Key Green Chemistry Research Areas - A Perspective from
Pharmaceutical Manufacturers
Membership as of August 1, 2006
Membership is open to all pharmaceutical research, development, and manufacturing companies. The Roundtable will be strongest when
all global pharmaceutical corporations are members.
ACS Green Chemistry Institute
Pharmaceutical Roundtable
Strategic Priorities
MissionTo catalyze the implementation of green chemistry and engineering in the pharmaceutical industry globally.
Strategic Priorities Informing and Influencing the Research Agenda
Tools for Innovation
Education Resource
Global Collaboration
Inform and Influence the Research Agenda
Identify commonly used reactions in Pharmaceutical Manufacturing Commonly used reactions Aspirational chemical transformations
Inform research community, encourage funding agencies
Selectively fund key research areas
Brainstorm
Ideas
Reactions we use now but would prefer better reagents
(i) Frequency of use
(ii) Waste assessment
(iii) Process hazard assessment
Aspirational
Reaction
list
Key Challenges
in Pharma
Manufacturing
Prioritise by
company vote
GSK
Merck
Pfizer
Lilly
Schering-Plough
AZ
Brainstorm Output
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
Key Message
Lot of commonality between the voting of the GCIrt companies
Prioritization Process
Reaction Frequency of usea
Waste Assessment
Hazard Assessment
Amide Formation
9.1 %
OH activation 2.0 %
Amide Reduction
0.6 %
Mitsunobu 0.2 %
Oxidations 4.0 %
Friedel-Crafts 1.2 %
Nitrations 1.2 %
Sulfonations 0.2 %
a Analysis of the Reactions used for the Preparation of Drug Candidate Molecules. Carey, J.S., Laffan, D., Thomson, C., Williams, M.T. Org. Biomol. Chem., 2006, 4, (12), 2337-2347
Reactions that GCI companies use now but would strongly prefer better reagents
Amide formation avoiding poor atom economy reagents
OH activation for nucleophilic substitution Reduction of amides without hydride reagents Oxidation/Epoxidation methods without the
use of chlorinated solvents Safe and environmentally friendly Mitsunobu
reactions Friedel-Craft reactions on unactivated systems Nitrations
- 6 votes
- 5 votes- 4 votes
- 4 votes
- 3 votes
- 2 votes
- 2 votes
Reactions that GCI companies use now but would strongly prefer better reagents
Amide formation avoiding poor atom economy reagents
OH activation for nucleophilic substitution Reduction of amides without hydride reagents Oxidation/Epoxidation methods without the
use of chlorinated solvents Safe and environmentally friendly Mitsunobu
reactions
Friedel-Craft reactions on unactivated systems Nitrations
- 6 votes
- 5 votes
- 4 votes
- 4 votes
- 3 votes
- 2 votes
- 2 votes
More Aspirational Reactions
C-H activation of aromatics (cross couplings avoiding the preparation of haloaromatics)
Aldehyde or ketone + NH3 + ‘X’ to give chiral amine Asymmetric hydrogenation of unfunctionalised
olefins/enamines/imines New green Fluorination methods under mild conditions N-Centred chemistry avoiding azides, hydrazine etc Asymmetric hydroamination Green sources of electrophilic nitrogen (not TsN3, nitroso
or diimide) Asymmetric hydrocyanation
- 6 votes
- 4 votes
- 4 votes
- 4 votes
- 4 votes
- 2 votes
- 2 votes
- 2 votes
More Aspirational Reactions
C-H activation of aromatics (cross couplings avoiding the preparation of haloaromatics)
Aldehyde or ketone + NH3 + ‘X’ to give chiral amine Asymmetric hydrogenation of unfunctionalised
olefins/enamines/imines New green Fluorination methods under mild conditions N-Centred chemistry avoiding azides, hydrazine etc
Asymmetric hydroamination Green sources of electrophilic nitrogen (not TsN3, nitroso
or diimide) Asymmetric hydrocyanation
- 6 votes
- 4 votes
- 4 votes
- 4 votes
- 4 votes
- 2 votes
- 2 votes
- 2 votes
Key Challenges
Current Reactions Amide Formation, OH activation, Amide Reduction,
Green Mitsunobu reactions, Oxidation/Epoxidations More Aspirational Reactions
C-H activation or aromatics, chiral amine synthesis, Asymmetric Hydrogenation, Green Fluorination Methods, N-Centred Chemistry
Key Ideas outside the Reaction theme Solvent less Reactor Cleaning Green alternatives to polar aprotic solvents
Questions for Discussion
Are there anymore key research areas that did not come up in our brainstorm ?
Is anyone working (or know of people working) on the key chemistry challenges ?
Any good ideas to solve some of these problems ? What are the best funding opportunities ?
How do we best tap into them ? These projects are tough and challenging. How do we entice
researchers to focus their efforts on these problems ?