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Process for mass production of GMP paclitaxel and related taxanes

Imported: 23 Feb '17 | Published: 22 Oct '02

Gertrude C. Kasitu, Japheth Noah, Qasim Khan

USPTO - Utility Patents

Abstract

A process for the purification of paclitaxel and/or cephalomannine and/or 10-DAB III and/or 9-DHAB III is described. A series of extractions, separations, and purifications provides these products in commercial quantities with high purity. The source for these natural products is from readily available renewable biomaterials, such as leaves and stems from the yew,

T. canadensis.

Description

BRIEF DESCRIPTION OF THE FIGURES

Other objects, advantages and features of the present invention will be readily appreciated as the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying figures, in which like reference numerals designate like parts throughout the figures thereof and wherein:

FIG. 1 depicts the formula for paclitaxel, docetaxel, cephalomannine, 9-dihydro-13-acetylbaccatin III, baccatin III, and 10-DAB III.

FIG. 2 is a flow diagram for the isolation and purification of paclitaxel, cephalomannine, 9-dihydro-13-acetylbaccatin III, and 10-DAB III.

FIG. 3 is a flow diagram for the isolation and purification of paclitaxel, cephalomannine, 9-dihydro-13-acetylbaccatin III, and 10-DAB III.

FIG. 4 is a flow diagram for the isolation and purification of paclitaxel, cephalomannine, 9-dihydro-13-acetylbaccatin III, and 10-DAB III.

FIG. 5 is a flow diagram for the isolation and purification of paclitaxel, cephalomannine, 9-dihydro-13-acetylbaccatin III, and 10-DAB III.

Claims

1. A method for preparing at least one purified taxane, comprising the steps of:

2. The method of claim 1, further comprising the step of triturating the taxanes from step g), thereby causing a single taxane to precipitate from solution.

3. The method of claim 2, wherein the single taxane is 9-DHAB III.

4. The method of claim 1, wherein the biomaterial is fresh or dried leaves and stems.

5. The method of claim 1, wherein the non-polar solvent is dichloromethane or a mixture of dichloromethane and ethyl acetate.

6. The method of claim 1, wherein the polar solvent is selected from the group consisting of acetone, tetrahydrofuran, methanol, ethanol, isopropyl alcohol and combinations thereof.

7. The method of claim 1, further comprising the steps of:

8. The method of claim 1, further comprising the steps of:

9. The method of claim 8, wherein the scavenging reagent is selected from the group consisting of tris(2-ethylamino)amine polymer, metal carbonates and tertiary amines.

10. The method of claim 1, wherein the solid support is aluminum trioxide.

11. A method of extraction of taxanes from a biomaterial, comprising the steps of:

12. The method of claim 11, further comprising the step of contacting the polar extract with an adsorbent suitable for chromatography.

13. The method of claim 11, wherein the non-polar solvent is hexane.

14. The method of claim 11, wherein the polar solvent is a low molecular weight alcohol.

15. The method of claim 14, wherein the low molecular weight alcohol is selected from the group consisting of ethanol, methanol and isopropanol.

16. A method of extraction of taxanes from a biomaterial, comprising the steps of:

17. The method of claim 16, wherein the adsorbent is florosil.

18. The method of claim 16, wherein the non-polar solvent is hexane.

19. The method of claim 16, wherein the polar solvent is ethyl acetate.

20. The method of claim 16, wherein the solvent combination is a gradient of non-polar and polar solvents, the solvent gradient beginning at 75% non-polar solvent (v/v) to 25% (v/v).

21. A method of extraction of taxanes from a biomaterial, comprising the steps of:

22. The method of claim 21, further comprising the step of contacting the polar extract with an adsorbent suitable for chromatography.

23. The method of claim 21, wherein the non-polar solvent is hexane.

24. The method of claim 21, wherein the polar solvent is a low molecular weight alcohol.

25. The method of claim 24, wherein the low molecular weight alcohol is selected from the group consisting of ethanol, methanol and isopropanol.