This document summarizes green chemistry principles and some examples of their application in pharmaceutical synthesis. It defines green chemistry as reducing waste, hazardous substances, energy usage, and risk through the 12 principles developed by Anastas and Warner. These principles include prevention of waste, safer solvents and auxiliaries, designing for energy efficiency and degradation. It then provides examples of applying these principles to the syntheses of ibuprofen, sildenafil citrate, and pregabalin to make the processes safer and more sustainable.

1. Green Chemistry
Introduced to;
Dr. Heba M.Hesham
T.A. of Pharmaceutical Chemistry, Faculty of Pharmacy -Ain
Shams University, Abbasia, Cairo, Egypt.
Prepared& presented by;
Muhammad Talaat Qassem, ID.446
Muhammad Nazir Mazen, ID.456
Muhammad Azouz Muhammad, ID.448
Mahmoud Ahmed Mandour, ID.458
Muhammad Hazem Sayed, ID.438
Muhammad Gamal Riad, ID.
Faculty of Pharmacy -Ain Shams University, Abbasia, Cairo,
Egypt.

2. Green Chemistry

3. Green Chemistry
Paul Anastas: Father of Green Chemistry
*The concept of green chemistry was formally established at the
ENVIRONMENTAL PROTECTION AGENCY 15 years ago in
response to the Pollution Prevention Act of 1990.
*Paul T. Anastas for the first time in 1991 coined the term Green
Chemistry.
Though it is said that the concept was originated by Trevor Kletz
in his 1978 paper where he proposed that chemists should seek
alternative processes to those involving more dangerous substances
and conditions.

4. Green Chemistry
*Definition: Reducing of:
”The utilization of a set of -Waste
principles; 12 priciples:
-Material
The use or generation
of hazardous substances -Hazardous
in the design, manufacture
and application of chemical -Energy
products.”
-Risk
-Cost

5. Principles of Green Chemistry
Paul T. Anastas and John C. Warner developed 12 principles of green
chemistry, which help to explain what the definition means in practice.
1. Prevention
2. Atom Economy
3. Less Hazardous Chemical Synthesis
4. Designing Safer Chemicals
5. Safer Solvents and Auxiliaries
6. Design for Energy Efficiency
7. Use of Renewable Feedstocks
8. Reduce Derivatives
9. Catalysis
10. Design for Degradation
11. Real-time Analysis for Pollution Prevention.
12. Inherently Safer Chemistry for Accident Prevention.

6. Principles of Green Chemistry
1.Prevention Of Waste: 2.Atom Economy:
*It is better to prevent waste than *Synthetic methods should be
to treat or clean up waste after designed to maximize the
it is formed. incorporation of all the
materials used in the process
into the final product.

7. Principles of Green Chemistry
3.Less Hazardous Chemical Synthesis
*Wherever practicable, synthetic methodologies should be designed to use
and generate substances that possess little or no toxicity to human health and
the environment.
Ex. THALIDOMIDE
“is an unsafe drug is for lessening
the effect of nausea and vomiting
during pregnancy.”
****The child born to women taking the drug
suffers from birth defects like deformed-limbs.

8. Principles of Green Chemistry
4.Designing Safer Chemical 5.Safer Solvents and Auxiliaries
*Chemical products should *The use of auxiliary substances
designed to preserve efficacy (e.g. solvents, separation agents,etc.)
of function while reducing toxicity. should be made unnecessary wherever
possible and innocuous when used.
*Choosing of reagents that pose
the least risk and generate only *Ex.:
safe by-products. One major problem with many solvents is
their volatility that may damage
environment and human health.
*Ex.:
In the manufacture of Polystyrene,
CFC’s which contribute to ozone depletion *To avoid this many Rx. are carried out in
and global warming are replaced by 𝑪𝑶 𝟐. safer green solvents like ionic liquids,
supercritical 𝑪𝑶 𝟐 fluid etc. which maintain
the solvency of the material and are not
volatile.

9. Principles of Green Chemistry
6.Design for Energy Efficiency
* Energy requirements should be recognized for their environmental and
economic impacts and should be minimized. Synthetic methods should be
conducted at ambient temperature and pressure.
*In any chemical synthesis the energy requirement should be kept low:
1. If the starting material is soluble in the particular solvent, the reaction
mixture has to be heated till the reaction is complete.
2. If the final product is impure it has to be purified by distillation or
recrystallization .
All these steps involve the use of high amount of energy which is
uneconomical.

10. Principles of Green Chemistry
7.Use of Renewable Feedstocks
*A raw material or feedstock should be renewable rather than depleting
wherever technically and economically practicable.
*Ex.:
1. Substances like 𝑪𝑶 𝟐 (generated from natural sources) and methane gas
(marsh gas) are considered as renewable starting materials.
2. Polymers from Renewable Resources: Poly(lactic acid)

11. Principles of Green Chemistry
8.Reduce Derivatives
*Reduce derivatives - Unnecessary derivatization (blocking group,
protection/deprotection, temporary modification) should be avoided
whenever possible.
9.Catalysis
*Catalytic reagents (as selective as possible) are superior to stoichiometric
reagents.
Use of a catalyst facilitates transformation without the catalyst being
consumed in the reaction and without being incorporated in the final product.

12. Principles of Green Chemistry
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 break down into innocuous degradation products.
*Ex.:
1.Sulfonated detergents 2.Chlorofluorocarbons (CFCs)
- Alkylbenzene sulfonates. - Do not break down, persist in atmosphere
and contribute to destruction of ozone layer.
- Foam in sewage plants,
rivers and streams. 3.DDT
- Tends to bio-accumulate
- Alkene group into the chain in many plant and animal species and
increases degradation. incorporate into the food chain
resulting in population decline of beneficial
- Persistence was due to long insects and animals
alkyl chain

13. Principles of Green Chemistry
11.Real-time Analysis for Pollution Prevention
*Analytical methodologies need to be further
developed to allow for real-time, in-process
monitoring and control prior to the formation
of hazardous substances.
*Knowing when your product is “done” can save a lot of wasted time and
energy!

14. Principles of Green Chemistry
12.Inherently Safer Chemistry for Accident Prevention
*Substances and the form of a substance used in a chemical process
should be chosen to minimize potential for chemical accidents, including releases,
explosions, and fires.
*Ex.:
December 3, 1984 –
poison gas; methyl isocyanate (MIC) leaked
from a Union Carbide India Limited (UCIL)
pesticide plant in Bhopal,
Madhya Pradesh.
- killing thousands instantly and injuring many more
(many of who died later of exposure).
- Up to 20,000 people have died as a result of exposure (3-8,000 instantly).
- More than 120,000 still suffer from ailments caused by exposure.

15. Principles of Green Chemistry
12.Inherently Safer Chemistry for Accident Prevention
* December 3, 1984 –
Methyl isocyanate (MIC) Disaster!

16. Synthesis Of Some Pharmaceutical Compounds
Involving Basic Principles Of Green Chemistry

17. Synthesis Of Some Pharmaceutical Compounds
Involving Basic Principles Of Green Chemistry
1.Synthesis Of Ibuprofen
*analgesics (pain killers)
*Boots Company of England in1960s.
*It is a 6 step process and results in large quantities of by-products.

18. Synthesis Of Some Pharmaceutical Compounds
Involving Basic Principles Of Green Chemistry
1.Synthesis Of Ibuprofen
*Green Chemistry Route *BHC Company *Classic route of synthesis *Boots Company

19. Synthesis Of Some Pharmaceutical Compounds Involving
Basic Principles Of Green Chemistry
2.The development of Pfizer’s production process for sildenafil
citrate
*The reduction of solvent use is a normal aim of the development of the
commercial synthesis of a pharmaceutical.
*For sildenafil citrate a reduction in solvent use from 1300 l 𝑲𝒈−𝟏 for the
original medicinal chemistry route to 7 l 𝑲𝒈−𝟏
for the final commercial route
(with solvent recovery and recycling) was achieved.
*As well as using less solvent, the commercial process also uses less
harmful solvents.

20. Synthesis Of Some Pharmaceutical Compounds Involving Basic
Principles Of Green Chemistry
2.Synthesis of Sildenafil citrate
*The optimized medicinal chemistry route to sildenafil citrate (Viagra)

21. Synthesis Of Some Pharmaceutical Compounds Involving Basic
Principles Of Green Chemistry
2.Synthesis of Sildenafil citrate
*The commercial route to sildenafil citrate (Viagra)-Green Chemistry Scheme!

22. Synthesis Of Some Pharmaceutical Compounds Involving Basic
Principles Of Green Chemistry
3. Pfizer’s chemoenzymatic synthesis of pregabalin
*Treatment for central nervous system disorders.
*Synthesis: a Knoevenagel condensation, followed by cyanation, introducing a
chiral Centre as a racemic mixture, then hydrolysis, decarboxylation and
hydrogenation in methanol to yield a γ-aminoacid….
*The generation of the γ-aminoacid as a racemic mixture and the
need to obtain the enantiomerically pure pregabalin led to both waste
of the compound itself and the use of large amounts of solvents.

23. Synthesis Of Some Pharmaceutical Compounds Involving Basic
Principles Of Green Chemistry
3. Pfizer’s chemoenzymatic synthesis of pregabalin
*The original commercial synthesis of pregabalin
*Mitsubishi Rayon’s synthesis of acrylamide
*Whole-cell biocatalysis

24. ***Reference
(1) Breslow, R. The Greening of Chemistry. Chem. & Eng. (7) ISSN: 1751-8253 (Print) 1751-7192 (Online)
News 1996, (Aug 26), 72. Journal homepage:
(2) Anastas, P.T.;Williamson, T.C., Eds.; Green Chemistry: http://www.tandfonline.com/loi/tgcl20
Frontiers in Benign Chemical Syntheses and (8) http://dx.doi.org/10.1098/rspa.2015.0502
Processes;Oxford University Press: Oxford, UK,
1998.
(3) Anastas, P.;Warner, J., Eds.; Green Chemistry:
Theory and Practice;Oxford University Press: Oxford,
UK, 1998.
(4) Sheldon, R.A. Chem. Ind. 1992, 23, 903906;Sheldon,
R.A. Chem. Tech. 1994, 24, 3847.
(5) Jimenez-Gonzalez, C.;Curzons, A.D.;Constable,
D.J.C.;Cunningham, V.L. Int. J. LCA 2004, 9, 115
121.
(6) Curzons, A.D.;Jimenez-Gonzalez, C.; Duncan, A.L.;
Constable, D.J.C.;Cunningham, V.L. Int. J. LCA
2007, 12, 272280.

25. **Reference
(9) http://rspa.royalsocietypublishing.org/content/471/2183/20150502
(10) http://www.chm.bris.ac.uk/motm/ibuprofen/synthesis.htm
(11) http://www.chemicalforums.com/index.php?topic=79951.0
(12) http://www.gettyimages.com/event/archive-images-of-bhopal-gas-tragedy-521372553#medical-staff-
giving-eye-drops-to-a-victim-of-bhopal-gas-tragedy-on-a-picture-id458178740
Done by God's goodness