Synthesis of triethylenetetramines

• US 8,394,992 B2
• Filed: 10/07/2011
• Issued: 03/12/2013
• Est. Priority Date: 07/19/2004
• Status: Expired due to Fees

• Current Assignee: Philera New Zealand Limited
• Original Assignee: Philera New Zealand Limited
• Inventors: Jonas, Marco, Vaulont, Irene, Soi, Antonio, Schmidt, Gunther
• Primary Examiner(s): Davis, Brian J
• Application Number:
  US13/269,399
• Publication Number:
  US 20120029203A1
• Time in Patent Office: 522 Days
• Field of Search: None
• US Class Current: 564/512
• 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 triethylenetetramine dihydrochloride, comprising:

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

(b) removing said chloride 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.

2. The process of claim 1, wherein the base is sodium methoxide or sodium ethoxide.

3. The process of claim 1, wherein the solvent is ethanol or methanol.

4. The process of claim 1, wherein the removal in step (b) of the chloride salt is by precipitation.

5. The process of claim 4, wherein the precipitate is removed by filtration.

6. The process of claim 4, wherein the precipitate is washed with a solvent.

7. The process of claim 6, wherein the solvent is tert-butylmethylether.

8. The process of claim 1, wherein the acid has been pre-dissolved in a solvent prior to its addition to the free triethylenetetramine.

9. The process of claim 1, wherein the alcohol is ethanol, methanol, or isopropanol.

10. The process of claim 1, wherein about 4 equivalents of sodium methoxide are mixed with about 1 equivalent of triethylenetetramine tetrahydrochloride.

11. The process of claim 10, wherein the triethylenetetramine tetrahydrochloride is in a mixture of methanol and ethanol.

12. The process of claim 1, wherein the triethylenetetramine dihydrochloride product precipitates in yield greater than about 86%.

13. The process of claim 1, wherein purity of the triethylenetetramine dihydrochloride product is about 100%, as determined using the methods set forth in USP27-NF22 (page 1890) for analysis of trientine.

14. The process of claim 13, wherein the triethylenetetramine dihydrochloride product has less than about 10 ppm heavy metals as determined by USP <

231>

II.

15. The process of claim 1, wherein precipitating said triethylenetetramine dihydrochloride in step (d) comprises adding seed crystals of triethylenetetramine dihydrochloride.

16. The process of claim 1, wherein said triethylenetetramine dihydrochloride is crystalline.

17. The process of claim 16, wherein said crystalline triethylenetetramine dihydrochloride is a thermodynamic polymorph.