Process for the preparation of thyroid hormones and salts thereof

• US 8,759,572 B2
• Filed: 12/17/2010
• Issued: 06/24/2014
• Est. Priority Date: 12/18/2009
• Status: Active Grant

• Current Assignee: Bracco Imaging S.p.A. (Bracco SPA)
• Original Assignee: Bracco Imaging S.p.A. (Bracco SPA)
• Inventors: Viscardi, Carlo Felice, Cappelletti, Enrico, Galimberti, Laura, Sini, Loredana, Gazzetto, Sonia
• Primary Examiner(s): Zucker, Paul A
• Application Number:
  US13/515,712
• Publication Number:
  US 20120296113A1
• Time in Patent Office: 1,285 Days
• US Class Current: 562/447
• CPC Class Codes: C07C 227/16 by reactions not involving the amino or carboxyl groups
• CPC Class Codes: C07C 229/36 with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton

Abstract

The present invention generally refers to a process for the preparation of L-thyroxine derivatives. More in particular, the present invention relates to a iodination reaction of an aromatic derivative with an appropriate iodinating agent, so to afford the related iodinated compound as disodium salt, which may represent a useful intermediate for the synthesis of the L-thyroxine mono-sodium salt, and the free form thereof.

Claims

1. A process for the preparation of a thyroid hormone derivative of formula II:

2. The process according to claim 1, wherein the aliphatic amine is a linear mono C₁-C₄ amine.

3. The process of claim 2, wherein said aliphatic amine is ethylamine.

4. The process according to claim 1, wherein the molar ratio between NaI and I₂ in the iodinating agent is from 1 to 4.

5. The process according to claim 4, wherein the molar ratio between NaI and I₂ in the iodinating agent is from 2 to 3.

6. The process according to any one of claim 1 or 4, wherein the iodinating agent is added to a solution comprising compound I and the aliphatic amine, at a temperature not higher than 25°

C.

7. The process according to claim 1, wherein the iodinating agent is prepared in distilled water.

8. The process according to any one of claim 1 or 4, further comprising re-suspending the compound of formula II in an alkaline aqueous solution, adding an organic or inorganic acid to the aqueous solution, to a pH of 9-11 and isolating the mono-sodium derivative of formula III:

9. The process according to claim 8, wherein the acid is acetic acid.

10. The process according to claim 8, wherein the acid is added to the aqueous solution of II, heated to a temperature of 70°

C. to 95°

C., and cooling the resulting solution to a temperature of 10°

C. to 15°

C.

11. The process according to claim 10, wherein the acid is added to the aqueous solution of II at a temperature of 82°

C. to 85°

C.

12. The process according to claim 8, wherein the water content of the aqueous solution of II is from 11 w/w to 25 w/w.

13. The process according to claim 12, wherein the water content of the aqueous solution of II is from 11 w/w to 15 w/w.

14. The process according to claim 10, wherein the acid is added to the aqueous solution of II at a temperature of 75°

C. to 88°

C., and said solution has a content of water from 11 to 15 w/w.

15. The process according to claim 14, wherein said acid is acetic acid.

16. The process according to claim 15, wherein said temperature is 82°

C. to 85°

C.