Process for the preparation of a sulfated derivative of 3,5-diiodo-O-[3-iodophenyl]-L-tyrosine

Patent metadata

Field	Value
Publication number	US-9890116-B2
Application number	US-201214110237-A
Country	US
Kind code	B2
Filing date	Apr 5, 2012
Priority date	Nov 13, 2002
Publication date	Feb 13, 2018
Grant date	Feb 13, 2018

Abstract

The present invention relates to a process for the preparation of the mono sodium salt of the derivative 3,5-diiodo-O-[3-iodo-4-(sulphooxy)phenyl]-L-tyrosine (T3S) by starting from the corresponding phenolic compound, in the presence of chloro-sulfonic acid and dimethylacetamide as a solvent. The so obtained T3S compound may conveniently be isolated in a pure form as a solid in good yields. The present invention further relates to the process for T3S preparation, wherein the starting reagent is T2 and further comprising the formulation of such compound in tablets. Furthermore, the invention discloses non-radioactive immunoassays based on T3S derivatives.

First claim

The invention claimed is:

1. A process for the preparation of a sulfated from of a thyroid hormone having formula II (T 3 S) according to the following reaction:

wherein:
M is an alkaline metal;
comprising the steps of:
a) saltation of a compound of formula I with chlorosulfonic acid (CSA) in the presence of dimethylacetamide (DMAC), wherein the molar ratio of CSA to the compound of formula I is from 4 to 10, and wherein more than 90% of the compound of formula I is converted to the sulfated derivative;
b) salification of the sulfated derivative to give a compound of formula II, in an aqueous solution of an alkaline metal inorganic salt; and
c) purification of die formula II compound by chromatography on macroreticular aromatic polymeric matrix and elution with a decreasing polarity solution.

2. The process according to claim 1 , wherein said inorganic salt is a sodium salt.

3. The process according to claim 1 , wherein in step a) the concentration of the compound of formula I in DMAC is from 0.060 to 0.090 mol/L of DMC.

4. The process according to claim 1 , wherein the sulfation reaction in step a) is carried out at a temperature below 10° C.

5. The process according to claim 4 , wherein the solfation in step a) is left to occur for at least 2 hours.

6. The process according to claim 4 , wherein the sulfation reaction step a) is carried out at a temperature from −10° C. to 8° C.

7. The process according to claim 1 , wherein the salification according to step b) is carried out in an aqueous solution of N a HCO 3 .

8. The process according to claim 1 , wherein step c) is preceded by a filtration step.

9. The process according to claim 1 , wherein said decreasing polarity solution has a ratio of water to polar solvent from 1.0:0 to 0.7:0.3.

10. The process according to any one of claims 8 - 9 , wherein after elution, the solution is concentrated to at least 10 g of Formula II compound/kg, and the solution is brought to pH values from 5.5 to 6.5.

11. The process according to claim 1 , wherein the compound of formula II is obtained as a solid after treatment with an organic polar solvent.

12. The process according to claim 11 , wherein said polar organic solvent is selected from the group consisting of: acetone, ethanol, isopropanol and acetonitrile.

13. The process according to claim 11 , wherein the compound of formula II in the solid form is further micronized.

14. The process according to an one of claims 11 - 13 , which comprises further admixing the solid and/or micronized form of the compound of formula II, optionally in combination with levo-thyroxine (T4), with at least one diluent selected from the group consisting of: cellulose or a derivative thereof, kaolin, starch and inorganic alkaline salts selected from: calcium and magnesium carbonate.

15. The process according to claim 14 , wherein the mixture of the compound of formula II and the diluent which is microcrystalline cellulose, is further admixed with
at least one glidant agent selected from the group consisting of: glycerol dibehenate, tribasic calcium phosphate, talc, starch and starch derivatives, and
at least one disintegerant selected from the group consisting of: croscatmellose or derivatives thereof, crospovidone, polymethylacrylates, maltodextrin, sodium glycolate starch, pre-gelatinized starch, and sodium alginate, and then formulated in tablets by direct compression of the mixture.

16. The process according to clam 15 , wherein said mixture is further admixed with at least one lubricating agent selected from the group consisting of: magnesium stearate, zinc stearate, colloidal hydrated silica and collidal silicon dioxide, before being formulated in tablets by direct compression.

17. The process aecording to claim 1 , wherein the reagent of formula I is obtained by iodinating a 3′,5 di-iodothyronine (T2) with an iodinating agent in an aqueous media and in the presence of an aliphatic amine.

18. The process according to claim 17 , wherein the iodinating agent is a mixture comprising I 2 /Nal.

19. The process according claim 1 , wherein M is Na.

20. The process according to claim 1 wherein the molar ratio is from 7 to 9.

Assignees

• Anelli Pier Lucio
• Argese Maria
• Lattuada Luciano
• Gazzetto Sonia
• Galimberti Laura
• Boi Valeria
• Cavalieri Livio
• Vella Fulvia
• Bracco Imaging Spa

Inventors

• Anelli Pier Lucio
• Argese Maria
• Lattuada Luciano
• Gazzetto Sonia
• Galimberti Laura
• Boi Valeria
• Cavalieri Livio
• Vella Fulvia

Classifications

• C07C309/42

  having the sulfo groups bound to carbon atoms of non-condensed six-membered aromatic rings · CPC title

• C07C303/24 Primary

  of esters of sulfuric acids · CPC title

• A61K9/2054

  Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose · CPC title

• C07D495/04

  Ortho-condensed systems · CPC title

• C07C227/16

  by reactions not involving the amino or carboxyl groups · CPC title