BORTEZOMIB AND PROCESS FOR PRODUCING SAME

• US 20100226597A1
• Filed: 09/12/2008
• Published: 09/09/2010
• Est. Priority Date: 09/12/2007
• Status: Abandoned Application

• Current Assignee: Dr. Reddy's Lab., Inc. (Dr. Reddy's Laboratories Ltd.), Dr. Reddy's Laboratories Ltd.
• Original Assignee: Dr. Reddy's Lab., Inc. (Dr. Reddy's Laboratories Ltd.), Dr. Reddy's Laboratories Ltd.
• Inventors: Gunda, Nageshwar, Hanmanthu, Mallesha, Murki, Veerendeer, Ramdoss, Suresh Kumar, Mopidevi, Narasimha Naidu, Pulla, Ramaseshagiri Rao, Manda, Amarendhar, Kadaboina, Rajasekhar, Palle, Raghavendracharyulu Venkata
• Application Number:
  US12/677,872
• Publication Number:
  US 20100226597A1
• Time in Patent Office: Days
• US Class Current: 383/113
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds

Abstract

The present application provides a process for the preparation of Bortezomib, its intermediates and process for crystalline forms of Bortezomib.

Claims

1. A process for preparing substantially pure Bortezomib comprising:

a) Providing a solution of Bortezomib in an organic solvent selected from alcohols, halogenated solvents, esters and hydrocarbons, nitriles, hydrocarbons, ethers, or mixtures thereof;

b) adding, where necessary, an anti-solvent to the solution obtained in step a); and

c) isolating the solid product from step a) or step b).

2. The process according to claim 1, wherein said anti-solvent in step b) is selected from water, hydrocarbons, ethers, or mixtures thereof, with the proviso that it is not the same as the solvent used in step a).

3. A process for the preparation of Bortezomib comprising the steps of:

a) reacting (N-[(1S)-2-[[(1R)-1-[(3aS,4S,6S,7aR)-hexahydro-3a,5,5-trimethyl-4,6-methano-1,3,2-benzodioxaborol-2-yl]-3-methylbutylamino]-2-oxo-1-(phenylmethyl)ethyl]Pyrazinecarboxamide (Formula IX)

with an organic boronic acid acceptor and aqueous HCl in the presence of an alcohol solvent and an aliphatic hydrocarbon solvent;

b) separating the aqueous layer;

c) extracting the aqueous layer with a water immiscible organic solvent, which is not an aliphatic hydrocarbon solvent; and

d) isolating Bortezomib.

4. The process according to claim 3, wherein said organic boronic acid acceptor is selected from butyl boronic acid, isobutyl boronic acid, phenylboronic acid, and benzyl boronic acid.

5. The process according to claim 3, wherein the amount of organic boronic acid used in step a) ranges from about 1 to about 1.5 molar equivalents, per molar equivalent of the compound of Formula IX.

6. The process according to claim 3, wherein the concentration of aqueous HCl ranges from about 0.5N to about 3N.

7. The process of claim 3, wherein said alcohol solvent is selected from C1-C4 alcohols.

8. The process of claim 3, wherein said hydrocarbon solvent is selected from C4-C10 straight or branched alkanes or cycloalkanes.

9. The process of claim 3, wherein the organic solvent in step c) has solubility in water less than about 10% w/w.

10. The process of claim 3, wherein said water immiscible organic solvent is selected from alcohols (C4-C7), halogenated solvents, esters, or mixtures thereof.

11. The process of claim 3, wherein said isolation in step (d) is performed by cooling, seeding, adding an organic anti-solvent to the reaction mixture or a combination thereof.

13. The method of claim 11 wherein said organic anti-solvent is selected from hydrocarbons, halohydrocarbons, esters, or mixtures thereof.

12. (canceled)

14. A process for the preparation of crystalline Form-A of Bortezomib, which comprises precipitating a crystalline Bortezomib from a solution containing Bortezomib in an alcoholic solvent, wherein said crystalline Bortezomib has an X-ray powder diffraction pattern substantially in accordance with FIG. 2.

15. The process of claim 14, which comprises:

a) providing a solution of Bortezomib in an alcohol;

b) adding water to precipitate the solid; and

c) isolating the crystalline Bortezomib having an X-ray powder diffraction pattern substantially in accordance with FIG. 2.

16. The process of claim 15, wherein said alcohol is methanol or ethanol.

17. A process for the preparation of crystalline Form B of Bortezomib, comprising:

a) providing a solution of Bortezomib in a halogenated alkane solvent or an ester solvent;

b) adding an aromatic hydrocarbon to precipitate a solid; and

optionally

c) isolating the obtained solid.

18. The process of claim 17, wherein said crystalline Form B of Bortezomib has an X-ray powder diffraction pattern substantially in accordance with FIG. 5.

19. The process of claim 17, wherein said halogenated alkane is dichloromethane, or 1,2-dichloroethane and chloroform, and said ester solvent is ethyl acetate, isopropyl acetate, tertiary butyl acetate or a mixture thereof.

20. The process of claim 17, wherein said aromatic hydrocarbon solvent in step b) is toluene, xylene or a mixture thereof.

21. A process for the preparation of a compound of Formula III

comprising preparing a boronate complex—

compound of formula X

by reacting the compound of formula-II

with lithium diisopropyl amide in the presence of a Lewis acid catalyst, a water miscible ether solvent and an excess of dichloromethane, followed by rearrangement of a boronate complex of formula-X.

22. The process of claim 21, wherein dichloromethane is utilized at about 4 Moles to about 8 Moles per mole of compound of formula II.

23. The process of claim 21, wherein a water miscible ether solvent is a cyclic ether solvent.

24. The process of claim 21, wherein a water miscible ether solvent is THF.

25. The process of claim 21, comprising:

I. Adding a lithium diisopropyl amide mixture to a solution of the compound of formula-II

in a solvent mixture comprising dichloromethane and a water miscible ether solvent followed by maintaining the resulting solution at a temperature of about −

40 to −

70°

C.,

II. Adding a mixture of zinc chloride in tetrahydrofuran into the product of step I followed by maintaining the reaction mass at a temperature of about −

40 to −

70°

C.,

III. Raising the reaction temperature to about 10°

C. to ambient temperature,

IV. Adding an aqueous acid solution; and

V. Optionally, separating the organic layer containing the compound of formula-III; and

VI. isolating the compound of formula-III.

26. The process of claim 25, wherein said lithium diisopropyl amide mixture is prepared using diisopropyl amine and n-hexyl lithium.

27. The process of claim 25, wherein said organic layer in step V is concentrated to isolate the compound of formula-III.

29. The process of claim 25, wherein the amount of Zinc chloride ranges from about 1.2 to about 2 moles per mole of the compound of formula II.

30. The process of claim 21, wherein said Lewis acid catalyst is Zinc chloride.

28. (canceled)

31. (canceled)

32. A process for the preparation of intermediate of Formula VIII

comprising reacting pyrazine carboxylic acid with L-phenylalanine in the presence of an alkyl or aryl chloroformate.

33. The process of claim 32, wherein an alkyl or aryl chloroformate is ethylchloroformate, benzylchloroformate, or para-nitrophenylchloroformate.

34. A compound of the following formula in the solid state.

35. The compound according to claim 34 characterized by a peak at m/z=383.19 in negative ion mode in a mass spectral analysis.

36. The compound according to claim 34 characterized by a peak at m/z=367.4 in positive ion mode in a mass spectral analysis.

37. The compound according to claim 34 characterized by an absence of peaks at m/z=1121, 1099, and 1137 in a mass spectral analysis, which peaks correspond to sodium, proton, and potassium adducts of trimeric boroxine.

38. The compound according to claim 34 is, being Bortezomib form A.

39. The compound according to claim 34, having a moisture content up to about 5% w/w.

40. Bortezomib exhibiting a maximum degradation of about 0.2% or from the initial purity when stored for a minimum of about three months.

41. A storage system for Bortezomib comprising:

a. At least one external sealed polymeric bag;

b. At least one internal sealed polymeric bag containing Bortezomib sealed within said at least one external sealed polymeric bag; and

c. An oxygen absorbent and interposed between the external polymeric bag and the internal polymeric bag.

42. The storage system of claim 41 further comprising a moisture absorbent interposed between the external polymeric bag and the internal polymeric bag.

43. The storage system of claim 41 further comprising at least one laminated aluminum bag in which the at least one external sealed polymeric bag is itself sealed.

45. The storage system of claim 41 wherein the oxygen absorbent is selected from the group consisting of ascorbic acid, or iron powder containing materials.

46. The storage system of claim 42 wherein the moisture absorbent is selected from the group consisting of aluminum oxide, calcium chloride, CaSO₄, molecular sieves, and silica gel.

47. The storage system according to claim 41 further comprising an inert atmosphere interposed between the external polymeric bag and the internal polymeric bag.

44. (canceled)