The document discusses process chemistry and its role in drug development based on case studies from Merck. It describes how process research aims to design efficient, environmentally friendly chemical syntheses for drug substances. Case studies on drugs like Remoxipride, Crixivan, Emend, and L778,123 illustrate how process innovations like new routes and catalysts improved atom economy, yield, safety, and cost compared to original routes. The document also outlines 12 principles of green chemistry and lessons learned on unlocking the potential of process innovation to gain competitive advantages.

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”

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

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

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

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

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

79. Unlocking the Potential of Process Innovation

85. 1,3-Asymmetric Induction Yoshida JACS 1984 , 1079

86. pH Dependence of Outcome

87. pH Dependence of Outcome

88. Marckwald Mechanism