Synthesis of boronic ester and acid compounds

• US 20050240047A1
• Filed: 03/24/2005
• Published: 10/27/2005
• 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: Lo, Young, Kulkarni, Vithalanand R., Koellner, Christoph, Geiser, Achim, Hett, Robert, Bishop, John E., Pickersgill, I. Fraser, Chiu, Fang-Ting, Gomez, Jean-Marc, Ammoscato, Vince, Munk, Stephen
• Granted Patent: US 7,714,159 B2
• Time in Patent Office: Days
• 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 20% v/v of the reaction mixture.

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

6. 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.

7. The process of claim 6, 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.

8. The process of claim 7, wherein the ether solvent that has low miscibility with water constitutes at least about 70% v/v of the reaction mixture.

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

ate”

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

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

ate”

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

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

ate”

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

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

ate”

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

13. 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.

14. The process of claim 13, wherein the Lewis acid is moist.

15. The process of claim 13, 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).

16. The process of claim 13, 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).

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

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

19. 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).

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

21. The process of claim 1, wherein R⁴ and R⁵, taken together with the intervening oxygen and boron atoms, form an optionally substituted 5-membered ring.

22. The process of claim 21, wherein R⁴ and R⁵ together are a chiral moiety.

23. The process of claim 22, wherein the boron “

ate”

complex of formula (II) is;

24. The process of claim 22, 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.

25. The process of claim 22, 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

26. The process of claim 22, 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.

27. The process of claim 26, characterized by at least two of the features (a)-(h).

28. The process of claim 26, characterized by at least three of the features (a)-(h).

29. The process of claim 26, characterized by all eight of the features (a)-(h).

30. The process of claim 24, 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).

31. The process of claim 26, wherein the residue comprises at least about five moles of the boronic ester compound of formula (I).

32. The process of claim 31, 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.

33. The process of claim 31, 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.

47. The composition of claim 36, wherein all of the boronic ester compound of formula (I) present in the composition is produced in a single batch run of the process according to claim 1.

34. 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):

37. The composition of any one of claims 34-36, wherein the solubility of water in the ether solvent is less than about 2% w/w.

38. The composition of any one of claims 34-36, 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.

39. The composition of any one of claims 34-36, wherein R¹ is C_1-8 aliphatic, C_6-10 aryl, or (C_6-10 aryl)(C_1-6 aliphatic).

40. The composition of any one of claims 34-36, 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

41. The composition of any one of claims 34-36, wherein R⁴ and R⁵, taken together with the intervening oxygen and boron atoms, form an optionally substituted 5-membered ring.

42. The composition of any one of claims 34-36, wherein the compound of formula (I) is

35. 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):

36. 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):

44. The composition of claim 36 comprising at least about 20 moles of the boronic ester compound of formula (I).

45. The composition of claim 36, 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.

46. The composition of claim 36, wherein all of the boronic ester compound of formula (I) present in the composition is produced in a single batch run.

48. The composition of claim 36, wherein at least one of the following features is present:

(a) R³ is chloro;

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

(c) R² is hydrogen; and

(d) R¹ is C_1-4 aliphatic.

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

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

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

52. The process of claim 50 or 51, 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.

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

53. The process of claim 51, wherein the organic solvent in step (a) is selected from the group consisting of acetonitrile, toluene, hexane, heptane, and mixtures thereof.

54. The process of claim 51, wherein the organic solvent in step (a) is an ether solvent that has low miscibility with water.

55. The process of claim 54, wherein the solutions in steps (a) and (c) each comprise the same ether solvent.

56. The process of claim 55, 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).

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

58. The process of claim 57, wherein the reaction mixture in step (c) comprises an organic solvent in which the byproduct M¹-R³ has low solubility.

59. The process of claim 58, wherein M¹ is Li and R³ is Cl.

60. The process of claim 59, 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.

61. The process of claim 57, wherein the reaction in step (c) is conducted at a reaction temperature in the range of about −

100°

C. to about 50°

C.

62. The process of claim 61, wherein the reaction temperature is in the range of about −

50°

C. to about 25°

C.

63. The process of claim 61, wherein the reaction temperature is in the range of about −

30°

C. to about 0°

C.

64. The process of claim 57, 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.

65. The process of claim 64, wherein the acid is trifluoroacetic acid.

66. The process of claim 57, wherein step (c) further comprises filtering the reaction mixture to provide a filtrate comprising the compound of formula (VIII).

67. The process of claim 66, 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.

68. The process of claim 66, wherein the filtrate is used directly in step (d).

69. The process of claim 57, further comprising the step:

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

wherein;

P¹ is an amino group blocking moiety;

R⁷ is selected from the group consisting of hydrogen, C_1-10aliphatic, optionally substituted C_6-10aryl, or C_1-6aliphatic-R⁸; and

R⁸ is selected from the group consisting of alkoxy, alkylthio, optionally substituted aryl, heteroaryl, and heterocyclyl groups, and optionally protected amino, hydroxy, and guanidino groups; and

X is OH or a leaving group;

to form a compound of formula (X);

wherein each of P¹, R¹, R⁴, R⁵, and R⁷ is as defined above.

70. The process of claim 69, wherein P¹ is a cleavable protecting group.

71. The process of claim 70, further comprising the steps:

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

or an acid addition salt thereof, wherein each of R¹, R⁴, R⁵, and R⁷ is as defined above;

(g) coupling the compound of formula (XI) with a reagent of formula P²—

X, wherein P² is an amino group blocking moiety and X is a leaving group, to form a compound of formula (XII);

 

wherein each of P², R¹, R⁴, R⁵, and R⁷ are as defined above; and

(h) deprotecting the boronic acid moiety to form a compound of formula (XIII);

or a boronic acid anhydride thereof, wherein each of P¹, R¹, and R⁷ are as defined above.

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

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

74. The process of claim 73, characterized by at least one of the following features (1)-(5):

(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 (XIX) 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 protecting group removing step (f) comprises the steps;

(i) treating the compound of formula (XX) with HCl in ethyl acetate;

(ii) adding heptane to the reaction mixture; and

(iii) isolating by crystallization the compound of formula (XXI) as its HCl addition salt;

(4) the coupling step (g) comprises the steps;

(i) coupling the compound of formula (XXI) with 2-pyrazine-carboxylic acid in the presence of 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; and

(5) the boronic acid deprotecting step (h) 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.

75. The process of claim 74, characterized by all five features (1)-(5).

76. The process of claim 74, wherein step (h)(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.

77. The process of claim 76, wherein in step (h)(iii)(3), the aqueous layer is washed with dichloromethane.

78. The process of claim 76, wherein in step (h)(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.

79. The process of claim 78, wherein addition of hexane or heptane results in crystallization of a cyclic trimeric boronic acid anhydride of formula (XXIV):

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

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

81. The process of claim 80, 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.

82. The process of claim 81, 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.

83. The process of claim 82, wherein addition of hexane or heptane results in crystallization of a cyclic trimeric boronic acid anhydride of formula (XXIV):

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

85. The process of claim 84, 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.

86. The process of claim 85, 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.

87. The process of claim 86, wherein in step (f′

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

88. The process of claim 86, 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.

89. The process of claim 88, wherein addition of hexane or heptane results in crystallization of a cyclic trimeric boronic acid anhydride of formula (XXIV):

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