Process For The Preparation Of A Sulfated Derivative Of 3,5-Diiodo-O-[3-Iodophenyl]-L-Tyrosine

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 chlorosulfonic 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.

1 . A process for the preparation of a sulfated form 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) sulfation of a compound of formula I with chlorosulfonic acid (CSA) in the presence of dimethylacetamide (DMAC); and 
 b) salification to give a compound of formula II, in an aqueous solution of an alkaline metal inorganic salt. 
 
       
     
     
         2 . The process according to  claim 1 , wherein said inorganic salt is a sodium salt. 
     
     
         3 . The process according to  claim 1 , wherein the molar ratio between CSA and the compound of formula I is 4 to 10. 
     
     
         4 . The process according to  claim 1 , wherein in step a) the concentration of the compound of formula I in DMAC is 0.060 to 0.090 mol/L of DMAC. 
     
     
         5 . The process according to  claim 1 , wherein the sulfation reaction in step a) is carried out at a temperature below 10° C. 
     
     
         6 . The process according to  claim 5 , wherein the sulfation in step a) is left to occur for at least 2 hours. 
     
     
         7 . The process according to  claim 1 , wherein the salification according to step b) is carried out in an aqueous solution of NaHCO 3 . 
     
     
         8 . The process according to  claim 1 , further comprising a step c) of purification of the compound of formula II by chromatography on a polymeric adsorbent solid phase, elution with a decreasing polarity mixture of water and an organic solvent, wherein said step c) is optionally preceded by a filtration step. 
     
     
         9 . The process according to  claim 8 , wherein said decreasing polarity mixture is a mixture of water and an organic polar solvent. 
     
     
         10 . The process according to  claim 8 , wherein after elution, the solution is concentrated tip to at least 10 g of Formula II compound/kg, and the solution is brought to pH values of 5.5 to 6.5. 
     
     
         11 . The process according to  claim 10 , 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 any 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 derivatives thereof, at least one disintegrant selected from the group consisting of: croscarmellose or derivatives thereof, crospovidone, polymethylacrylates, maltodextrin, sodium glycolate starch, pre-gelatinized starch, sodium alginate, and optionally, a lubricating agent selected from the group consisting of: magnesium stearate, zinc stearate, colloidal hydrated silica and colloidal silicon dioxide, and then formulated in tablets by direct compression of the mixture. 
     
     
         16 . The process according 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. 
     
     
         17 - 27 . (canceled) 
     
     
         28 . The process according to  claim 1 , wherein M is Na. 
     
     
         29 . The process according to  claim 3 , wherein the molar ratio is 7 to 9. 
     
     
         30 . The process according to  claim 5 , wherein the sulfation reaction in step a) is carried out at a temperature comprised from −10° C. to 8° C. 
     
     
         31 . The process according to  claim 9 , wherein in said mixture of water and an organic polar solvent the ratio of water to polar solvent is 1.0:0 to 0.7:0.3. 
     
     
         32 . The process according to  claim 16 , wherein the iodinating agent is a mixture comprising I 2 /NaI.