Selective acylation of secondary hydroxyl groups
The invention provides methods and compositions for selectively acylating a specific hydroxyl group in a molecule of interest containing at least two unprotected secondary hydroxyl groups. Although the methods and compositions of the invention have general applicability, they are particularly useful in the selective acylation of taxane molecules.
1. A method of selectively acylating a taxane molecule, the method comprising the steps of
(a) providing a solution of tetrahydrofuran and a taxane molecule having the formula:
wherein
R 1 is hydrogen;
R 2 is a benzoyl group;
R 4 is an acetate group;
R 7 is hydrogen;
R 10 is hydrogen or an acetate group; and
Rx is N═CHRc or —NHC(O)R n , wherein Rc is an alkyl group, an aryl group, an arylalkyl group, an vinyl group, or an ether group; and R n is an alkyl group, an aryl group, an arylalkyl group, a vinyl group, or an ether group; and
(b) contacting the solution with a hindered base and an acylating agent thereby to selectively acylate the hydroxyl group located at the C-2′ position,
wherein the hindered base is selected from the group consisting of pyridine derivatives substituted at least at the 2-position, N,N-diisopropylisobutylamine, N-ethyldicyclohexylamine, triethylmntine, trilsopropylanilne, tripropylamine, iniidazole, 1,5-diazabicylo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, and 1,8-diazabicylo[5.4.0]undec-7-ene.
2. The method of claim 1 , wherein the acylating agent is an acid halide.
3. The method of claim 2 , wherein the acid halide is an acid chloride.
4. The method of claim 2 , wherein the acid halide is selected from the group consisting of benzoyl halide, tigloyl halide, hexanoyl halide, butyryl halide, 2 -methylbutyryl halide, phenylacetyl halide, furoyl balide, and tert-butyl halofonnate.
5. The method of claim 1 , wherein the hindered base is a pyiidine derivative substituted at least at the 2-position.
6. The method of claim 4 , wherein the hindered base is N-ethyldicyclohexylanune.
7. The method of claim 1 , wherein the hindered base is selected from the group consisting of 2,6-lutidine and 2,4,6-collidine.
8. The method of claim 1 further comprising the step of crystallizing the acylated compound with at least one solubilizing solvent and optionally at least one antisolvent.
9. The method of claim 8 , wherein the at least one solubilizing solvent is a halogenated hydrocarbon.
10. The method of claim 8 , wherein the solubilizing solvent is selected form the group consisting of acetone, methyl tert butyl ether, trifluorotoluene, or THF.
11. The method of claim 8 , wherein the solubilizing solvent is methylene chloride.
12. The method of claim 8 , wherein the at least one solubilizing solvent is methylene chloride and the antisolvent is hexane.
13. The method of claim 8 , wherein the antisolvent is a hydrocarbon alkane.
14. The method of claim 1 wherein R 10 is hydrogen.
15. The method of claim 1 wherein R 10 is an acetate group.
16. The method of claim 14 wherein Rx is N═CHRc, and Rc is selected from the group consisting of phenyl, 1-methyl-1-propenyl, n-pentyl, propyl, 1-methyl-propyl, benzyl; 2furanyl, and tert-butoxy.
17. The method of claim 14 wherein Rx is —NHC(O)R n , and R n is selected from the group consisting of phenyl, 1-methyl-1-propenyl, n-pentyl, propyl, 1-methyl-propyl, benzyl, 2-Ibranyl, and tert-butoxy.
18. The method of claim 15 wherein Rx is N═CHR, and R is selected from the group consisting of phenyl, 1-methyl-1-propenyl, n-pentyl, propyl, 1-methyl-propyl, benzyl, 2-furanyl, and tert-butoxy.
19. The method of claim 15 wherein Rx is —NHC(O)R n , and R n is selected from the group consisting of phenyl, 1-methyl-1-propenyl, n-pentyl, propyl, 1-methyl-propyl, beniyl, 2-furmnyl, and tert-butoxy.
20. A method of selectively acylating a taxane molecule, the method comprising the steps of
(a) providing a solution of tetrahydrofuran and a taxane molecule having the formula:
wherein
R 1 is hydrogen;
R 2 is a benzoyl group;
R 4 is an acetate group;
R 7 is hydrogen;
R 10 is hydrogen or an acetate group; and
Rx is N═CHRc or —NHC(O)R n , wherein Rc is an alkyl group, an aryl group, an arylalkyl group, an vinyl group, or an ether group; and R n is an alkyl group, an aryl group, an arylalkyl group, a vinyl group, or an ether group; and
(b) adding 2,6-lutidine or N ethyldicyclohexylaniine and an acid chloride to the solution thereby to selectively acylate the hydroxyl group located at the C-2′ position.
21. The method of claim 20 wherein R 10 is hydrogen.
22. The method of claim 20 wherein R 10 is an acetate group.
23. The method of claim 21 wherein Rx is N═CHRc, and Rc is selected from the group consisting of phenyl, 1-methyl-1-propenyl, n-pentyl, propyl, 1-methyl-propyl, benzyl; 2furanyl, and tert-butoxy.
24. The method of claim 21 wherein Rx is —NHC(O)R n , and R n is selected from the group consisting of phenyl, 1-methyl-1-propenyl, n-pentyl, propyl, 1-methyl-propyl, benzyl, 2-furanyl, and tert(-butoxy.
25. The method of claim 22 wherein Rx is N═CHR, and R is selected from the group consisting of phenyl, 1-methyl-1-propenyl, n-pentyl, propyl, 1-methyl-propyl, beuzyl, 2furanyl, and tert-butoxy.
26. The method of claim 22 wherein Rx is —NHC(O)R n , and R n is selected from the group consisting of phenyl, 1-methyl-1-propenyl, n-pentyl, propyl, 1-methyl-propyl, benzyl, 2-furanly, and tert-butoxy.
27. The method of claim 23 wherein the acid chloride is selected from the group consisting of benzoyl chloride, tigloyl chloride, hexanoyl chloride, butyryl chloride, 2-methylbutyryl chloride, phenylacetyl chloride, furoyl chloride, and tert butyl chioroformate.
28. The method of claim 24 wherein the acid chloride is selected from the group consisting of berazoyl chloride, tigloyl chloride, hexanoyl chloride, butyryl chloride, 2-methylbutyryl chloride, phenylacetyl chloride, furoyl chloride, and tert-butyl chloroformate.
29. The method of claim 25 wherein the acid chloride is selected from the group consisting of berazoyl chloride, tigloyl chloride, hexanoyl chloride, butyryl chloride, 2-methylbutyryl chloride, phenylacetyl chloride, furoyl chloride, and tert-butyl chloroformate.
30. The method of claim 26 wherein the acid chloride is selected from the group consisting of benzoyl chloride, tigloyl chloride, hexanoyl chloride, butyryl chloride, 2-methylbutyryl chloride, phenylacetyl chloride, furoyl chloride, and tert-butyl chioroformnate.
31. The method of claim 20 wherein R 10 is an acetate group, Rx is —NHC(O)R n , wherein R n is phenyl, and the acid chloride is benzoyl chloride.
32. The method of claim 20 wherein R 10 is an acetate group, Rx is —NHC(O)R n , wherein R n is 1-methyl-1-propenyl, and the acid chloride is benzoyl chloride.
33. The method of claim 20 wherein R 10 is an acetate group, Rx is —NHC(O)R n , wherein R n is n-pentyl, and the acid chloride is benzoyl chloride.
34. The method of claim 20 further comprising the step of crystallizing the acylated compound with at least one solubilizing solvent and optionally at least one antisolvent.
35. The method of claim 34 , wherein the at least one solubilizing solvent is a halogenated hydrocarbon.
36. The method of claim 34 , wherein the solubilizing solvent is selected form the group consisting of acetone, methyl tert butyl ether, trifluorotoluene, or THF.
37. The method of claim 34 , wherein the solubilizing solvent is methylene chloride.
38. The method of claim 34 , wherein the at least one solubilizing solvent is methylene chloride and the antisolvent is hexane.
39. The method of claim 34 , wherein the antisolvent is a hydrocarbon alkane.
40. The method of claim 1 , wherein the method results in at least about 95% of an ending taxane acylated at the C-2′ position and less than about 0.1% of the starting texans remains unreacted after the contacting step.
41. The method of claim 40 , wherein the method results in at least about 99% of an ending taxane acylated at the C-2′ position.
42. The method of claim 20 , wherein the method results in at least about 95% of an ending taxane acylated at the C-2′ position and less than about 0.1% of the starting taxane remains unreacted after the contacting step.
43. The method of claim 42 , wherein the method results in at least about 99% of an ending taxane acylated at the C-2′ position.