Green Chemistry Principles

How Green was my Process ?: Case Studies of the Role of Process Chemistry in Drug Development Steven A. Weissman (Ph.D. ’87) Tufts University 29March 2004 “ Industrial Strength Chemistry”

Overview
What is Process Research ?
12 Principles of Green Chemistry
Case Studies-Merck Process Research
Lesson Learned: “Unlocking the Potential of Process Innovation”
Q & A

Net Cost: $802 Million Invested Over 15 Years 5,000–10,000 Screened 250 Enter Preclinical Testing 5 Enter Clinical Testing 1 Compound Success Rates by Stage 16 14 12 10 8 6 4 2 0 Phase II 100–300 Patient Volunteers Used to Look for Efficacy and Side Effects Phase III 1,000–5,000 Patient Volunteers Used to Monitor Adverse Reactions to Long-Term Use FDA Review Approval Additional Post-Marketing Testing Phase I 20–80 Healthy Volunteers Used to Determine Safety and Dosage Preclinical Testing Laboratory and Animal Testing Discovery (2–10 Years) Years New Product Development – A Risky and Expensive Proposition Source: Tufts Center for the Study of Drug Development Approved by the FDA

Mission :
To design elegant, practical, efficient, environmentally benign and economically viable chemical syntheses for Merck drug substances (“active pharmaceutical ingredient” (API))
Pre-Clinical: 50 g - 5 kg: Safety Assessment, formulation, metabolism
Clinical : 50-500 kg: Ph I-III human trials, long-term safety
Post Clinical : transfer process technology to Manufacturing (1000 kg - metric ton quantities/yr; depending on dose)

Advent of Process Research
MSc Degree- Univ. Liverpool
Dedicated ACS Journal ( Org Process R&D)
Dedicated Conferences (ACS, Gordon)
Books/Courses
C&E News cover stories
Wall Street Journal cover story

“ The ideal chemical process is that which a one-armed operator can perform by pouring the reactants into a bath tub and collecting pure product from the drain hole”
Sir John Conforth
(1975 Nobel Prize: Chemistry)

An amalgam of:
Modern synthetic organic methodology
Physicochemical properties
Salt selection: based on stability, suitability
Solid State Properties: Solvent dependant
Crystal Morphology: internal shape-affects solubility, stability
Crystal Habit: external shape-affects flowability, mixability
Particle Size: can affect bioavailability
Purification/Isolation technologies

Chemical Engineering principles: mixing, heat transfer, vessel configuration
Practical Process Aspects:
Safety
Quality
Cost
Reproducibility
Ruggedness

Process Research: Customers Med Chem Clinical Chem E R&D Pharm R&D Safety Analytical Process

Process Research: Customers responsible for developing In-process assay and critical evaluation of drug substance and intermediates Med Chem Clinical Chem E R&D Pharm R&D Safety Analytical Process

Process Research: Customers responsible for toxicity studies: (carcinogen, teratogen, gene toxicity ) Med Chem Clinical Chem E R&D Pharm R&D Safety Analytical Process

Process Research: Customers responsible for formulating drug substance (API) into drug product Med Chem Clinical Chem E R&D Pharm R&D Safety Analytical Process

Process Research: Customers Oversee process transfer into Pilot plants Med Chem Clinical Chem E R&D Pharm R&D Safety Analytical Process

Process Research: Customers Conducts clinical trials (Ph I-III) and evaluates data Med Chem Clinical Chem E R&D Pharm R&D Safety Analytical Process

Process Research: Customers Discovers new chemical entities (NCE’s) and prepares intitial quantities Med Chem Clinical Chem E R&D Pharm R&D Safety Analytical Process

Other Customers
Patent : drafting, inventorship, litigation
Outsourcing : work with vendors on tech transfer; setting specs; qualifying
Regulatory : drafting of NDA; process range finding
Manufacturing: transfer of process
‘ know-how’; oversee start-up

Developed in 1997 by:
Paul Anastas- EPA
Prof John Warner- UMass-Boston
Presidential Green Chemistry Challenge

Prevention : It is better to prevent waste than to treat/clean up after its created.

2. Atom Economy : synthetic methods should be designed to incorporate all the atoms used in the process into the final product
% atom economy =
100 x MW of all atoms utilized
MW of all reagents/reactants used
Example of 100% efficiency: Rearrangements, Diels-Alder

Atom Economy:Example Atom Economy = (MW of atoms utilized/MW of all reactants) X 100 = (137/275) X 100 = 50%

3. Minimize Hazardous Conditions:
Design process to avoid using reagents that pose safety threat
12. Safer Chemistry-Accident Prevention:
Design processes that minimize hazards to environment and human health

4. Design Safer Products:
Products should be designed to effect their desired function while minimizing toxicity
Example: Use of single enantiomer drug vs racemate

5. Use Safer Solvents/Auxiliaries
Use of innocuous solvents should be considered (e.g. water, supercritical CO 2 )
Avoid use of unnecessary substances
(e.g. drying agents, column chromatography)

6. Design for Energy Efficiency:
Energy requirements for a process should be recognized for environmental and economic impact
Examples : avoid extreme cryogenics (-78 o C)
Avoid prolonged reaction times

7. Use of Renewable Raw Materials:
Use a renewable source rather that depleting whenever technically and
economically feasible.
example: plant-derived RM; microbial reactions

8. Minimize Derivatization :
Avoid the use of protecting groups when possible as it add steps, requires extra reagents and generates more waste.

9. Catalysis:
Use of catalytic reagents is far superior than stoichiometric amounts
Example: using air as a source of oxygen for oxidation reaction

10. Design for Degradation:
Ideally, process products and by-products should breakdown into innocuous materials and/or do not persist in the environment

11. Real Time Analysis:
Analytical methods designed for ‘real-time’
In-process monitoring/control of a reaction
Example: Reactor-IR (in-situ probe for monitoring reactions)

Process Economics - Minimize inventory cost of API via:
Low cost RM
Productive/Efficient Reactions
High Yield
Highly concentrated
Few Steps
Short time cycles
Few Vessels

Case Studies from Merck
Remoxipride-----schizophrenia
Crixivan-----AIDS
Emend-----Depression, Emesis
L778,123----Cancer

Case Study 1: Remoxipride Selective Dopamine-2 Antagonist Indication: Anti-psychotic (Depression/Schizophrenia) Clinical Trials: halted in 1993 due to anemia side-effects

Original Bromination

Improved Bromination

Other Examples Auerbach, Weissman Tet Letters 1993, 931

Useful Methodology

Case Study 2: Crixivan ® HIV Protease Inhibitor-AIDS therapy FDA Approval - March 1996 Fastest FDA Approval Ever (42 Days) Daily Dosage: 2400 mg

Retrosynthetic Analysis of Crixivan-I

Retrosynthetic Analysis of Crixivan-II

Synthesis of Pyrazine Carboxamide Drawbacks: 1. Use of costly Oxalyl Chloride 2. CO and CO 2 by-products 3. Lengthy time cycle due to exothermic amination reaction 4. Need for 3 equiv of volatile t -butylamine 5. Filtration/Disposal of voluminous amine hydrochloride salt

Improved Route to Pyrazine Carboxamide

Atom Economy Comparison A: 179/[124+127+73+73] = 45 % B: 179/[105 + 98 +74 +18] = 61%

Chiral Piperazine via Resolution/Racemization

Original Route to cis-Amino Indanol Drawbacks: Low Yield No Recycle of (+)-isomer

Asymmetric Route to CAI N H 2 O H N H 2 O H O t - B u t - B u O N M n N H H O O t - B u t - B u 0 . 7 % S , S - M n I I ( s a l e n ) C l / a q N a O C l T a r t a r i c A c i d ; B a s e ( - ) C A I 5 0 % O v e r a l l C a t a l y t i c O x i d a n t : O l e u m , C H 3 C N ; H 2 O 7 8 % @ 8 7 % e e > 9 9 % e e L T e t r a h e d r o n L e t t . 1 9 9 5 , 3 6 , 3 9 9 3 . S R G r e e n C h e m i s t r y P r i n c i p l e s : P r e v e n t i o n ( R e d u c e d W a s t e ) C a t a l y s i s

Synthesis of Acetonide

Glycidyl Introduction with (S)-Glycidyl Tosylate

Glycidyl Introduction with Allylation/Epoxidation

Epoxide Synthesis Epoxidation----Instantaneous reaction: Performed in continuous stirred tank reactor (CSTR) on Manufacturing scale

End Game: Coupling

End Game: Alkylation

Crixivan: Summary
Overall nine step yield from CAI to sulfate salt is > 60%
Efficient assembly of optically pure fragments to produce Crixivan®
Chiral synthesis of cis -aminoindanol via novel Ritter reaction
Diastereoselective syn epoxidation of 2-benzyl-4-enamide intermediate via the iodohydrin
Novel asymmetric hydrogenation of differentially protected tetrahydropiperazine
17,000 gallons of solvent passed through the process train daily at its peak !

Case Study #3: L778,123 Maligres et al J. Heterocyclic Chem. 2003 , 229

Med Chem Route: Imidazole Drawbacks : (1) costly starting material; (2) double protection/deprotection

Marckwald Route to Imidazole

Delapine/Marckwald Route

Dethionation: Green Approach Green Principles: Prevention/Degradation

Case Study #3: L778,123 Maligres et al J. Heterocyclic Chem. 2003 , 229

Med Chem Route: Piperazinone

Piperazinone:New Route Weissman et. al. Tetrahedron Lett . 1998 , 7459

L778,123: Summary

Case Study #4: Synthesis of Emend

Disconnection

Diastereoselective Reduction

Med Chem Route to Vinyl Ether Drawbacks: (1) use of toxic NaCN; (2) costly resolving agent; (3) Lack of racemization/recycle

Petasis Methylenation Drawbacks : Titanocene reagent is very expensive and potentially hazardous------recycling imperative--  HUGE capital investment

Vinyl Ether via Hofmann Elimination ?

Synthesis of Aminodiol

Morpholine Synthesis

Morpholine via Novel Condensation ? Petasis et. al. JACS 1997 , 119, 445.

Synthesis of Bicyclic Acetal

Regioselective ‘Hofmann’ Elimination

Summary

Unlocking the Potential of Process Innovation

Industry Challenges
Increased Regulatory controls (FDA, EPA)
Downward Pricing Pressure
Greater Competition in treatment options
More complex molecules
Corporate consolidation
Dwindling # of diseases to conquer

Lessons Learned
Process Development as a Competitive Weapon/Leveraging Capabilities
“ The power of process development lies in how it helps companies achieve accelerated time to market, rapid production ramp-up and a stronger proprietary position”

Lessons Learned
“ A firm that can develop sophisticated process technologies more rapidly and with fewer development resources has strategic options that less capable competitors lack ”

Further Reading
Practical Process Research & Development; Neal Anderson
The Merck Druggernaut: The Inside Story of a Pharmaceutical Giant ; Fran Hawthorne
The Development Factory: Unlocking the Potential of Process Innovation ; Gary P. Pisano
Principles of Process Research and Chemical Development in the Pharmaceutical Industry ; Oljan Repic
Process Chemistry in the Pharmaceutical Industry; Kumar Gadamasetti

1,3-Asymmetric Induction Yoshida JACS 1984 , 1079

pH Dependence of Outcome

Marckwald Mechanism

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Green Chemistry Principles

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