Semi-synthesis of taxane intermediates and aziridine analogues and their conversion to paclitaxel and docetaxel

• US 20070027331A1
• Filed: 03/09/2006
• Published: 02/01/2007
• Est. Priority Date: 02/24/2004
• Status: Abandoned Application

• Current Assignee: Innovational Holdings, LLC (Johnson & Johnson)
• Original Assignee: Innovational Holdings, LLC (Johnson & Johnson)
• Inventors: Naidu, Ragina
• Application Number:
  US11/372,476
• Publication Number:
  US 20070027331A1
• Time in Patent Office: Days
• US Class Current: 549/510
• CPC Class Codes: C07D 305/14 condensed with carbocyclic rings or ring systems

Abstract

A process is provided for the semi-synthesis of taxane intermediates and aziridine analogues of cephalomannne and baccatin III intermediates, and the conversion of such intermediates and analogues to paclitaxel and docetaxel.

Claims

1. A process for preparing a taxane comprising the steps of:

converting cephalomannine to a taxane intermediate having the structure;

wherein R is at each occurrence independently selected from hydrogen and a hydroxy-protecting group; and

converting the taxane intermediate to paclitaxel or docetaxel.

2. The process of claim 1 wherein the taxane intermediate is converted to paclitaxel.

3. The process of claim 1 wherein the taxane intermediate is converted to docetaxel.

4. The process of claim 1 wherein the step of converting cephalomannine to the taxane intermediate further comprises the steps of:

converting cephalomannine to a cephalomannine aziridine analogue having the structure;

wherein R is at each occurrence independently selected from hydrogen and a hydroxy-protecting group; and

converting the cephalomannine aziridine analogue to the taxane intermediate.

5. The process of claim 1 wherein the step of converting cephalomannine to the taxane intermediate comprises reacting cephalomannine with formic acid.

6. The process of claim 1 wherein the step of converting cephalomannine to the taxane intermediate further comprises the reaction sequence:

7. The process of claim 1 wherein the step of converting cephalomannine to the taxane intermediate further comprises the steps of:

converting cephalomannine to a cephalomannine epoxide analogue having the structure;

wherein R is at each occurrence independently selected from hydrogen and a hydroxy-protecting group;

converting the cephalomannine epoxide analogue to a cephalomannine azido alcohol analogue having the structure;

wherein R is at each occurrence independently selected from hydrogen and a hydroxy-protecting group; and

converting the cephalomannine azido alcohol analogue to the taxane intermediate.

8. A process for preparing a taxane comprising the steps of:

converting cinnamoyl halide to a cinnamoyl halide aziridine intermediate having the structure;

wherein X is halogen;

reacting the cinnamoyl halide aziridine intermediate with protected baccatin III to provide a protected baccatin III aziridine intermediate having the structure;

wherein R is selected from hydrogen and a hydroxy-protecting group;

converting the protected baccatin III aziridine intermediate to a taxane intermediate having the structure;

wherein R is selected from hydrogen and a hydroxy-protecting group; and

converting the taxane intermediate to paclitaxel or docetaxel.

9. The process of claim 8, wherein X is chloro.

10. A process for preparing a taxane comprising the steps of:

converting cinnamoyl halide to a cinnamoyl halide aziridine intermediate having the structure;

wherein X is halogen;

converting the cinnamoyl halide aziridine intermediate to an open chain cinnamoyl halide intermediate having the structure;

wherein X is halogen;

reacting the open chain cinnamoyl halide intermediate with protected baccatin III to provide a protected baccatin III intermediate having the structure;

wherein R is selected from hydrogen and a hydroxy-protecting group;

converting the protected baccatin III intermediate to a taxane intermediate having the structure;

wherein R is selected from hydrogen and a hydroxy-protecting group; and

converting the taxane intermediate to paclitaxel or docetaxel.

11. The process of claim 10, wherein X is chloro.

12. The process of claim 10, wherein the step of reacting the open chain cinnamoyl halide intermediate with protected baccatin III further comprises the steps of:

converting the open chain cinnamoyl halide intermediate to a β

-lactam intermediate having the structure;

reacting the β

-lactam intermediate with protected baccatin III to provide the protected baccatin III intermediate.

13. A process for preparing docetaxel from cephalomannine comprising the reaction sequence: