Method for iodinating amiodarone hydrochloride intermediate

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to an iodination method of an amiodarone hydrochloride intermediate. The iodination method comprises the following steps: mixing 2-butyl-3-(4-hydroxybenzoyl) benzofuran, hypoiodate and an alcohol solvent, and carrying out a substitution reaction, so as to obtain the 2-butyl-3-(3, 5-diiodine-4-hydroxybenzoyl) benzofuran. According to the method, 2-butyl-3-(3, 5-diiodo-4-hydroxybenzoyl) benzofuran is generated through a substitution reaction by taking 2-butyl-3-(4-hydroxybenzoyl) benzofuran as a raw material and hypoiodate as an iodination reagent. According to the iodination method disclosed by the invention, all iodine in the hypoiodate can participate in the substitution reaction, the atom utilization rate of the iodine element is maximized, and the loss of the iodine element is reduced to the minimum, so that the recovery operation of the iodine is avoided. In addition, the iodination method provided by the invention is high in product yield, and the product yield can reach 90% or above.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and particularly relates to an iodination method for an amiodarone hydrochloride intermediate. Background Art

[0002] Amiodarone hydrochloride is a widely used antiarrhythmic drug with stable efficacy and low side effects. The chemical name of amiodarone hydrochloride is 2-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran hydrochloride, and its structural formula is shown below:

[0003]

[0004] The traditional synthesis of amiodarone hydrochloride requires iodination of the intermediate 2-butyl-3-(4-hydroxybenzoyl)benzofuran to form 2-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran. This synthesis method has been developed and used in industrialization. The synthesis reaction formula is shown below:

[0005]

[0006] In the above-mentioned traditional iodination process, elemental iodine is used as an iodination reagent. The molar ratio of elemental iodine to 2-butyl-3-(4-hydroxybenzoyl)benzofuran is more than 2:1 to achieve complete iodination. After the iodination reaction occurs, at least half of the elemental iodine forms sodium iodide (sodium iodide does not continue to participate in the iodination reaction). It is necessary to reclaim the iodine element in the sodium iodide, which is complicated to operate. Therefore, it is of great significance to develop a synthetic method with a simple process and high iodine utilization rate. Summary of the Invention

[0007] In view of this, the object of the present invention is to provide an iodination method for an amiodarone hydrochloride intermediate. The iodination method of the present invention maximizes the atomic utilization rate of the iodine element, avoids the iodine recovery operation, and has a simple process.

[0008] The present invention provides a method for iodination of an amiodarone hydrochloride intermediate, wherein the amiodarone hydrochloride intermediate is 2-butyl-3-(4-hydroxybenzoyl)benzofuran. The iodination method comprises the following steps:

[0009] 2-butyl-3-(4-hydroxybenzoyl)benzofuran, hypoiodite and an alcohol solvent are mixed to carry out a substitution reaction to obtain 2-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran.

[0010] Preferably, the hypoiodite is used in the form of a hypoiodite solution, and the preparation method of the hypoiodite solution comprises the following steps:

[0011] The method comprises mixing elemental iodine, alkaline substance, iodate and alcohol solvent to carry out redox reaction to obtain a hypoiodite-containing solution.

[0012] Preferably, the molar ratio of the elemental iodine to the alkaline substance is 1:2-3, and the alkaline substance includes sodium acetate and / or potassium acetate.

[0013] Preferably, the molar ratio of the elemental iodine to the iodate is 1:0.5-0.55, and the iodate includes potassium iodate and / or sodium iodate.

[0014] Preferably, the temperature of the redox reaction is 20-70° C., and the time is 2-4 hours.

[0015] Preferably, the 2-butyl-3-(4-hydroxybenzoyl)benzofuran, hypoiodite and alcohol solvent are mixed as follows: 2-butyl-3-(4-hydroxybenzoyl)benzofuran and the alcohol solvent are first mixed, the temperature is raised to the substitution reaction temperature, and then the hypoiodite solution is added dropwise.

[0016] Preferably, the temperature of the substitution reaction is 40-90° C., and the time is 2-8 hours.

[0017] Preferably, the molar ratio of the 2-butyl-3-(4-hydroxybenzoyl)benzofuran to hypoiodite is 1:2 to 2.2.

[0018] Preferably, the alcohol solvent includes one or more of methanol, ethanol and isopropanol.

[0019] Compared with the prior art, the present invention has the following beneficial effects:

[0020] The invention provides an iodination method for an amiodarone hydrochloride intermediate. The amiodarone hydrochloride intermediate is 2-butyl-3-(4-hydroxybenzoyl)benzofuran. The iodination method comprises the following steps: mixing 2-butyl-3-(4-hydroxybenzoyl)benzofuran, hypoiodite and an alcohol solvent to carry out a substitution reaction to obtain 2-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran.

[0021] The present invention uses 2-butyl-3-(4-hydroxybenzoyl)benzofuran as a raw material, uses hypoiodite as an iodination reagent, and a substitution reaction generates 2-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran. In the iodination method of the present invention, all the iodine in the hypoiodite can participate in the substitution reaction, the atomic utilization rate of the iodine element is maximized, the loss of the iodine element is minimized, thereby avoiding the iodine recovery operation. Moreover, the iodination method of the present invention has a high product yield. The results of the embodiment show that the yield of 2-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran can be prepared by the iodination method of the present invention with a yield of more than 90%.

[0022] Furthermore, the present invention involves mixing elemental iodine, an alkaline substance, and an iodate in an alcoholic solvent to produce a hypoiodite solution, which is then added dropwise to an alcoholic solution of 2-butyl-3-(4-hydroxybenzoyl)benzofuran to produce 2-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran. The iodination method is simple, avoids iodine recovery, is low-cost, and has good atom economy.

[0023] The iodination method of the present invention does not involve Cl in the iodine substitution reaction process. - , it has low corrosion to equipment and high feasibility for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0025] Figure 1 This is the mass spectrum of 2-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran obtained in Example 1;

[0026] Figure 2 This is the HPLC spectrum of 2-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran obtained in Example 1. DETAILED DESCRIPTION

[0027] The present invention provides a method for iodination of an amiodarone hydrochloride intermediate, wherein the amiodarone hydrochloride intermediate is 2-butyl-3-(4-hydroxybenzoyl)benzofuran. The iodination method comprises the following steps:

[0028] 2-butyl-3-(4-hydroxybenzoyl)benzofuran, hypoiodite and an alcohol solvent are mixed to carry out a substitution reaction to obtain 2-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran.

[0029] In the present invention, unless otherwise specified, the materials and equipment used are commercially available products in the art.

[0030] In the present invention, the structural formula of the 2-butyl-3-(4-hydroxybenzoyl)benzofuran is shown in Formula I, and the structural formula of the 2-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran is shown in Formula II:

[0031]

[0032] In the present invention, the hypoiodite is preferably used in the form of a hypoiodite solution, and the preparation method of the hypoiodite solution preferably comprises the following steps:

[0033] Elemental iodine, alkaline substances, iodate and alcohol solvent are mixed to carry out redox reaction to obtain a hypoiodite-containing solution.

[0034] The alkaline substance preferably includes sodium acetate and / or potassium acetate. The molar ratio of the elemental iodine to the alkaline substance is preferably 1:2-3, specifically 1:2.1, 1:2.2 or 1:2.5.

[0035] The iodate preferably includes potassium iodate and / or sodium iodate. The molar ratio of elemental iodine to iodate is preferably 1:0.5 to 0.55, specifically 1:0.5, 1:0.51, or 1:0.55. The iodate is preferably used in the form of an aqueous iodate solution.

[0036] The alcohol solvent preferably includes one or more of methanol, ethanol and isopropanol. The present invention has no special requirements on the amount of the alcohol solvent, as long as it can ensure the smooth progress of the reaction.

[0037] The mixing of elemental iodine, alkaline substance, iodate, and alcoholic solvent is preferably performed by first mixing elemental iodine, alkaline substance, and alcoholic solvent, heating to a redox reaction temperature, and then dropwise adding an aqueous iodate solution; the dropwise addition is preferably completed within 1 to 2 hours. The resulting hypoiodite-containing solution preferably contains an alcoholic solvent and water.

[0038] The temperature of the redox reaction is preferably 20-70°C, specifically 30-40°C, 40-55°C or 55-70°C; when the alcohol solvent is methanol, the temperature of the redox reaction is preferably 30-40°C; when the alcohol solvent is ethanol, the temperature of the redox reaction is preferably 40-55°C; when the alcohol solvent is isopropanol, the temperature of the redox reaction is preferably 55-70°C. The redox reaction time is preferably 2-4h, specifically 2h, 3h or 4h. The redox reaction is preferably carried out under stirring, and the reaction formula of the redox reaction is shown below (wherein M is Na or K):

[0039]

[0040] In the present invention, the molar ratio of the 2-butyl-3-(4-hydroxybenzoyl)benzofuran to elemental iodine is preferably 1:0.8-0.9, specifically 1:0.85.

[0041] In the present invention, the mixing of 2-butyl-3-(4-hydroxybenzoyl)benzofuran, hypoiodite and alcohol solvent is preferably carried out as follows: 2-butyl-3-(4-hydroxybenzoyl)benzofuran and alcohol solvent are first mixed, the temperature is raised to the substitution reaction temperature, and then the hypoiodite solution is added dropwise; the addition is preferably completed within 1 to 2 hours.

[0042] In the present invention, the alcohol solvent preferably includes one or more of methanol, ethanol and isopropanol; the present invention has no special requirements on the amount of the alcohol solvent, as long as it can ensure the substitution reaction proceeds smoothly.

[0043] In the present invention, the molar ratio of 2-butyl-3-(4-hydroxybenzoyl)benzofuran to hypoiodite is preferably 1:2 to 2.2, specifically 1:2.1.

[0044] In the present invention, the substitution reaction is a benzene ring substitution reaction, and the temperature of the substitution reaction is preferably 40 to 90°C, specifically 60 to 70°C, 70 to 75°C, or 80 to 90°C; when the alcohol solvent is methanol, the temperature of the substitution reaction is preferably 60 to 70°C; when the alcohol solvent is ethanol, the temperature of the substitution reaction is preferably 70 to 75°C; when the alcohol solvent is isopropanol, the temperature of the substitution reaction is preferably 80 to 90°C. The time of the substitution reaction is preferably 2 to 8 hours, specifically 3 hours, 4 hours, or 6 hours. The substitution reaction is preferably carried out under reflux. The time of the substitution reaction is counted from the time the hypoiodite-containing solution is added dropwise. The reaction formula of the substitution reaction is shown below (wherein M is Na or K):

[0045]

[0046] In the present invention, the substitution reaction preferably further includes post-treatment, and the post-treatment preferably includes: decolorizing the obtained reaction solution, adjusting the pH value of the decolorized solution to 2-3 with hydrochloric acid, crystallizing, solid-liquid separation, and washing and drying the obtained solid to obtain 2-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran.

[0047] The decolorization preferably uses sodium thiosulfate, and the amount of the sodium thiosulfate used is preferably 0.2 times the molar amount of 2-butyl-3-(4-hydroxybenzoyl)benzofuran. The decolorization can reduce excess iodine to negative monovalent iodine.

[0048] The pH value is preferably adjusted to 2.5-3.

[0049] The crystallization is preferably carried out under stirring, and the crystallization temperature is preferably room temperature, specifically 20 to 30°C.

[0050] The solid-liquid separation is preferably suction filtration; the washing is preferably water rinsing, the temperature of the water rinsing is preferably 20-30°C, the amount of water used for the water rinsing is preferably 10 times the mass of 2-butyl-3-(4-hydroxybenzoyl)benzofuran, and the function of the water rinsing is to remove salts (such as sodium chloride or potassium chloride). After the washing, it is preferably further included to remove impurities, and the impurity removal preferably includes: mixing the solid after water rinsing with an alcohol solvent and refluxing, cooling and crystallizing, solid-liquid separation and water rinsing again; the temperature of the cooling and crystallization is preferably 0-5°C. The temperature of the drying is preferably 50°C, and the time is preferably 6-8 hours.

[0051] The iodination method of an amiodarone hydrochloride intermediate provided by the present invention has the advantages of simple process, low cost and high atom utilization rate.

[0052] To further illustrate the present invention, the iodination method of the amiodarone hydrochloride intermediate provided by the present invention is described in detail below with reference to the accompanying drawings and examples, but they should not be construed as limiting the scope of protection of the present invention.

[0053] Example 1

[0054] Preparation of 2-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran (II):

[0055] Add 14.7 g (57.9 mmol) of iodine, 50 mL of methanol, and 11.3 g (115 mmol) of potassium acetate to a reaction flask at room temperature, raise the temperature to 30-40°C, add potassium iodate aqueous solution (6.25 g (i.e., 29.2 mmol) of potassium iodate + 30 mL of water) dropwise, and stir for 4 hours to obtain a potassium hypoiodite solution (the solvent includes methanol and water).

[0056] At room temperature, 20 g (67.9 mmol) of 2-butyl-3-(4-hydroxybenzoyl)benzofuran and 200 mL of methanol were added to the reaction flask, stirred and dissolved, and the temperature was raised to 60-70 ° C. The potassium hypoiodite solution was added dropwise to the reaction flask. After the addition was complete, the reaction was continued for 6 hours. Sodium thiosulfate solution (3.4 g of sodium thiosulfate, 13.6 mmol) and 80 mL of water were added, and the temperature was maintained at 60-70 ° C. Decolorization was performed for half an hour, and the temperature was lowered to 20-30 ° C. The reaction mixture was added dropwise. Adjust the pH to 2.5-3 with concentrated hydrochloric acid, keep warm and stir for half an hour, filter with suction, rinse the filter cake with 100 g of water, return the filter cake to the reaction flask, add 50 mL of methanol to the reaction flask, raise the temperature to reflux, keep warm for half an hour, cool to 0-5°C, filter with suction, rinse the filter cake with 20 g of water to obtain a wet product, and dry the wet product with hot air at 50°C for 8 hours to obtain 35.5 g of white powder, i.e. 2-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran, with a yield of 95.7%.

[0057] Example 2

[0058] Preparation of 2-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran (II):

[0059] Add 14.7 g (57.9 mmol) of iodine, 50 mL of ethanol, and 11.3 g (115 mmol) of potassium acetate to a reaction flask at room temperature, raise the temperature to 40-55°C, add potassium iodate aqueous solution (6.25 g (i.e., 29.2 mmol) of potassium iodate + 30 mL of water) dropwise, and stir for 3 hours to obtain a potassium hypoiodite solution.

[0060] At room temperature, 20 g (67.9 mmol) of 2-butyl-3-(4-hydroxybenzoyl)benzofuran and 200 mL of ethanol were added to the reaction flask, stirred and dissolved, and the temperature was raised to 70-75 ° C. The potassium hypoiodite solution was added dropwise to the reaction flask. After the addition was complete, the reaction was continued for 4 hours. Sodium thiosulfate solution (3.4 g of sodium thiosulfate, 13.6 mmol) and 80 mL of water were added, and the temperature was maintained at 70-75 ° C. Decolorization was performed for half an hour, and the temperature was lowered to 20-30 ° C. The reaction mixture was added dropwise. Adjust the pH to 2.5-3 with concentrated hydrochloric acid, keep warm and stir for half an hour, filter with suction, rinse the filter cake with 100 g of water, return the filter cake to the reaction flask, add 50 mL of ethanol to the reaction flask, raise the temperature to reflux, keep warm for half an hour, cool to 0-5°C, filter with suction, rinse the filter cake with 20 g of water to obtain a wet product, and dry the wet product with hot air at 50°C for 8 hours to obtain 35.4 g of white powder, i.e. 2-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran, with a yield of 95.4%.

[0061] Example 3

[0062] Preparation of 2-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran (II):

[0063] Add 14.7 g (57.9 mmol) of iodine, 50 mL of isopropanol, and 11.3 g (115 mmol) of potassium acetate to a reaction flask at room temperature, raise the temperature to 55-70°C, add potassium iodate aqueous solution (6.25 g (i.e., 29.2 mmol) of potassium iodate + 30 mL of water) dropwise, and stir for 2 hours to obtain a potassium hypoiodite solution.

[0064] At room temperature, 20 g (67.9 mmol) of 2-butyl-3-(4-hydroxybenzoyl)benzofuran and 200 mL of isopropyl alcohol were added to the reaction flask, stirred and dissolved, and the temperature was raised to 80-90°C. The potassium hypoiodite solution was added dropwise to the reaction flask. After the addition was complete, the reaction was continued for 3 hours. Sodium thiosulfate solution (3.4 g of sodium thiosulfate, 13.6 mmol) and 80 mL of water were added, and the temperature was maintained at 80-90°C. The mixture was decolorized for half an hour, cooled to 20-30°C, and added dropwise. Adjust the pH to 2.5-3 with concentrated hydrochloric acid, keep warm and stir for half an hour, filter with suction, rinse the filter cake with 100 g of water, return the filter cake to the reaction flask, add 50 mL of isopropanol to the reaction flask, raise the temperature to reflux, keep warm for half an hour, cool to 0-5°C, filter with suction, rinse the filter cake with 20 g of water to obtain a wet product, and dry the wet product with hot air at 50°C for 8 hours to obtain 35.2 g of white powder, i.e. 2-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran, with a yield of 94.9%.

[0065] Example 4

[0066] Preparation of 2-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran (II)

[0067] Add 14.7 g (57.9 mmol) of iodine, 50 mL of methanol, and 9.4 g (115 mmol) of sodium acetate to a reaction flask at room temperature, raise the temperature to 30-40°C, add potassium iodate aqueous solution (6.25 g (i.e., 29.2 mmol) of potassium iodate + 30 mL of water) dropwise, and stir for 4 hours to obtain a hypoiodite solution (including sodium hypoiodite and potassium hypoiodite).

[0068] At room temperature, 20 g (67.9 mmol) of 2-butyl-3-(4-hydroxybenzoyl)benzofuran and 200 mL of methanol were added to the reaction flask, stirred and dissolved, and the temperature was raised to 60-70 ° C. The hypoiodite solution was added dropwise to the reaction flask. After the addition was complete, the reaction was continued for 6 hours. Sodium thiosulfate solution (3.4 g of sodium thiosulfate, 13.6 mmol) and 80 mL of water were added, and the temperature was maintained at 60-70 ° C. Decolorization was performed for half an hour, and the temperature was lowered to 20-30 ° C. The mixture was added dropwise. Adjust the pH to 2.5-3 with concentrated hydrochloric acid, keep warm and stir for half an hour, filter with suction, rinse the filter cake with 100 g of water, return the filter cake to the reaction flask, add 50 mL of methanol to the reaction flask, raise the temperature to reflux, keep warm for half an hour, cool to 0-5°C, filter with suction, rinse the filter cake with 20 g of water to obtain a wet product, and dry the wet product with hot air at 50°C for 8 hours to obtain 35.0 g of white powder, i.e. 2-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran, with a yield of 94.3%.

[0069] Example 5

[0070] Preparation of 2-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran (II)

[0071] Add 14.7 g (57.9 mmol) of iodine, 50 mL of methanol, and 9.4 g (115 mmol) of sodium acetate to a reaction flask at room temperature, raise the temperature to 30-40°C, add dropwise an aqueous sodium iodate solution (5.78 g (i.e., 29.2 mmol) of sodium iodate + 30 mL of water), and stir for 4 hours to obtain a sodium hypoiodite solution.

[0072] At room temperature, 20 g (67.9 mmol) of 2-butyl-3-(4-hydroxybenzoyl)benzofuran and 200 mL of methanol were added to the reaction flask, stirred and dissolved, and the temperature was raised to 60-70 ° C. The sodium hypoiodite solution was added dropwise to the reaction flask. After the addition was complete, the reaction was continued for 3 hours. Sodium thiosulfate solution (3.4 g of sodium thiosulfate, 13.6 mmol) and 80 mL of water were added, and the temperature was maintained at 60-70 ° C. Decolorization was performed for half an hour, and the temperature was lowered to 20-30 ° C. The reaction mixture was added dropwise. Adjust the pH to 2.5-3 with concentrated hydrochloric acid, keep warm and stir for half an hour, filter with suction, rinse the filter cake with 100 g of water, return the filter cake to the reaction flask, add 50 mL of methanol to the reaction flask, raise the temperature to reflux, keep warm for half an hour, cool to 0-5°C, filter with suction, rinse the filter cake with 20 g of water to obtain a wet product, and dry the wet product with hot air at 50°C for 8 hours to obtain 35.3 g of white powder, i.e. 2-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran, with a yield of 95.1%.

[0073] The mass spectrum and HPLC spectra of the product obtained in Example 1 are as follows: Figures 1-2 shown; from Figures 1-2 It can be seen that the structure of the obtained product is 2-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran, and the purity is 99.65%. Table 1 is a statistical table of liquid phase data of the products obtained in Examples 1 to 5:

[0074] Table 1 Liquid phase data statistics of the products obtained in Examples 1 to 5

[0075]

[0076] Comparative Example 1

[0077] Preparation of 2-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran (II):

[0078] Add 14.7 g (57.9 mmol) of iodine, 50 mL of methanol, and 6.4 g (114 mmol) of potassium hydroxide to a reaction flask at room temperature, raise the temperature to 30-40°C, add potassium iodate aqueous solution (6.25 g (i.e., 29.2 mmol) of potassium iodate + 30 mL of water) dropwise, and stir for 4 hours to obtain a potassium hypoiodite solution.

[0079] At room temperature, 20 g (67.9 mmol) of 2-butyl-3-(4-hydroxybenzoyl)benzofuran and 200 mL of methanol were added to the reaction flask, stirred and dissolved, and the temperature was raised to 60-70 ° C. The potassium hypoiodite solution was added dropwise to the reaction flask. After the addition was complete, the reaction was continued for 6 hours. Sodium thiosulfate solution (3.4 g of sodium thiosulfate, 13.6 mmol) and 80 mL of water were added, and the temperature was maintained at 60-70 ° C. Decolorization was performed for half an hour, and the temperature was lowered to 20-30 ° C. The reaction mixture was added dropwise. Adjust the pH to 2.5-3 with concentrated hydrochloric acid, keep warm and stir for half an hour, filter with suction, rinse the filter cake with 100g of water, return the filter cake to the reaction flask, add 50mL of methanol to the reaction flask, raise the temperature to reflux, keep warm for half an hour, cool to 0-5°C, filter with suction, rinse the filter cake with 20g of water to obtain a wet product, and dry the wet product with hot air at 50°C for 8 hours to obtain 28.3g of white powder, which is 2-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran, with a yield of 76.3%. Table 2 shows the liquid phase data of the product obtained in Comparative Example 1:

[0080] Table 2 Liquid phase data of the product obtained in Comparative Example 1

[0081]

[0082] It can be seen from the data of Example 1 and Comparative Example 1 that potassium hydroxide is used as the alkaline substance, which is too alkaline. When a solution containing potassium hypoiodite is added dropwise to a solution of 2-butyl-3-(4-hydroxybenzoyl)benzofuran alcohol, the overall alkalinity of the reaction solution is too strong, resulting in the target product being easily iodinated, the monoiodine impurity being too high, and the yield of the target product being low.

[0083] Although the above embodiments provide a detailed description of the present invention, they are only part of the embodiments of the present invention, not all of the embodiments. People can also obtain other embodiments based on the embodiments of the present invention without creative work, and these embodiments all fall within the scope of protection of the present invention.

Claims

1. A method for iodination of an amiodarone hydrochloride intermediate, wherein the amiodarone hydrochloride intermediate is 2-butyl-3-(4-hydroxybenzoyl)benzofuran, characterized in that: The iodination method comprises the following steps: 2-butyl-3-(4-hydroxybenzoyl)benzofuran, hypoiodite and an alcohol solvent are mixed to carry out a substitution reaction to obtain 2-butyl-3-(3,5-diiodo-4-hydroxybenzoyl)benzofuran.

2. The iodination method according to claim 1, wherein The hypoiodite is used in the form of a hypoiodite solution, and the preparation method of the hypoiodite solution comprises the following steps: Elemental iodine, alkaline substances, iodate and alcohol solvent are mixed to carry out redox reaction to obtain a hypoiodite-containing solution.

3. The iodination method according to claim 2, wherein The molar ratio of the elemental iodine to the alkaline substance is 1:2-3, and the alkaline substance includes sodium acetate and / or potassium acetate.

4. The iodination method according to claim 2, wherein The molar ratio of the elemental iodine to the iodate is 1:0.5-0.55, and the iodate includes potassium iodate and / or sodium iodate.

5. The iodination method according to claim 2, wherein The temperature of the redox reaction is 20-70° C., and the time is 2-4 hours.

6. The iodination method according to any one of claims 2 to 5, characterized in that The 2-butyl-3-(4-hydroxybenzoyl)benzofuran, hypoiodite and alcohol solvent are mixed as follows: 2-butyl-3-(4-hydroxybenzoyl)benzofuran and the alcohol solvent are first mixed, the temperature is raised to the substitution reaction temperature, and then the hypoiodite solution is added dropwise.

7. The iodination method according to claim 1, wherein The temperature of the substitution reaction is 40-90° C., and the time is 2-8 hours.

8. The iodination method according to claim 1 or 7, characterized in that The molar ratio of the 2-butyl-3-(4-hydroxybenzoyl)benzofuran to hypoiodite is 1:2 to 2.

2.

9. The iodination method according to claim 1, wherein The alcohol solvent includes one or more of methanol, ethanol and isopropanol.

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