Process for Preparing of Bortezomib

• US 20150246935A1
• Filed: 09/11/2013
• Published: 09/03/2015
• Est. Priority Date: 09/11/2012
• Status: Active Grant

• Current Assignee: Cipla (EU) Limited (Cipla Limited)
• Original Assignee: Cipla (EU) Limited (Cipla Limited)
• Inventors: Rao, Dharmaraj Ramachandra, Kankan, Rajendra Narayanrao, Pathi, Srinivas Laxminarayan, Puppala, Ravikumar
• Granted Patent: US 9,505,787 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: C07D 241/20 Nitrogen atoms nitro radicals C07D241/16
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07F 5/04 Esters of boric acids

Abstract

The present invention provides improved processes for the preparation of Bortezomib, tert-butyl[1-({(1S)-3-methyl-1-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}amino)-1-oxo-3-phenylpropan-2-yl]carbamate of formula (IV) and N-{(1S)-3-methyl-1-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl} phenylalanine of formula (V). Compound (IV) is prepared by coupling (1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethyl-hexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butan-1-amine of formula (II) or its salt with N-(tert-butoxycarbonyl)-L-phenylalanine of formula (III) in a first solvent in the presence of a first coupling agent and a first base, wherein the coupling process does not comprise solvent exchange. Compound (V) is prepared by deprotecting compound (IV) using an alcoholic solution of an inorganic acid.

Claims

1. A process for the preparation of Bortezomib, said process comprising:

a) coupling (1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaboral-2-yl]butan-1-amine of formula (II) or its salt

2. The process according to claim 1, wherein step a) does not comprise solvent exchange.

4. The process according to claim 1, wherein the first solvent is selected from the group consisting of dichloromethane, dichloroethane, toluene, dimethyl formamide, dimethyl sulfoxide and mixtures thereof.

5. The process according to claim 4, wherein the first solvent is dichloromethane.

6. The process according to claim 1, wherein the first coupling agent is selected from the group consisting of O-(benzotriazol-1-yl)-N,N,N′

, N′

-tetramethyl-uronium tetrafluoroborate (TBTU), dicyclohexylcarbodiimide (DCC), O-benzotriazole-N,N′

,N′

-tetramethyl uronium hexafluoro phosphate (HBTU), benzotriazol-1-yloxytripyrrolidino-phosphonium hexafluorophosphate and 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (EDC HCl).

7. The process according to claim 1, wherein the first coupling agent is used with a first additive.

8. The process according to claim 7, wherein the first additive is selected from the group consisting of 1-hydroxybenzotriazole (HOBT), N-hydroxysuccinimide (HOSu), 2-hydroxypyridine-N-oxide (HOPO), 1-hydroxy-7-azabenzotriazole (HOAt) and N-hydroxy-5-norbornene-2,3-dicarboximide (HONB).

9. The process according to claim 1, wherein the first coupling agent is ECC HCl and the first additive is HOBt.

10. The process according to claim 1, wherein the first base is selected from N,N-diisopropyl ethyl amine and triethyl amine.

12. The process according to claim 1, wherein the inorganic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid and sulphuric acid.

13. The process according to claim 1, wherein the alcohol is selected from the group consisting of ethanol, methanol, isopropanol and mixtures thereof.

14. The process according to claim 1, wherein the alcoholic solution of an inorganic acid is isopropanolic hydrochloric acid.

15. The process according to claim 1, wherein the deprotection of compound (IV) is carried out in situ without isolation of compound (IV).

16. The process according to claim 1, wherein the deprotection of compound (IV) is carried out at a temperature of from 15 to 35°

C.

17. The process according to claim 16, wherein the deprotection of compound (IV) is carried out at a temperature of from 20 to 30°

C.

18. The process according to claim 1, wherein the second solvent is selected from the group consisting of toluene and ethyl acetate.

19. The process according to claim 18, wherein the second solvent is toluene.

20. The process according to claim 1, wherein the second coupling agent is selected from the group consisting of O-(benzotriazol-1-yl)-N,N,N′

,N′

-tetramethyluronium tetrafluoroborate (TBTU), dicyclohexylcarbodiimide (DCC), O-benzotriazole-N,N′

,N′

-tetramethyl uronium hexafluoro phosphate (HBTU), benzotriazol-1-yloxytripyrrolidino-phosphonium hexafluorophosphate and 1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (EDC HCl).

21. The process according to claim 20 wherein the second coupling agent is TBTU.

22. The process according to claim 1, wherein the second coupling agent is used with a second additive.

23. The process according to claim 22, wherein the second additive is selected from the group consisting of 1-hydroxybenzotriazole (HOBT), N-hydroxysuccinimide (HOSu), 2-hydroxypyridine-N-oxide (HOPO), 1-hydroxy-7-azabenzotriazole (HOAt) and N-hydroxy-5-norbornene-2,3-cicarboximide (HONB).

24. The process according to claim 1, wherein the second base is selected from N,N-diisopropyl ethyl amine and triethyl amine.

25. The process according to claim 1, wherein the deprotection of compound (VII) is carried oat by treating compound (VII) with a boronic acid acceptor in an alcoholic solvent.

26. The process according to claim 25, wherein the boronic acid acceptor is selected from the group consisting of isobutyl boronic acid, 2-methyl-1-propyl boronic acid, trifluoroacetic acid, hydrochloric acid, hydrobromic acid and mixtures thereof.

27. The process according to claim 25, wherein the alcoholic solvent is selected from the group consisting of ethanol, methanol, isopropanol, n-propanol, n-butanol, isobutanol and mixtures thereof.

32. Bortezomib or its anhydride prepared according to the process of claim 1.

33. Bortezomib or its anhydride according to claim 32, comprising below the detectable limit of deboronated impurity (VIII) and dimer impurity (IX).

3. A process comprising a) coupling (1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butan-1-amine of formula (II) or its salt with N-(tert-butoxycarbonyl)-L-phenylalanine of formula (III) in a first solvent in the presence of a first coupling agent and a first base to obtain tert-butyl[1-({(1S)-3-methyl-1-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}amino)-1-oxo-3-phenylpropan-2-yl]carbamate of formula (IV) wherein the process does not comprise solvent exchange.

28. Tert-butyl[1-({(1S)-3-methyl-1-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2- yl]butyl}amino)-1-oxo-3-phenylpropan-2-yl]carbamate of formula (IV) prepared according to the process of claim 3.

29. Compound (IV) according to claim 28, comprising below the detectable limit of the following two impurities:

11. A process comprising b) preparing N-{(1S)-3-methyl-1-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2- benzodioxaborol-2-yl]butyl} phenylalanine of formula (V) or its salt by deprotecting tert-butyl[1-({(1S)-3-methyl-1-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexa-hydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}amino)-1-oxo-3-phenylpropan-2-yl]carbamate of formula (IV) using an alcoholic solution of an inorganic acid.

30. N-{(1S)-3-methyl-1-[(3aS,4S,6S,7aS)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl} phenylalanine of formula (V) or its salt prepared according to the process of claim 11.

31. Compound (V) or its salt according to claim 30, comprising below the detectable limit of deboronated impurity (VIII) and dimer impurity (IX).

34-36. -36. (canceled)