Process for the synthesis of the compound 5,7-diiodo-1-oxaspiro[2,5]octa-4,7-dien-6-one

Abstract

A process for the synthesis of the compound 5,7-diiodo-1-oxaspiro[2,5]octa-4,7-dien-6-one. This process for the synthesis of the compound 5,7-diiodo-1-oxaspiro[2,5]octa-4,7-dien-6-one comprises an oxidation reaction of 4-hydroxy-3,5-diiodobenzyl alcohol with a hypochlorite oxidant, in particular selected from sodium, calcium and potassium hypochlorite. This process allows a significant improvement in yield in a simple and inexpensive manner.

Description

[0001] DESCRIPTION Title of the invention: Process for the synthesis of the compound 5,7-diiodo-1-oxaspiro[2,5]octa-4,7-dien-6-one 1. Subject of the invention 5 The invention relates to a new process for the synthesis of compound 1, 5,7-diiodo-1-oxaspiro[2,5]octa-4,7-dien-6-one, CAS-No. 197230-76-5, which is a potential intermediate for the synthesis of Levothyrox, in particular, as described in Tetrahedron Letters, Vol. 38, No. 40, pp. 6965-6968, 1997. 10 1 2. State of the prior art The reaction with the highest yield of compound 1 to date involving the oxidation of 4-Hydroxy-3,5-diiodobenzyl alcohol (compound 2) with sodium bismuthate (conditions shown in Scheme 1) is described in Tetrahedron Letters, Vol.38, No.40, pp.6965-6968, 1997 (page 6966, compound 9). Scheme 1 20 The desired compound 1 is obtained with a yield of 37%. This synthesis route is also described in the patent: Halogenated Phenols for diagnostics, antioxidant protection and drug delivery, WO 2013 / 010102 A2, with a spiroepoxide yield of 42% (Ex.3 pages 98 and 99). 5 The second known synthesis route is described in Organic Letters 2019, 21, 6504−6507, and proceeds in two steps from compound 2: First step: A bis-dichloroacetate derivative is first formed with a yield of 97%, see Scheme 2. 10 Scheme 2 Second step: the intermediate diester is then oxidized with hydrogen peroxide and potassium hydroxide in acetonitrile, and the desired spiroepoxide 1 is obtained in a yield of only 20% (see Scheme 3, compound 2m on page 6505 of the same article). Scheme 3 This method makes it possible to obtain the desired compound 1, but the yield is not satisfactory, and even lower than with sodium bismuthate in direct oxidation. Furthermore, it involves toxic solvents (classified as CMR) such as pyridine and dichloromethane. 5 It is interesting to note that the non-iodinated analogue (compound 2a in this publication) is obtained by this method with a significantly higher yield of 66%, indicating that di-iodinated derivatives are more difficult to synthesize with satisfactory yields. 3. Aims of the invention 10 The invention aims to solve the technical problem of obtaining a direct or one-step synthesis of the compound 5,7-diiodo-1-oxaspiro[2,5]octa-4,7-dien-6-one, with an excellent yield, and using one or more non-toxic reagents and a reaction medium. The invention aims to solve this technical problem with a short reaction time, of the order of a few minutes.The invention also aims to solve this technical problem by starting from an available, inexpensive substance. The invention also aims to solve these problems according to a simple, safe, reliable, reproducible and usable solution on an industrial scale in order to avoid any agent likely to cause environmental problems. 4. Summary and detailed description of the process according to the invention: The invention solves these technical problems for the first time from an available starting substance, 4-Hydroxy-3,5-diiodobenzyl alcohol 25, the synthesis of which from 4-hydroxybenzyl alcohol has also been the subject of a patent filed by INNOVERDA published under No. FR 3,113,904B2.Thus, the invention relates to a process for the direct synthesis in a single step of the compound 5,7-diiodo-1-oxaspiro[2,5]octa-4,7-dien-6-one from 4-Hydroxy-3,5-diiodobenzyl alcohol, characterized in that an oxidation reaction of 4-Hydroxy-3,5-diiodobenzyl alcohol is carried out with an oxidant comprising or consisting of a hypochlorite, in particular chosen from sodium, calcium, potassium hypochlorite, or mixtures thereof. According to the invention, according to a particular embodiment, this oxidation reaction is carried out in a two-phase reaction medium comprising a polar organic solvent of ether type and an aqueous solution. According to a particular embodiment, the polar organic solvent of ether type is chosen from methyl tert-butyl ether (MTBE), tert-amyl methyl ether (TAME), diethyl ether, and methyl cyclopentyl ether, or mixtures thereof.According to another particular embodiment, the aqueous solution is chosen from water, in particular demineralized water, or an aqueous buffer, in particular an aqueous buffer whose pH is between 5 and 8, better still between 6 and 7. A suitable aqueous buffer is an acetate buffer. According to yet another particular embodiment, the relative molar ratio between the hypochlorite oxidant and the 4-Hydroxy-3,5-diiodobenzyl alcohol is between 2 and 3, in particular between 2 and 2.5. According to another particular embodiment, the volume ratio of the aqueous solution relative to the total volume of the aqueous solution and the polar organic solvent of ether type is between 2 and 21%, in particular between 5 and 12%, even better about 6%.According to a particular embodiment variant, the temperature of the reaction medium is between approximately 0 and room temperature or below room temperature, in particular between approximately 0 and approximately 21°C. According to yet another particular embodiment, the reaction time is between 1 and 15 minutes, in particular between 4 and 10 minutes. According to yet another particular embodiment, the 4-hydroxy-3,5-diiodobenzyl alcohol is dissolved in the polar organic solvent and the hypochlorite oxidant is dissolved in the aqueous solution. According to yet another particular embodiment, the molar concentration of the hypochlorite oxidant in the aqueous solution is from 0.5M to 1.5M.According to yet another particular embodiment, the aqueous solution 5 is added gradually to the polar organic solution, in particular dropwise, over a period of time of 1 to 15 minutes, in particular 4 to 10 minutes, with stirring, in particular vigorous stirring. By vigorous stirring is meant stirring creating a vortex as is well known to those skilled in the art. This vortex is generally achieved with a rotation speed between 800 - 1200 revolutions per minute. According to yet another particular embodiment of the invention, 4-Hydroxy-3,5-diiodobenzyl alcohol is used directly as the starting material, which is oxidized with sodium or calcium hypochlorite:. 15 Scheme 4 It is recalled here that compound 2 can be prepared from 4-hydroxybenzyl alcohol by the process described in the INNOVERDA patent FR- 3,113,904B2. With this oxidant, yields of up to 65% are surprisingly and unexpectedly obtained, with short reaction times of a few minutes. Compared to the known state of the art, the invention provides the following substantial improvements: 1. The yield is increased, practically double that of the best method; 25 2. The process uses an inexpensive oxidant; 3. The reaction time is very short, only a few minutes; 4. The process can be carried out at room temperature. 5. The process does not use toxic heavy metals or rare metals and the resulting by-products of the oxidant are non-toxic (H2O and NaCl).Thus, the invention implements the use of hypochlorite salts for the 5 synthesis of the compound 1,5,7-diiodo-1-oxaspiro[2,5]octa-4,7-dien-6-one, a di-iodinated spiro-epoxide, surprisingly and unexpectedly resulting in a high yield in a few minutes. The use of sodium and calcium hypochlorite as an oxidant in a chemical reaction is not new. 10 In 2015, Ishihara et al describe in Chemistry Letters 2015, 44, 381–383 the use of this oxidant for the oxidative de-aromatization of phenols. Different spiro derivatives are described, such as spirolactones, spirolactams etc. No spiro-epoxide type compounds are described in this publication, 15 nor any examples of reactions with di-iodinated phenols. For example, obtaining the compounds listed in Scheme 5 by oxidation with sodium hypochlorite is described in this publication Chemistry Letters 2015, see page 382:. 20 Diagram 5 In 2020, the same authors describe in Nature Chemistry 2020, 12, 353–362, the use of the oxidant, sodium hypochlorite, to generate ortho-quinone-methide type derivatives from phenolic derivatives, which are then transformed, for example, into spiro-epoxide derivatives, see 25 diagrams 6 and 7. (Extract from Figure 5d of the publication Nat. Chem.12, 353–362 (2020)) 5 (Excerpt from Figure 5e of the publication Nat. Chem.12, 353–362 (2020)) In these examples, no diiodinated derivative is obtained, and no example uses a 4-hydroxybenzylalcohol derivative as a starting material. 10 Furthermore, by applying different conditions described in this article by Ishihara in 2020, the desired compound 1 is obtained with yields of less than 21% (comparative examples 42 and 43). The surprising fact of the process of the invention is therefore that the oxidation of compound 2 can be carried out in a single step with yields much higher than what is known, and this for a diiodinated compound.According to the invention, according to the embodiments giving the best 5 results: ^ Solvents of the ether type are used in a two-phase medium, in the presence of a certain percentage of aqueous solution or final water, between 2 and 21%, in particular between 5 and 12%, and even better approximately 6% (Examples 1, 7 and 8) and a concentration of hypochlorite in the water or aqueous solution, between 0.5M and 1.5M. ^ As polar organic solvent, an ether chosen from methyl tert-butyl ether (MTBE), tert-amyl methyl ether (TAME), diethyl ether or methyl cyclopentyl ether is used. (Examples 1, 2, 3 and 4). 15 ^ A buffer solution, for example at a pH between 5 and 8, better between 6 and 7, for example an acetate buffer solution (example 11), can be used as the aqueous solution.Surprisingly, other solvents such as dimethyl carbonate, 2-methyl tetrahydrofuran, isopropyl acetate, n-butanol, ethanol, anisole, toluene, n-heptane, cyclohexane, dimethyl sulfoxide, acetonitrile, N,N-dimethylformamide respectively give significantly lower or zero yields of the desired compound. (Respectively Examples 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 and 33). 25 ^ between 2-3, in particular 2-2.5, equivalents of oxidant are used (Example 1). Surprisingly, other oxidants, such as potassium hydrogen persulfate (Oxone), sodium bismuthate, iodobenzene diacetate (PIDA), tetra-n-butylammonium triiodide (TBAI3) and bromine with sodium hydroxide, respectively, do not allow obtaining the desired compound 1 (Respectively examples 37, 38, 39, 40, 41, 42 and 43). ^ a temperature between 0 and 21 °C (Examples 1, 5, 6, 34 and 35).Experimental Part In the description and the claims all % are given by weight, the temperature is expressed in °C or is by default the ambient temperature, the pressure is the atmospheric pressure, unless otherwise indicated. By ambient temperature, we mean a temperature usually between approximately 20°C and 25°C. I) EXAMPLES ACCORDING TO THE INVENTION Example 1 according to the invention: Optimal protocol 4-hydroxy-3,5-diiodobenzyl alcohol of. be prepared from 10 4-hydroxy benzyl alcohol, according to one of examples 1 to 8 of the INNOVERDA patent FR-3,113,904B2. 100 mg (266 µmoles) of 4-hydroxy-3,5-diiodobenzyl alcohol is dissolved in 11 mL of methyl tert-butyl ether (MTBE). Separately, 87.5-131 mg (532-798 µmoles) of sodium hypochlorite pentahydrate is dissolved in 15 0.7 mL of demineralized water. Alternatively, 286 µL (532 µmol) of a commercial sodium hypochlorite solution (11-15% active chlorine) is dissolved in 414 µL of demineralized water. The aqueous fraction is added dropwise over 10 minutes to the organic fraction with vigorous stirring at 21 °C. The reaction is stirred for 5-20 minutes. The reaction is stopped by adding 10 mL of 10% sodium bisulfite solution. 63% of 5,7-diiodo-1-oxaspiro[2,5]octa-4,7-dien-6one (compound 1) is obtained.The reaction solution can be used directly, for example for the synthesis of Levothyrox, as is known to those skilled in the art, in particular as described in Tetrahedron Letters, Vol. 38, No. 40, pp. 6965-6968, 1997. Additional Examples according to the invention Change of ether solvent Example 2: the procedure is as described in example 1 but using tert-amyl methyl ether instead of methyl tert-butyl ether (MTBE), 61% of compound 1 is obtained. Example 3: the procedure is as described in example 1 but using diethyl ether instead of methyl tert-butyl ether (MTBE), 61% of compound 1 is obtained. Example 4: the procedure is as described in example 1 but using methyl cyclopentyl ether instead of methyl tert-butyl ether (MTBE), 50% of compound 1 is obtained. Change of temperature: the procedure is as described in example 1 except for the modification described in Table I below.10 Table I- Change in Temperature Examples Modifications Yield (compound 1) Example 5 The aqueous fraction containing 61% sodium hypochlorite is added at 0 °C. Example 6 The aqueous fraction containing 60% sodium hypochlorite is added at 10 °C. Change in concentration of compound 2: The procedure is as described in Example 1 except for the modification described in Table II below. 15 Table II- Change in Concentration of compound 2 Examples Modifications Yield (compound 1) Example 7 Using 207 mg (550 µmol) of 4-hydroxy-3,5- 65% diiodobenzyl alcohol in 11 mL of methyl tert-butyl ether and 181 mg (1.10 mmol) of sodium hypochlorite pentahydrate in 1.45 mL of deionized water. Example 8 Using 414 mg (1.10 mmol) of 4-hydroxy-3,5-63% diiodobenzyl alcohol in 11 mL of methyl tert-butyl ether and 362 mg (2.20 mmol) of sodium hypochlorite pentahydrate in 2.89 mL of demineralized water.Change of scale: Proceeding as described in Example 1 with the exception of the modification described in Table III below. Table III- Change of scale Examples Modifications Yield (compound 1) Example 9 1.0 g of 4-hydroxy-3,5-diiodobenzyl alcohol 53% is used as starting material. All other reagents are increased in proportion (x10). Example 10 2.5 g of 4-hydroxy-3,5-diiodobenzyl alcohol 53% is used as starting material. All other reagents are increased in proportion (x25). II) EXAMPLE 11 According to the invention and COMPARATIVE EXAMPLES Change of the nature of the aqueous phase with a buffer: Proceeding as described in Example 1 with the exception of the modification described in Table IV below. Table IV- Change in the nature of the aqueous phase with a buffer and variation in pH Examples Modifications Yield (compound 1) Example of Use of acetate buffer (AcOH / AcONa) 59% the invention 11 0.1M pH = 6 instead of demineralized water. Example of Use of phosphate buffer (NaH2PO4 / 42% Na2HPO4) 0.1M pH = 7 instead of demineralized water. Example of Use of borate buffer (B(OH)3 / NaOH) 38% comparative 13 0.1M pH = 8.6 instead of demineralized water. Example of Use of acetate buffer (AcOH / AcONa) 29% comparative 14 0.1M pH = 5 instead of demineralized water. Example of Use of acetate buffer (AcOH / AcONa) 0% comparative 15 0.1M pH = 4 instead of demineralized water. Change in the percentage of water: Example of the invention 16: 100 mg (266 µmoles) of 4-hydroxy-3,5-diiodobenzyl alcohol is dissolved in 11 mL of ethyl acetate. Separately, 58.2 mg (354 µmoles) of sodium hypochlorite pentahydrate is dissolved in 0.7 mL of demineralized water (final organic / water ratio 94 / 6). The aqueous fraction is added to the organic fraction with vigorous stirring and at 21 °C. The reaction is stirred for 5 minutes.The reaction is stopped by adding 10 mL of 10% sodium bisulfite solution. 41% of 5,7-diiodo-10 1-oxaspiro[2,5]octa-4,7-dien-6one (compound 1) is obtained. The procedure is as described in Example 16 of the invention above with the exception of the modification described in Table V below for Comparative Examples 17 to 21. 15 Table V- Variations in the percentage of water Examples Modifications Yields comparative (compound 1) Example Final organic / water ratio 0 / 100 1% comparative 17 Example Final organic / water ratio 50 / 50 10% comparative 18 Example Final organic / water ratio 90 / 10 25% comparative 19 Example Final organic / water ratio 98.5 / 1.5 9% comparative 20 Example Final organic / water ratio 100 / 0 0% comparative 21 Change of organic solvent: The procedure is as described in Comparative Example 16 with the exception of the modification described in Table VI below concerning Comparative Examples 22 to 33.Table VI- Change of polar organic solvent Examples Modifications Yield invention and (compound 1) Comparative Example Series Use of dimethyl carbonate 37% instead of 22 methyl tert-butyl ether. Comparative Example Series Ether Use of 2-methyl tetrahydrofuran 23% instead of 23 methyl tert-butyl ether. Comparative Example Series Ester Use of isopropyl acetate 31% instead of 24 methyl tert-butyl ether. Comparative Example Series Protic Use of n-butanol 1% instead of 25 methyl tert-butyl ether. Comparative Example Series Use of ethanol 0% instead of 26 methyl tert-butyl ether. Comparative Example Series Aromatic Use of anisole 5% instead of 27 methyl tert-butyl ether. Comparative Example Series Use of toluene 0% instead of 28 methyl tert-butyl ether. Example Series Use of n-heptane 0% comparative hydrocarbon instead of methyl tert-butyl ether.Example Use of comparative 0% cyclohexane instead of methyl tert-butyl ether. Example Dipolar series Use of comparative 0% aprotic dimethyl sulfoxide instead of methyl tert-butyl ether. Example Use of comparative 1% acetonitrile instead of methyl tert-butyl ether. Example Use of comparative 0% N,N- dimethylformamide instead of methyl tert-butyl ether. Modification of the reaction temperature: Continuing from Examples 5 and 6, the procedure is as described in Example 1 with the exception of the modification described in Table VII below, concerning Comparative Examples 34 and 35. 5 Table VII- MODIFICATION OF THE TEMPERATURE Examples Modifications Comparative Yield (compound 1) Example The aqueous fraction containing 4% comparative hypochlorite is added at -10 °C. 34 Example The aqueous fraction containing 7% comparative hypochlorite is added at 30°C.35 Comparison with other oxidants: Example of the invention 36: 100 mg (266 µmol) of 4-hydroxy-3,5-diiodobenzyl alcohol is dissolved in 11 mL of methyl tert-butyl ether. Separately, 38.0 mg (266 µmol) of calcium hypochlorite is dissolved in 0.7 mL of demineralized water. The aqueous fraction is added dropwise over 10 minutes to the organic fraction with vigorous stirring and at 21 °C. The reaction is stirred for 5 minutes. The reaction is stopped by adding 10 mL of a 10% sodium bisulfite solution. 38% of 5,7-diiodo-1-oxaspiro[2,5]octa-4,7-dien-6one (compound 1) is obtained. Comparative Example 37: 100 mg (266 µmol) of 4-hydroxy-3,5-diiodobenzyl alcohol is dissolved in 11 mL of ethyl acetate and 0.7 mL of demineralized water. 482 mg (353 µmol) of potassium hydrogen persulfate is added in one portion to the organic fraction under vigorous stirring and at 21 °C. The reaction is stirred for 5 minutes.The reaction is stopped by adding 10 mL of 10% sodium bisulfite solution. 0% of 5,7-diiodo-1-oxaspiro[2,5]octa-4,7-dien-6one (compound 1) is obtained. 25 Comparative Example 38: 100 mg (266 µmol) of 4-hydroxy-3,5-diiodobenzyl alcohol is dissolved in 11 mL of ethyl acetate and 0.7 mL of demineralized water. 117 mg (354 µmol) of sodium bismuthate is added in one portion to the organic fraction with vigorous stirring and at 21 °C. The reaction is stirred for 5 minutes. The reaction is stopped by adding 10 mL of 10% sodium bisulfite solution. 1% 5 of 5,7-diiodo-1-oxaspiro[2,5]octa-4,7-dien-6one (compound 1) is obtained. Comparative Example 39: 37.8 mg (101 µmol) of 4-hydroxy-3,5-diiodobenzyl alcohol is dissolved in 18 mL of dry acetonitrile. Separately, under argon, 40.8 mg (127 µmol) of iodobenzene diacetate is dissolved in 2 mL of ethyl acetate.Under argon, the small organic fraction is added in one portion to the large organic fraction with vigorous stirring and at 0 °C. Under argon, the reaction is stirred for 30 minutes. The reaction is stopped by adding 10 mL of a 10% sodium bisulfite solution. 2% of 5,7-diiodo-1-oxaspiro[2,5]octa-4,7-dien-6one (compound 1) is obtained. 15 Comparative Example 40: 100 mg (266 µmol) of 4-hydroxy-3,5-diiodobenzyl alcohol and 36.8 mg (266 µmol) of potassium carbonate are dissolved in 10 mL of ethyl acetate and 0.7 mL of demineralized water. Separately, 136 mg (266 µmol) of tetra-n-butylammonium triiodide is dissolved in 1 mL of ethyl acetate. The small organic fraction 20 is added in one portion to the large organic fraction under vigorous stirring and at 21 °C. The reaction is stopped by the addition of 10 mL of demineralized water. 0% of 5,7-diiodo-1-oxaspiro[2,5]octa-4,7-dien-6one (compound 1) is obtained.Comparative Example 41: 100 mg (266 µmol) of 4-hydroxy-3,5-diiodobenzyl alcohol is dissolved in 11 mL of ethyl acetate. Separately, 28.4 mg (710 µmol) of sodium hydroxide and 56.7 mg (355 µmol) of bromine are dissolved in 0.7 mL of demineralized water and premixed for 2 minutes. The aqueous fraction is added in one portion to the organic fraction under vigorous stirring and at 21 °C. Reaction 30 is stopped by the addition of 10 mL of a 10% sodium bisulfite solution. 0% of 5,7-diiodo-1-oxaspiro[2,5]octa-4,7-dien-6one (compound 1) is obtained. Comparative Example 42: 100 mg (266 µmol) of 4-hydroxy-3,5-diiodobenzyl alcohol and 6.84 mg (26.6 µmol) of tetrabutylammonium iodide are dissolved in 11 mL of ethyl acetate. Separately, 58.2 mg (354 µmol) of sodium hypochlorite pentahydrate is dissolved in 0.7 mL of demineralized water (Final organic / water ratio 94 / 6).The aqueous fraction is added to the organic fraction with vigorous stirring and at 21 °C. The reaction is stirred for 15 minutes. The reaction is stopped by adding 10 mL of 10% sodium bisulfite solution. 21% of 5,7-diiodo-1-oxaspiro[2,5]octa-4,7-dien-6one (compound 1) is obtained. Comparative Example 43: 100 mg (266 µmol) of 4-hydroxy-3,5- diiodobenzyl alcohol is dissolved in 11 mL of toluene. Separately, 219 mg (1.33 mmol) of sodium hypochlorite pentahydrate is dissolved in 11 mL of demineralized water (final organic / water ratio 50 / 50). The aqueous fraction is added to the organic fraction with vigorous stirring and at 21 °C. The reaction is stirred for 120 minutes. The reaction is stopped by adding 10 mL of 10% sodium bisulfite solution. 2% of 5,7-diiodo-1-oxaspiro[2,5]octa-4,7-dien-6one (compound 1) is obtained. References 1. Grzegorz M. Salamonczyk, Vibha B. Oza and Charles J. Sih, Tetrahedron Letters, 1997, 38, 40, 6965-6968. 2.Halogenated Phenols for Diagnostics, Antioxidant Protection and Drug Delivery, WO2013 / 010102 A2 3. Michael F. McLaughlin, Elizabeth Massolo, Thomas A. Cope, and Jeffrey S. Johnson, Org. Lett.2019, 21, 6504–6507. 4. Mohammed Uyanik, Niiha Sasakura, Mitsuyoshi Kuwahata, Yasukazu Ejima, and Kazuaki Ishihara, Chem. Lett.2015, 44, 381–383. | doi:10.1246 / cl.141130 5. Mohammed Uyanik, Kohei Nishioka, Ryutaro Kondo, and Kazuaki Ishihara. Chemoselective oxidative generation of ortho-quinone methides and tandem transformations. Nat. Chem.2020, 12, 353–362. doi:10.1038 / s41557-020-0433-4.

Claims

CLAIMS 1. Process for the direct or one-step synthesis of the compound 5,7-diiodo-1-oxaspiro[2,5]octa-4,7-dien-6-one (compound 1) from 4-Hydroxy-3,5-diiodobenzyl alcohol (compound 2) characterized in that an oxidation reaction of 4-Hydroxy-3,5-diiodobenzyl alcohol is carried out with an oxidant comprising a hypochlorite, in particular chosen from sodium, calcium and potassium hypochlorite, or mixtures thereof.

2. Process according to claim 1, characterized in that the oxidation reaction takes place in a two-phase reaction medium comprising a polar organic solvent of ether type and an aqueous solution.

3. Method according to claim 2, characterized in that the polar organic solvent of ether type is chosen from methyl tert-butyl ether (MTBE), tert-amyl methyl ether (TAME), diethyl ether and methyl 15 cyclopentyl ether, or mixtures thereof. 4.Method according to claim 2 or 3, characterized in that the aqueous solution is chosen from water, in particular demineralized water, or an aqueous buffer, in particular an aqueous buffer whose pH is between 5 and 8, better still between 6 and 7, for example an aqueous acetate buffer.

5. Method according to one of claims 1 to 4, characterized in that the relative molar ratio between the oxidant and the 4-Hydroxy-3,5-diiodobenzyl alcohol is between 2 and 3, in particular between 2 and 2.

5.

6. Method according to one of claims 2 to 5, characterized in that the volume ratio of the aqueous solution relative to the total volume of the aqueous solution and the polar organic solvent of ether type is between 2 and 21%, in particular between 5 and 12%, even better is approximately 6%. 7.Process according to one of claims 1 to 6, characterized in that the temperature of the reaction medium is between 0 and room temperature or lower than room temperature, room temperature being defined as between 20 and 25°C.

8. Process according to claim 7, characterized in that the temperature of the reaction medium is between 0 and 21°C.

9. Process according to one of claims 1 to 8, characterized in that the reaction time is between 1 and 15 minutes, in particular between 4 and 10 minutes.

10. Process according to one of claims 2 to 7, characterized in that the 4-hydroxy-3,5-diiodobenzyl alcohol is dissolved in the polar organic solvent and the oxidant is dissolved in the aqueous solution.

11. Process according to one of claims 2 to 10, characterized in that the molar concentration of the hypochlorite oxidant in the water or aqueous solution is from 0.5M to 1.5M.

12. Method according to one of claims 2 to 11, characterized in that the aqueous solution is added to the polar organic solution, drop by drop, over a period of time of 1 to 15 minutes, in particular 4 to 10 minutes, with stirring.

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