Synthesis of boronic ester and acid compounds

• US 7,714,159 B2
• Filed: 03/24/2005
• Issued: 05/11/2010
• Est. Priority Date: 03/30/2004
• Status: Active Grant

• Current Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Original Assignee: Millennium Pharmaceuticals Incorporated (Takeda Pharmaceutical Company Limited)
• Inventors: Koellner, Christoph, Geiser, Achim, Hett, Robert, Bishop, John E., Pickersgill, I. Fraser, Gomez, Jean-Marc
• Primary Examiner(s): SHIAO, REI TSANG
• Application Number:
  US11/088,667
• Publication Number:
  US 20050240047A1
• Time in Patent Office: 1,874 Days
• Field of Search: 558/288
• US Class Current: 558/288
• 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 large-scale process for preparing a boronic ester compound of formula (I):

2. The process of claim 1, wherein the reaction mixture comprises a coordinating co-solvent.

3. The process of claim 2, wherein the coordinating co-solvent is selected from the group consisting of tetrahydrofuran, dioxane, water, and mixtures thereof.

4. The process of claim 3, wherein the coordinating co-solvent constitutes no more than about 15% v/v of the reaction mixture.

5. The process of claim 1, wherein the solubility of water in the ether solvent that has low miscibility with water is less than about 2% w/w.

6. The process of claim 5, wherein the ether solvent that has low miscibility with water is selected from the group consisting of tert-butyl methyl ether, tert-butyl ethyl ether, tert-amyl methyl ether, isopropyl ether, and mixtures thereof.

7. The process of claim 1, wherein at least about 5 moles of the boron “

ate”

complex of formula (II) are provided in step (a).

8. The process of claim 1, wherein at least about 20 moles of the boron “

ate”

complex of formula (II) are provided in step (a).

9. The process of claim 1, wherein at least about 50 moles of the boron “

ate”

complex of formula (II) are provided in step (a).

10. The process of claim 1, wherein at least about 100 moles of the boron “

ate”

complex of formula (II) are provided in step (a).

11. The process of claim 1, wherein the Lewis acid is selected from the group consisting of zinc chloride, zinc bromide, ferric chloride, and ferric bromide.

12. The process of claim 11, wherein the Lewis acid is moist.

13. The process of claim 12, wherein in step (a) the boron “

ate”

complex of formula (II) is provided in a solution comprising an ether solvent that has low miscibility with water, and the contacting step (b) comprises the steps;

(i) providing a solution comprising a Lewis acid and tetrahydrofuran; and

(ii) adding the Lewis acid solution to the solution of the boron “

ate”

complex of formula (II) from step (a).

14. The process of claim 11, wherein in step (a) the boron “

ate”

complex of formula (II) is provided in a solution comprising an ether solvent that has low miscibility with water, and the contacting step (b) comprises the steps;

(i) providing a solution comprising a Lewis acid and water; and

(ii) adding the Lewis acid solution to the solution of the boron “

ate”

complex of formula (II) from step (a).

15. The process of claim 1, wherein Y is a halogen.

16. The process of claim 1, wherein Y is chloro.

17. The process of claim 1, wherein R¹ is C_1-8 aliphatic, C_6-10 aryl, or (C_6-10 aryl)(C_1-6 aliphatic).

18. The process of claim 1, wherein M⁺ is selected from the group consisting of Li⁺, Na⁺, and K⁺.

19. The process of claim 1, wherein R⁴ and R⁵ together are a chiral moiety.

20. The process of claim 19, wherein the boron “

ate”

complex of formula (II) is;

21. The process of claim 19, wherein step (b) provides the boronic ester compound of formula (I) wherein the carbon atom bearing R¹, R², and R³ is a chiral center having a diastereomeric ratio of at least about 96:

4 relative to a chiral center in the R⁴—

R⁵ chiral moiety.

22. The process of claim 19, wherein step (b) provides the boronic ester compound of formula (I) wherein the carbon atom bearing R¹, R², and R³ is a chiral center having a diastereomeric ratio of at least about 97:

3 relative to a chiral center in the R⁴—

R⁵ chiral moiety.

23. The process of claim 19, characterized by at least one of the following features:

(a) the contacting step (b) is conducted in a reaction mixture comprising tert-butyl methyl ether;

(b) the Lewis acid is zinc chloride;

(c) at least about 5 moles of the boronic ester of formula (II) are provided in step (a);

(d) the contacting step (b) is performed at a reaction temperature in the range of about −

60°

C. to about −

30°

C.;

(e) the Lewis acid is moist;

(f) Y is chloro;

(g) R³ is chloro;

(h) R² is hydrogen; and

(i) R¹ is C_1-4aliphatic.

24. The process of claim 23, characterized by at least two of the features (a)-(i).

25. The process of claim 23, characterized by at least three of the features (a)-(i).

26. The process of claim 23, characterized by all nine of the features (a)-(i).

27. The process of claim 21, further comprising:

(c) washing the reaction mixture with an aqueous solution; and

(d) concentrating the washed reaction mixture by removal of solvents to afford a residue comprising the boronic ester compound of formula (I).

28. The process of claim 27, wherein the residue comprises at least about five moles of the boronic ester compound of formula (I).

29. The process of claim 28, wherein the boronic ester compound of formula (I) present in the residue has a diastereomeric ratio of at least about 96:

4 at the carbon atom bearing R¹, R², and R³, relative to a chiral center in the R⁴—

R⁵ chiral moiety.

30. The process of claim 28, wherein the boronic ester compound of formula (I) present in the residue has a diastereomeric ratio of at least about 97:

3 at the carbon atom bearing R¹, R², and R³, relative to a chiral center in the R⁴—

R⁵ chiral moiety.