Large-scale synthesis of a selective inhibitor of the norepinephrine transporter: Mechanistic aspects of conversion of indolinone diol to indolinone aminoalcohol and process implications

Organic Process Research and Development

Volumn 13, Issue 5, 2009, Pages 880-887

  Alimardanov, Asaf ^a   Gontcharov, Alexander ^a   Nikitenko, Antonia ^a   Chan, Anita W ^a   Ding, Zhixian ^a   Ghosh, Mousumi ^a   Levent, Mahmut ^a   Raveendranath, Panolil ^c   Ren, Jianxin ^a   Zhou, Maotang ^a   Mahaney, Paige E ^b   McComas, Casey C ^b   Ashcroft, Joseph ^a   Potoski, John R ^a  

^a WYETH RESEARCH   (United States)

^b PFIZER INC   (United States)

^c NONE

Author keywords

[No Author keywords available]

Indexed keywords

EID: 70449393475     PISSN: 10836160     EISSN: 1520586X     Source Type: Journal    
DOI: 10.1021/op900141r     Document Type: Article

References (30)

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3. (c) Hajos, M.; Fleishaker, J. C.; Filipiak-Reisner, J. K.; Brown, M. T.; Wong, E. H. W. CNS Drug Rev. 2004, 10, 23.
4. (d) McCormack, P. L.; Keating, G. M. Drugs 2004, 64, 2567.
5. Kim, C. Y.; Mahaney, P. E.; Trybulski, E. J.; Zhang, P.; Terefenko, E. A.; McComas, C. C.; Marella, M. A.; Coghlan, R. D.; Heffernan, G. D.; Cohn, S. T.; Vu, A. T.; Sabatucci, J. P.; Ye, F. Phenylamino-propanol Derivatives and Methods of Their Use. U.S. Patent 7, 517, 899, 2009.
6. Wu, Y.; Wilk, B. K.; Ding, Z.; Shi, X.; Wu, C. C.; Raveendranath, P.; Durutlic, H. Process for the Synthesis of Progesterone Receptor Modulators. U.S. Patent Publ. Appl. US 2007/027327, 2007.
7. (a) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765.
8. (b) For a recent example of large-scale asymmetric epoxidation, see: Henegar, K. E.; Cebula, M. Org. Process Res. Dev. 2007, 11, 354.
9. For indolinone deprotonation for epoxide opening, see: Proudfoot, J. R.; Regan, J. R.; Thomson, D. S.; Kuzmich, D.; Lee, T. W.; Hammach, A.; Ralph, M. S.; Zindell, R.; Bekkali, Y. Preparation of Propanol and Propylamine Derivatives and Their Use as Glucocorticoid Ligands. WO 2004/063163, 2004.
10. (b) Gillman, K.; Bocchino, D. M. Preparation of Monosaccharides Prodrugs of Fluorooxindoles Useful in Treatment of Disorders Which are Responsive to the Opening of Potassium Channels. U.S. Patent Publ. Appl. US 2004/0152646, 2004.
11. (c) For amide deprotonation for epoxide opening, see: Albanese, D.; Landini, D.; Penso, M. Tetrahedron 1997, 53, 4787.
12. (d) Chan, W. N.; Evans, J. M.; Hadley, M. S.; Herdon, H. J.; Jerman, J. C.; Morgan, H. K. A.; Stean, T. O.; Thompson, M.; Upton, N.; Vong, A. K. J. Med. Chem. 1996, 39, 4537.
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18. (c) Martinelli, M. J.; Vaidyanathan, R.; Pawlak, J. M.; Nayyar, N. K.; Dhokte, U. P.; Doecke, C. W.; Zollars, L. M. H.; Moher, E. D.; Khau, V. V.; Kosmrli, B. J. Am. Chem. Soc. 2002, 124, 3578.
19. (a) An example of a related imidate salt formation from tertiary amide at elevated temperature has been reported: Osornio, Y. M.; Miranda, L. D.; Cruz-Almanza, R.; Muchowski, J. M. Tetrahedron Lett. 2004, 45, 2855.
20. (b) Examples of imidate salt formation from A-(γ-haloalkyl)- phthalimide or-amide derivatives on treatment with Ag salts have been reported: Huenig, S.; Geldern, L. J. Prakt. Chem. 1964, 24, 246.
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22. (d) For cyclic imide formation via O-alkylation of secondary amides under basic conditions, see for example: Wang, X.; Gross, P. H. J. Org. Chem. 1995, 60, 1201.
23. For hydrolysis of imidate salts, see ref 9c and Deslongchamps, P.; Dube, S.; Lebreux, C.; Patterson, D. R.; Taillefer, R. Can. J. Chem. 1975, 53, 2791, and references cited therein.
24. Both bis-tosylate and the unreacted diol go through the rsteps of the synthesis unchanged and can be removed when the HCl salt of the product 1 is prepared.
25. Alternative approaches involving conversion of diol 6 to the terminal epoxide 8 via Mitsunobu protocol or sequential treatment with trimethyl orthoacetate, acetyl bromide, and base were explored and found to be less efficient.
26. Gao, Y.; Sharpless, K. B. J. Am. Chem. Soc. 1988, 110, 7538.
27. The corresponding cyclic carbonate could also be formed from amidine diol 10 by treatment with triphosgene. However, its intramolecular ring opening-ring closing proceeded much slower and was incomplete even after 1.5 h at 40 °C, with a 4:1 ratio of 16 and 1 observed after basic hydrolysis. The reaction could be accelerated and driven to completion by the addition of Et3N, albeit at the expense of selectivity (1.7:1 ratio of 16 and 1 after NaOH treatment).
28. Boulet, S. L.; Filla, S. A.; Gallagher, P. T.; Hudziak, K. J.; Johansson, A. M.; Karanjawala, R. E.; Masters, J. J.; Matassa, V.; Mathes, B. M.; Rathmell, R. E.; Whatton, M. A.; Wolfe, C. N. 3-Aryloxy/thio-2,3-substituted Propanamines and their Use in Inhibiting Serotonin and Norepinephrine Reuptake. WO 2004/043903, 2004.
29. Hansen, R. M.; Sharpless, K. B. J. Org. Chem. 1986, 51, 1922.
30. Optimization of preparation of 1 was finalized after the first kilo-lab campaign, in preparation for the second one. The project was deprioritized before the second campaign. Optimized lab-scale demorun procedure is described.