Prof. Bhalchandra M. Bhanage

Head, Department of Chemistry

Institute of Chemical Technology,

Mumbai, India.

E-mail : bm.bhanage@ictmumbai.edu.in

1

@Industrial Seminar on “Green Chemistry & Green Engineering” for Pharma API

Industry, on 27 and 28th April 2015 at at Hotel Green Park, Greenlands, Begumpet,

Hyderabad, Organized by Green ChemisTree Foundation

Relevance of 12 Principles of Green Chemistry

in Pharma API Manufacturing

GREEN CHEMISTRY

DEFINITIONGreen Chemistry is the utilisation of a set of principles that reduces or eliminates the use or generation of hazardous substances in the design, manufacture and application of chemical products .

GREEN CHEMISTRY IS ABOUT

• Waste Minimisation at Source

• Use of Catalysts in place of Reagents

• Using Non-Toxic Reagents

• Use of Renewable Resources

• Improved Atom Efficiency

• Use of Solvent Free or Recyclable Environmentally Benign Solvent systems

1. PreventionIt is better to prevent waste than to treat or clean up waste after it has been created.

2. Atom EconomySynthetic methods should be designed to maximise the incorporation of all materialsused in the process into the final product.

3. Less Hazardous Chemical SynthesisWherever practicable, synthetic methods should be designed to use and generatesubstances that possess little or no toxicity to people or the environment.

4. Designing Safer ChemicalsChemical products should be designed to effect their desired function while minimisingtheir toxicity.

5. Safer Solvents and AuxiliariesThe use of auxiliary substances (e.g., solvents or separation agents) should be madeunnecessary whenever possible and innocuous when used.

6. Design for Energy EfficiencyEnergy requirements of chemical processes should be recognised for their environmentaland economic impacts and should be minimised. If possible, synthetic methods should beconducted at ambient temperature and pressure.

The 12 Principles of Green Chemistry (1-6)

7 Use of Renewable FeedstocksA raw material or feedstock should be renewable rather than depleting whenever technically and

economically practicable.

8 Reduce DerivativesUnnecessary derivatization (use of blocking groups, protection/de-protection, and temporary modification of

physical/chemical processes) should be minimised or avoided if possible, because such steps require

additional reagents and can generate waste.

9 CatalysisCatalytic reagents (as selective as possible) are superior to stoichiometric reagents.

10 Design for DegradationChemical products should be designed so that at the end of their function they break down into innocuous

degradation products and do not persist in the environment.

11 Real-time Analysis for Pollution PreventionAnalytical methodologies need to be further developed to allow for real-time, in-process monitoring and

control prior to the formation of hazardous substances.

12 Inherently Safer Chemistry for Accident PreventionSubstances and the form of a substance used in a chemical process should be chosen to minimise the

potential for chemical accidents, including releases, explosions, and fires.

The 12 Principles of Green Chemistry (7-12)

E-factor

API Manufacturing Issues

• Batch-based processes

• Multi-step synthesis, transformations –intermediates

• Isolations (purification)

• Extensive use of multiple organic solvents and reagents – varying degrees of toxicity

• Limited health data on intermediates

API Manufacturing Issues

• Processes – solid/liquid – filtration, drying, etc

• Purity and yield

• 7-11 years between development and manufacture – Regulatory steps (Phase I-III)

• 10% success rate for new drug development

• Outsourcing process steps

• Once process is approved by regulators, any changes are hard to implement

Atom EconomyOrganic Chemistry & Percent Yield

Epoxidation of an alkene using a peroxyacid

O O

OH

Cl

+

O

100% yield

Percent yield:Percent yield:

% yield = (actual yield/theoretical yield) x 100

What is missing?

What co-products are made?

How much waste is generated?

Is the waste benign waste?

Are the co-products benign and/or useable?How much energy is required?

Are purification steps needed?

What solvents are used? (are they benign and/or reusable?

Is the “catalyst” truly a catalyst? (stoichiometric vs. catalytic?)

Balanced Reaction

Balanced chemical reaction of the epoxidation of styrene

O O

OH

Cl

+

O

+

O OH

Cl

Atom Economy

Atom Economy

% AE = (FW of atoms utilized/FW of all reactants) X 100

Balanced Equations

Focuses on the reagents

Stoichiometry?

How efficient is the reaction in practice?

Solvents?

Energy?

Atom Economy

Balanced chemical reaction of the epoxidation of styrene

O O

OH

Cl

+

O

+

O OH

Cl

Assume 100% yield.

100% of the desired epoxide product is recovered.

100% formation of the co-product: m-chlorobenzoic acid

A.E. of this reaction is 23%.

77% of the products are waste.

Classic Route to Ibuprofen

Ac2O

AlCl3

CO CH3

HCl, AcOH, Al W aste

ClCH2CO

2Et

NaOEt

OEtO

2C

HCl

H2O / H+

O HC

AcOH

NH2OH

O HNN

H2O / H+

HO2C

NH3

% Atom Economy = (FW of atoms utilized/FW of all reactants) X 100

= (206/514.5) X 100 = 40%

Hoechst Route To Ibuprofen

O

HF

AcOH

Ac2O

H2 / Ni

OH

CO, Pd

HO2C

% Atom Economy = (FW of atoms utilized/FW of all reactants) X 100

= (206/266) X 100 = 77%

Oxidation : Atom Economy

Of various oxidants

Less Hazardous Chemical Synthesis

Disadvantages

phosgene is highly toxic, corrosive

requires large amount of CH2Cl2

polycarbonate contaminated with Cl impurities

OH OHCl Cl

O

+NaOH

O O *

O

* n

Whenever practicable, synthetic methodologies should be designed

to use and generate substances that possess little or no toxicity to

human health and the environment.

e.g. Polycarbonate Synthesis: Phosgene Process

Designing Safer Chemicals:

Case Study: Antifoulants

Antifoulants are generally dispersed in the paint as it is

applied to the hull. Organotin compounds have traditionally

been used, particularly tributyltin oxide (TBTO). TBTO

works by gradually leaching from the hull killing the

fouling organisms in the surrounding area

TBTO and other organotin antifoulants have long half-lives

in the environment (half-life of TBTO in seawater is > 6

months). They also bioconcentrate in marine organisms (the

concentration of TBTO in marine organisms to be 104 times

greater than in the surrounding water).

Organotin compounds are chronically toxic to marine life

and can enter food chain. They are bioaccumulative.

Designing Safer Chemicals:

Case Study: Antifoulants

Sea-Nine® 211

http://www.rohmhaas.com/seanine/index.html

Rohm and Haas

Presidential Green Chemistry Challenge Award, 1996

The active ingredient in Sea-Nine® 211, 4,5-dichloro-2-n-octyl-4-

isothiazolin-3-one (DCOI), is a member of the isothiazolone family

of antifoulants.

5. Safer Solvents and

Auxiliaries

The use of auxiliary substances (solvents,

separation agents, etc.) should be made

unnecessary whenever possible and, when

used, innocuous.

Safer Solvents

• Solvent Substitution

• Water as a solvent

• New solvents

– Ionic liquids

– Supercritical fluids

Preferred Useable Undesirable

Water Cyclohexane Pentane

Acetone Heptane Hexane(s)

Ethanol Toluene Di-isopropyl ether

2-Propanol Methylcyclohexane Diethyl ether

1-Propanol Methyl t-butyl ether Dichloromethane

Ethyl acetate Isooctane Dichloroethane

Isopropyl acetate Acetonitrile Chloroform

Methanol 2-MethylTHF Dimethyl formamide

Methyl ethyl ketone Tetrahydrofuran N-Methylpyrrolidinone

1-Butanol Xylenes Pyridine

t-Butanol Dimethyl sulfoxide Dimethyl acetate

Acetic acid Dioxane

Ethylene glycol Dimethoxyethane

Benzene

Carbon tetrachloride

“Green chemistry tools to influence a medicinal chemistry and research chemistry based organization”

Dunn and Perry, et. al., Green Chem., 2008, 10, 31-36

Solvent Selection

Red Solvent Flash point (°C) Reason

Pentane -49 Very low flash point, good alternative available.

Hexane(s) -23 More toxic than the alternative heptane, classified as a HAP in the US.

Di-isopropyl ether -12 Very powerful peroxide former, good alternative ethers available.

Diethyl ether -40 Very low flash point, good alternative ethers available.

Dichloromethane n/a High volume use, regulated by EU solvent directive, classified as HAP in US.

Dichloroethane 15 Carcinogen, classified as a HAP in the US.

Chloroform n/a Carcinogen, classified as a HAP in the US.

Dimethyl formamide 57 Toxicity, strongly regulated by EU Solvent Directive, classified as HAP in the US.

N-Methylpyrrolidinone 86 Toxicity, strongly regulated by EU Solvent Directive.

Pyridine 20 Carcinogenic/mutagenic/reprotoxic (CMR) category 3 carcinogen, toxicity, very low threshold limit value (TLV) for worker exposures.

Dimethyl acetate 70 Toxicity, strongly regulated by EU Solvent Directive.

Dioxane 12 CMR category 3 carcinogen, classified as HAP in US.

Dimethoxyethane 0 CMR category 2 carcinogen, toxicity.

Benzene -11 Avoid use: CMR category 1 carcinogen, toxic to humans and environment, very low TLV (0.5 ppm), strongly regulated in EU and the US (HAP).

Carbon tetrachloride n/a Avoid use: CMR category 3 carcinogen, toxic, ozone depletor, banned under the Montreal protocol, not available for large-scale use, strongly regulated in the EU and the US (HAP).

“Green chemistry tools to influence a medicinal chemistry and research chemistry based organization”

Dunn and Perry, et. al., Green Chem., 2008, 10, 31-36

Undesirable Solvent Alternative

Pentane Heptane

Hexane(s) Heptane

Di-isopropyl ether or diethyl ether 2-MeTHF or tert-butyl methyl ether

Dioxane or dimethoxyethane 2-MeTHF or tert-butyl methyl ether

Chloroform, dichloroethane or carbon

tetrachloride

Dichloromethane

Dimethyl formamide, dimethyl

acetamide or N-methylpyrrolidinone

Acetonitrile

Pyridine Et3N (if pyridine is used as a base)

Dichloromethane (extractions) EtOAc, MTBE, toluene, 2-MeTHF

Dichloromethane (chromatography) EtOAc/heptane

Benzene Toluene

Solvent replacement table

“Green chemistry tools to influence a medicinal chemistry and research chemistry based organization”

Dunn and Perry, et. al., Green Chem., 2008, 10, 31-36

List of solvents and

thier limits

Safer solvents: Supercritical fluids

A SCF is defined as a substance above its critical temperature (TC) and critical pressure (PC). The critical

point represents the highest temperature and pressure at which the substance can exist as a vapor and

liquid in equilibrium.

Principle 5: Benign solvents

Carbon-carbon bond formation in water

Diels-Alder, Barbier-Grignard, pericyclic

Indium-mediated cyclopentanoid formation

Li, Tulane University

R2

O O Cl Cl

base

O

R2

O

Cl

R1

R1

In/H2O

OH

R2

OR1

7. Use of Renewable Feedstock

A raw material or feedstock should be

renewable rather than depleting whenever

technically and economically practical.

Petroleum Products [Hydrocarbons]

Biomaterials [Carbohydrates, Proteins, Lipids]

Highly Functionalized Molecules

Singly Functionalized Compounds [Olefins, Alkylchlorides]

Highly Functionalized Molecules

Polymers from Renewable Resources:

Polyhydroxyalkanoates (PHAs)• Fermentation of glucose in the presence of bacteria and propanoic acid (product

contains 5-20% polyhydroxyvalerate)

• Similar to polypropene and polyethene

• Biodegradable (credit card)

O

HO

OH

OH

OH

OH

Alcaligenes eutrophus

propanoic acid

R

O

O

R = Me, polydroxybutyrate

R = Et, polyhydroxyvalerate

n

Polymers from Renewable Resources:

Poly(lactic acid)

Raw Materials from Renewable Resources:

The BioFine Process

O

HO

O

Paper mill

sludge

Levulinic acid

Municipal solid waste

and waste paper

Agricultural

residues,

Waste wood

Green Chemistry Challenge Award

1999 Small Business Award

Levulinic acid as a platform chemical

O

HO

O

O

H2N

OH

O

O

HO

DALA (-amino levulinic acid)

(non-toxic, biodegradable herbicide)

O

HO

O

OH

C

CH3

CH2

CH2

C

O

OHHO

Diphenolic acid

Acrylic acidSuccinic acid

O

THF

O

MTHF

(fuel additive)

HO

OH

butanediol

OO

gamma

butyrolactone

8. Reduce Derivatives

Unnecessary derivatization (blocking

group, protection/deprotection, temporary

modification of physical/chemical

processes) should be avoided whenever

possible.

Protecting Groups

2 synthetic steps are added each time one

is used

Overall yield and atom economy will

decrease

“Protecting groups are used because

there is no direct way to solve the

problem without them.”

9. Catalysis

Catalytic reagents (as selective as

possible) are superior to stoichiometric

reagents.

Heterogeneous vs Homogenous

• Distinct solid phase

• Readily separated

• Readily regenerated & recycled

• Rates not as fast

• Diffusion limited

• Sensitive to poisons

• Lower selectivity

• Long service life

• High energy process

• Poor mechanistic understanding

• Same phase as rxn medium

• Difficult to separate

• Expensive and/or difficult to

separate

• Very high rates

• Not diffusion controlled

• Robust to poisons

• High selectivity

• Short service life

• Mild conditions

• Mechanisms well understood

Heterogeneous vs Homogenous

• Distinct solid phase

• Readily separated

• Readily regenerated &

recycled

• Rates not as fast

• Diffusion limited

• Sensitive to poisons

• Lower selectivity

• Long service life

• High energy process

• Poor mechanistic understanding

• Same phase as rxn medium

• Difficult to separate

• Expensive and/or difficult to

separate

• Very high rates

• Not diffusion controlled

• Robust to poisons

• High selectivity

• Short service life

• Mild conditions

• Mechanisms well understood

Green

catalyst

Principle 9: Catalysis

Improved synthesis of a central nervous system compound

interdisciplinary approach, combining chemistry,

microbiology, and engineering

For every 100 kg product,

300 kg chromium waste eliminated

34,000 liters solvent eliminated

Eli Lilly and Company

Principle 9: Catalysis

Synthesis of disodium iminodiacetate (DSIDA)

filter catalyst from waste stream, no additional

purification required

Replacement for the Strecker process

utilized NH3, CH2O, HCN, HCl

Monsanto Company

NOH OH

H

Cu catalyst NNaO ONa

O OH

DSIDA

+ 2 NaOHH2O /

+ 4 H2

Biocatalysis• Enzymes or whole-cell

microorganisms

• Benefits

– Fast rxns due to correct orientations

– Orientation of site gives high

stereospecificity

– Substrate specificity

– Water soluble

– Naturally occurring

– Moderate conditions

– Possibility for tandem rxns (one-

pot)

Kinetic resolution of a racemic mixture

Kinetic resolution of a racemic mixture

the presence of a chiral object (the enzyme) converts one of the enantiomers into product at a greater reaction rate than the other enantiomer.

10. Design for Degradation

Chemical products should be

designed so that at the end of

their function they do not persist

in the environment and instead

break down into innocuous

degradation products.

Persistence• Early examples:

• Sulfonated detergents

– Alkylbenzene sulfonates – 1950’s & 60’s

– Foam in sewage plants, rivers and streams

– Persistence was due to long alkyl chain

– Introduction of alkene group into the chain increased

degradation

• Chlorofluorocarbons (CFCs)

– Do not break down, persist in atmosphere and

contribute to destruction of ozone layer

• DDT

– Bioaccumulate and cause thinning of egg shells

Degradation of Polymers:Polylactic Acid

Manufactured from renewable resources

Corn or wheat; agricultural waste in

future

Uses 20-50% fewer fossil fuels than

conventional plastics

PLA products can be recycled or

composted

Cargill Dow

12. Inherently Safer Chemistry for

Accident Prevention

Substance and the form of a substance

used in a chemical process should be

chosen so as to minimize the potential for

chemical accidents, including releases,

explosions, and fires. : Avoid Phosgene

Cyanide

Design Safer Chemicals

• Water-based acrylic alkyd paints with low VOCs that can be

made from recycled soda bottle plastic (PET), acrylics, and

soybean oil. In 2010, Sherwin-Williams manufactured

enough of these new paints to eliminate over 800,000

pounds of VOCs.

• Foam cushioning are conventionally manufactured from

petroleum products. Cargill’s BiOH™ polyols are

manufactured from renewable, biological sources such as

vegetable oils. Each million pounds of BiOH™ polyols

saves nearly 700,000 pounds of crude oil. Cargill’s process

reduces total energy use by 23 percent and carbon dioxide

emissions by 36 percent.

51

Phenolic ethers, Pharmaceuticals,

Flavours and Fragrances Quaternarium ammoniumcompounds

Surfactants, Softeners, Electronics

Diphenyl carbonate

Aromatic polycarbonates

Methylisocianate production

Allylcarbonates

Optical organic glassesAliphatic polycarbonate diols

Polyuretans

Oxoalcohol carbonates

Synthetic lubricants

Dialkyl Carbonates

Green solvents

Paints, adhesives

Policarbonate 53 %

Coatings and paintings 28%

Agrochemicals 12%

Pharm. &

Cosmetics 5%

Electrolite

solv.2%

Design Safer Chemicals

Dimethyl Carbonate Tree and Its Industrial

Uses

F. Aricò,M. Chiurato, J. Peltier and Pietro Tundo Eur. J. Org. Chem. 2012, 3223–3228

US EPA Presidential Green Chemistry Award

Promotes and recognizes green chemistry

Five Categories

1. Alternative synthetic pathways

2. Alternative reaction conditions

3. Design of safer chemicals

4. Small business

5. Academic investigator

Source: http://www.epa.gov/greenchemistry

“Alternative synthetic pathways Award”

• 1999 Lilly Research Laboratories (Talampanel)

• 2000 Roche Colorado Corp (Cymevene®)

• 2002 Pfizer, Inc (Zoloft®)

• 2004 Bristol-Meyers Squibb Company (Taxol)

• 2005 Merck & Co. Inc. (Emend®)

• 2006 Merck & Co. Inc. (Januvia®)

• 2006 Codexis, Inc. for Atorvastatin (Lipitor®)

• 2010 Merck & Co. Inc. and Codexis, Inc. (Januvia™ II generation)

54

Presidential Green Chemistry

Challenge Award

• Established in 1995 by the EPA

• For innovations in cleaner, cheaper and smarter chemistry

www.epa.gov/greenchemistry/presgcc.html

http://pubs.acs.org/cen/coverstory/8026/8026greenchemistry.html

HN

N

O

H2N

N

N

OOH

HO

Cytovene®2000 Roche Corp.

Reduced liquid waste: 1120 metric tons / yearReduced solid waste: 25 metric tons / year

HN

Cl

Cl

HCl

Zoloft®

2002 Pfizer, Inc.

Reduced waste:

HCl (conc): 150 metric tons / year

TiO2: 440 metric tons / year

HN

HN N

O

N

O O

F

CF3

CF3

Emend®2005 Merck

Reduced waste:340,000 L / metric ton

55

Emend® - Aprepitant

• hNK1 receptor antagonist (IC50 = 0.09 nM)1

• Treatment of chemotherapy-induced emesis2

• FDA approval in 2003

• 2005 Presidential Green Chemistry Challenge Award3

• Entered preclinical trials in 19931

1 Hale, J. J. et al; J. Med. Chem. 1998, 41, 4607-4614. 2 Rupniak, N. M. et al; Eur. J. Pharmacol. 1997, 326, 201-209.3 http://www.epa.gov/greenchemistry/past.html

HN

NH

N

O

CF3

CF3

O

N

O

F

2

3

56

General Considerations for Process Chemistry

• Avoid column chromatography

• Seeding helps crystallization

• Avoid desiccants, use azeotrope

• Avoid solvents with flash point < 15 ºC

• Ether, hexanes, DCM

• Temperature range -40 to 120 ºC

• Avoid protecting groups

• Impurities of > 0.1% must be analyzed

57

Presidential Green Chemistry Challenge

Award – 2005:Emend synthesis

• Convergent synthesis

– Overall yield 55% (6 steps)

– Uses 20% of raw materials as

original synthesis

– Reduce waste by 85%

• 340,000L / metric ton aprepitant

http://www.epa.gov/greenchemistry/past.html

C&E News June 27, 2005 pg 40-43

N

O OH

O

Ph

CF3

CF3

OH

HN

NH

N

O

F

BrMg

CF3

CF3

O

N

O

F

HN

NH

N

O

Cl

Green Chemistry Example – Bristol-

Myers Squibb Taxol®

• Development of a green synthesis for Taxol®

manufacture via plant cell fermentation and

extraction

• Paclitaxel, the active ingredient in the anticancer

drug Taxol® originally isolated from yew tree

bark

2004 Presidential Green Chemistry Challenge

Alternative Synthetic Pathways Award

www.epa.gov/greenchemistry/aspa04.html

• Natural purification from yew tree bark

- 0.0004% paclitaxel

- Stripping bark and extraction process kills tree – not sustainable

- Yews take 200 yrs to mature – ecosystem impact

• Chemical synthesis of paclitaxel

- 40 steps, 2% yield

• Semisynthetic route from naturally occurring yew-based 10-deacetylbaccatin III

- 11 chemical transformations, 7 isolations

- 13 solvents

- 13 reagents, catalysts, etc

www.epa.gov/greenchemistry/aspa04.html

Pfizer’s results

Use of Solvent Replacement Guide resulted in:

• 50% reduction in chlorinated solvent use across the whole

of their research division (more than 1600 lab based

synthetic organic chemists, and four scale-up facilities)

during 2004-2006.

• Reduction in the use of an undesirable ether by 97% over

the same two year period

• Heptane used over hexane (more toxic) and pentane (much

more flammable)

“Green chemistry tools to influence a medicinal chemistry and research chemistry based organization”

Dunn and Perry, et. al., Green Chem., 2008, 10, 31-36

First preparative route to

sildenafil citrate.

Convergent commercial

preparation of sildenafil citrate

Redesign of the Sertraline Process

Sertraline: active ingredient in Zoloft

Combined process

Doubled yield

Ethanol replaced CH2Cl2, THF, toluene, and

hexane

Eliminated use of 140 metric tons/year TiCl4

Eliminated 150 metric tons/year 35% HCl

Pfizer

Early process synthesis of sertraline

Comparison of routes between the old and new commercial synthesis

of sertraline HCl.

Less Hazardous Chemical Synthesis

Classic batch approach

produces ca 3000 Kg of

waste each Kg of amino

ketone

R1

O

R2

NH2

Synthesis of amino ketones

Automate flow approach using safer

solvent produces only 2.3 Kg of waste

each Kg of amino ketone

> 99.9% reductionAdv. Synth. Catal. 2012, 354, 908–916

Research to Commercialization: Thomas Swan & Co Ltd

Multi-purpose plant using supercritical fluids

First full-scale facility for continuous, multi-purpose

synthesis, including

Hydrogenations

Friedel-Crafts reactions

Hydroformylations

Etherifications

Technology developed with the University of

Nottingham

Reactions in Supercritical Fluids

Formation of cyclic ethers

Hydrogenation

Poliakoff, University of Nottingham

HO OH

acid catalyst

O+ H2O

NO2 NH2Pd or Pt catalyst

propane, 80 bar

150-250 0C

Principle 1: Waste prevention

Cytovene

antiviral agent used in the treatment of cytomegalovirus

(CMV) retinitis infections

AIDS and solid-tissue transplant patients

Improved synthesis

reduced chemical processing steps from 6 to 2

reduced number of reagents and intermediates from 22

to 11

eliminated 1.12 million kg/year liquid waste

eliminated 25,300 kg/year solid waste

increased overall yield by 25%

Alternative Synthetic Pathways

Sodium iminodisuccinate

Biodegradable, environmentally friendly chelating agent

Synthesized in a waste-free process

Eliminates use of hydrogen cyanideBayer Corporation and Bayer AG

2001 Alternative Synthetic Pathways Award Winner

O

O

O

NaOH NH3 ONa

ONaNaO

NaON

H

O O

O O

Principle 4: Reduce Toxicity

Spinosad: a natural product for insect control

produced by Saccharopolyspora spinosa

isolated from Caribbean soil sample

demonstrates high selectivity, low toxicity

Dow AgroSciences

OO

H

O

HH

HH

OMe

OMe

OMe

O

O

OO

R

Me2N

Spinosyn A: R = HSpinosyn D: R = CH3

Small Business Award

PYROCOOL Technologies, Inc.

PYROCOOL F.E.F. (Fire Extinguishing Foam)

0.4% aqueous mixture of highly biodegradable

nonionic surfactants, anionic surfactants, and

amphoteric surfactants

replacement for halon gases and aqueous film

forming foams (AFFFs)

Principle 7: Renewable feedstocks

CO2 feedstock in polycarbonate synthesis

Improved Zn catalyst yields faster reaction, uses

milder reaction conditions

Coates et al., Cornell University

O

+ CO2

500 C, 100 psi CO2

catalyst

O*

O *

O

n

N NZn

OAc

iPr

iPr

Pri

Pri

catalyst =

Boric Acid-Mediated Amidation

Direct amidation of carboxylic acids with amines

Boric acid: nontoxic, safe, inexpensive

Eliminates use of SOCl2, PCl3, phosgene

Widely applicableEmisphere Technologies, Inc

R OH

O

H N

R'

R''R N

O

R'

R''

H2O+cat B(OH)3

toluene

reflux

+

Principle 12: Minimize hazard

Catalytically synthesize methylisocyanate to reduce risk of exposure

– eliminates use of phosgeneManzer, DuPont

Old Synthesis of Methylisocyanate

New Synthesis of Methylisocyanate

CH3NH2 + COCl2 CH3NCO + HCl

CH3NH2 + CO CH3NHCHOcatalyst

CH3NHCHO + O2

catalystCH3NCO

Reactions to be considered

• Green Mitsunobu Reactions

• Reduction of amides avoiding LAH and Diborane

• Bromination Reactions

• Sulfonation reactions

• Amide Formation avoiding poor atom economy reagents

• Nitration reactions

• F/C Reactions on unactivated substrates

• Demethylation Reactions

• Ester Hydrolysis

• OH activation for nucleophillic substitution

• Epoxidation

• Oxidation

• Wittig Chemistry without (Ph3PO)

• Radical Chemistry without Bu3SnH

• Solventless Reactor Cleaning

• Polar Aprotic replacements for NMP, DMSO, DMAc, DMF etc

• Asymmetric Hydrocyanation

• Aldehyde or Ketone + NH3 + “X” to give a chiral amine

• N-Centred chemistry avoiding azides hydrazines etc

• Asymmetric Hydrolysis of nitriles

• Asymmetric Hydrogenation of unfunctionalised olefins/enamines/imines

• Asymmetric Hydroformylation

• C-H activation of aromatics

• C-H activation of alkyl groups

• New Green Fluorination Methods

• Oxygen Nucleophiles with high reactivity

• Green sources of electrophilic Nitrogen

• Asymmetric Hydroamination of olefins

• Asymmetric Hydration of olefins

• Organocatalysis

• ROH + ArCl to give ROAr

Resources

• Green Chemistry in the

Pharmaceutical Industry,

Peter J.

Dunn (Editor), Andrew

Wells (Editor), Michael T.

Williams (Editor), ISBN:

978-3-527-32418-7, 388

pages,March 2010

Resources

• Green Chemistry Articles of Interest to the

Pharmaceutical Industry, Org. Process Res.

Dev., 2013, 17 (11), pp 1394–1405

Area of work

● Catalysis

● Ultrasound and microwave assisted organic reactions and

catalysis.

● Nanomaterials synthesis

● Ionic Liquids

● Catalysis and reactions in supercritical carbon dioxide.

● Carbon dioxide fixation into valuable chemicals

● Carbon monoxide fixation into valuable chemicals

● Enzymatic Catalysis

79

Formal Courses in Green Technology and

Sustainable Development

Degree Courses

Inclusion of Green Chemistry as a subject in all

U.G. courses of ICT – Chemical Engineering,

Chemical Technologies and Pharmaceutical

Sciences

a) M. Tech. Course ( 4 semesters) full time

b) M. Tech. Course (6 semesters ) part time

c) Ph. D. degree ( 3 years )

81

M.Tech. - Green Technology

In view of the global growing demand for specialised workforce in green

chemistry and technology Institute of Chemical Technology has started a

multidisciplinary postgraduate course i.e. Master of Green Technology.

The course is the first of its kind in the country and has been gaining

increasing response from the students and chemical industry.

The first batch of M. Tech. (Green Technology) in 2010 evidenced

enrolment of 14 students followed by enrolment of 27 students for the

second batch in 2011.

Most of these students are pursuing their interest in green chemistry and

technology by joining for Ph.D. course in green technology.

Fresh M. Tech. pass out students from the two batches have also found

good industrial placements with companies like E-value Serve, Loreal etc. to

name a few.

82

An efficient & heterogeneous

recyclable palladium catalyst for chemoselective

conjugate reduction of α,β-unsaturated

carbonyls in aqueous medium

D. B. Bagal, Z. S.

Qureshi K. P.

Dhake, S. R. Khan and

B. M. Bhanage

An highly efficient PS-Pd-NHC catalytic system has been

developed for chemoselective conjugate reduction of α,β-

unsaturated carbonyl compounds providing good to excellent

conversion with remarkable chemoselectivity (up to 100%). The

developed protocol is more advantageous due to use of

HCOONa as hydrogen source, environmentally

benign water assolvent and effective catalyst recyclability.

Green Chem., 2011, 13,

1490–1494

83

Pd/C-Catalyzed Synthesis of Oxamates by Oxidative Cross

Double Carbonylation of Amines and Alcohols under Co-

catalyst, Base, Dehydrating Agent, and Ligand-Free

Conditions

S.T. Gadge and B.M.

Bhanage

This work reports a mild, efficient, and ligand-free Pd/C-

catalyzed protocol for the oxidative cross double carbonylation

of amines and alcohols. Notably, the reaction does not requires

any base, co-catalyst, dehydrating agent, or ligand. Pd/C solves

the problem of catalyst recovery, and the catalyst was recycled

up to six times.

J. Org. Chem., 2013,

78 (13), 6793–6797

84

Shape selectivity using ionic liquids for the preparation of

silver

and silver sulphide nanomaterials

Amol B. Patil and

Bhalchandra.M.

Bhanage

Electrodeposition of silver and silver sulphide was carried out from

two protic ionic liquids. A change of the anion moiety of ionic liquid

was found to bring about significant changes in the morphology of the

nanocrystalline silver and silver sulphide deposits obtained. Effects of

various parameters like deposition overpotential, change of the

substrate, deposition time, etc. on the particle size and shape were

studied. It was found that a change of anions of the ionic liquid from

acetate to nitrate results in a wide difference in the morphology of the

deposits obtained. Acetate containing ionic liquids result in globular

nanocrystalline deposits whereas nitrate containing ionic liquids result

in flat plates or sheets of silver deposits. Similar results were obtained

for silver sulphide nanocrystals.

Phys. Chem. Chem. Phys.,

2014, 16, 3027--3035

85

Oxidative Aminocarbonylation of Terminal Alkynes for the

Synthesis of Alk-2-ynamides by Using Palladium-on-Carbon

as Efficient, Heterogeneous, Phosphine-Free, and Reusable

Catalyst

S.T. Gadge, M. V. Khedkar,

S. R. Lanke, B.M. Bhanage

Palladium-on-carbon (Pd/C)-catalyzed oxidative

aminocarbonylations of alk-1-ynes with secondary amines

provide the corresponding alk-2-ynamides in a good to excellent

yields. This new methodology is applicable for the synthesis of a

wide range of biologically active alk-2-ynamide derivatives. The

developed protocol avoids the use of phosphine ligands, with an

additional advantage of palladium catalyst recovery and reuse for

up to four consecutive cycles.

Advanced Synthesis &

Catalysis Volume

354, Issue 10, pages

2049–2056.

86

Palladium on Carbon: An Efficient, Heterogeneous and

Reusable Catalytic System for Carbonylative Synthesis of N-

Substituted Phthalimides

Mayur V. Khedkar, Shoeb R.

Khan, Dinesh N. Sawant,

Dattatraya B. Bagal,

Bhalchandra M. Bhanage

The application of palladium on carbon (Pd/C) as a heterogeneous

recyclable catalyst was investigated for the double carbonylation of o-

dihaloarenes with amines providing excellent yield of N-substituted

phthalimides in shorter reaction time as compared to earlier reported

homogeneous protocols. Furthermore, the scope of the developed

protocol was applied for the synthesis N-substituted phthalimides

fromo-halobenzoates and o-halobenzoic acid via a single step

carbonylative cyclization reaction. The developed methodology

describes an efficient one-step approach for the synthesis of an

important class of heterocycles and tolerates a wide variety of

functional groups. It circumvents the use of phosphine ligands with an

additional advantage of catalyst recyclability for up to eight

consecutive cycles.

Advanced Synthesis &

Catalysis Volume 353, Issue

18, 3415–3422,

87

Amine functionalized MCM-41: an efficient heterogeneous recyclable

catalyst for the synthesis of quinazoline-2,4(1H,3H)-diones from

carbon dioxide and 2-aminobenzonitriles in water

Deepak B. Nale

Surjyakanta Rana

Kulamani Parida,

Bhalchandra M. Bhanage

A simple covalently linked amine functionalized MCM-41 were

investigated as a highly efficient, heterogeneous and recyclable

mesoporous catalytic protocol for the synthesis of a wide variety of

quinazoline-2,4(1H,3H)-diones derivatives from 2-aminobenzonitriles and

carbon dioxide in aqueous reaction medium. This catalytic system

represents a heterogeneous and environmentally benign protocol. The

effect of various reaction parameters, such as influences of solvent,

temperature, CO2 pressure and time for the synthesis of quinazoline-

2,4(1H,3H)-diones were studied. The developed protocol can be applicable

for the synthesis of most important key intermediate 6,7-

dimethoxyquinazoline-2,4(1H,3H)-dione and several biologically active

derivatives such as Prazosin, Bunazosin and Doxazosin. Besides this, the

developed catalyst could be reused for five consecutive recycles without

any significant loss in its catalytic activity.

Catal. Sci. Technol., 2014,

DOI: 10.1039/C3CY00992K

88

Asymmetric Ring Opening of meso-Epoxides with Aromatic

Amines Using (R)-(+)-BINOL-Sc(OTf)3-NMM Complex as

an Efficient Catalyst

Ganesh V. More, Bhalchandra

M. Bhanage

European Journal of Organic

Chemistry 2013,30, pages

6900–6906

This work reports the asymmetric ring-opening reaction

of meso-epoxides with aromatic amines by using the highly

efficient in situ generated (R)-(+)-BINOL-Sc(OTf)3-N-

methylmorpholine complex. The asymmetric ring opening

of cis-stilbene oxide with various substituted aromatic amines

gave enantioenriched β-amino alcohols in good yields and with

excellent enantioselectivities when the reaction was conducted

at 0 °C for 12 h. The reaction proceeded under mild conditions

using simple and inexpensive starting materials such as (R)-(+)-

1,1′-bi-2-naphthol [(R)-(+)-BINOL], meso-stilbene oxide,

aniline derivatives, and 4 Å molecular sieves.

Ultrasound Assisted Regioselective Nitration

of Phenol using Dilute Nitric Acid in a

Biphasic Medium: Case study

A. Vogel, Fourth ed., Longman, London, 1978.

59% 41%

OH OH

NO2

HNO3

H2SO

4

OH

NO2

+

Prior Art

Acid Anhydrides

Metal Nitrates

N2O5

Solid Acid Catalysts (Cat Commun.2002, 3, 67.)

Surfactant (Tetrahedron 1988, 44, 4555.)

Ionic Liquids (J.O.C. 2001, 66, 35)

Microwave(Abstr.Papers.Am.Chem.Soc.1999,217,224-ENVR,Part I)

Ultrasound (Ulrason. Sonochem. 2007, 14, 41-45.)

Disadvantages

Lower Yield & Selectivity

Longer Reaction Time

Expensive Reagents

Sophisticated Techniques

Environmentally Hazardous

Ultrasound is widely used for improving the

traditional reactions that use expensive reagents,

strongly acidic conditions, long reaction times,

high temperatures, unsatisfactory yields and

incompatibility with other functional groups

Introduction

Nitration using PTC under sonication

OH

R

OH

NO2

R

OH

NO2

R

++ 6wt% HNO3

))), 25 oC

PTC

Ultrasound promoted regioselective nitration of phenols using dilute

nitric acid in the presence of phase transfer catalyst.

N.S.Nandurkar, M.J.Bhanushali, S.R.Jagtap and B.M.Bhanage

Ulrason. Sonochem. 2007, 14, 41-45.

Indian Patent No. IN 241202, (2010).

Regioselective nitration of phenol

R

OH

R

OH

R

OH

NO2

NO2

+)))))

9wt%HNO3

Improved Process for nitration of phenol using diluted nitric acid alone as the

nitrating agent under sonication.

N. S. Nandurkar, M. J. Bhanushali, A.G. Panda, B. M. Bhanage

Indian Patent No. IN 247957, (20011)

No Substrate Condition Time Conversion

(%)

Selectivity

p-nito o-nito

1 Phenol Silent 46 h 30 49 48

3 Phenol ((((( 2 h 94 70 27

3 o-cresol Silent 48 h 29 50 48

4 o-cresol ((((( 2 h 90 67 29

5 m-cresol Silent 48 h 25 50 47

6 m-cresol ((((( 2 h 85 63 34

7 p-cresol Silent 48 h 27 - 85

8 p-cresol ((((( 2 h 100 - 96

9 o-chlorophenol Silent 48 h 22 49 48

10 o-chlorophenol ((((( 2 h 83 60 36

11 p-chlorophenol Silent 48 h 20 - 87

12 p-chlorophenol ((((( 2 h 80 - 94

Table 7. Nitration of phenols and substituted phenols

using dilute nitric acid.

Substrate (5 mmol); nitric acid (70 wt%, 10 mmol) calculated amount of water to make 9 wt%

nitric acid (wt/wt); 1,2-dichloroethane (10 ml); agitation speed 200 rpm; temp 28-30 0C.

Our advantages over the conventional nitration

procedures

Higher yield and selectivity

Significant enhancement in reaction rate

Use of dilute Nitric acid (9 wt%)

No additives

Compatibility with various functional groups

No side reactions

9797

Sulfonation under sonication: No

need of oleum

H2SO4

SO3H

)))))

25-30oC

+

Conc.R R

Z. S. Qureshi, B. M. Bhanage, Ultrasonics Sonochemistry, 2009, 16, 308-311

Indian Patent IN 247765

Thank you……