An improved method for separating paclitaxel and cephalomannine using ozone and Girard reagents

Journal of Organic Chemistry

Volumn 61, Issue 25, 1996, Pages 9038-9040

  Beckvermit, Jeff T ^a   Anziano, Dominick J ^a   Murray, Christopher K ^a  

^a Hauser Chemical Research Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CEPHALOMANNINE; PACLITAXEL;

ARTICLE; DERIVATIZATION; DRUG PURIFICATION; TECHNIQUE;

EID: 0030472710     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo961402l     Document Type: Article

References (28)

1. Bristol-Myers Squibb announced in early 1995 that paclitaxel produced via a semisynthetic route starting from 10-deacetylbaccatin was approved by the FDA. All GMP bulk drug for clinical trials and clinical use prior to 1995 was produced via isolation from Taxus brevifolia bark.
2. For recent reviews about taxoid chemistry see: (a) Kingston, D. G. I.; Molinero, A. A.; Rimoldi, J. M. Fortsch. Chem. Org. Naturst. 1993, 61, 1.
3. (b) Nicolaou, K. C.; Dai, W. M.; Guy, R. K. Angew. Chem., Int. Ed. Engl. 1994,33,15.
4. Taxol®: Science and Applications; Suffness, M., Ed.; CRC Press: New York, 1995.
5. (a) Powell, R. G.; Miller, R. W.; Smith, C. R., Jr. J. Chem. Soc., Chem. Commun. 1979, 102.
6. (b) Senilh, V.; Blechert, S.; Colin, M.; Guenard, D.; Picot, F.; Potier, P.; Varenne, P. J. Nat. Prod. 1984, 47, 131.
7. (a) Rao describes Chromatographie methods for separating 1 and 2: Rao, K. V. Method for the Isolation and Purification of Taxane Derivatives, WO 92/07842, May 14, 1992.
8. (b) Analytical separation of 1 and 2 using HPLC is also difficult. Analytical methods are described in reference 5. For a superior analytical method see reference 5c.
9. (a) Witherup, K. M.; Look, S. A.; Stasko, M. W.; McCloud, T. G.; Issaq, H. J.; Muschik, G. M. J. Liq. Chromatogr. 1989, 12, 2117.
10. (b) Cardellina, J. H., III. J. Liq. Chromatogr. 1991, JW, 659.
11. Richheimer, S. L.; Tinnermeier, D. M.; Timmons, D. W. Anal. Chem. 1992,64, 2323.
12. (a) Murray, C. K.; Beckvermit, J. T.; Ziebarth, T. D. U.S. Patent No. 5,334,732, Aug 2, 1994.
13. (b) Murray, C. K.; Beckvermit, J. T.; Ziebarth, T. D. U.S. Patent No. 5,336,684, Aug 9, 1994.
14. Murray, C. K.; Beckvermit, J. T.; Anziano, D. J. U.S. Patent No. 5,364,947, Nov 15,1994.
15. Rao, K. V.; Hanuman, J. B.; Alvarez, C.; Stoy, M.; Juchum, J.; Davies, R. M.; Baxley, R. Pharmaceut. Res. 1995,12, 1003.
16. Jitrangsri, C. Ph.D. Thesis, 1986, Virginia Polytechnic Institute and State University, Blacksburg, Virginia.
17. Kingston, D. G. I.; Gunatilaka, A. A. L.; Ivey, C. A. J. Nat. Prod. 1992, 55, 259.
18. Rimoldi, J. M.; Molinero, A. A.; Chordia, M. D.; Gharpure, M. M.; Kingston, D. G. I. J. Nat. Prod. 1996, 59, 167.
19. (a) Bailey, P. S. Ozonation in Organic Chemistry, Olefinic Compounds; Academic Press: New York, 1978; Vol. 1.
20. (b) Yamamoto, Y.; Niki, E.; Kamiya, Y. J. Org. Chem. 1981, 46, 250.
21. A portion of this work was presented at the 208th American Chemical Society National Meeting, Division of Medicinal Chemistry, Poster 65, Washington D.C., Aug. 12, 1994.
22. Girard reagents have been used extensively for separating mixtures of steroids, (a) Girard, A. Organic Syntheses; Wiley: New York, 1943; Collect. Vol. p 85.
23. (b) Wheeler, O. H. Chem. Rev. 1962, 62, 205.
24. 6b Complete bioactivity studies including in vivo evaluation relative to paclitaxel are pending.
25. For Taxus extracts or semipurified Taxus extracts, additional taxanes with accessible olefin groups, for example, taxusin and brevifoliol, are also oxidized by ozone, as well as, lignins and other oxidizable impurities.15
26. (a) For chemical conversions of taxusin see: Miyazaki, M.; Shimuzu, K.; Mishima, H.; Kuragayashi, M. Chem. Pharm. Bull. 1968, 16, 546.
27. (b) For a chemical conversion of brevifoliol see: Georg, G. I., Cheravullath, Z. S.; Velde, D. V.; Ye, Q. M.; Mitscher, L. A. Biorg. Med. Chem. Lett. 1993, 3, 1345.
28. A similar separation of oxidized cephalomannine 3, and paclitaxel 1, can be accomplished by stirring an acetic acid solution of the two compounds with a hydrazide reagent bound to a solid phase. Compound 3 is converted to a hydrazone bound to a solid phase and can be filtered away from the paclitaxel remaining in solution.