Process for the preparation of bortezomib mannitol ester

• US 10,023,611 B2
• Filed: 04/16/2014
• Issued: 07/17/2018
• Est. Priority Date: 04/16/2013
• Status: Expired due to Fees

• Current Assignee: Cipla (EU) Limited (Cipla Limited)
• Original Assignee: Cipla (EU) Limited (Cipla Limited)
• Inventors: Puppala, Ravikumar, Pathi, Srinivas Laxminarayan, Rao, Dharmaraj Ramachandra, Kankan, Rajendra Narayanrao
• Primary Examiner(s): Cordero Garcia, Marcela M
• Assistant Examiner(s): Lee, Jia-Hai
• Application Number:
  US14/784,866
• Publication Number:
  US 20160075736A1
• Time in Patent Office: 1,553 Days
• Field of Search: None
• CPC Class Codes: A01N 43/48 having rings with two nitrogen atoms as the only ring hetero atoms
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 38/05 Dipeptides
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07K 5/06191 containing heteroatoms different from O, S, or N

Abstract

A novel and improved process for preparation of bortezomib mannitol ester is derived, which process avoids excessive use of solvents, involves convenient, industrially feasible and economical techniques, and provides improvements in purity over processes known in the art.

Claims

1. A process for the preparation of bortezomib-mannitol ester (compound B),

2. The process according to claim 1 wherein the step (b) is carried out at a temperature of less than 35°

C.

3. The process according to claim 1 wherein, after the mannitol is added to the first solution, the first solution is mixed for less than 30 minutes.

4. The process according to claim 1 wherein the mannitol is D-mannitol, and wherein the bortezomib-mannitol ester is bortezomib D-mannitol ester having the following structure

5. The process according to claim 1 wherein the first solution is free of water.

6. The process according to claim 1 wherein the removing of the first solvent in step (c) comprises evaporating the first solvent from the first solution.

7. The process according to claim 6 wherein the step of evaporating comprises subjecting the first solution to a temperature less than 30°

C.

8. The process according to claim 6 wherein the step of evaporating comprises subjecting the first solution to a pressure less than 1 atmosphere.

9. The process according to claim 1 wherein the first solvent is not frozen prior to the step of removing the first solvent from the first solution.

10. The process according to claim 1 wherein the step of isolating comprises filtering the bortezomib-mannitol ester from the second solvent.

11. The process according to claim 1, further comprising sterilizing the first solution by filtration.

12. The process according to claim 11 wherein the first solution is filtered after step (a) and before step (b), and wherein said mannitol is sterile.

13. The process according to claim 11 wherein the filtration is carried out by passing the first solution through a sub-micron filter.

14. The process according to claim 11 wherein the filtration is carried out by passing the first solution through a first filter having a pore size less than 0.50 microns.

15. The process according to claim 11 wherein the filtration is carried out by passing the first solution through a second filter having a pore size less than 0.25 microns.

16. The process according to claim 1 wherein the step (b) is carried out at a temperature of less than 30°

C.

17. The process according to claim 1 wherein, after the mannitol is added to the first solution, the first solution is mixed for less than 20 minutes.

18. The process according to claim 6 wherein the step of evaporating comprises subjecting the first solution to a temperature less than 25°

C.