Method for preparing highly pure anhydrous crystalline docetaxel
A method for preparing highly pure anhydrous crystalline docetaxel is provided. The method for preparing highly pure anhydrous crystalline docetaxel enables preparation of anhydrous crystalline docetaxel that has purity of 99.5% or more, and is useful as an anticancer agent due to remarkably low residual solvent content compared to the standard of residual solvents in drugs.
1. A method for preparing anhydrous crystalline docetaxel having purity of 99.5% or more comprising:
(a) primarily purifying semi-synthesized docetaxel by low-pressure normal-phase chromatography;
(b) secondarily purifying the primarily purified docetaxel by low-pressure reversed-phase chromatography;
(c) adding acid in the concentration of 0.05%(v/v) to 10%(v/v) of docetaxel aliquot obtained after the secondary purification of docetaxcel of (b) to concentrate the secondarily purified docetaxel; and
(d) recrystallizing the concentrated docetaxel of (c).
2. A method for preparing anhydrous crystalline docetaxel having purity of 99.5% or more comprising:
(a) primarily purifying semi-synthesized docetaxel by low-pressure normal-phase chromatography;
(b) secondarily purifying the primarily purified docetaxel by high-pressure reversed-phase chromatography;
(c) adding acid in the concentration of 0.05%(v/v) to 10%(v/v) of docetaxel aliquot obtained after the secondary purification of docetaxcel of (b) to concentrate the secondarily purified docetaxel; and
(d) recrystallizing the concentrated docetaxel of (c).
3. A method for preparing anhydrous crystalline docetaxel having purity of 99.5% or more comprising:
(a) primarily purifying semi-synthesized docetaxel by low-pressure reversed-phase chromatography;
(b) adding acid in the concentration of 0.05%(v/v) to 10%(v/v) of docetaxel aliquot obtained after the primary purification of docetaxcel of (a) to concentrate the primarily purified docetaxel
(c) secondarily purifying the concentrated docetaxel by high-pressure normal-phase chromatography; and
(d) recrystallizing the secondarily purified docetaxel.
4. The method according to claims 1 , wherein in case the low-pressure normal-phase chromatography is performed, a developing solvent selected from the group consisting of C1-2 halogenated alkanes, a C1-6 organic solvent, and a combination thereof is used.
5. The method according to claim 4 , wherein the C1-2 halogenated alkanes are at least one selected from the group consisting of dichloromethane and chloroform, and the C1-6 organic solvent is at least one selected from the group consisting of methanol, benzene, acetone, hexane, and ethylacetate.
6. The method according to claims 1 , wherein in case the low-pressure reversed-phase chromatography is performed, a developing solvent selected from the group consisting of a C1-3 organic solvent, purified water, and a combination thereof is used.
7. The method according to claim 6 , wherein the C1-3 organic solvent is at least one selected from the group consisting of C1-3 alcohol and acetonitrile.
8. The method according to claim 1 , wherein the acid is at least one selected from the group consisting of acetic acid, formic acid and trifluoroacetic acid.
9. The method according to claim 1 , wherein the recrystallization solvent is at least one selected from the group consisting of acetone and hexane.
10. The method according to claim 9 , wherein both acetone and hexane are used as the recrystallization solvent, and, after acetone is introduced so that the concentration of docetaxel becomes 1%(w/v) to 30%(w/v), hexane is introduced in a volume of 1 to 10 times of the amount of acetone introduced.
11. The method according to claim 2 , wherein in case the low-pressure normal-phase chromatography is performed, a developing solvent selected from the group consisting of C1-2 halogenated alkanes, a C1-6 organic solvent, and a combination thereof is used.
12. The method according to claim 3 , wherein in case the high-pressure normal-pressure chromatography is performed, a developing solvent selected from the group consisting of C1-2 halogenated alkanes, a C1-6 organic solvent, and a combination thereof is used.
13. The method according to claim 11 , wherein the C1-2 halogenated alkanes are at least one selected from the group consisting of dichloromethane and chloroform, and the C1-6 organic solvent is at least one selected from the group consisting of methanol, benzene, acetone, hexane, and ethylacetate.
14. The method according to claim 12 , wherein the C1-2 halogenated alkanes are at least one selected from the group consisting of dichloromethane and chloroform, and the C1-6 organic solvent is at least one selected from the group consisting of methanol, benzene, acetone, hexane, and ethylacetate.
15. The method according to claim 2 , wherein in case the high-pressure reversed chromatography is performed, a developing solvent selected from the group consisting of a C1-3 organic solvent, purified water, and a combination thereof is used.
16. The method according to claim 3 , wherein in case the low-pressure reversed-phase chromatography is performed, a developing solvent selected from the group consisting of a C1-3 organic solvent, purified water, and a combination thereof is used.
17. The method according to claim 15 , wherein the C1-3 organic solvent is at least one selected from the group consisting of C1-3 alcohol and acetonitrile.
18. The method according to claim 16 , wherein the C1-3 organic solvent is at least one selected from the group consisting of C1-3 alcohol and acetonitrile.
19. The method according to claim 2 , wherein the acid is at least one selected from the group consisting of acetic acid, formic acid and trifluoroacetic acid.
20. The method according to claim 3 , wherein the acid is at least one selected from the group consisting of acetic acid, formic acid and trifluoroacetic acid.
21. The method according to claim 2 , wherein the recrystallization solvent is at least one selected from the group consisting of acetone and hexane.
22. The method according to claim 3 , wherein the recrystallization solvent is at least one selected from the group consisting of acetone and hexane.
23. The method according to claim 21 , wherein both acetone and hexane are used as the recrystallization solvent, and, after acetone is introduced so that the concentration of docetaxel becomes 1%(wlv) to 30%(w/v), hexane is introduced in a volume of 1 to 10 times of the amount of acetone introduced.
24. The method according to claim 22 , wherein both acetone and hexane are used as the recrystallization solvent, and, after acetone is introduced so that the concentration of docetaxel becomes 1%(w/v) to 30%(w/v), hexane is introduced in a volume of 1 to 10 times of the amount of acetone introduced.