Boron-mediated amidation of carboxylic acids

• US 6,384,278 B1
• Filed: 02/05/2001
• Issued: 05/07/2002
• Est. Priority Date: 02/04/2000
• Status: Expired due to Fees

• Current Assignee: Emisphere Technologies, Inc. (Novo Nordisk A/S)
• Original Assignee: Emisphere Technologies, Inc. (Novo Nordisk A/S)
• Inventors: Ye, Feng, Tang, Pingwah
• Primary Examiner(s): Barts, Samuel
• Assistant Examiner(s): Price, Elvis O.
• Application Number:
  US09/778,047
• Time in Patent Office: 456 Days
• Field of Search: 564/138, 564/136, 564/139, 564/133, 564/134, 564/135, 564/141, 564/142, 564/123, 564/199, 564/200
• US Class Current: 564/123
• CPC Class Codes: C07C 231/02 from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
• CPC Class Codes: C07C 233/25 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton

Abstract

The present invention provides an inexpensive one-step method for preparing an aromatic carboxamide, such as a phenyl substituted carboxamide) by reacting an aromatic amine (e.g. a phenylamine) and a carboxylic acid (e.g. an alkanoic acid or ester thereof) in the presence of a boron containing compound (e.g. boronic acid or boric acid) and, optionally, a chelating agent (e.g. a 2-pyridinylamine).

Claims

1. A method for preparing a carboxamide having the formula

wherein

R¹, R², R³, R⁴, and R⁵ are independently hydrogen, —

OH, —

O—

R⁷, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, carboxyl, substituted or unsubstituted alkoxycarbonyl, halogen, nitrile, —

OC(O)CH₃, —

SO₃H, or —

NR¹³R¹⁴;

R⁶ is C₁-C₁₂ alkyl;

R⁶ is optionally substituted with one or more alkenyl, alkoxycarbonyl, carboxyl, —

OH, or halogen;

R⁷ is hydrogen, alkyl, or aryl; and

R¹³ and R¹⁴ are independently hydrogen, C₁-C₄ alkyl, or oxygen,

the method comprising reacting

(a) an aromatic amine having the formula

(b) an acid

in the presence of a boron containing compound to form the carboxamide, wherein the acid has the formula

wherein R¹⁵ is a C₁-C₁₂ alkyl and R¹⁶ is an alkyl.

2. The method of claim 1, wherein R¹⁶ is C₁-C₃ alkyl.

3. The method of claim 1, wherein the boron containing compound has the formula R⁸—

B(OH)₂, wherein R⁸ is —

OH;

aryl;

C₁-C₈ alkyl, optionally substituted with C₁-C₃ alkyl;

or a polymer.

4. The method of claim 3, wherein the boron containing compound is boric acid.

5. The method of claim 1, wherein the molar ratio of aromatic amine to the acid ranges from about 1:

1 to about 1;

1.1.

6. The method of claim 5, wherein the molar ratio of aromatic amine to the acid ranges from about 1:

1 to about 1;

1.03.

7. The method of claim 1, wherein the molar ratio of boron containing compound to aromatic amine ranges from about 1:

100 to about 1;

1.

8. The method of claim 7, wherein the molar ratio of boron containing compound to aromatic amine ranges from about 1:

50 to about 1;

4.

9. The method of claim 1, wherein the reaction mixture comprises from about 0.1 to about 4 moles of aromatic amine, from about 0.1 to about 4 moles of the acid, and from about 0.001 to about 4 moles of boron containing compound per liter of reaction mixture.

10. The method of claim 9, wherein the reaction mixture comprises about 0.5 moles of aromatic amine per liter of reaction mixture.

11. The method of claim 1, wherein the reaction is performed in the presence of a chelating agent.

12. The method of claim 1, wherein the reaction is performed in a solvent.

13. The method of claim 12, wherein the solvent comprises an aromatic solvent, hydrocarbon solvent, or any combination of any of the foregoing.

14. The method of claim 13, wherein the solvent comprises benzene, xylene, mesitylene, toluene, hexane, octane, or any combination of any of the foregoing.

15. The method of claim 14, wherein the solvent comprises toluene.

16. The method of claim 1, further comprising purifying the carboxamide.

17. A method for preparing a carboximide having the formula

wherein

R¹, R², R³, R⁴, and R⁵ are independently hydrogen, —

OH, —

O—

R⁷, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, carboxyl, substituted or unsubstituted alkoxycarbonyl, halogen, nitrile, —

OC(O)CH₃, —

SO₃H, or —

NR¹³R¹⁴;

R⁶ is C₁-C₁₂ alkyl;

R⁶ is optionally substituted with one or more alkenyl, alkoxycarbonyl, carboxyl, —

OH, or halogen;

R⁷ is hydrogen, alkyl, or aryl; and

R¹³ and R¹⁴ are independently hydrogen, C₁-C₄ alkyl, or oxygen,

the method comprising reacting

(a) an aromatic amine having the formula

(b) an acid having the formula R⁶—

COOH

in the presence of a boron containing compound and a 2-pyridinylamine to form the carboxamide.

18. The method of claim 17, wherein the acid has the formula

wherein R¹⁵ is a C₁-C₁₂ alkyl and R¹⁶ is an alkyl.

19. The method of claim 18, wherein R¹⁶ is C₁-C₃ alkyl.

20. The method of claim 17, wherein the boron containing compound has the formula R⁸—

B(OH)₂, wherein R⁸is —

OH;

aryl;

C₁-C₈alkyl, optionally substituted with C₁-C₃ alkyl;

or a polymer.

21. The method of claim 20, wherein the boron containing compound is boric acid.

22. The method of claim 17, wherein the 2-pyridinylamine has the formula

wherein R⁹, R¹⁰, R¹¹, and R¹² are independently hydrogen, substituted or unsubstituted C₁-C₄ alkyl, or substituted or unsubstitued aryl.

23. The method of claim 22, wherein the 2-pyridinylamine is 2-amino-4-picoline, 2-amino-5-picoline, 2-amino-6-picoline, 2-amino-4,6-dimethylpyridine, or any combination of any of the foregoing.

24. The method of claim 23, wherein the 2-pyridinylamine is 2-amino-5-picoline.

25. The method of claim 17, wherein the molar ratio of aromatic amine to the acid ranges from about 1:

1 to about 1;

1.1.

26. The method of claim 25, wherein the molar ratio of aromatic amine to the acid ranges from about 1:

1 to about 1;

1.03.

27. The method of claim 17, wherein the molar ratio of boron containing compound to 2-pyridinylamine ranges from about 10:

1 to about 1;

5.

28. The method of claim 27, wherein the molar ratio of boron containing compound to 2-pyridinylamine is about 1:

1.

29. The method of claim 17, wherein the molar ratio of boron containing compound to aromatic amine ranges from about 1:

100 to about 1;

1.

30. The method of claim 29, wherein the molar ratio of boron containing compound to aromatic amine ranges from about 1:

50 to about 1;

4.

31. The method of claim 17, wherein the reaction mixture comprises from about 0.1 to about 4 moles of aromatic amine, from about 0.1 to about 4 moles of the acid, from about 0.001 to about 4 moles of boron containing compound, and from about 0.001 moles to about 8 moles of 2-pyridinylamine per liter of reaction mixture.

32. The method of claim 31, wherein the reaction mixture comprises about 0.5 moles of aromatic amine per liter of reaction mixture.

33. The method of claim 17, wherein the reaction is performed in a solvent.

34. The method of claim 33, wherein the solvent comprises an aromatic solvent, hydrocarbon solvent, or any combination of any of the foregoing.

35. The method of claim 34, wherein the solvent comprises benzene, xylene, mesitylene, toluene, hexane, octane, or any combination of any of the foregoing.

36. The method of claim 35, wherein the solvent comprises toluene.

37. The method of claim 17, further comprising purifying the carboxamide.

38. A method for preparing a carboxamide having the formula

wherein

R¹, R², R³, R⁴, and R⁵ are independently hydrogen, —

OH, —

O—

R⁷, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, carboxyl, substituted or unsubstituted alkoxycarbonyl, halogen, nitrile, —

OC(O)CH₃, —

SO₃H, or —

NR¹³R¹⁴;

R⁷ is hydrogen, alkyl, or aryl;

R¹³ and R¹⁴ are independently hydrogen, C₁-C₄ alkyl, or oxygen; and

R¹⁵ is C₁-C₁₂ alkyl,

the method comprising;

(i) reacting (a) an aromatic amine having the formula

with (b) an acid having the formula

wherein R¹⁵ is a C₁-C₁₂ alkyl and R¹⁶ is an alkyl, in the presence of a boron containing compound and to form an intermediate having the formula

(ii) hydrolyzing the intermediate to form the carboxamide.

39. The method of claim 38, wherein R¹⁶ is C₁-C₃ alkyl.

40. The method of claim 38, wherein the boron containing compound is boric acid.

41. The method of claim 38, wherein the reaction step is performed in the presence of a chelating agent.

42. The method of claim 41, wherein the chelating agent is a 2-pyridinylamine.

43. The method of claim 42, wherein the chelating agent is a 2-amino-5-picoline.

44. A method for preparing a phenyl substituted carboxamide comprising reacting (a) an aromatic amine and (b) an alkanoic acid or ester thereof in the presence of a boron containing compound, wherein a chelating agent is present during the reaction step.

45. A method for preparing a carboxamide having the formula

wherein

R¹, R², R³, R⁴, and R⁵ are independently hydrogen, —

OH, —

O—

R⁷, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, carboxyl, substituted or unsubstituted alkoxycarbonyl, halogen, nitrile, —

OC(O)CH₃, —

SO₃H, or —

NR¹³R¹⁴;

R⁶ is C₁-C₁₂ alkyl;

R⁶ is optionally substituted with one or more alkenyl, alkoxycarbonyl, carboxyl, —

OH, or halogen;

R⁷ is hydrogen, alkyl, or aryl; and

R¹³ and R¹⁴ are independently hydrogen, C₁-C₄ alkyl, or oxygen,

the method comprising reacting

(a) an aromatic amine having the formula

(b) an acid having the formula R⁶—

COOH

in the presence of a boron containing compound to form the carboxamide, wherein the boron containing compound has the formula R⁸—

B(OH)₂, wherein R⁸ is —

OH;

aryl;

C₁-C₈ alkyl, optionally substituted with C₁-C₃ alkyl;

or a polymer.

46. The method of claim 45, wherein the acid has the formula

wherein R¹⁵ is a C₁-C₁₂ alkyl and R¹⁶ is an alkyl.

47. The method of claim 46, wherein R¹⁶ is C₁-C₃ alkyl.

48. The method of claim 45, wherein the boron containing compound is boric acid.

49. The method of claim 45, wherein the molar ratio of aromatic amine to the acid ranges from about 1:

1 to about 1;

1.1.

50. The method of claim 49, wherein the molar ratio of aromatic amine to the acid ranges from about 1:

1 to about 1;

1.03.

51. The method of claim 45, wherein the molar ratio of boron containing compound to aromatic amine ranges from about 1:

100 to about 1;

1.

52. The method of claim 51, wherein the molar ratio of boron containing compound to aromatic amine ranges from about 1:

50 to about 1;

4.

53. The method of claim 45, wherein the reaction mixture comprises from about 0.1 to about 4 moles of aromatic amine, from about 0.1 to about 4 moles of the acid, and from about 0.001 to about 4 moles of boron containing compound per liter of reaction mixture.

54. The method of claim 53, wherein the reaction mixture comprises about 0.5 moles of aromatic amine per liter of reaction mixture.

55. The method of claim 45, wherein the reaction is performed in the presence of a chelating agent.

56. The method of claim 45, wherein the reaction is performed in a solvent.

57. The method of claim 56, wherein the solvent comprises an aromatic solvent, hydrocarbon solvent, or any combination of any of the foregoing.

58. The method of claim 57, wherein the solvent comprises benzene, xylene, mesitylene, toluene, hexane, octane, or any combination of any of the foregoing.

59. The method of claim 58, wherein the solvent comprises toluene.

60. The method of claim 45, further comprising purifying the carboxamide.