Facile method for synthesizing baccatin III compounds
A process for synthesizing a C-7 protected baccatin III compound represented by formula (A), which comprises reacting a 10-deacetylbaccatin III compound represented by formula (B) with a protecting agent and an acylating agent in the presence of a secondary amine and a nitrogen-containing compound. Also, a process for synthesizing a C-7 protected 10-deacetylbaccatin III compound represented by formula (C), which comprises reacting a 10-deacetylbaccatin III compound represented by formula (B) with a protecting agent in the presence of a secondary amine and a nitrogen-containing compound. In both processes the nitrogen-containing compound is selected from a nitrogen-containing heterocycle or a trialkylamine. When the nitrogen-containing heterocycle is selected, it may be an unsubstituted or a substituted pyridine or an unsubstituted or a substituted pyrazine. When a trialkylamine is selected, it may be, for example, triethylamine or diisopropylethylamine. wherein PG 1 represents the organic residue of the protecting agent, PG 2 represents the organic residue of the acylating agent, and R represents a simple or substituted aryl group or a heterocyclic group.
1. A process for synthesizing a compound represented by formula (A), which comprises reacting a 10-deacetylbaccatin III compound represented by formula (B) with a protecting agent in the presence of a secondary amine and a nitrogen-containing compound selected from a trialkylamine or a nitrogen-containing heterocycle selected from the group consisting of unsubstituted or substituted pyridine and unsubstituted or substituted pyrazine, and then with an acylating agent,
wherein PG 1 represents the organic residue of the protecting agent, PG 2 represents the organic residue of the acylating agent, and R represents a simple or substituted aryl group or a heterocyclic group.
2. The process according to claim 1 , wherein the aryl group is a group represented by the following formula:
wherein R′s may be the same or different and each represents H, an electron withdrawing group or an electron donating group, and n represents 0 or an integer of from 1 to 3.
3. The process according to claim 1 , wherein the aryl group represented by R is phenyl or substituted phenyl.
4. The process according to claim 2 , wherein the electron withdrawing group is selected from the group consisting of —F, —NO 2 , —CN, —Cl, —CHF 2 and —CF 3 .
5. The process according to claim 2 , wherein the electron donating group is selected from the group consisting of —NR 7 R 8 and —OR 9 , wherein R 7 and R 8 are the same or different and each represents a linear alkyl group having 1 to 10 carbon atoms, a branched or cyclic alkyl group having 3 to 10 carbon atoms, or an unsubstituted or substituted aryl group having 6 to 10 carbon atoms, and R 9 represents a linear alkyl group having 1 to 10 carbon atoms, or a branched or cyclic alkyl group having 3 to 10 carbon atoms.
6. The process according to claim 2 , wherein R′ represents —OCH 3 or chloro.
7. The process according to claim 1 , wherein the aryl group represented by R is selected from the group consisting of methoxyphenyl, dimethoxyphenyl and chiorophenyl.
8. The process according to claim 1 , wherein the aryl group represented by R is selected from the group consisting of the following formulae:
9. The process according to claim 5 , wherein R 7 and R 8 are the same or different and each represents a linear alkyl group having 1 to 4 carbon atoms, or a branched or cyclic alkyl group having 3 to 4 carbon atoms.
10. The process according to claim 5 , wherein R 7 and R 8 are the same and represent a linear alkyl group having 1 to 10 carbon atoms, a branched or cyclic alkyl group having 3 to 10 carbon atoms, or an unsubstituted or substituted aryl group having 6 to 10 carbon atoms.
11. The process according to claim 5 , wherein —NR 7 R 8 is selected from the group consisting of dimethyl amino, diethyl amino, dipropyl amino and dibutyl amino, wherein the propyl moiety represents normal-propyl or isopropyl, and the butyl moiety represents normal-butyl, secondary butyl, tertiary butyl or isobutyl.
12. The process according to claim 1 , wherein the heterocyclic group represented by R is a 3 to 7 membered ring having 1 to 2 hetero atoms selected from the group consisting of oxygen, nitrogen and sulfur.
13. The process according to claim 1 , wherein the heterocyclic group represented by R is selected from the group consisting of furyl, dihydrofuryl, tetrahydrofuryl, pyrollyl, pyrrolidinyl, thienyl, thiazolyl, imidazolyl, pyridyl, morpholinyl, piperidinyl, piperazinyl and oxazolyl.
14. The process according to claim 1 , wherein the heterocyclic group represented by R is selected from thienyl or furyl.
15. The process according to claim 1 , wherein the heterocyclic group represented by R is selected from the following formulae:
16. The process according to claim 1 , wherein PG 1 is trialkylsilyl.
17. The process according to claim 1 , wherein PG 2 is acyl.
18. The process according to claim 16 or 17 , wherein PG 1 is triethylsilyl and PG 2 is acetyl.
19. The process according to claim 1 , wherein the protecting agent is an organosilane compound.
20. The process according to claim 1 , wherein the protecting agent is an organosilane compound represented by the formula (R″) 3 SiX, wherein R″s may be the same or different, and each independently represents methyl, ethyl, normal-propyl, isopropyl or tert-butyl, and X represents a leaving group.
21. The process according to claim 20 , wherein the leaving group represented by X is selected from the group consisting of a halogen atom, tosylate, mesylate, and trifluoromethanesulfonate.
22. The process according to claim 1 , wherein the protecting agent is chlorotriethylsilane.
23. The process according to claim 1 , wherein the acylating agent is selected from the group consisting of acyl halides and acyl anhydrides.
24. The process according to claim 1 , wherein the acylating agent is selected from the group consisting of acetyl chloride and acetic anhydride.
25. The process according to claim 24 , wherein the acylating agent is acetic anhydride.
26. The process according to claim 1 , wherein the secondary amine is a substituted imidazole.
27. The process according to claim 1 , wherein the secondary amine is imidazole.
28. The process according to claim 1 , wherein the nitrogen-containing compound is a nitrogen-containing heterocycle selected from the group consisting of pyridine, 2-picoline, 3-picoline, 4-picoline, pyrazine and methylpyrazine or a trialkylamine selected from the group consisting of trimethylamine, triethylamine, diisopropylethylamine, tri-n-propylamine, and tri-n-butylamine.
29. The process according to claim 1 , wherein the nitrogen-containing compound is pyridine or triethylamine.
30. The process according to claim 1 , wherein the nitrogen-containing compound is anhydrous.
31. The process according to claim 1 , wherein the amount of the protecting agent is about 2 equivalents based on the amount of the 10-deacetylbaccatin III compound represented by formula (B).
32. The process according to claim 1 , wherein the amount of the acylating agent is in a range of from about 1 to about 20 equivalents based on the amount of the 10-deacetylbaccatin III compound represented by formula (B).
33. The process according to claim 1 , wherein the amount of the secondary amine is about 2 to about 6 equivalents based on the amount of the 10-deacetylbaccatin III compound represented by formula (B).
34. The process according to claim 1 , wherein the amount of the nitrogen-containing compound is about about 0.5 mL per 0.1 g of the 10-deacetylbaccatin III compound represented by formula (B).
35. The process according to claim 1 , wherein the process is carried out at ambient temperature.
36. The process according to claim 1 , wherein the process is carried out in a dry atmosphere.
37. The process according to claim 1 , wherein the process is carried out at ambient atmosphere.
38. The process according to claim 1 , wherein the process is substantially complete in less than about 5 hours.
39. A process for synthesizing a compound represented by formula (C), which comprises reacting a 10-deacetylbaccatin III compound represented by formula (B) with a protecting agent in the presence of a secondary amine and a nitrogen-containing compound selected from a trialkylamine or a nitrogen-containing heterocycle selected from the group consisting of unsubstituted or substituted pyridine and unsubstituted or substituted pyrazine,
wherein PG 1 represents the organic residue of the protecting agent, and R represents a simple or substituted aryl group or a heterocyclic group.
40. The process according to claim 39 , wherein the aryl group represented by R is a group represented by the following formula:
wherein R′s may be the same or different and each represents H, an electron withdrawing group or an electron donating group, and n represents 0 or an integer of from 1 to 3.
41. The process according to claim 39 , wherein the aryl group represented by R is phenyl or substituted phenyl.
42. The process according to claim 40 , wherein the electron withdrawing group is selected from the group consisting of —F, —NO 2 , —CN, —Cl, —CHF 2 and —CF 3 .
43. The process according to claim 40 , wherein the electron donating group is selected from the group consisting of —NR 7 R 8 and —OR 9 , wherein R 7 and R 8 are the same or different and each represents a linear alkyl group having 1 to 10 carbon atoms, a branched or cyclic alkyl group having 3 to 10 carbon atoms, or an unsubstituted or substituted aryl group having 6 to 10 carbon atoms, and R 9 represents a linear alkyl group having 1 to 10 carbon atoms, or a branched or cyclic alkyl group having 3 to 10 carbon atoms.
44. The process according to claim 40 , wherein R′ represents —OCH 3 or chloro.
45. The process according to claim 39 , wherein the aryl group represented by R is selected from the group consisting of methoxyphenyl, dimethoxyphenyl and chlorophenyl.
46. The process according to claim 39 , wherein the aryl group represented by R is selected from the group consisting of the following formulae:
47. The process according to claim 43 , wherein R 7 and R 8 are the same or different and each represents a linear alkyl group having 1 to 4 carbon atoms, or a branched or cyclic alkyl group having 3 to 4 carbon atoms.
48. The process according to claim 43 , wherein R 7 and R 8 are the same and represent a linear alkyl group having 1 to 10 carbon atoms, a branched or cyclic alkyl group having 3 to 10 carbon atoms, or an unsubstituted or substituted aryl group having 6 to 10 carbon atoms.
49. The process according to claim 43 , wherein the —NR 7 R 8 is selected from the group consisting of dimethyl amino, diethyl amino, dipropyl amino and dibutyl amino, wherein the propyl moiety represents normal-propyl or isopropyl, and the butyl moiety represents normal-butyl, secondary butyl, tertiary butyl or isobutyl.
50. The process according to claim 39 , wherein the heterocyclic group represented by R is a 3 to 7 membered ring having 1 to 2 hetero atoms selected from the group consisting of oxygen, nitrogen and sulfur.
51. The process according to claim 39 , wherein the heterocyclic group represented by R is selected from the group consisting of furyl, dihydrofuryl, tetrahydrofuryl, pyrollyl, pyrrolidinyl, thienyl, thiazolyl, imidazolyl, pyridyl, morpholinyl, piperidinyl, piperazinyl and oxazolyl.
52. The process according to claim 39 , wherein the heterocyclic group represented by R is thienyl or furyl.
53. The process according to claim 39 , wherein the heterocyclic group represented by R is selected from the following formula:
54. The process according to claim 39 , wherein PG 1 is trialkylsilyl.
55. The process according to claim 39 , wherein the protecting agent is an organosilane compound.
56. The process according to claim 39 , wherein the protecting agent is an organosilane compound represented by the formula (R″) 3 SiX, wherein R″s may be same or different, and each independently represents methyl, ethyl, normal-propyl, isopropyl or tert-butyl, and X represents a leaving group.
57. The process according to claim 56 , wherein the leaving group represented by X is selected from the group consisting of a halogen atom, tosylate, mesylate, and trifluoromethanesulfonate.
58. The process according to claim 39 , wherein the protecting agent is chlorotriethylsilane.
59. The process according to claim 39 , wherein the secondary amine is a substituted imidazole.
60. The process according to claim 39 , wherein the secondary amine is imidazole.
61. The process according to claim 39 , wherein the nitrogen-containing compound is a nitrogen-containing heterocycle selected from the group consisting of pyridine, 2-picoline, 3-picoline, 4-picoline, pyrazine and methylpyrazine or a trialkylamine selected from the group consisting of trimethylamine, triethylamine, diisopropylethylamine, tri-n-propylamine, and tri-n-butylamine.
62. The process according to claim 39 , wherein the nitrogen-containing compound is pyridine or triethylamine.
63. The process according to claim 39 , wherein the nitrogen-containing compound is anhydrous.
64. The process according to claim 39 , wherein the process is carried out at ambient temperature.
65. The process according to claim 39 , wherein the process is carried out in a dry atmosphere.
66. The process according to claim 39 , wherein the process is carried out at ambient atmosphere.
67. The process according to claim 39 , wherein the process is substantially complete in less than about 20 minutes.
68. The process according to claim 39 , wherein the amount of the protecting agent is about 2 equivalents based on the amount of the 10-deacetylbaccatin III compound represented by formula (B).
69. The process according to claim 39 , wherein the amount of the secondary amine is about 2 to about 6 equivalents based on the amount of the 10-deacetylbaccatin III compound represented by formula (B).