Commercialization and late-stage development of a semisynthetic antifungal API: Anidulafungin/D-fructose (eraxis)

Organic Process Research and Development

Volumn 12, Issue 3, 2008, Pages 447-455

  Norris, Timothy ^a   VanAlsten, John ^a   Hubbs, Stephen ^a   Ewing, Marcus ^a   Cai, Weiling ^a   Jorgensen, Matthew L ^a   Bordner, Jon ^a   Jensen, Grace O ^a  

^a PFIZER INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

EID: 58149162963     PISSN: 10836160     EISSN: 1520586X     Source Type: Journal    
DOI: 10.1021/op800055h     Document Type: Article

References (26)

1. Trade name Eraxis (United States of America), Ecalta (European Union).
2. (a) Bergogne-Berezin, E. Antibiotiques 2007, 9 (3), 212-215.
3. (b) Debono, M.; Turner, W. W.; LaGrandeur L; Burkhardt, F. J.; Nissen, J. S.; Nichols, K. K.; Rodriguez, M. J.; Zweifel, M. J.; Zeckner, D. J. J. Med. Chem. 1995, 38 (17), 3271-3281.
4. (c) DeBono, M; Gordee. R. S. Annul. Rev. Microbiol. 1994, 48, 471-497. See pp 477-486 on glucan synthase inhibitors.
5. Larew, L. A.; Milton, N; Sabatowski, J. L.; Moder, K. P. U.S. Patent 7,041,637 B2, May 9, 2006.
6. Benz, F.; Knüsel, F.; Nüesch, J.; Treichler, H.; Voser, W.; Nyfeler, R.; Keller-Schierlexin, W. Helv. Chim. Acta 1974. 57, 2459-2477.
7. (a) Boeck, L. D.; Fukuda, D. S.; Abbott, B. J.; DeBono, M. J. Antibiot. 1989, 42 (3), 382-388.
8. (b) DeBono, M.; Abbott, B. J.; Fukuda. D. S.; Barnhart, M.; Willard, K. E.; Molloy, R. M.: Michel, K. H.; Turner, J. R.; Butler, T. F.; Hunt, A. H. Antibiotics 1989, 42 (3), 389-397.
9. A difference map revealed that the chloride was disordered. On further examination a new difference map revealed a number of water molecules of crystallization. It had been noted that crystals of this material lost their ability to diffract X-rays when allowed to stand at room temperature. To avoid this degradation the crystals were stored at 23 to > 50°C and were quickly sealed in epoxy before data were collected. Crystals treated in this manner gave a good diffraction pattern to a resolution of 1 Å. The degradation of the crystals was most likely due to the loss of water. This made the estimation of the amounts of water prone to error. On the basis of thermal parameters it was estimated that 5.5 water molecules were present in the crystal structure. The water was located in nine sites. Two of these sites were estimated at full occupancy and seven at half occupancy (hence, the estimate of 5.5 water molecules).
10. Balkovec, J, M.; Black, R., M.; Hammond, J. V.; Heck, J. V.; Zambias, G. A.; Bartizal, K.; Kropp, H.; Trainor, C.; Schwartz, R., E., C.; McFadden, D. C.; Nollstadt, K. N.; Pittarelli, L., A.; Powles, M., A.; Schmatz, D., M. J. Med. Chem. 1992, 35 (1), 194-198, See page 196.
11. 4-(Pentyloxy)-1,1 :4,1-terphenyl-4-carboxylic acid.
12. (a) Scherer, S.; Haber, S. Patent WO 00/50375, August 31, 2000.
13. (b) Milton, N.; Moder, K., P.; Sabatowski, J., L.; Sweetana, S. A. U.S. Patent 6,960,564 B2. November 1. 2005.
14. 1-({[4-(Pentyloxy)-1,1:4,1-terphenyl-4-yl]carbonyi}oxy)-1H-1,2, 3-benzotriazole.
15. (a) Katritzky. A. R.; Malhorta, N.; Fan, W-Q; Anders, E J. Chem. Soc., Perkin Trans. 2 1991, 1545-1547.
16. (b) Singh, J; Fox, R.; Wong, M; Kissick, T. P.; Moniot, J. L. J. Org. Chem. 1988, 53 (1), 205-208.
17. -1 based on literature precedents.
18. For early examples: (a) Debono, M. Turner, W. W. LaGrandeur, LBurkhardt, F. J. Nissen, J. S. Nichols, K. K. Rodriguez, M. J, Zweifel, M. J. Zeckner, D. J. J. Med. Chem. 1995, 38 (17), 3271-3281. See specifically the Experimental Section starting on page 3278.
19. First-generation processes produce 1 in about 65% yield; on the same calculation basis, second-generation processes yield ~85%,
20. This provides a stable form that best suits the requirements of formulation to produce a sterile lyophilized solid in a dispensing vial.
21. This may be due to the tendency of the macromolecule to ultimately form a largely disordered solid when characterized after drying when solvent molecules are removed from the crystal matrix. Any apparent crystalline ordered form initially formed rapidly reverts to a disordered form on standing.
22. Bassett, D. C. CRC Crit. Rev. Solid State Mater. Sci. 1984. 12, 97-163.
23. Crash-cooled solid anidulafungin/D-fructose products from supersaturated solutions do not possess such well-defined powder X-ray diffraction peaks.
24. Photomicrographs: upper left: 42 °C, upper right: 37 °C, lower left: 30°C, and lower right: 20°C.
25. The large glass transition observed in first-generation material has been eliminated. First- and second-generation anidulafungin/D-fructose materials do not exhibit a definitive melting transition.
26. Even if more 9 is produced at the top end of the temperature range, it is readily purged by the protocol described.