1. A method for producing a 2-hydroxypropyl-beta-cyclodextrin inclusion complex of taxol, said 2-hydroxypropyl-beta-cyclodextrin having a degree of substitution of about 0.4 to about 0.9, wherein the method comprises admixing the 2-hydroxypropyl-beta-cyclodextrin with taxol at a molar ratio of 1-1000 times with respect to taxol.
2. A method according to claim 1 which is conducted in an aqueous system, or an organic solvent-water system.
3. A method according to claim 1 which is conducted in an ethanol-water mixture.
4. A method according to claim 3 wherein the taxol is dissolved in ethanol and the 2-hydroxypropyl-beta-cyclodextrin is dissolved in water.
5. A method for improving the solubility of taxol, said method comprising:
(i) dissolving taxol in ethanol;
(ii) dissolving 2-hydroxypropyl-beta-cyclodextrin, having a degree of substitution of about 0.4 to about 0.9, in water;
(iii) admixing the solution from step (i) with the solution from step (ii) and stirring, shaking or heating.
6. A method according to claim 4 comprising adding the 2-hydroxypropyl-beta-cyclodextrin in water to the ethanolic taxol solution.
7. A method according to claim 4 comprising adding the ethanolic taxol solution to the 2-hydroxypropyl-beta-cyclodextrin in water.
8. A method according to claim 1 wherein the molar ratio of 2-hydroxypropyl-beta-cyclodextrin to taxol is 1-1000:1.
9. The method of claim 1 wherein the molar ratio is 10:1.
10. The method of claim wherein the molar ratio is 5:1.
11. The method of claim 1 wherein the molar ratio is 1:1.
12. The method of claim 1 wherein the reaction time is from 1 minute to 48 hours.
13. The method of claim 1 wherein the 2-hydroxypropyl-beta-cyclodextrin is present in a concentration of 0.0001 to 200% by weight, based on the weight of water.
14. The method of claim 1 wherein the 2-hydroxypropyl-beta-cyclodextrin is present in a concentration of 1 to 50% by weight, based on the weight of water.
15. The method of claim 1 wherein the 2-hydroxypropyl-beta-cyclodextrin is present in a concentration of 1 to 100,000,000 times the mole amount of the taxol.
16. The method of claim 1 wherein the 2-hydroxypropyl-beta-cyclodextrin is present in an amount of 100 to 100,000 times the mole amount of the taxol.
17. The method of claim 1 wherein the reaction is carried out at a temperature of about 15 to 90\xb0 C.
18. The method of claim 1 wherein the reaction is carried out at a temperature of about 15 to 40\xb0 C.
19. A 2-hydroxypropyl-beta-cyclodextrin inclusion complex of taxol, wherein said 2-hydroxypropyl-beta-cyclodextrin has a degree of substitution of about 0.4 to about 0.9.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A process for preparing acid cefoxitin of formula (I)
wherein:
(A) a compound of formula (II)
or a trimethylsilyl derivative thereof is dissolved in methylene chloride and then reacted at a temperature between \u221280\xb0and \u221295\xb0 C. with at least one positive chlorine donor selected from the group consisting of ethyl dichlorourethane and N-chloro-succinimide, and with sodium methylate dissolved in methanol, to give a compound of formula (IV)
(B) the compound of formula (IV) is desacetylated with an aqueous sodium hydroxide solution to give a compound of formula (V)
and finally
(C) the compound of formula (V) is carbamoylated by reaction with chlorosulphonylisocyanate in tetrahydrofuran at a temperature between \u221245\xb0 and \u221250\xb0 C., to give the aforesaid acid cefoxitin of formula (I), which is isolated in acid form; and wherein said process of preparing acid cefoxitin of formula (I) is carried out without any separation of intermediates.
2. A process as claimed in 1, wherein the positive chlorine donor is ethyl dichlorourethane.
3. A process as claimed in claim 1, wherein the positive chlorine donor is N-chlorosuccinimide.
4. A process for preparing acid cefoxitin of formula (I)
wherein:
(A) a compound of formula (II)
or a trimethylsilyl derivative thereof is dissolved in methylene chloride and then reacted at a temperature between \u221280\xb0 and \u221295\xb0 C. with at least one positive chlorine donor selected from the group consisting of ethyl dichlorourethane and N-chloro-succinimide, and with sodium methylate dissolved in methanol, to give a compound of formula (IV)
(B) the compound of formula (IV) is desacetylated with an aqueous sodium hydroxide solution to give a compound of formula (V)
and finally
(C) the compound of formula (V) is carbamoylated by reaction with chlorosulphonylisocyanate in tetrahydrofuran at a temperature between \u221245\xb0 and \u221250\xb0 C., to give the aforesaid acid cefoxitin of formula (I), which is isolated in acid form; whereby acid cefoxitin of formula (I) is prepared without isolation of intermediates.
5. A process as claimed in claim 4, wherein the positive chlorine donor is ethyl dichlorourethane.
6. A process as claimed in claim 4, wherein the positive chlorine donor is N-chlorosuccinimide.