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Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
Green Chemistry  Principles
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Green Chemistry Principles

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Green Chemistry talk presented at Tufts University

Green Chemistry talk presented at Tufts University

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  • Reasons to kill a PCC: Lack of efficacy, safety concerns, metabolism issues (half-life), stability
  • Regulatory- talk of CMC (“chemistry and manufacturing controls”) section
  • 12 Principles of Green Chemistry Developed in 1997 by: Paul Anastas – EPA Prof John Warner – UMass-Boston
  • 1 st generation epoxide synth
  • Farnesyl transferase inhibitor
  • Farnesyl transferase inhibitor
  • Farnesyl transferase inhibitor
  • Features:
  • Known from Med Chem route
  • Strecker reaction gives hydroxy aminonitrile, followed by hydrolysis of CN to acid and cyclization to OXAZINONE BCSA= bromo-CSA (Resolution agent)
  • Mannich boronic acid condensation
  • Lactol hydroxyl selectively activated Benzylic alcohol better Nu Proceeds w/ typical SN2 inversion Traditional acetal forming conditions did not work (acid)
  • Hofmann rules apply only to acylic systems- otherwise would expect vinyl ether product
  • Iodolactonization of  - unsaturated amides
  • Iminolactone = intermediate
  • Breakdown of hydroxy-N,O-acetal differs based on pH
  • Transcript

    • 1. 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”
    • 2. Overview <ul><li>What is Process Research ? </li></ul><ul><li>12 Principles of Green Chemistry </li></ul><ul><li>Case Studies-Merck Process Research </li></ul><ul><li>Lesson Learned: “Unlocking the Potential of Process Innovation” </li></ul><ul><li>Q & A </li></ul>
    • 3. 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
    • 4. What is Process Research ? <ul><li>Mission : </li></ul><ul><li>To design elegant, practical, efficient, environmentally benign and economically viable chemical syntheses for Merck drug substances (“active pharmaceutical ingredient” (API)) </li></ul><ul><li>Pre-Clinical: 50 g - 5 kg: Safety Assessment, formulation, metabolism </li></ul><ul><li>Clinical : 50-500 kg: Ph I-III human trials, long-term safety </li></ul><ul><li>Post Clinical : transfer process technology to Manufacturing (1000 kg - metric ton quantities/yr; depending on dose) </li></ul>
    • 5. Advent of Process Research <ul><li>MSc Degree- Univ. Liverpool </li></ul><ul><li>Dedicated ACS Journal ( Org Process R&D) </li></ul><ul><li>Dedicated Conferences (ACS, Gordon) </li></ul><ul><li>Books/Courses </li></ul><ul><li>C&E News cover stories </li></ul><ul><li>Wall Street Journal cover story </li></ul>
    • 6. What is Process Research ? <ul><li>“ 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” </li></ul><ul><li>Sir John Conforth </li></ul><ul><li>(1975 Nobel Prize: Chemistry) </li></ul>
    • 7. What is Process Research ? <ul><li>An amalgam of: </li></ul><ul><li>Modern synthetic organic methodology </li></ul><ul><li>Physicochemical properties </li></ul><ul><ul><li>Salt selection: based on stability, suitability </li></ul></ul><ul><ul><li>Solid State Properties: Solvent dependant </li></ul></ul><ul><ul><ul><li>Crystal Morphology: internal shape-affects solubility, stability </li></ul></ul></ul><ul><ul><ul><li>Crystal Habit: external shape-affects flowability, mixability </li></ul></ul></ul><ul><ul><ul><li>Particle Size: can affect bioavailability </li></ul></ul></ul><ul><li>Purification/Isolation technologies </li></ul>
    • 8. What is Process Research ? <ul><li>Chemical Engineering principles: mixing, heat transfer, vessel configuration </li></ul><ul><li>Practical Process Aspects: </li></ul><ul><ul><li>Safety </li></ul></ul><ul><ul><li>Quality </li></ul></ul><ul><ul><li>Cost </li></ul></ul><ul><ul><li>Reproducibility </li></ul></ul><ul><ul><li>Ruggedness </li></ul></ul>
    • 9. Process Research: Customers Med Chem Clinical Chem E R&D Pharm R&D Safety Analytical Process
    • 10. 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
    • 11. Process Research: Customers responsible for toxicity studies: (carcinogen, teratogen, gene toxicity ) Med Chem Clinical Chem E R&D Pharm R&D Safety Analytical Process
    • 12. 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
    • 13. Process Research: Customers Oversee process transfer into Pilot plants Med Chem Clinical Chem E R&D Pharm R&D Safety Analytical Process
    • 14. 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
    • 15. 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
    • 16. Other Customers <ul><li>Patent : drafting, inventorship, litigation </li></ul><ul><li>Outsourcing : work with vendors on tech transfer; setting specs; qualifying </li></ul><ul><li>Regulatory : drafting of NDA; process range finding </li></ul><ul><li>Manufacturing: transfer of process </li></ul><ul><li>‘ know-how’; oversee start-up </li></ul>
    • 17. 12 Principles of Green Chemistry <ul><li>Developed in 1997 by: </li></ul><ul><li>Paul Anastas- EPA </li></ul><ul><li>Prof John Warner- UMass-Boston </li></ul><ul><li>Presidential Green Chemistry Challenge </li></ul>
    • 18. 12 Principles of Green Chemistry <ul><li>Prevention : It is better to prevent waste than to treat/clean up after its created. </li></ul>
    • 19. 12 Principles of Green Chemistry <ul><li>2. Atom Economy : synthetic methods should be designed to incorporate all the atoms used in the process into the final product </li></ul><ul><li>% atom economy = </li></ul><ul><li>100 x MW of all atoms utilized </li></ul><ul><li>MW of all reagents/reactants used </li></ul><ul><li>Example of 100% efficiency: Rearrangements, Diels-Alder </li></ul>
    • 20. Atom Economy:Example Atom Economy = (MW of atoms utilized/MW of all reactants) X 100 = (137/275) X 100 = 50%
    • 21. 12 Principles of Green Chemistry <ul><li>3. Minimize Hazardous Conditions: </li></ul><ul><li>Design process to avoid using reagents that pose safety threat </li></ul><ul><li>12. Safer Chemistry-Accident Prevention: </li></ul><ul><li>Design processes that minimize hazards to environment and human health </li></ul>
    • 22. 12 Principles of Green Chemistry <ul><li>4. Design Safer Products: </li></ul><ul><li>Products should be designed to effect their desired function while minimizing toxicity </li></ul><ul><li>Example: Use of single enantiomer drug vs racemate </li></ul>
    • 23. 12 Principles of Green Chemistry <ul><li>5. Use Safer Solvents/Auxiliaries </li></ul><ul><li>Use of innocuous solvents should be considered (e.g. water, supercritical CO 2 ) </li></ul><ul><li>Avoid use of unnecessary substances </li></ul><ul><li>(e.g. drying agents, column chromatography) </li></ul>
    • 24. 12 Principles of Green Chemistry <ul><li>6. Design for Energy Efficiency: </li></ul><ul><li>Energy requirements for a process should be recognized for environmental and economic impact </li></ul><ul><li>Examples : avoid extreme cryogenics (-78 o C) </li></ul><ul><li>Avoid prolonged reaction times </li></ul>
    • 25. 12 Principles of Green Chemistry <ul><li>7. Use of Renewable Raw Materials: </li></ul><ul><li>Use a renewable source rather that depleting whenever technically and </li></ul><ul><li>economically feasible. </li></ul><ul><li>example: plant-derived RM; microbial reactions </li></ul>
    • 26. 12 Principles of Green Chemistry <ul><li>8. Minimize Derivatization : </li></ul><ul><li>Avoid the use of protecting groups when possible as it add steps, requires extra reagents and generates more waste. </li></ul>
    • 27. 12 Principles of Green Chemistry <ul><li>9. Catalysis: </li></ul><ul><li>Use of catalytic reagents is far superior than stoichiometric amounts </li></ul><ul><li>Example: using air as a source of oxygen for oxidation reaction </li></ul>
    • 28. 12 Principles of Green Chemistry <ul><li>10. Design for Degradation: </li></ul><ul><li>Ideally, process products and by-products should breakdown into innocuous materials and/or do not persist in the environment </li></ul>
    • 29. 12 Principles of Green Chemistry <ul><li>11. Real Time Analysis: </li></ul><ul><li>Analytical methods designed for ‘real-time’ </li></ul><ul><li>In-process monitoring/control of a reaction </li></ul><ul><li>Example: Reactor-IR (in-situ probe for monitoring reactions) </li></ul>
    • 30. 13 Principles of Green Chemistry <ul><li>Process Economics - Minimize inventory cost of API via: </li></ul><ul><li>Low cost RM </li></ul><ul><li>Productive/Efficient Reactions </li></ul><ul><ul><li>High Yield </li></ul></ul><ul><ul><li>Highly concentrated </li></ul></ul><ul><ul><li>Few Steps </li></ul></ul><ul><ul><li>Short time cycles </li></ul></ul><ul><ul><li>Few Vessels </li></ul></ul>
    • 31. Case Studies from Merck <ul><li>Remoxipride-----schizophrenia </li></ul><ul><li>Crixivan-----AIDS </li></ul><ul><li>Emend-----Depression, Emesis </li></ul><ul><li>L778,123----Cancer </li></ul>
    • 32. Case Study 1: Remoxipride Selective Dopamine-2 Antagonist Indication: Anti-psychotic (Depression/Schizophrenia) Clinical Trials: halted in 1993 due to anemia side-effects
    • 33. Original Bromination
    • 34. Improved Bromination
    • 35. Other Examples Auerbach, Weissman Tet Letters 1993, 931
    • 36. Useful Methodology
    • 37. Case Study 2: Crixivan ® HIV Protease Inhibitor-AIDS therapy FDA Approval - March 1996 Fastest FDA Approval Ever (42 Days) Daily Dosage: 2400 mg
    • 38. Retrosynthetic Analysis of Crixivan-I
    • 39. Retrosynthetic Analysis of Crixivan-II
    • 40. 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
    • 41. Improved Route to Pyrazine Carboxamide
    • 42. Atom Economy Comparison A: 179/[124+127+73+73] = 45 % B: 179/[105 + 98 +74 +18] = 61%
    • 43. Chiral Piperazine via Resolution/Racemization
    • 44. Retrosynthetic Analysis of Crixivan-II
    • 45. Original Route to cis-Amino Indanol Drawbacks: Low Yield No Recycle of (+)-isomer
    • 46. 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
    • 47. Retrosynthetic Analysis of Crixivan-II
    • 48. Synthesis of Acetonide
    • 49. Glycidyl Introduction with (S)-Glycidyl Tosylate
    • 50. Glycidyl Introduction with Allylation/Epoxidation
    • 51. Epoxide Synthesis Epoxidation----Instantaneous reaction: Performed in continuous stirred tank reactor (CSTR) on Manufacturing scale
    • 52. End Game: Coupling
    • 53. End Game: Alkylation
    • 54. Crixivan: Summary <ul><li>Overall nine step yield from CAI to sulfate salt is > 60% </li></ul><ul><li>Efficient assembly of optically pure fragments to produce Crixivan® </li></ul><ul><li>Chiral synthesis of cis -aminoindanol via novel Ritter reaction </li></ul><ul><li>Diastereoselective syn epoxidation of 2-benzyl-4-enamide intermediate via the iodohydrin </li></ul><ul><li>Novel asymmetric hydrogenation of differentially protected tetrahydropiperazine </li></ul><ul><li>17,000 gallons of solvent passed through the process train daily at its peak ! </li></ul>
    • 55. Case Study #3: L778,123 Maligres et al J. Heterocyclic Chem. 2003 , 229
    • 56. Case Study #3: L778,123 Maligres et al J. Heterocyclic Chem. 2003 , 229
    • 57. Med Chem Route: Imidazole Drawbacks : (1) costly starting material; (2) double protection/deprotection
    • 58. Marckwald Route to Imidazole
    • 59. Delapine/Marckwald Route
    • 60. Delapine/Marckwald Route
    • 61. Dethionation: Green Approach Green Principles: Prevention/Degradation
    • 62. Case Study #3: L778,123 Maligres et al J. Heterocyclic Chem. 2003 , 229
    • 63. Med Chem Route: Piperazinone
    • 64. Piperazinone:New Route Weissman et. al. Tetrahedron Lett . 1998 , 7459
    • 65. L778,123: Summary
    • 66. Case Study #4: Synthesis of Emend
    • 67. Disconnection
    • 68. Diastereoselective Reduction
    • 69. Med Chem Route to Vinyl Ether Drawbacks: (1) use of toxic NaCN; (2) costly resolving agent; (3) Lack of racemization/recycle
    • 70. Petasis Methylenation Drawbacks : Titanocene reagent is very expensive and potentially hazardous------recycling imperative--  HUGE capital investment
    • 71. Vinyl Ether via Hofmann Elimination ?
    • 72. Synthesis of Aminodiol
    • 73. Morpholine Synthesis
    • 74. Morpholine via Novel Condensation ? Petasis et. al. JACS 1997 , 119, 445.
    • 75. Synthesis of Bicyclic Acetal
    • 76. Regioselective ‘Hofmann’ Elimination
    • 77. Summary
    • 78.  
    • 79. Unlocking the Potential of Process Innovation
    • 80. Industry Challenges <ul><li>Increased Regulatory controls (FDA, EPA) </li></ul><ul><li>Downward Pricing Pressure </li></ul><ul><li>Greater Competition in treatment options </li></ul><ul><li>More complex molecules </li></ul><ul><li>Corporate consolidation </li></ul><ul><li>Dwindling # of diseases to conquer </li></ul>
    • 81. Lessons Learned <ul><li>Process Development as a Competitive Weapon/Leveraging Capabilities </li></ul><ul><li>“ 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” </li></ul>
    • 82. Lessons Learned <ul><li>“ A firm that can develop sophisticated process technologies more rapidly and with fewer development resources has strategic options that less capable competitors lack ” </li></ul>
    • 83. Further Reading <ul><li>Practical Process Research & Development; Neal Anderson </li></ul><ul><li>The Merck Druggernaut: The Inside Story of a Pharmaceutical Giant ; Fran Hawthorne </li></ul><ul><li>The Development Factory: Unlocking the Potential of Process Innovation ; Gary P. Pisano </li></ul><ul><li>Principles of Process Research and Chemical Development in the Pharmaceutical Industry ; Oljan Repic </li></ul><ul><li>Process Chemistry in the Pharmaceutical Industry; Kumar Gadamasetti </li></ul>
    • 84.  
    • 85. 1,3-Asymmetric Induction Yoshida JACS 1984 , 1079
    • 86. pH Dependence of Outcome
    • 87. pH Dependence of Outcome
    • 88. Marckwald Mechanism

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