Patent EA-002576-B1 (EA)
Title: Method for acylating 10-deacetylbaccatin iii selectively at the c-10 position
Inventor: SISTI NICHOLAS J
IPC: A61K31/337
Filed: 1999-01-21
Abstract: 1. A method of acylating 10-deacetylbaccatin III at a C-10 position over hydroxyl, characterized in that it comprises the following steps: (a) dissolving of 10-deacetylbaccatin III in an ether solvent therefor to form a first solution; (b) mixing a solution containing a lithium salt into the first solution to form a second solution; (c) adding a base selected from a group consisting of trialkyl amines and pyridine to the second solution base thereby to form a third solution; and (d) combining the third solution with an acylating agent to form a fourth solution such that baccatin III is formed in the fourth solution. 2. A method according to Claim 1 wherein approximately one equivalent of lithium salt in solution is added to the first solution to form the second solution. 3. A method according to Claim 2 wherein the lithium salt is dissolved in tetrahydrofuran. 4. A method according to Claim 1 wherein approximately two equivalents of the base is added to the second solution to form the third solution. 5. A method according to Claim 1 wherein the third solution is added to a solution containing the acylating agent to form the fourth solution. 6. A method according to Claim 1 including the step of stirring the fourth solution for a period of at least one hour and a half. 7. A method according to Claim 1 including the step of quenching the fourth solution with a suitable quenching compound that is effective to eliminate excess of said acylating agent therefrom to produce a fifth solution. 8. A method according to Claim 7 including the step of diluting said fifth solution with ethylacetate to form an organic phase and an aqueous phase. 9. A method according to Claim 8 including the step of washing the organic phase with one normal HCl and saturated brine thereafter reducing the organic phase to a first residue. 10. A method according to Claim 9 including the step of purifying the first residue to afford baccatin III. 11. A method according to Claim 1 wherein said ether solvent is selected from a group consisting of: tetrahydrofuran and polyethers. 12. A method according to Claim 1 wherein said ether solvent is anhydrous. 13. A method according to Claim 1 wherein said acylating agent is acetylchloride. 14. A method according to Claim 1 wherein said quenching compound is ammonium chloride solution. 15. A method according to Claim 1 wherein the steps are performed at a temperature of between -10 degree C and 30 degree C. 16. A method according to Claim 1 wherein one to two equivalents of a lithium salt, dissolved in tetrahydrofuran, is mixed into the first solution to form a second solution at the temperature of between -10 degree C and 30 degree C. 17. A method according to Claim 1 wherein 1.1 equivalents of a lithium salt, dissolved in tetrahydrofuran, is mixed into the first solution to form the second solution. 18. A method according to Claim 1 wherein said lithium salt is selected from a group consisting of lithium chloride and lithium iodide. 19. A method according to Claim 18 wherein said lithium salt is lithium chloride. 20. A method according to Claim 1 wherein two equivalents of said base are mixed into the second solution to form a third solution. 21. A method according to Claim 20 wherein about five equivalents of said base are mixed into the second solution to form a third solution. 22. A method according to Claim 21 wherein said base is triethylamine. 23. A method according to Claim 1 wherein the third solution is added to a solution of two to ten equivalents of acylating agent to form the fourth solution. 24. A method according to Claim 23 wherein about five equivalents of the acylating agent is dissolved in THF into which the third solution is added to form a fourth solution. 25. A method according to Claim 1 wherein said fourth solution is stirred for about twenty-four hours. 26. A method of acylating 10-deacetylbaccatin III preferably at a C-10 position over a hydroxyl, comprising the steps of: (a) dissolving 10-deacetylbaccatin III in an ether solvent therefore to form a first solution at a temperature of between -10 degree C and 30 degree C; (b) mixing a solution of at least one equivalent of a lithium salt into the first solution to form a second solution; (c) adding at least an equivalent of a base selected from a group consisting of trialkylamines and pyridine to the second solution to form a third solution; (d) adding the third solution at a temperature of between -10 degree C and 30 degree C to a solution of acylating agent in an acceptable ether solvent to form a fourth solution; (e) stirring the fourth solution for a selected interval of time; (f) quenching the fourth solution with a suitable quenching compound that is effective to eliminate excess of said acylating agent therefrom to produce a fifth solution; (g) diluting said fifth solution with ethylacetate to form an organic phase and an aqueous phase; (h) washing said organic phase with HCl and saturated brine; (i) reducing in vacuo said organic phase to a first residue; and (j) purifying said first residue to afford baccatin III. 27. A method according to Claim 26 wherein said lithium salt is selected from a group consisting of lithium chloride and lithium iodide. 28. A method according to Claim 26 wherein said fourth solution is stirred for one hour and a half to twenty-four hours.