Synthesis of triethylenetetramines

• US 7,582,796 B2
• Filed: 07/19/2005
• Issued: 09/01/2009
• Est. Priority Date: 07/19/2004
• Status: Active Grant

• Current Assignee: Philera New Zealand Limited
• Original Assignee: Protemix Corporation Limited
• Inventors: Soi, Antonio, Schmidt, Gunther, Vaulont, Irene, Jonas, Marco
• Primary Examiner(s): Davis; Brian J
• Application Number:
  US11/184,761
• Publication Number:
  US 20060041170A1
• Time in Patent Office: 1,505 Days
• Field of Search: None
• US Class Current: 564/487
• 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, 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-pheny-1-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 benzylidene-(2-{3-[2-(benzylidene-amino)-ethyl]-2-phenyl-imidazolidin-1-yl}-ethyl)-amine is prepared by reacting triethylenetetramine with benzaldehyde.

7. The process of claim 6, further comprising purifying said benzylidene-(2-{3-[2-(benzylidene-amino)-ethyl]-2-phenyl-imidazolidin-1-yl}-ethyl)-amine.

8. 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.

9. 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.

10. The process of claims 2, 3, 5, or 9, wherein the reduction is conducted by reaction with LiAlH₃OMe.

11. 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.

12. The process of claim 11, comprising purifying said (3-cyanomethyl-2-phenyl-imidazolidin-1-yl)-acetonitrile.

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) 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.

14. 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.

15. The process of claim 14, wherein said acid is succinic acid, and wherein said hydrolysis produces triethylenetetramine disuccinate.

16. The process of claim 14, wherein said acid is hydrochloric acid, and wherein said hydrolysis produces triethylenetetramine tetrahydrochloride.

17. 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) and formula (III):

18. The process of claim 17, wherein said compound of formula (I) is prepared by reducing a compound of formula (IV)

19. The process of claim 17, 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)

20. The process of claim 17, 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)

21. The process of claim 17, wherein said compound of formula (III) is prepared by reacting triethylenetetramine or a salt thereof with an imidazolidine-forming amine protecting group reagent.

22. The process of claim 17, wherein said compound of formula (III) is prepared by reacting a compound of formula (I) with an imidazolidine-forming amine protecting group reagent.

23. The process of claim 17, wherein said compound of formula (III) is prepared by

(a) reducing a compound of formula (IV)

24. The process of claim 17, 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)

25. The process of claim 17, 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. 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)

26. The process of claim 17, 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.