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 ?