Green Chemistry Principles


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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
  • Green Chemistry Principles

    1. 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. 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. 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. 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. 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. 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. 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. 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. 9. Process Research: Customers Med Chem Clinical Chem E R&D Pharm R&D Safety Analytical Process
    10. 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. 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. 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. 13. Process Research: Customers Oversee process transfer into Pilot plants Med Chem Clinical Chem E R&D Pharm R&D Safety Analytical Process
    14. 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. 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. 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. 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. 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. 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. 20. Atom Economy:Example Atom Economy = (MW of atoms utilized/MW of all reactants) X 100 = (137/275) X 100 = 50%
    21. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 33. Original Bromination
    34. 34. Improved Bromination
    35. 35. Other Examples Auerbach, Weissman Tet Letters 1993, 931
    36. 36. Useful Methodology
    37. 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. 38. Retrosynthetic Analysis of Crixivan-I
    39. 39. Retrosynthetic Analysis of Crixivan-II
    40. 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. 41. Improved Route to Pyrazine Carboxamide
    42. 42. Atom Economy Comparison A: 179/[124+127+73+73] = 45 % B: 179/[105 + 98 +74 +18] = 61%
    43. 43. Chiral Piperazine via Resolution/Racemization
    44. 44. Retrosynthetic Analysis of Crixivan-II
    45. 45. Original Route to cis-Amino Indanol Drawbacks: Low Yield No Recycle of (+)-isomer
    46. 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. 47. Retrosynthetic Analysis of Crixivan-II
    48. 48. Synthesis of Acetonide
    49. 49. Glycidyl Introduction with (S)-Glycidyl Tosylate
    50. 50. Glycidyl Introduction with Allylation/Epoxidation
    51. 51. Epoxide Synthesis Epoxidation----Instantaneous reaction: Performed in continuous stirred tank reactor (CSTR) on Manufacturing scale
    52. 52. End Game: Coupling
    53. 53. End Game: Alkylation
    54. 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. 55. Case Study #3: L778,123 Maligres et al J. Heterocyclic Chem. 2003 , 229
    56. 56. Case Study #3: L778,123 Maligres et al J. Heterocyclic Chem. 2003 , 229
    57. 57. Med Chem Route: Imidazole Drawbacks : (1) costly starting material; (2) double protection/deprotection
    58. 58. Marckwald Route to Imidazole
    59. 59. Delapine/Marckwald Route
    60. 60. Delapine/Marckwald Route
    61. 61. Dethionation: Green Approach Green Principles: Prevention/Degradation
    62. 62. Case Study #3: L778,123 Maligres et al J. Heterocyclic Chem. 2003 , 229
    63. 63. Med Chem Route: Piperazinone
    64. 64. Piperazinone:New Route Weissman et. al. Tetrahedron Lett . 1998 , 7459
    65. 65. L778,123: Summary
    66. 66. Case Study #4: Synthesis of Emend
    67. 67. Disconnection
    68. 68. Diastereoselective Reduction
    69. 69. Med Chem Route to Vinyl Ether Drawbacks: (1) use of toxic NaCN; (2) costly resolving agent; (3) Lack of racemization/recycle
    70. 70. Petasis Methylenation Drawbacks : Titanocene reagent is very expensive and potentially hazardous------recycling imperative--  HUGE capital investment
    71. 71. Vinyl Ether via Hofmann Elimination ?
    72. 72. Synthesis of Aminodiol
    73. 73. Morpholine Synthesis
    74. 74. Morpholine via Novel Condensation ? Petasis et. al. JACS 1997 , 119, 445.
    75. 75. Synthesis of Bicyclic Acetal
    76. 76. Regioselective ‘Hofmann’ Elimination
    77. 77. Summary
    78. 79. Unlocking the Potential of Process Innovation
    79. 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>
    80. 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>
    81. 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>
    82. 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>
    83. 85. 1,3-Asymmetric Induction Yoshida JACS 1984 , 1079
    84. 86. pH Dependence of Outcome
    85. 87. pH Dependence of Outcome
    86. 88. Marckwald Mechanism