SYNTHESIS OF BORONIC ESTER AND ACID COMPOUNDS

• US 20130005968A1
• Filed: 09/14/2012
• Published: 01/03/2013
• Est. Priority Date: 03/30/2004
• Status: Abandoned Application

• Current Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Original Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Inventors: Bishop, John E., Koellner, Christoph, Gomez, Jean-Marc, Geiser, Achim, Hett, Robert, Ammoscato, Vince, Munk, Stephen, Lo, Young, Chiu, Fang-Ting, Kulkarni, Vithalanand R., Pickersgill, I. Fraser
• Application Number:
  US13/615,894
• Publication Number:
  US 20130005968A1
• Time in Patent Office: Days
• US Class Current: 544/229
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07F 5/025 Boronic and borinic acid compounds
• CPC Class Codes: C07F 5/04 Esters of boric acids
• CPC Class Codes: C07K 5/06191 containing heteroatoms different from O, S, or N
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention relates to the synthesis of boronic ester and acid compounds. More particularly, the invention provides improved synthetic processes for the large-scale production of boronic ester and acid compounds, including the peptide boronic acid proteasome inhibitor bortezomib.

Claims

1. A composition comprising an ether solvent that has low miscibility with water and at least about ten moles of a boronic ester compound of formula (I):

4. The composition of any one of claims 1-3, wherein the solubility of water in the ether solvent is less than about 2% w/w.

5. The composition of any one of claims 1-3, wherein the ether solvent is selected from the group consisting of tert-butyl methyl ether, tert-butyl ethyl ether, tert-amyl methyl ether, isopropyl ether, and mixtures thereof.

6. The composition of any one of claims 1-3, wherein R¹ is C_1-8 aliphatic, C_6-10 aryl, or (C_6-10 aryl)(C_1-6 aliphatic).

7. The composition of any one of claims 1-3, characterized by at least one of the following features:

(a) R³ is chloro;

(b) R² is hydrogen; and

(c) R¹ is C_1-4 aliphatic

8. The composition of any one of claims 1-3, wherein the compound of formula (I) is

2. A composition comprising an ether solvent that has low miscibility with water and at least about ten moles of a boronic ester compound of formula (I):

21. The process of claim 2Q, wherein step (b) provides a product solution comprising the boronic ester of formula (III), and the product solution from step (b) is used in step (c) without isolation of the boronic ester of formula (III).

3. A composition comprising an ether solvent that has low miscibility with water and at least about ten moles of a boronic ester compound of formula (I):

10. The composition of claim 3 comprising at least about 20 moles of the boronic ester compound of formula (I).

11. The composition of claim 3, wherein the carbon atom to which R¹, R², and R³ are attached has a diastereomeric ratio of at least about 97:

3, relative to a chiral center in the R⁴—

R⁵ chiral moiety.

12. The composition of claim 3, wherein all of the boronic ester compound of formula (I) present in the composition is produced in a single batch run.

13. The composition of claim 3, wherein at least one of the following features is present:

(a) R³ is chloro;

(b) the boronic ester compound of formula (I) is;

9. A composition comprising at least about ten moles of a boronic ester compound of formula (I):

14. A large-scale process for preparing a boronic ester compound of formula (I):

15. A large-scale process for preparing a boronic ester compound of formula (I):

17. The process of claim 15 or 16, wherein the sterically hindered base is an alkali metal dialkylamide base of formula M²N(R#)₂, wherein M² is selected from the group consisting of Li, Na, and K, and each R#, independently, is a branched or cyclic C_3-6 aliphatic.

16. A large-scale process for preparing a boronic ester compound of formula (I):

18. The process of claim 16, wherein the organic solvent in step (a) is selected from the group consisting of acetonitrile, toluene, hexane, heptane, and mixtures thereof.

19. The process of claim 16, wherein the organic solvent in step (a) is an ether solvent that has low miscibility with water, wherein the solubility of water in the ether solvent that has low miscibility with water is less than about 5% w/w.

20. The process of claim 19, wherein the solutions in steps (a) and (c) each comprise the same ether solvent.

22. A large-scale process for preparing an aminoboronic ester compound of formula (VII):

23. The process of claim 22, wherein the reaction mixture in step (c) comprises an organic solvent in which the byproduct M¹-R³ has low solubility.

24. The process of claim 23, wherein M¹ is Li and R³ is Cl.

25. The process of claim 24, wherein the reaction mixture in step (c) comprises an organic solvent selected from the group consisting of methylcyclohexane, cyclohexane, heptane, hexane, toluene, and mixtures thereof.

26. The process of claim 22, wherein the reaction in step (c) is conducted at a reaction temperature in the range of about −

100°

C. to about 50°

C.

27. The process of claim 26, wherein the reaction temperature is in the range of about −

50°

C. to about 25°

C.

28. The process of claim 26, wherein the reaction temperature is in the range of about −

30°

C. to about 0°

C.

29. The process of claim 22, wherein step (d) comprises treating the compound of formula (VIII) with an acid and isolating the compound of formula (VII) as the acid addition salt.

30. The process of claim 29, wherein the acid is trifluoroacetic acid.

31. The process of claim 22, wherein step (c) further comprises filtering the reaction mixture to provide a filtrate comprising the compound of formula (VIII).

32. The process of claim 31, wherein in step (c), the reagent of formula M¹-N(Si(R⁶)₃)₂ is added to the reaction mixture as a solution comprising tetrahydrofuran, and step (c) further comprises removing the tetrahydrofuran before filtering the reaction mixture.

33. The process of claim 31, wherein the filtrate is used directly in step (d).

34. The process of claim 22, further comprising the step:

(e) coupling the compound of formula (VII) with a compound of formula (IX);

35. The process of claim 34, wherein P¹ is a cleavable protecting group.

36. The process of claim 35, further comprising the steps:

(f) cleaving the protecting group P¹ to form a compound of formula (XI);

37. A large-scale process for preparing an aminoboronic ester compound of formula (VIM) or (VIIb):

38. A large-scale process for forming a compound of formula (XIV):

39. The process of claim 38, wherein step (dd)(iii) comprises the steps:

(1) separating the solvent layers;

(2) adjusting the aqueous layer to basic pH;

(3) washing the aqueous layer with an organic solvent; and

(4) adjusting the aqueous layer to a pH less than about 8.

40. The process of claim 39, wherein in step (dd)(iv), the compound of formula (XIV), or a boronic acid anhydride thereof, is extracted into dichloromethane, the solvent is exchanged to ethyl acetate, an the compound of formula (XIV), or a boronic acid anhydride thereof, is crystallized by addition of hexane or heptane.

41. The process of claim 40, wherein addition of hexane or heptane results in crystallization of a cyclic trimeric boronic acid anhydride of formula (XXIV):

48. A composition comprising at least one kilogram of a compound of formula (XXIV):

42. A large-scale process for forming a compound of formula (XIV):

43. The process of claim 42, characterized by at least one of the following features (1)-(3):

(1) In the boron “

ate”

complex of formula (XV), R³ and Y both are chloro.

(2) The coupling step (e′

) comprises the steps;

(i) coupling the compound of formula (XVIII) with a compound of formula (XIXa) wherein X is OH in the presence of 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) and a tertiary amine in dichloromethane;

(ii) performing a solvent exchange to replace dichloromethane with ethyl acetate; and

(iii) performing an aqueous wash of the ethyl acetate solution.

(3) The boronic acid deprotecting step (f′

) comprises the steps;

(i) providing a biphasic mixture comprising the compound of formula (XXIII), an organic boronic acid acceptor, a lower alkanol, a C_5-8 hydrocarbon solvent, and aqueous mineral acid;

(ii) stirring the biphasic mixture to afford the compound of formula (XIV);

(iii) separating the solvent layers; and

(iv) extracting the compound of formula (XIV), or a boronic acid anhydride thereof, into an organic solvent.

44. The process of claim 43, wherein step (f′

)(iii) comprises the steps;

(1) separating the solvent layers;

(2) adjusting the aqueous layer to basic pH;

(3) washing the aqueous layer with an organic solvent; and

(4) adjusting the aqueous layer to a pH less than about 8.

45. The process of claim 44, wherein in step (f′

)(iii)(3), the aqueous layer is washed with dichloromethane.

46. The process of claim 44, wherein in step (f′

)(iv), the compound of formula (XIV), or a boronic acid anhydride thereof, is extracted into dichloromethane, the solvent is exchanged to ethyl acetate, an the compound of formula (XIV), or a boronic acid anhydride thereof, is crystallized by addition of hexane or heptane.

47. The process of claim 46, wherein addition of hexane or heptane results in crystallization of a cyclic trimeric boronic acid anhydride of formula (XXIV):

49. A composition comprising at least one kilogram of a compound of formula (XXIV):