Process For The Preparation Of Thyroid Hormones And Salts Thereof

• US 20120296113A1
• Filed: 12/17/2010
• Published: 11/22/2012
• 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, Gazzetto, Sonia, Sini, Loredana
• Granted Patent: US 8,759,572 B2
• Time in Patent Office: Days
• US Class Current: 562/444
• 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,

comprising reacting a compound of formula I:

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 claims 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 preparing a hydroalcoholic alkaline solution of the compound of formula II, having a pH of at least 11, heating to a temperature comprised from 40°

C. to 80°

C., cooling to a temperature comprised from 5°

C. to 20°

C. and isolating the compound II as a pure solid.

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

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

11. The process according to claim 9, wherein the acid is added to the aqueous solution of II, heated to a temperature comprised from 70°

C. to 95°

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

C. to 15°

C.

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

C. to 85°

C.

13. The process according to claim 9, wherein the water content of the aqueous solution of II is comprised from 11 w/w to 25 w/w.

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

15. The process according to claim 11, wherein the acid is added to the aqueous solution of II at a temperature comprised from 75°

C. to 88°

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

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

17. The process according to claim 16, wherein said temperature is comprised from 82°

C. to 85°

C.