The role of new technologies in defining a manufacturing process for ppara agonist ly518674

Organic Process Research and Development

Volumn 13, Issue 2, 2009, Pages 131-143

  Argentine, Mark D ^a   Braden, Timothy M ^a   Czarnik, Jeffrey ^a   Conder, Edward W ^a   Dunlap, Steven E ^a   Fennell, Jared W ^a   LaPack, Mark A ^a   Rothhaar, Roger R ^a   Scherer, R Brian ^a   Schmid, Christopher R ^a   Vicenzi, Jeffrey T ^a   Wei, Jeffrey G ^a   Werner, John A ^a   Roginski, Robert T ^b  

^a ELI LILLY AND COMPANY   (United States)

^b EIGENVECTOR RESEARCH INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 66049144555     PISSN: 10836160     EISSN: 1520586X     Source Type: Journal    
DOI: 10.1021/op8002486     Document Type: Article

References (63)

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2. See ICH Guidelines Q8, Annex to Q8, and Q9; Available online at: http://www.ich.org/cache/compo/363-272-l.html.
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4. Ganzer, W. P., Materna, J. A., Mitchell, M. B., Wall, L. K. Current Thoughts on Critical Process Parameters and API Synthesis. Pharmaceutical Technology; July 2, 2005. Available online at http://pharmtech.findpharma. com/pharmtech/content/printContentPopup. jsp?id=170114.
5. (a) Wang, X.; Barr, R. J.; Bean, J. S.; Kauffman, R. F.; Mayhugh, D. R.; Montrose-Rafizadeh, C.; Renner, J.; Saeed, A.; Singh, J.; Zink, R. W.; Mantlo, N. B. Abstracts of Papers, MEDI-363; 224th ACS National Meeting, Boston, MA, U.S.A., August 18-22, 2002,
6. American Chemical Society: Washington, D.C., 2002.
7. (b) Mantlo, N. B.; Collado Cano, I.; Dominianni, S. J.; Etgen, G. J., Jr.; Garcia-Paredes, C.; Johnston, R. D.; Letourneau, M. E.; Martinelli, M. J.; Mayhugh, D. R.; Saeed, A.; Thompson, R. C.; Wang, X.; Coffey, D. S.; Schmid, C. R.; Vicenzi, J. T.; Xu, Y. Peroxisome Proliferator Activated Receptor Alpha Agonists. WO/2002/0238553, 2002.
8. (c) For a discussion of the SAR, see: Xu, Y.; Mayhugh, D.; Saeed, A.; Wang, X.; Thompson, R. C.; Dominianni, S. J.; Kauffman, R. F.; Singh, J.; Bean, J. S.; Bensch, W. R.; Barr, R. J.; Osborne, J.; Montrose-Rafizadeh, C.; Zink, R. W.; Yumibe, N. P.; Huang, N.; Luffer-Atlas, D.; Rungta, D.; Maise, D. E.; Mantlo, N. B. J. Med. Chem. 2003, 46, 5121-5124.
9. (d) For a discussion of the pharmacology, see: Singh, J. P.; Kauffman, R.; Bensch, W.; Wang, G.; McClelland, P.; Bean, J.; Montrose, C.; Mantlo, N.; Wagle, A. Mol. Pharmacol. 2005, 68, 763-768.
10. "Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-dependent transcription factors. [They] participate in a broad spectrum of biological processes, including cell differentiation, energy balance, lipid metabolism, insulin sensitivity, bone formation, inflammation and tissue remodeling." Quote taken from: Guan, Y.; Zhang, Y.; Breyer, M. D. Drug News Perspect. 2002, 15, 147-154.
11. For a recent review of PPARα in the pathogenesis of metabolic syndrome in relation to diabetes and atherosclerosis, see: (a) Staels, B. Ther. Res. 2006, 27, 1347-1358.
12. See the following for specific therapeutic areas: (b) Human metabolic syndrome: Azhar, S.; Kelley, G. Future Lipidol. 2007, 2, 31-53.
13. (c) Immunosuppressiveagents: Cunard, R. Curr. Opin. Invest. Druss 2005, 6, 467-472.
14. (d) Diabetic nephropathy: Varghese, Z.; Moorhead, J. F.; Ruan, X. Z. Kidney Int. 2006, 69, 1490-1491.
15. Nissen, S. E.; Nicholls, S. J.; Wolski, K.; Howey, D. C.; McErlean, E.; Wang, M.-D.; Gomez, E. V.; Russo, J. M. J. Am. Med. Assoc. 2007, 297, 1362-1373.
16. Braden, T. M.; Coffey, D. S.; Doecke, C. W.; LeTourneau, M. E.; Martinelli, M. J.; Meyer, C. L.; Miller, R. D.; Pawlak, J. M.; Pedersen, S. W.; Schmid, C. R.; Shaw, B. W.; Staszak, M. A.; Vicenzi, J. T. Ors. Process Res. Dev. 2007, 11, 431-440.
17. For the preparation of 4, see: (a) Schmid, C. R.; Beck, C. A.; Cronin, J. S.; Staszak, M. A. Org. Process Res. Dev. 2004, 8, 670-673.
18. For an alternative approach using HBr, see: (b) Delhaye, L.; Diker, K.; Donck, T.; Merschaert, A. Green Chem. 2006, 8, 181-182.
19. A brief summary of this work has been disclosed previously: Fennell, J. W.; Dunlap, S. E.; Metzler, R.; Vicenzi, J. T.; Werner, J. A. Abstracts of Papers; ORGN-009. 234th ACS National Meeting, Boston, MA, United States, August 19-23, 2007; American Chemical Society: Washington, D.C., 2007.
20. API impurity levels were as follows: 9 (0.26%), 10 (0.05%) 11 (0.18%) 12 (0.18%), 13 (0.10), and 14 (0.12%). The HPLC method for this analysis is described in the Supporting Information.
21. Molnar Institut fur angewandte Chromatographie, Schneeglockchen-strasse 47, D-10407 Berlin, Germany; http://www.molnar-institut.com/cd/indexe.htm.
22. Details of this work have recently been reported: Scherer, R. B.; Argentine, M. D.; Werner, J. A. Utilization of Technological Advances in HPLC to Improve Separations and Cycle Times, Abstract #551; HPLC 2006, San Francisco, CA, 2006.
23. See the Supporting Information for an illustration of the use of a data export method that enabled the preparation of nine multicomponent reaction profiles in less than 30 min from the raw data in 63 chromatograms.
24. For preparation of the benzyl hydrazine from the corresponding chloride, see: Finneman, J. I.; Fishbein, J. C. J. Am. Chem. Soc. 1995, 117, 4228-4239.
25. The ratios of 16:17 were: 82:18, 80:20, 76:24 at 5, 20, and 50 °C, respectively.
26. ICH Harmonised Tripartite Guideline. Impurities: Guideline For Residual Solvents QC3 (R3), revised November 2005. See: http://www.ich.org/ cache/compo/363-272-l.htmWQ3C.
27. For useful discussions on the use of process analytical technology on crystallization processes, see: (a) Yu, L. X.; Lionberger, R. A.; Raw, A. S.; D'Costa, R.; Wu, H.; Hussain, A. S. Adv. Drug Delivery Rev. 2004, 56, 349-369.
28. (b) Birch, M.; Fussell, S. J.; Higginson, P. D.; McDowall, N.; Marziano, I. Org. Process Res. Dev. 2005, 9, 360-364.
29. (c) Barrett, P.; Smith, B.; Worlitschek, J.; Bracken, V.; O'Sullivan, B.; O'Grady, D. Org. Process Res. Dev. 2005, 9, 348-355.
30. Lower amounts of cosolvent resulted in agglomerates of smaller-sized crystals, while higher amounts of cosolvent (e.g., 15% v/v) resulted in a sticky solid and a biphasic filtrate.
31. 2O at 25 ° C. However, in the present system, precipitation of the products would be expected to drive the reaction to completion: Baker, E. M.; Gilbert, E. C. J. Am. Chem. Soc. 1942, 64, 2777-2780.
32. Williams, A.; Jencks, W. P. J. Chem. Soc., Perkin Trans. 2 1974, 1753-1759.
33. Kinetics for the aqueous hydrolysis of cyanate have been well characterized. For a recent reference with a summary of the literature, see: DeMartini, N.; Murzin, D. Y.; Forssen, M.; Hupa, M. Ind. Ens. Chem. Res. 2004, 43, 4815-4821.
34. Levenspiel, O. The Chemical Reactor Omnibook, Oregon State University Bookstores: Corvalis, OR, 1996; p 2.3.S. and subsequent manipulation in the Supporting Information.
35. MATLAB function fminbnd: This algorithm uses golden section search and parabolic interpolation.
36. Treatment of acylsemicarbazide 7 with aqueous NaOH (20 h at 40 °C followed by 24 h at 100 °C), using conditions similar to those described in ref 5c, affords LY518674 (1) in a single step (77% yield). However, isolation and purification of 8, followed by saponification to give 1, provides a better impurity-control strategy than the one-step process.
37. Carson, J.; Reist, E. J. J. Org. Chem. 1958, 23, 1492-1496.
38. 4 with EtOH. For kinetic studies, see: (a) Theodore, S.; Sai, P. S. T. Can. J. Chem. Ens. 2001, 79, 54-64.
39. (b) Chen, L.; Johnson, B. D.; Grinberg, N.; Bicker, G. R.; Ellison, D. K. J. Liq. Chromatogr. Relat. Technol 1998, 21, 1259-1272.
40. (c) Clark, D. J.; Williams, G. J. Chem. Soc. 1957, 4218-4221.
41. (d) Deno, N.; Newman, M. J. Am. Chem. Soc. 1950, 72, 3852-3856.
42. 3 4.25 ppm (dq): Sen, A.; Benvenuto, M.; Lin, M.; Hutson, A.; Basickes, N. J. Am. Chem. Soc. 1994, 116, 998-1003.
43. Plots of the solubility vs temperature and solubility vs percent of n-heptane are included in the Supporting Information.
44. a values were measured by potentiometric titrations at three concentrations of dioxane water and extrapolating to pure water using a Yasuda - Shedlovsky plot. Baertschi, S.; et al. Unpublished results, Eli Lilly and Company.
45. Residual levels up to 0.5% are acceptable for Class 3 solvents without justification (ref 18).
46. At 23 ° C, the solubility of 1 is 3.7 mg/mL in anhydrous EtOAc vs 38.1 mg/mL in water-saturated EtOAc and 100 mg/mL in water-saturated EtOAc containing 2 wt % EtOH (see ref 9). Acetic acid is also formed during the hydrolysis of EtOAc but does not significantly impact the solubility of 1 in EtOAc.
47. Mersmann, A., Ed. Crystallization Technology Handbook, 2nd ed.; Marcel Dekker: New York, 2001.
48. ICH Harmonised Tripartite Guideline. Impurities in New Drug Substances Q3A (R2), revised October 2006. Available on-line at: http://www.ich.org/ cache/compo/363-272-l.htmliQ3 A(R).
49. (a) For a discussion of the liquid-liquid-solid equilibria for the ternary system of n-BuOH/water/KCl, see: (b) Gomis, V.; Ruiz, F.; Asensi, J. C.; Saquete, M. D. J. Chem. Eng. Data 1996, 41, 188-191.
50. (a) For a detailed investigation of an explosion of 30% aqueous KOCN that occurred in a vented drum, see: Pinsky, M. L.; Vickery, T. P.; Freeman, K. P. J. Loss Prev. Process Ind. 1990, 3, 345-348.
51. 3-. See also: Urben, P. G., Ed. Bretherick's Handbook of Reactive Chemical Hazards, 6th ed.; Butterworth-Heinemann: Oxford, Boston, 1999; Vol. 1, pp 201-202.
52. 2 levels ranged from about 9 ppm in the laboratory to 3.4 ppm in the pilot plant. Typically, 0.5 h was required for the deoxygenation of laboratory runs, and approximately 1 h was required for deoxygenation in the pilot plant.
53. In-line filtration removes any hydrazone impurity that formed due to oxidative degradation of the starting hydrazine.
54. 3 from the titration results in Part 2.
55. The KOCN solution may be added at a constant rate over 1 h.
56. The reaction time can be determined using the kinetic model described in this paper. Typically, the reaction should be stirred at least 6 h to ensure complete conversion of KOCN.
57. See Supporting Information for HPLC and UPLC purity methods, including retention times and relative response factors for individual components.
58. EtOAc was added to scavenge any hydroxide in order to prevent ester hydrolysis during the reaction.
59. Some of the NaOEt was consumed by dehydrobromination of the alkylating agent.
60. 3 typically removes 1.5-2% residual 4, 1.5-2% of diacid 10, and 3-5% 5. Using a slight excess eliminates the need for an in-process assay.
61. Samples were quenched into MeOH containing 1% pyridine (v/v) and analyzed by the UPLC purity method. See the Supporting Information for method conditions.
62. Analytical data for compound 7 is included in the Supporting Information.
63. 4 (6.51 kg, 65.0 mol) to absolute 2B-3 EtOH (23 L, 394 mol) and stored at room temperaturze.