluro synthesis from lactic acid
COOH COCl
1) AcOH COOH SOCl2
OH 2) Ac2O OOCCH3
OOCCH3
Lactic acid
Acetolat Acetoluro
15Waste treatment and
iodine recovery
• Classical waste thermal degradation
• Sequencing Batch Biofilter Granular Reactor
(SBBGR) technology: low sludge production, high
biomass concentration and high COD conversion
capacity
• Wet air oxidation
•Iodine recovery by granulated active carbon
16Future perspectives:
a couple of examples
• Greener synthesis of serinol, maybe from glycerol
OH ? NH2
HO OH HO OH
• Direct amidation of iodoanilines with lactic acid
OH OH
O NH O NH
COOH OH
OH
I I I I
OH O
OH OH
NH NH
H 2N
OH ? NH
OH
I O OH I O
Iopamidol
17Conclusions
Pharma companies have accepted the challenge of
developing green and sustainable products/processes.
Sustainability will change deeply the manufacturing
approach of pharma industries.
The search for product sustainability is a true
opportunity for pharma industries to change their
business model.
Correct application of green chemistry generate
simultaneous benefits for the environment, society and
economy.
18Thank you
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