You are on page 1of 46

Cortona, September 19-23, 2010 Conference QdB/PAT: Advanced Technological and Regulatory Developments Impacting Pharmaceutical Manufacturing and

Control

Green Processing
Prof. Attilio Citterio Dipartimento CMIC Giulio Natta https://corsi.chem.polimi.it/citterio/

Greener Products (EPP) Selected by Combining Existing Standards


Environmentally Preferable, Well Managed, Sustainable

Recycled content Organic Low emitting Energy efficient Biodegradable


Focus on: Product attributes: Product Content Emission Profile Performance characteristics

EPP

Focus on: Process: Energy Consumption Source Defects Waste Generation Air & Water Emissions

Renewable energy ISO 14000 ISO 9000 LCI/LCA GHG Registry

Green Processing Cortona 2010

Chemical Characteristic Categories & Subcategories


Subcategory Criteria

A. Physical Safety

Fire Reactivity
Special

Flammability Explosivity
Corrosive Oxidant Radioactive

B. Human Health

Acute Chronic Air Water Soil

LD50, CMR

C. Ecological Impact
(includes long-term impacts used in life cycle analyses)

GHG, OD Solubility, ecotoxicity Persistence (PBT, vPvB, vPTor vBT))

Green Processing Cortona 2010

Examples of Successful Substitution of Hazardous Chemicals


1. Electronic manufacture with CO2 (2.0 g memory chip needs 1.7 kg of chemicals and fossil fuel as well as 32 kg of water) 2. Boat paint without tin (as alternative to Tributyltin, Rohm and Haas introduced a broad spectrum antifoulant of isothiazolone family) 3. Fire extinguishers without freons (Pyrocool Technologies, Inc. developed non fluorine based fire extinguishing foam (FEF)) 4. Dry cleaning without perc (ScCO2 as viable alternative to 100,000 drycleaners worldwide using percholorethylene as solvent) 5. Car coatings without lead (PPG Industries developed a lead-free cathodic epoxy electrocoat for applications in automotive) 6. Lumber without arsenic (Chemical Specialties, Inc. introduced alkaline copper quaternary (ACQ) wood preservative as alternative to chromated copper arsenate (CCA) (40 million/y pounds of As and 64 of Cr(VI)) 7. Safe metal working fluids without depleting resources (bio-based oil and surfactants in MFW formulation to replace petroleum-based products eliminating several other components (2 billion gallons annually)
JB Manley, PT Anastas, BW Cue Jr. Journal of Cleaner Production 16 (2008) 743-750 Green Processing Cortona 2010

Environmental Chemicals In the News: Nanoparticle Concern


Simultaneous development of products and management of unintentional consequences
Internal dose in biological systems

What physiochemical properties determine the absorption, distribution and elimination of nanomaterials?
Early biological effects and altered structure/

function What physiochemical properties determine biocompatibility?


Adverse effects What are the critical determinants of toxicity for

those that are toxic?

Size of nanomaterials is an essential parameter? What when nanomaterials are chemically bound to matrix?
Green Processing Cortona 2010

Reduction of Products/Materials Impact

Chemistry Facilities Process

Supply chain

Energy
After

Packaging

H2O

Before reduction of environmental footprint

Green Processing Cortona 2010

Greener Processes: Primary Categories

Material Efficiency & Waste Prevention Energy Water Safety Renewability Product Quality

Other:
Social Responsibility Inventory Storage included in materials efficiency and waste

prevention Process Optimization/Substitution Best Available Technology (BAT)

Green Processing Cortona 2010

Process Improvement vs. Innovation


Aim Process optimization Performance improvement of existing concepts Focus Interdisciplinarity

Model, Weak num. method Kinetics/Therm.

Process Systems Multi-scale integration Model, software Modest Engineering of existing/new concepts Process intensification Development of new concepts of process, steps & equipment Experiment, phenomenon, interphase PAT, QdB Strong Chemistry/Catalysis, applied physics materials science, electronics

Green Processing Cortona 2010

Process Intensification Strategy

Kinetics Process Heat transfer

Hydrodynamic Mass transfer


R. Bakker in Reengineering the Chemical Processing Plant, Marcel Dekker Ed., 2003

Kinetics Process

Reach the inherent kinetics of phenomena Maximize the transfer rate Fick Law : flow = coefficient x interface x gradient
Green Processing Cortona 2010

Novel/Alternative Processes
Routes at increased concentration or even solvent-free Routes at elevated temperature and/or pressure (simple O.C.) Routes mixing the reactants all at once (domino reactions) Routes using unstable intermediates (in case toxic and/or hazardous) Routes in the explosive or thermal runaway regime Process simplification e.g. routes omitting the need of catalysts or (complex) separation UO Gathering

Hessel, V. et al.; Angew. Chem. IE 43 (2004) 406 ER Murphy, et al.; Angew. Chem. 119 (2007) 1764

Green Processing Cortona 2010

Process Characteristics of an Intensified Plant

Raw Materials
(Sustainable)

Green Chemistry
Good EA and RMI Low solvents Het. Catalysts Safe reagents

Intensified Process

Product

Low residence times, minimal effluent separation, energetic efficiency, zero wastes, limited supply, improved intrinsic safety, process flexibility, or specification adaptability (QdB), fast answer to market, improved controls (PAT), just in time production on order.

Green Processing Cortona 2010

Green Metric related to Chemical Reactions: Non Stoichiometric Conditions


A + MW (g/mol) a Moles x Mass (g) ax Conservation Mass Law: B b z bz Q + q y qy P p y py

ax + bz = qy + py +w, z > x, = z - x Yield, =

p p = Atom economy, AE = a+b q+ p


Reaction mass efficiency, RME =

( )( AE ) py py p = = = ax + bx ax + bz a + b + (b / x) SF

py y = px x

b b = 1+ Stoichiometric factor, SF = 1 + x (a + b) x (q + p) q Environmental impact factor based on MW, E = p qy + w 1 = 1 Environmental impact factor based on actual mass, Em = py ( )( AE )
Green Processing Cortona 2010

Reaction Mass Efficiency Master Equation


1 1 1 = RME = ( )( AE ) MRP AE ( ) ( )( ) SF SF ( AE ) [ c + s + ] 1+ ( SF ) ( m p )
Parameters: reaction yield AE atom economy SF stoichiometric factor; MRP

SF =1 implies no excess reagents SF > 1 implies excess reagents used materials recovery parameter

Based on the law of conservation of mass for balanced chemical reaction/equation.


Andraos, J. Org. Proc. Res. Develop. 2005, 9, 149; 404

Green Processing Cortona 2010

Key Process Metrics


Process Mass Intensity:

( An + Sn ) PMI = ( P + Q)
An = mass of raw materials input to the process less any amount recovered and recycled as an integral part of the process Sn = mass of ancillary materials less any amount recovered and recycled as an integral part of the process P = mass of recovered product, Q = mass of recovered co-product Key Question: Water to be included or considered as a separate category?

Green Processing Cortona 2010

Linear vs. Convergent Syntheses

7 Steps, 80% yield per step


1 2 3 4 5 6 1 2 3 7 4

5 7 6

W = 24 S = 35

W = 16 S = 24

W = total wt of all SM S = sum of steps each SM must pass through


J.S. Hendrickson, Pure App Chern, 1988, 60 (11), 1563.
Green Processing Cortona 2010

Linear Synthetic Sequences


S3 S4 Sn+1

S1 + S2

P1 w1

P2 w2

P3 w3

Pn wn

wj =mass of waste in step j; cj = mass of catalyst in step j sj = mass of solvent in step j; pj = MW of target product in step j j = fractional yield in step j; x = moles of reagents in step 1 (scale reaction)

Assumption; stoichiometric conditions in each step


Em ,total =

(w
j =1

+ cj + sj )
n

pn x j j =1

RMEtotal

1 = 1 + En ,total

Overall yield = j
j =1

Theoretical mass of final product = pn x

Product yields is true only if all of collected intermediate product Pj is committed to Succeeding (j + 1)th step.

Green Processing Cortona 2010

Algorithm for Convergent Sequences


1. Analyze each linear sequence as above 2. Normalize scales of each sequence by multiplying smaller scale sequence by a factor given by
large scale sequence xlarge overall factor = small scale sequence x small overall

3. Analyze convergent step using larger scale of two sequences. 4. Sequence of steps following convergent step are analyzed as per algorithm for linear sequences using larger scale of two preceding sequences. 5. Overall yield for entire process is given by
total = (overall yield for larger scale path)(yield of convergent step)(overall yield for forward steps)

Green Processing Cortona 2010

Unfriendliness Factor Q
In order to take into account the different toxicity of products, the Q factor is introduced. The product of E factor and Q factor (EQ factor) it is an indicator of efficiency/environmental impact of a reaction: EQ Factor = E factor x unfriendliness factor Q Q quantifies the undesirable character of by-products/wastes
Q = 0 for water Q=1 for benign salts as NaCl Q up to 1000 for very toxic products

Waste prevention is always preferred over waste remediation

Green Processing Cortona 2010

Energy to Normalise Environmental Impacts


Energy is one of the major constraints on the production process. Because energy is currently produced from depleting resources, there is a natural limit to how much energy can be produced. Therefore, less energy-intensive processes are more sustainable. The analysis must take in consideration the contributions of the energy to transport, the manufacturing process, support to labour, production of energy itself, but also contributions from end-of-life and complete emissions abatement. Energy resources Energy transformation system Fuels Level I. Direct fuel use Level II. Input to process Level III. Raw materials Level IV. Capital
Green Processing Cortona 2010

Gross Energy requirements

Green Metrics in Energy (Chemical Processes)


total process energy (MJ) mass of product (kg) total solvent recovery energy (MJ) Ers = mass of product (kg)

En =

Level of energy performance of chemical process.


Level 0 Level 1 Level 2 Base case Benchmark heat integration Optimum heat integration Energy requirement by an unimproved process, energy produced bu a process and recovered is included. Minor improvements including heat exchange networks, improved solvents, incorporation of power generation Optimized heat exchange flowsheet, change in process conditions that enable further heat integration (the basic aspects of the process such as catalysts, feedstock etc are the same as in base case) The same reaction chemistry as in base case but can incorporate changes in feedstock, improved catalyst, different process configuration, alternative separation techniques. Change of enthalpy of reaction at standard conditions assuming 100% yield.

Level 3

Process redesign

Level 4

Theoretical energy requirement

Green Processing Cortona 2010

Environmental Performance Metrics in Chemical Manufacturing and for Chemical Products


Manufacturing
Resource Related Material intensity

Product Use
Material intensity

Percent first-pass yield Percent ultimate yield Percent process uptime Percent atomic efficiency Percent post-consumer waste used Material efficiency (unit consumptions, including water/pound of product)

Value per kg Pounds replaced Resources saved


Energy intensity

Energy intensity

BTUs/pound Total energy use Minimum "practical" energy use

Value/BTU used Energy saved by use


Renewable

Packaging Total kgs kgs/kg of product


Green Processing Cortona 2010

Percent of product Recyclable

Environmental Performance Metrics in Chemical Manufacturing and for Chemical Products


Manufacturing
Environmental-Burden Related

Product use Packaging Recyclable Biodegradable

Environmental incidents Frequency Severity Practical worst-case scenario Toxic dispersion Airborne toxics Carcinogens Volatile organics Particulates Acid gases "Hazardous" wastes Aquatic toxicity/oxygen demand Listed hazardous air (and water) pollutants TRI chemicals (EPCRA Title III Section 313) 33/50 chemicals
Green Processing Cortona 2010

Toxic dispersion Global warming Ozone depletion Persistence Bioaccumulative Hormone mimics

Carbon Dioxide as Green Solvent, Reagent and Raw Material


Solvent Polymer Processing Microelectronics Processing Textile Dyeing
Reactive dyes (Y > 95%)
O O S R O O S O O

Dye Solubility ln(xP/Pref) = A + c(-ref)


10x10-6 10x10-6 333.15 K 333.15 363.15 KK 363.15 393.15 KK 393.15 K data Calculated Calculated data 8x10-6 8x10-6

Mole fraction of DY54 Mole fraction of DY54

6x10-6 6x10-6

Monitored on line by Vis. op.f.


4x10-6 4x10-6 2x10-6 2x10-6 0 0 0.0 0.0 0.2 0.2 0.4 0.4 0.6 0.6 0.8 0.8 1.0 1.0

Density of CO2 (g/cm3)3 Density of CO2 (g/cm )

Reagent
NH2 NaNO2 X ROH/H2O, CO2 (5-65 bar) -NaHCO3

+ N2

HCO3
X

H2O2 -N2, -CO2 X

50-93 %

Raw Material
O O OH

O O O OH

C O

Coates catalyst

Green Processing Cortona 2010

a) Alternative Reagents to Prevent Waste


Aromatic polyiodination (Synthesis of Contrast Agents)
3 ICl / mHX - 3 HCl / - mHX
R

R I R1 I I R

3/2 I2 / ox. agent


R

R1

- 3 HY (3/2 H2O) 6/5 I2 / 3/5 HIO3 - 9/5 H2O

Iodinating Atom agent Economy ICl 78% I2 100% 94% I2/HIO3 I2/H2O2 91%

Alternative process based on HIO3 (from natural NaIO3) :


R 5 R1 R + 6 I2 + 3 HIO3
H+

R I 5 R1 I R I + 9 H2O

Monitored on line by redox electrode

Recovery of wasted iodine I- + HIO3 + H+ I2 + H2O


Green Processing Cortona 2010

b) Alternative Process Design Reduction of RMI Synthesis of 6-oxo-5H-dibenzo[b,f]azepine

NO2 CH3 RONa

O2N

NO2 H2/Ni

H2N

NH2

H+/

N H

Pd/maleate S 8/ RX

N R

1) NBS, 2) base

N R

N H

1) COCl2, 2) NH3

NaCNO/

RME = 0.06 RMI = 19.3

N
CONH2

4 steps

N
CONH2

6-oxocarbamazepine

carbamazepine

DE Pat.DE-Os 2.011.087; Be Pat.N.597.793; Jp Pat N. 73.066; Eur.pat.EP 0.028.028


Green Processing Cortona 2010

E Factor and Energy Balance in the Production of 10-Oxo-5-Carbamoyl5H-dibenzo[b,f]azepine


Step 1 Step 2 Step 3 Step 4 Step 5 Step 6 Step 7 Step 8 Step 9 Step 10 Step 11 Total "E" factor Energy (x 100Kcal) 7,26 6,60 0,92 1,38 7,48 16,96 1,70 2,37 5,49 15,30 Step 10 1,25 1,50 Step 7 3,08 0,66 4,31 1,57 Step 4 1,65 1,10 Step 1 0,22 0,55 0,00 0,10 0,40 33,46 48,39

20,00

40,00

60,00

80,00

100,00

"E" factor

Energy (x 100Kcal)

Alternative process from key raw material


N CN

O O2 N CONH2

EA = 100%,

Green Processing Cortona 2010

Oxidations through Nitroxide Radicals: R2NO Chemistry


+e
Red.

.. N O .. N O .

+R

.+ N O pKa = - 5.5

+ R . (k = 109 M-1s-1)
H-abstraction

.. N O R
BDE = 68-77 kcal/mol (R = H)

-e
Ox.

N O

+ R-

Nitroxide Di t-Bu TEMPO 4-OH-TEMPO

E1/2 0.187 0.203 0.224

E1/2 (V) (H2O) 0.657 0.728 0.813

Nitroxide 4-O-TEMPO Fremy Salt Succinimide-N-oxyl

E1/2 (V) 0.301 0.901 1.112

Green Processing Cortona 2010

Keggin Systems for Alkylaromatic Oxidation with Molecular Oxygen


Defective Keggin (insertion of metal cations)

Keggin H4PVMo11O40 Approach: Combinatorial Catalysis


R

OH R' O O
redNPMoV

O2 (1 atm)

O R O O R'

. NO

N OH

oxNPMoV

1/2 O2 H2 O

1/2 O2

H2 O

Green Processing Cortona 2010

Oxidation of Benzylic Methylene by O2 Catalyzed by Defective NHPI/Keggin(V)/C


Runa 1 2 3
X

Aromatic
N CN
Cl

Product
X

Yield %b (X) 15(OH) 75(O)


Cl

Time (h) 2 4 6 3 5 2

N CN
X

19(OH) 68(O) 11(OH) 82(O) 12(OH) 64(O)

4 5 6
a
MeO MeO
MeO MeO

16(OH) 12(O)c
X

3(OH) 38(O)

reaction conditions: 50C, 1 atm O2, Cat. [Fe/Cu (2:1)] 2 %, NHPI 2%, CH3CN. bYields are obtained by GC-MS; runs 1 and 2 are on isolated product >95% purity (50 kg scale). C44% of the corresponding acid; 84% at 24 h.

Green Processing Cortona 2010

d) Processing of Materials: Carbon Nanotubes Production


MWCNT are produced with FBCCVD technology at Politecnico di Milano (10-15 walls, aggregated in bundles of 200 nm length) from ethylene and H2. When purified they contain < 2% inorganic impurity and < 1% amorphous carbon. Debundled by surfactants and polymers
Catalyst -Al2O3 / Fe

Green Processing Cortona 2010

CNT Combined Purification and Derivatization Process


Strong oxidant acid purification
(to eliminate catalyst and amorphous carbon)
COOH

OH

COOH
COOH

OH

OH

Arylation via radical reactions:

Arenediazonium cation /

R*

R*

R*

Water dispersed MWCNT (a) Without derivatisation (b) With covalent functionalisation

Green Processing Cortona 2010

Salt Free Arylation of MWCNT by CO2/NaNO2


Classical methods of arenediazonium salts generates as by-products large amounts of salts (RMI = 4-7).
Approach developed to overcome these limits:

CO2 + H2O
NH2

H2CO3

(pKa H CO = 3.3 ~ pKaHNO )


2 3 2

Yield monitored by redox electrode


NaNO2, CO2 (5-65 bar)

COOH

+ N2

HOOC

ROH/H2O, -NaHCO3

HCO3
COOH COOH

HOOC

80-95%

CNT-Polymer composites (dispersion/covalent attachment) - Polyesters, Polyurethanes, Epoxy resins


Green Processing Cortona 2010

Recovery of Silica Gel from Rice Hulls

SiO2

HX + 2 NaOH Na2SiO3 NaX + SiO2


140C

Sol/gel on line monitor

HX = CO2 + H2O

Surf. area: 40 m2/g SiO2 content: 86-90% Yield on SiO2: 85-89% Recovery of KCl: 3-4% Recovery of carbon black: 6-10% Recovery of MnO2 = 0.3%
Green Processing Cortona 2010

Surf. area = 150-200 m2/g SiO2 purity: 99%

Energy saved based on silica glass fusion: 82%

Organic Sustainable Raw Materials and Bioprocessing

Photosynthetic biomass Starchy crops Sugar crops Oil seeds Lignocellulosics Plants and animals wastes Water Atmospheric gases (e.g. CO2, methane)
Bioprocessing: A more natural and cost-effective means of converting natural feedstocks into platform chemicals

Green Processing Cortona 2010

Use Renewable Feedstocks


ENERGY
Wheat Sugar beet Rapeseed Linseed Cramble Potatoes Maize Hemp Barley Flax Nettle Cereal straw Short Rotation Coppice Miscantus

FUEL
Jatropha OSR

OIL
Olive Camelina Echium

STARCH

Calendula Peppermint Borage

FIBRE
Poppy

Heberlea

SPECIALTY

Green Processing Cortona 2010

The Biomass Triangle

FOOD

Animal Feed

Energy and Chemicals

Green Processing Cortona 2010

Biorefinery of Grain

Grain (Wheat)
Milled Bran
Pentosans: 25% Cellulose: 21% Crude fiber: 10% Protein: 13% Phytate: 4% Starch: 8% Total sugar: 5% Reducing sugars: 4% Lipid: 4% Vitamins: Choline, Inositol, Niacin, Tocopherols, Pantothenic acid, p-Aminobenzoic acid, Thiamine, Riboflavin, Folic acid, Biotin:

Milled Endosperm
Starch: 70% Protein: 10% Phytate: 0.5% Vitamins: Niacin, Biotin, Tocopherols, Pantothenic acid, Pyridoxine, Thiamine, Riboflavin, Folic acid, p-Aminobenzoic acid, Inositol.

Germ
Protein: 25% Total sugar: 17% Raffinose: 7% Lipid: 12% Phytate: 2% Vitamins: Niacin, Biotin Pyridoxine, Pantothenic acid, Thiamine, Riboflavin, p-Aminobenzoic, Folic acid, Inositol.

Aleurone layer

Protein: 18% Vitamins: Niacin, Pantothenic acid, Pyridoxine, Thiamine, Riboflavin, Betaine

Green Processing Cortona 2010

-4 -3 Oil -2 -1 Ethylene, Polyethylene Methanol, Ethanol


Green Processing Cortona 2010

Natural Gas Methane

Ethane

Glycerol
0 1 2 3 Limestone 4 Ox. N Coal Carbohydrates Lactic acid

Acetone Ethylene Glycol, Ethyl Acetate Polystyrene, Polyvinylchloride Phenol Polyester Acetic Acid

Matching Raw Material and Desired Product Oxidation States

Carbon Monoxide

Carbon Dioxide

The Biorefinery Using the Cn Bio-based Platforms


Chemistry that does not use oil, is recyclable, and biodegradable
C1
C1 platform dominated by the methane business. A basic building block for petrochemicals.

C2

C2 platform dominated by acetic acid and ethanol producers.

C3

C3 platform dominated by lactic acid for use in biodegradable polymers and other compounds (Cargill, Purac, Galactic) C3 platform from Glycerol is a remarkable alternative. C4 bio-based platform based on succinic acid

C4

C5

C5 platform reverts back to sugar compounds such as xylose

Green Processing Cortona 2010

Green Raw Materials: Glycerol as C3 Platform Acid-base Reactions


H

Biodiesel
O
OMe

O
-H2O -H2O
OH

O OH

FAME
O O O O O O

HO

OH

RCO2H

OR RO OCOR'
OH O O O
GLYCEROL CARBONATE

GLYCEROL

O OH

HCl -H2O
O

(RO)2CO (CO2)

OH

Fatty Acids

HX, RRC=CH2
XO
(RO)2CO NH3
O O NH

Cl

ROCOOR

OX O
OH

CH3
O O O

O O

O R GLYCEROL
DICARBONATES

R R'

Green Processing Cortona 2010

Green Raw Materials: Glycerol as C3 Platform Oxidative Reactions

2,3-dihydroxypropionic acid (Gold nanocluster, O2, Base) 95% COOH


C O

CH2OH CHOH COOH

COOH C O

CH2OH C O

CHO

CHO

CH2OH C O

COOH

O2/Au

HNO3 3-4 days


CH2OH CHOH CH2OH

CH2OH
Acetobacter Sp

Dihydroxyacetone

CH2OH CHOH CHO

H2O2 FeSO4, rt

H2O2 CaCO3 KHSO4 or K2SO4 200C 0,5~1h

COOH CHOH COOH

CHO C O CHO CHOH CHO COOH CHOH CHO

CH2 CH C N

CH2 CH CHO

CHO

(O2/NH3)
Green Processing Cortona 2010

Glycerol Reductive Processes


CH3
H2, cat. 150C 50 atm

CH3 CH2 CH3


OH HO O HO H OH OH

CHOH CH3 CHOH CH2OH


C-O bond breaking

3 CH3OH

CH2OH CH2OH
+ MeOH

CH3

C-C bond breaking

CH2OH CHOH
130C

glucose

CH2OH CH2OH
Clostridium CH2 Butyricum (40C)

RT organism

Micro

CH3 CH-I CH3

CH2OH CH2 CH2OH

HI

excess

CH2OH

1,3-propandiol

CH3 CH2 CH2OH

CH3 CH2 CH3

E. Chynoweth, ICIS Chem. Business (Weekly) 39 (1) (2006) 1. E.P. Maris, R.J. Davis Journal of Catalysis 249 (2007) 328337 C. Montassier, D. Giraud, J. Barbier, Polyol Conversion by Liquid Phase Heterogeneous Catalysis over Metals, Elsevier, Amsterdam, 1988, p. 165.

Green Processing Cortona 2010

Green Chemistry means that Engineering and Process must Adapt to a more Safety Oriented Chemistry

Green Processing Cortona 2010

Politecnico di Milano

Green Chemistry Group Dipartimento CMIC Giulio Natta Via Mancinelli 7, 20131 Milano

Thank you very much for your attention!


Green Processing Cortona 2010

Thymine Ribonucleotide Synthesis


O N HO H H OH O H N H OH O
O

O
Br

2,5

N O O O O Br O N O

OCOMe

MeCN/4h 55 %

1 One stage?
O N HO O N O

OCOMe

80 % Zn/MeCN/AcOH 25C/8 h
O N O O O O O N O

R'

.
OCOMe

KOH/MeOH 20C/5 h 93 %

-fragmentation

Overall Yield = 41 % E factor = 18

Green Processing Cortona 2010

c) Optimization of One-reactor Multistep Synthesis


Variables: - Solvent (10 + 10 mixtures) - Derivatiz./Reduction Time - Temperature - Metal catalysis (Ti, V, Cu)

O N HO H H OH O H N H OH O

1,1

Br OCOMe

MeCN/H2O(5%)(0.7 h, 10C) Zn/TiCl3/AcOH (1.5 h, 10C)


O N HO O N O

Overall Yield: 89% RMI = 4.2 (from 18)

Green Processing Cortona 2010