Synthesis of triethylenetetramines

• US 20060041170A1
• Filed: 07/19/2005
• Published: 02/23/2006
• Est. Priority Date: 07/19/2004
• Status: Active Grant

• Current Assignee: Philera New Zealand Limited
• Original Assignee: Protemix Corporation Limited
• Inventors: Schmidt, Gunther, Vaulont, Irene, Jonas, Marco, Soi, Antonio
• Granted Patent: US 7,582,796 B2
• Time in Patent Office: Days
• US Class Current: 564/463
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 39/04 Chelating agents
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07C 209/48 by reduction of nitriles
• CPC Class Codes: C07C 209/62 by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds C07C209/24 takes precedence
• CPC Class Codes: C07C 209/76 by nitration
• CPC Class Codes: C07C 211/10 Diaminoethanes
• CPC Class Codes: C07C 211/13 Amines containing three or more amino groups bound to the carbon skeleton
• CPC Class Codes: C07C 211/14 Amines containing amino groups bound to at least two aminoalkyl groups, e.g. diethylenetriamines
• CPC Class Codes: C07C 255/30 containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same unsaturated acyclic carbon skeleton
• CPC Class Codes: C07C 55/10 Succinic acid
• CPC Class Codes: C07C 57/145 Maleic acid
• CPC Class Codes: C07C 57/15 Fumaric acid
• CPC Class Codes: C07D 233/02 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 233/26 Radicals substituted by carbon atoms having three bonds to hetero atoms

Abstract

Methods and intermediates for synthesizing triethylenetetramine and salts thereof, as well as novel triethylenetetramine salts and their crystal structure, and triethylenetetramine salts of high purity.

Claims

1. A process for preparing triethylenetetramines or triethylenetetramine salts, comprising hydrolyzing in the presence of an acid a compound selected from the group consisting of 2-[3-(2-amino-ethyl)-2-phenyl-imidazolidin-1-yl]-ethylamine, (2-amino-ethyl)-{2-[(2-amino-ethyl)-tert-butoxycarbonyl-amino]-ethyl}-carbamic acid tert-butyl ester, and benzylidene-(2-{3-[2-(benzylidene-amino)-ethyl]-2-phenyl-imidazolidin-1-yl}-ethyl)-amine.

2. The process of claim 1, wherein said 2-[3-(2-amino-ethyl)-2-phenyl-imidazolidin-1-yl]-ethylamine is prepared by reducing (3-cyanomethyl-2-phenyl-imidazolidin-1-yl)-acetonitrile.

3. The process of claim 1, wherein said 2-[3-(2-amino-ethyl)-2-phenyl-imidazolidin-1-yl]-ethylamine is prepared by

(a) reacting [2-(cyanomethyl-amino)-ethylamino]-acetonitrile with benzaldehyde to prepare (3-cyanomethyl-2-phenyl-imidazolidin-1-yl)-acetonitrile;

and

(b) reducing said (3-cyanomethyl-2-phenyl-imidazolidin-1-yl)-acetonitrile.

4. The process of claim 3, comprising purifying said (3-cyanomethyl-2-phenyl-imidazolidin-1-yl)-acetonitrile.

5. The process of claim 1, wherein said 2-[3-(2-amino-ethyl)-2-phenyl-imidazolidin-1-yl]-ethylamine is prepared by

(a) alkylating ethylenediamine by reacting ethylenediamine with i. formaldehyde, a cyanide salt, and an acid;

or

ii. a haloacetonitrile and a base;

to prepare [2-(cyanomethyl-amino)-ethylamino]-acetonitrile;

(b) reacting [2-(cyanomethyl-amino)-ethylamino]-acetonitrile with benzaldehyde to prepare (3-cyanomethyl-2-phenyl-imidazolidin-1-yl)-acetonitrile; and

(c) reducing said (3-cyanomethyl-2-phenyl-imidazolidin-1-yl)-acetonitrile.

6. The process of claim 1, wherein said (2-amino-ethyl)-{2-[(2-amino-ethyl)-tert-butoxycarbonyl-amino]-ethyl}-carbamic acid tert-butyl ester is prepared by reducing [2-(tert-butoxycarbonyl-cyanomethyl-amino)-ethyl]-cyanomethyl-carbamic acid tert-butyl ester.

7. The process of claim 1, wherein said (2-amino-ethyl)-{2-[(2-amino-ethyl)-tert-butoxycarbonyl-amino]-ethyl}-carbamic acid tert-butyl ester is prepared by

(a) reacting [2-(cyanomethyl-amino)-ethylamino]-acetonitrile with Boc₂O to prepare [2-(tert-butoxycarbonyl-cyanomethyl-amino)-ethyl]-cyanomethyl-carbamic acid tert-butyl ester;

and

(b) reducing said [2-(tert-butoxycarbonyl-cyanomethyl-amino)-ethyl]-cyanomethyl-carbamic acid tert-butyl ester.

8. The process of claim 7, comprising purifying said [2-(tert-butoxycarbonyl-cyanomethyl-amino)-ethyl]-cyanomethyl-carbamic acid tert-butyl ester.

9. The process of claim 1, wherein said (2-amino-ethyl)-{2-[(2-amino-ethyl)-tert-butoxycarbonyl-amino]-ethyl}-carbamic acid tert-butyl ester is prepared by

(a) alkylating ethylenediamine by reacting ethylenediamine with

i. formaldehyde, a cyanide salt, and an acid;

or

ii. a haloacetonitrile and a base;

to prepare [2-(cyanomethyl-amino)-ethylamino]-acetonitrile;

(b) reacting said [2-(cyanomethyl-amino)-ethylamino]-acetonitrile with Boc₂O to prepare [2-(tert-butoxycarbonyl-cyanomethyl-amino)-ethyl]-cyanomethyl-carbamic acid tert-butyl ester; and

(c) reducing said [2-(tert-butoxycarbonyl-cyanomethyl-amino)-ethyl]-cyanomethyl-carbamic acid tert-butyl ester.

10. The process of claim 1, wherein said benzylidene-(2-{3-[2-(benzylidene-amino)-ethyl]-2-phenyl-imidazolidin-1-yl}-ethyl)-amine is prepared by reacting triethylenetetramine with benzaldehyde.

11. The process of claim 10, further comprising purifying said benzylidene-(2-{3-[2-(benzylidene-amino)-ethyl]-2-phenyl-imidazolidin-1-yl}-ethyl)-amine.

12. The process of claim 1, wherein said benzylidene-(2-{3-[2-(benzylidene-amino)-ethyl]-2-phenyl-imidazolidin-1-yl}-ethyl)-amine is prepared by reacting 2-[3-(2-amino-ethyl)-2-phenyl-imidazolidin-1-yl]-ethylamine with benzaldehyde.

13. The process of claim 1, wherein said benzylidene-(2-{3-[2-(benzylidene-amino)-ethyl]-2-phenyl-imidazolidin-1-yl}-ethyl)-amine is prepared by

(a) reducing (3-cyanomethyl-2-phenyl-imidazolidin-1-yl)-acetonitrile to form 2-[3-(2-amino-ethyl)-2-phenyl-imidazolidin-1-yl]-ethylamine;

and

(b) reacting said 2-[3-(2-amino-ethyl)-2-phenyl-imidazolidin-1-yl]-ethylamine with benzaldehyde.

14. The process of claims 2, 3, 5, 6, 7 or 13, wherein the reduction is conducted by reaction with LiAlH₃OMe.

15. The process of claim 1, wherein said benzylidene-(2-{3-[2-(benzylidene-amino)-ethyl]-2-phenyl-imidazolidin-1-yl}-ethyl)-amine is prepared by

(a) reacting [2-(cyanomethyl-amino)-ethylamino]-acetonitrile with benzaldehyde to produce (3-cyanomethyl-2-phenyl-imidazolidin-1-yl)-acetonitrile;

(b) reducing said (3-cyanomethyl-2-phenyl-imidazolidin-1-yl)-acetonitrile to form 2-[3-(2-amino-ethyl)-2-phenyl-imidazolidin-1-yl]-ethylamine; and

(c) reacting said 2-[3-(2-amino-ethyl)-2-phenyl-imidazolidin-1-yl]-ethylamine with benzaldehyde.

16. The process of claim 15, comprising purifying said (3-cyanomethyl-2-phenyl-imidazolidin-1-yl)-acetonitrile.

17. The process of claim 1, wherein said benzylidene-(2-{3-[2-(benzylidene-amino)-ethyl]-2-phenyl-imidazolidin-1-yl}-ethyl)-amine is prepared by

(a) alkylating ethylenediamine by reacting ethylenediamine with

i. formaldehyde, a cyanide salt, and an acid;

or

ii. a haloacetonitrile and a base;

to prepare [2-(cyanomethyl-amino)-ethylamino]-acetonitrile;

(b) reacting said [2-(cyanomethyl-amino)-ethylamino]-acetonitrile with benzaldehyde to prepare (3-cyanomethyl-2-phenyl-imidazolidin-1-yl)-acetonitrile;

(c) reducing said (3-cyanomethyl-2-phenyl-imidazolidin-1-yl)-acetonitrile to form 2-[3-(2-amino-ethyl)-2-phenyl-imidazolidin-1-yl]-ethylamine; and

(d) reacting said 2-[3-(2-amino-ethyl)-2-phenyl-imidazolidin-1-yl]-ethylamine with benzaldehyde.

18. The process of claim 1, wherein said acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propanoic acid, hydroxyacetic acid, pyruvic acid, oxalic acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-sulfonic acid, cyclamic acid, tartaric acid, succinic acid, malic acid, lactic acid, citric acid, maleic acid, salicyclic acid, p-aminosalicyclic acid, pamoic acid, and fumaric acid.

19. The process of claim 18, wherein said acid is succinic acid, and wherein said hydrolysis produces triethylenetetramine disuccinate.

20. The process of claim 18, wherein said acid is hydrochloric acid, and wherein said hydrolysis produces triethylenetetramine tetrahydrochloride.

54. A pharmaceutical composition comprising substantially pure triethylenetetramine disuccinate made in accordance with the process as defined in any one of claims 1 to 20 or 22 to 34.

21. A process for preparing triethylenetetramine dihydrochloride, comprising:

(a) reacting triethylenetetramine tetrahydrochloride with a base in a solvent to produce triethylenetetramine and hydrochloride salt;

(b) removing said hydrochloride salt from solution;

(c) reacting said triethylenetetramine with about 2 equivalents of concentrated hydrochloric acid to form triethylenetetramine dihydrochloride; and

(d) adding an alcohol to the solution and precipitating said triethylenetetramine dihydrochloride.

22. A process for preparing triethylenetetramine or a salt thereof, comprising hydrolyzing in the presence of an acid a compound selected from the group consisting of compounds of formula (I), formula (II), and formula (III)

23. The process of claim 22, wherein said compound of formula (I) is prepared by reducing a compound of formula (IV)

24. The process of claim 22, wherein said compound of formula (I) is prepared by

(a) reacting [2-(cyanomethyl-amino)-ethylamino]-acetonitrile with an imidazolidine-forming amine protecting group reagent to prepare a compound of formula (IV);

and

(b) reducing said compound of formula (IV).

25. The process of claim 22, wherein said compound of formula (I) is prepared by:

(a) alkylating ethylenediamine by reacting ethylenediamine with

i. formaldehyde, a cyanide salt, and an acid;

or

ii. a haloacetonitrile and a base;

to prepare [2-(cyanomethyl-amino)-ethylamino]-acetonitrile;

(b) reacting said [2-(cyanomethyl-amino)-ethylamino]-acetonitrile with an imidazolidine-forming amine protecting group reagent to prepare a compound of formula (IV); and

(c) reducing said compound of formula (IV).

26. The process of claim 22, wherein said compound of formula (II) is prepared by reduction of a compound of formula (VI)

27. The process of claim 22, wherein said compound of formula (II) is prepared by

(a) reacting [2-(cyanomethyl-amino)-ethylamino]-acetonitrile with an amine protecting group reagent to prepare a compound of formula (VI);

and

(b) reducing said compound of formula (VI).

28. The process of claim 22, wherein said compound of formula (II) is prepared by

(a) alkylating ethylenediamine by reacting ethylenediamine with

i. formaldehyde, a cyanide salt, and an acid;

or

ii. a haloacetonitrile and a base

to prepare [2-(cyanomethyl-amino)-ethylamino]-acetonitrile;

(b) reacting said [2-(cyanomethyl-amino)-ethylamino]-acetonitrile with an amine protecting group reagent to prepare a compound of formula (VI); and

(c) reducing said compound of formula (VI).

29. The process of claim 22, wherein said compound of formula (III) is prepared by reacting triethylenetetramine or a salt thereof with an imidazolidine-forming amine protecting group reagent.

30. The process of claim 22, wherein said compound of formula (III) is prepared by reacting a compound of formula (I) with an imidazolidine-forming amine protecting group reagent.

31. The process of claim 22, wherein said compound of formula (III) is prepared by

(a) reducing a compound of formula (IV) to form a compound of formula (I);

and

(b) reacting said compound of formula (I) with an imidazolidine-forming amine protecting group reagent.

32. The process of claim 22, wherein said compound of formula (III) is prepared by

(a) reacting [2-(cyanomethyl-amino)-ethylamino]-acetonitrile with an imidazolidine-forming amine protecting group to form a compound of formula (IV);

(b) reducing said compound of formula (IV) to form a compound of formula (I); and

(c) reacting said compound of formula (I) with an imidazolidine-forming amine protecting group reagent.

33. The process of claim 22, wherein said compound of formula (III) is prepared by

(a) alkylating ethylenediamine by reacting ethylenediamine with

i. formaldehyde, a cyanide salt, and an acid;

or

ii. a haloacetonitrile and a base

to prepare [2-(cyanomethyl-amino)-ethylamino]-acetonitrile;

(b) reacting said [2-(cyanomethyl-amino)-ethylamino]-acetonitrile with an imidazolidine-forming amine protecting group to form a compound of formula (IV);

(c) reducing said compound of formula (IV) to form a compound of formula (I); and

(d) reacting said compound of formula (I) with an imidazolidine-forming amine protecting group reagent.

34. The process of claim 22, wherein said acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propanoic acid, hydroxyacetic acid, pyruvic acid, oxalic acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-sulfonic acid, cyclamic acid, tartaric acid, succinic acid, malic acid, lactic acid, citric acid, maleic acid, salicyclic acid, p-aminosalicyclic acid, pamoic acid, and fumaric acid.

35. 2-[3-(2-amino-ethyl)-2-phenyl-imidazolidin-1-yl]-ethylamine.

36. The use of 2-[3-(2-amino-ethyl)-2-phenyl-imidazolidin-1-yl]-ethylamine as an intermediate in the synthesis of triethylenetetramine and salts thereof.

37. (3-cyanomethyl-2-phenyl-imidazolidin-1-yl)-acetonitrile.

38. The use of (3-cyanomethyl-2-phenyl-imidazolidin-1-yl)-acetonitrile as an intermediate in the synthesis of triethylenetetramine and salts thereof.

39. 2-(3-cyanomethyl-2-phenyl-imidazolidin-1-yl)-acetamide.

40. The use of 2-(3-cyanomethyl-2-phenyl-imidazolidin-1-yl)-acetamide as an intermediate in the synthesis of triethylenetetramine and salts thereof.

41. 2-(3-carbamoylmethyl-2-phenyl-imidazolidin-1-yl)-acetamide.

42. The use of 2-(3-carbamoylmethyl-2-phenyl-imidazolidin-1-yl)-acetamide as an intermediate in synthesis of triethylenetetramine and salts thereof.

43. Benzylidene-(2-{3-[2-(benzylidene-amino)-ethyl]-2-phenyl-imidazolidin-1-yl}-ethyl)-amine.

44. The use of benzylidene-(2-{3-[2-(benzylidene-amino)-ethyl]-2-phenyl-imidazolidin-1-yl}-ethyl)-amine as an intermediate in the synthesis of triethylenetetramine and salts thereof.

45. A polymorph of triethylenetetramine disuccinate, wherein said polymorph has a DSC extrapolated onset/peak melting temperature of from between about 170°

C. to about 190°

C.

46. A polymorph of claim 45 wherein said DSC extrapolated onset/peak melting temperature is 180.05/179.91°

C.

47. The polymorph of claim 45, wherein said polymorph has infrared peaks at wavenumbers at 3148, 1645, 1549, 1529, 1370, 1271, 1172, 1152, and 1033.

49. A polymorph of claim 47 wherein said DSC extrapolated onset/peak melting temperature is 121.96/122.78°

C.

48. A Form I polymorph of triethylenetetramine dihydrochloride, wherein said Form I polymorph is characterized by a DSC extrapolated onset/peak melting temperature of between about 111°

C. to 132°

C.

50. The Form I polymorph of claim 48, wherein said Form I polymorph is characterized by infrared peaks at wavenumbers 1043, 1116, 1300, 1328, 1557, 2833, 2895, 2902, and 3216.

52. A polymorph of claim 50 wherein said DSC extrapolated onset/peak melting temperature is 116.16/116.76°

C.

51. A Form II polymorph of triethylenetetramine dihydrochloride, wherein said Form II polymorph is characterized by a DSC extrapolated onset/peak melting temperature of from between about 106°

C. to about 126°

C.

53. The Form II polymorph of claim 51, wherein said Form II polymorph is characterized by infrared peaks at wave numbers 1039, 1116, 1352, 1519, 2954, 2986, 3276, and 3298.

55. A pharmaceutical composition comprising substantially pure triethylenetetramine disuccinate.

56. A pharmaceutical composition comprising substantially pure triethylenetetramine disuccinate and a pharmaceutically acceptable excipient.

57. Reduction of a nitrile by reacting a nitrile with LiAlH₃OMe

58. A substantially pure triethylenetetramine disuccinate.

59. An isolated triethylenetetramine disuccinate salt that has a purity range selected from the group consisting of 50%, 55%, 60% pure, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99% or 100% pure.

60. Substantially pure triethylenetetraminedisuccinate anhydrate.

73. A pharmaceutical composition comprising a compound according to any of claims 60, 61 or 62 and a pharmaceutically acceptable carrier.

61. Substantially pure triethylenetetramine tetramaleate dihydrate.

62. Substantially pure triethylenetetramine tetrafumarate tetrahydrate.

63. A composition comprising a substantially pure triethylenetetramine disuccinate crystal having alternating layers of triethylenetetramine molecules and succinate molecules.

64. A composition of claim 63 wherein the triethylenetetramine disuccinate is triethylenetetramine disuccinate anhydrate.

74. A pharmaceutical composition comprising a triethylenetetramine crystal in substantially the form according to any of claims 63, 65 or 66 and a pharmaceutically acceptable carrier.

65. A composition comprising a substantially pure triethylenetetramine maleate dihydrate crystal having alternating layers of triethylenetetramine molecules and maleate molecules 66. A composition comprising a substantially pure triethylenetetramine fumarate tetrahydrate crystal having alternating layers of triethylenetetramine molecules and fumarate molecules.

67. A crystal of a triethylenetetramine disuccinate having the structure defined by the co-ordinates of Table 3B.

75. A pharmaceutical composition comprising a triethylenetetramine crystal in substantially the form according to any of claims 67-71 or 72 and a pharmaceutically acceptable carrier.

68. A crystal of a triethylenetetramine disuccinate having the structure defined by the co-ordinates of Table 3C.

69. A crystal of a triethylenetetramine maleate dihydrate having the structure defined by the co-ordinates of Table 4B.

70. A crystal of a triethylenetetramine maleate dihydrate having the structure defined by the co-ordinates of Table 4C.

71. A crystal of a triethylenetetramine fumarate tetrahydrate having the structure defined by the co-ordinates of Table 5B.

72. A crystal of a triethylenetetramine fumarate tetrahydrate having the structure defined by the co-ordinates of Table 5C.