Preparation method of rosemeltirol intermediate

Abstract

The invention belongs to the technical field of synthesis of raw material medicines, and particularly relates to a preparation method of a rosmeltirol intermediate. According to the preparation method provided by the invention, a compound with a structure as shown in a formula 1 and 3, 5-dioxo-2, 3, 4, 5-tetrahydro-1, 2, 4-triazine-6-formonitrile are used as initial raw materials, and the target compound 2-(3, 5-dichloro-4-hydroxyphenyl)-3, 5-dioxo-2, 3, 4, 5-tetrahydro-1, 2, 4-triazine-6-formonitrile is obtained in one step through palladium catalytic coupling in an alkaline environment. According to the preparation method of the rosemeltirome intermediate (2-(3, 5-dichloro-4-hydroxyphenyl)-3, 5-dioxo-2, 3, 4, 5-tetrahydro-1, 2, 4-triazine-6-formonitrile, the chemical structural formula of which is as shown in the formula (I)), provided by the invention, the safety risk caused by diazotization reaction is avoided, and the yield of the rosemeltirome intermediate (2-(3, 5-dichloro-4-hydroxyphenyl)-3, 5-dioxo-2, 3, 4, 5-tetrahydro-1, 2, 4-triazine-6-formonitrile) is improved. The synthesis process route is simple, and only one-step reaction is needed; and the obtained product has high quality and is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of raw material drug synthesis, and particularly relates to a method for preparing a resmetirole intermediate. Background Art

[0002] Resmetiro (Rezdiffra) is a small molecule oral selective agonist drug targeting the liver's thyroid hormone receptor (THR)-β. It is highly selective and can be specifically taken up in the liver. On March 15, 2024, Resmetiro received marketing approval from the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with non-alcoholic steatohepatitis.

[0003] The compound 2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile is an important intermediate for preparing resmetiro, and its structure is shown in formula (I).

[0004]

[0005] Chinese patent CN118388458A discloses a complete synthesis process route of resmetirol comprising formula (I), such as Figure 1 As shown, Figure 1 The compound IV is a resmetirole intermediate having a structure shown in formula (I).

[0006] In the above route, the diazotization process is used to prepare compound III from compound I and compound II, but diazotization has a high safety risk and is not conducive to industrial scale-up production. Summary of the invention

[0007] The object of the present invention is to provide a method for preparing a resmetiro intermediate. The method for preparing the resmetiro intermediate (2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile, with a chemical structural formula as shown in formula (I)) provided by the present invention avoids the safety risks brought by a diazotization reaction; and the synthetic process route is simple, with only one-step reaction; the obtained product has high quality and is suitable for industrial production.

[0008] In order to achieve the above object, the present invention provides the following technical solutions:

[0009] The present invention provides a method for preparing a resmetirole intermediate, comprising the following steps:

[0010] The compound of the structure shown in Formula 1, 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile, a base, a palladium catalyst, a ligand of the palladium catalyst and an organic solvent are mixed, and a coupling reaction is carried out in a protective gas atmosphere to obtain a resmetirol intermediate of the structure shown in Formula (I);

[0011]

[0012] In formula 1: R is Br or I.

[0013] Preferably, the organic solvent includes one or more of N,N-dimethylformamide, toluene and dioxane.

[0014] Preferably, the coupling reaction temperature is 90-100°C.

[0015] Preferably, the molar ratio of the compound of the structure represented by Formula 1 to the 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile is 1:1.

[0016] Preferably, the base comprises an alkali metal carbonate.

[0017] Preferably, the molar ratio of the compound of the structure represented by Formula 1 to the base is 1:(2-3).

[0018] Preferably, the palladium catalyst comprises palladium acetate and / or bis(triphenylphosphine)palladium dichloride.

[0019] Preferably, the molar ratio of the compound having the structure represented by Formula 1 to the palladium catalyst is 1:(0.01-0.05).

[0020] Preferably, the ligand of the palladium catalyst is 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl.

[0021] Preferably, the molar ratio of the compound having the structure represented by Formula 1 to the ligand of the palladium catalyst is 1:(0.01-0.05).

[0022] The present invention provides a method for preparing a resmetirol intermediate, wherein the synthetic route is as follows: Figure 2As shown, it includes the following steps: mixing a compound of the structure shown in Formula 1, 3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile, a base, a palladium catalyst, a ligand of the palladium catalyst and an organic solvent, and performing a coupling reaction in a protective gas atmosphere to obtain a resmetiro intermediate of the structure shown in Formula (I). The preparation method provided by the present invention uses a compound of the structure shown in Formula 1 and 3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile as initial raw materials, and obtains the target compound 2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile in an alkaline environment by palladium catalytic coupling in one step. The preparation method of the resmetiro intermediate (2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile, chemical structure as shown in formula (I)) provided by the present invention avoids the safety risks brought by the diazotization reaction; and the synthetic process route is simple, with only one step reaction; the obtained 2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile product has high yield and high purity, and is suitable for industrial production. The results of the examples show that the yield of 2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile obtained by the preparation method provided by the present invention is ≥88%, and the HPLC purity is ≥99%.

[0023] Furthermore, in the present invention, the organic solvent includes one or more of N,N-dimethylformamide (DMF), toluene and dioxane; the temperature of the coupling reaction is 90-100°C. In the preparation method disclosed in the prior art CN1183388458A, in the step of preparing compound IV from compound III, N,N-dimethylacetamide is used as a solvent for heating reaction at 120°C. N,N-dimethylacetamide easily decomposes a small amount of dimethylamine at this temperature. Dimethylamine combines with the residual nitrite in the previous diazotization step to generate a highly toxic nitrosamine impurity N-nitrosodimethylamine, which poses a great quality risk to the final product resmetirox. The invention adopts Figure 2 In the synthetic route, when the organic solvent used includes one or more of DMF, toluene and dioxane, the reaction temperature is controlled to be 90-100° C., thereby avoiding the quality risk caused by nitrosamine impurities.

[0024] In summary, the preparation method of the resmetirol intermediate provided by the present invention avoids the safety risks brought by the diazotization reaction; and at the same time avoids the quality risks brought by nitrosamine impurities. The method provided by the present invention has a simple synthesis process route, with only one step reaction; does not involve the use of dangerous reactions and dangerous reagents, and has high safety; the obtained product has high quality (high yield and purity), and is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 A complete synthetic process map of resmetirol comprising the structural intermediate represented by formula (I) disclosed in the prior art CN118388458A;

[0026] Figure 2 The present invention provides a flow chart for the preparation of the resmetirole intermediate. DETAILED DESCRIPTION

[0027] The present invention provides a method for preparing a resmetirole intermediate, comprising the following steps:

[0028] The compound of the structure shown in Formula 1, 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile, a base, a palladium catalyst, a ligand of the palladium catalyst and an organic solvent are mixed, and a coupling reaction is carried out in a protective gas atmosphere to obtain a resmetirol intermediate of the structure shown in Formula (I);

[0029]

[0030] In formula 1: R is Br or I.

[0031] In the present invention, unless otherwise specified, all preparation raw materials / components are commercially available products well known to those skilled in the art or are prepared by methods well known to those skilled in the art.

[0032] In a specific embodiment of the present invention, R in Formula 1 is specifically Br, that is, the compound of the structure shown in Formula 1 is specifically 4-bromo-2,6-dichlorophenol. The chemical structure of 4-bromo-2,6-dichlorophenol is as follows:

[0033]

[0034] In the present invention, the chemical structural formula of the 3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile is as follows:

[0035]

[0036] In the present invention, the base preferably includes an alkali metal carbonate, and more preferably includes potassium carbonate and / or cesium carbonate.

[0037] In the present invention, the palladium catalyst preferably includes palladium acetate and / or bis(triphenylphosphine)palladium dichloride.

[0038] In the present invention, the ligand of the palladium catalyst is specifically 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-PHOS).

[0039] In the present invention, the organic solvent preferably includes one or more of N,N-dimethylformamide, toluene and dioxane, and specifically DMF, toluene or dioxane in the embodiments.

[0040] In the present invention, the molar ratio of the compound of the structure shown in Formula 1 to the 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile is preferably 1:1. The molar ratio of the compound of the structure shown in Formula 1 to the base is preferably 1:(2-3), and in the embodiment it is specifically 1:2 or 1:3. The molar ratio of the compound of the structure shown in Formula 1 to the palladium catalyst is preferably 1:(0.01-0.05), and in the embodiment it is specifically 1:0.05. The molar ratio of the compound of the structure shown in Formula 1 to the ligand of the palladium catalyst is preferably 1:(0.01-0.05), and in the embodiment it is specifically 1:0.05. The present invention has no special requirements for the amount of the organic solvent, as long as the above raw materials are mixed evenly and the coupling reaction proceeds smoothly.

[0041] In the present invention, the mixing preferably includes the following steps: mixing the compound of the structure shown in Formula 1, 3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile, a base, a palladium catalyst and a ligand of the palladium catalyst, and then adding an organic solvent to mix. In the present invention, the protective gas is preferably an inert gas or nitrogen, and specifically nitrogen in the embodiment. The temperature of the coupling reaction is preferably 90 to 100°C, and specifically 100°C, 90°C or 95°C in the embodiment. The time of the coupling reaction is preferably 4 to 5h.

[0042] In the present invention, after the coupling reaction is completed, a coupling reaction liquid is obtained. After obtaining the coupling reaction liquid, the present invention preferably includes: cooling the coupling reaction liquid to room temperature and stirring and mixing with water to obtain a mixed reaction liquid; separating the mixed reaction liquid from solid and liquid to obtain a solid product; drying the solid product to obtain a resmetirol intermediate having a structure shown in formula (I). The stirring and mixing time is preferably 1 to 2 hours. After the coupling reaction liquid is mixed with water, a white solid product is precipitated. The solid-liquid separation is preferably filtration. The drying temperature is preferably 50 to 60°C.

[0043] The yield of 2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile obtained by the preparation method provided by the present invention is ≥88%, and specifically 89%, 91%, 88%, 92%, 93% or 90% in the embodiments. The HPLC purity of 2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile obtained by the preparation method provided by the present invention is ≥99%, and specifically 98.5%, 99.2%, 99.0%, 99.3%, 99.3%, 99.1% in the embodiments. The preparation method provided by the present invention avoids the safety risks brought by the diazotization reaction; and at the same time avoids the quality risks brought by nitrosamine impurities. The method provided by the invention has a simple synthesis process route and only one step reaction; it does not involve the use of dangerous reactions and dangerous reagents, and has high safety; the obtained product has high quality (high yield and purity), and is suitable for industrial production

[0044] In order to further illustrate the present invention, the technical solutions provided by the present invention are described in detail below in conjunction with embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0045] In the following embodiments: Compound 1 is specifically 4-bromo-2,6-dichlorophenol, and Compound 2 is specifically 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile.

[0046] Example 1

[0047] Compound 1 (20.1 g, 0.1 mol), compound 2 (13.8 g, 0.1 mol), potassium carbonate (41.4 g, 0.3 mol), palladium acetate (1.12 g, 0.005 mol) and X-PHOS (2.38 g, 0.005 mol) were sequentially placed in a 500 mL three-necked flask, toluene (200 mL) was added and stirred evenly, nitrogen was replaced three times, and the mixture was heated to 100 ° C under nitrogen protection for 4 h. A large amount of solid was precipitated after cooling to room temperature, and it was filtered by suction. The filter cake was transferred to a 500 mL three-necked flask, water (200 mL) was added, stirred for 1 h, and filtered. The filter cake was dried at 50 ° C to constant weight to obtain 26.6 g of yellow solid, with a yield of 89% and a HPLC purity of 98.5%.

[0048] Example 2

[0049] Compound 1 (20.1 g, 0.1 mol), compound 2 (13.8 g, 0.1 mol), potassium carbonate (41.4 g, 0.3 mol), palladium acetate (1.12 g, 0.005 mol) and X-PHOS (2.38 g, 0.005 mol) were sequentially placed in a 1000 mL three-necked flask, and DMF (200 mL) was added and stirred evenly. The mixture was replaced with nitrogen three times, and heated to 90 ° C under nitrogen protection for 4 h. After cooling to room temperature, water (200 mL) was added to precipitate a large amount of solid, stirred for 1 h, and filtered. The filter cake was dried at 50 ° C to constant weight to obtain 27.2 g of yellow solid, with a yield of 91% and a HPLC purity of 99.2%.

[0050] Example 3

[0051] Compound 1 (20.1 g, 0.1 mol), compound 2 (13.8 g, 0.1 mol), potassium carbonate (41.4 g, 0.3 mol), palladium acetate (1.12 g, 0.005 mol) and X-PHOS (2.38 g, 0.005 mol) were sequentially placed in a 1000 mL three-necked flask, dioxane (200 mL) was added and stirred evenly, nitrogen was replaced three times, and the mixture was heated to 95 ° C under nitrogen protection for 4 h. After cooling to room temperature, water (200 mL) was added to precipitate a large amount of solid, stirred for 1 h, and filtered. The filter cake was dried at 50 ° C to constant weight to obtain 26.3 g of yellow solid, with a yield of 88% and a HPLC purity of 99.0%.

[0052] Example 4

[0053] Compound 1 (20.1 g, 0.1 mol), compound 2 (13.8 g, 0.1 mol), cesium carbonate (65.2 g, 0.2 mol), bis(triphenylphosphine)palladium dichloride (3.5 g, 0.005 mol) and X-PHOS (2.38 g, 0.005 mol) were sequentially put into a 1000 mL three-necked flask, toluene (200 mL) was added and stirred evenly, nitrogen was replaced three times, and the mixture was heated to 95 ° C under nitrogen protection for 4 h. A large amount of solid was precipitated after cooling to room temperature, and the solid was filtered. The filter cake was transferred to a 500 mL three-necked flask, water (200 mL) was added, stirred for 1 h, and filtered. The filter cake was dried at 50 ° C to constant weight to obtain 27.5 g of yellow solid, with a yield of 92% and a HPLC purity of 99.3%.

[0054] Example 5

[0055] Compound 1 (20.1 g, 0.1 mol), compound 2 (13.8 g, 0.1 mol), cesium carbonate (65.2 g, 0.2 mol), bis(triphenylphosphine)palladium dichloride (3.5 g, 0.005 mol) and X-PHOS (2.38 g, 0.005 mol) were sequentially placed in a 1000 mL three-necked flask, and DMF (200 mL) was added and stirred evenly. The mixture was replaced with nitrogen three times, and heated to 90 ° C under nitrogen protection for 4 h. After cooling to room temperature, water (200 mL) was added to precipitate a large amount of solid, stirred for 1 h, and filtered. The filter cake was dried at 50 ° C to constant weight to obtain 27.8 g of yellow solid, with a yield of 93% and a HPLC purity of 99.3%.

[0056] Example 6

[0057] Compound 1 (20.1 g, 0.1 mol), compound 2 (13.8 g, 0.1 mol), cesium carbonate (65.2 g, 0.2 mol), bis(triphenylphosphine)palladium dichloride (3.5 g, 0.005 mol) and X-PHOS (2.38 g, 0.005 mol) were sequentially placed in a 1000 mL three-necked flask, dioxane (200 mL) was added and stirred evenly, nitrogen was replaced three times, and the mixture was heated to 95 ° C under nitrogen protection for 4 h. After cooling to room temperature, water (200 mL) was added to precipitate a large amount of solid, stirred for 1 h, and filtered. The filter cake was dried at 50 ° C to constant weight to obtain 26.9 g of yellow solid, with a yield of 90% and a HPLC purity of 99.1%.

[0058] Comparative Example 1

[0059] Compound 1 (20.1 g, 0.1 mol), compound 2 (13.8 g, 0.1 mol), potassium carbonate (41.4 g, 0.3 mol), palladium acetate (1.12 g, 0.005 mol) and X-PHOS (2.38 g, 0.005 mol) were sequentially placed in a 1000 mL three-necked flask, acetonitrile (200 mL) was added and stirred evenly, nitrogen was replaced three times, and the mixture was heated to 95 ° C under nitrogen protection for 4 h. After cooling to room temperature, water (200 mL) was added to precipitate more solids, stirred for 1 h, and filtered. The filter cake was dried at 50 ° C to constant weight to obtain 22.4 g of yellow solid, with a yield of 75% and a HPLC purity of 97.3%.

[0060] Comparative Example 1 is compared with Example 3. The organic solvent used in Comparative Example 1 is acetonitrile. Under the same other reaction conditions, the organic solvent used in Example 3 is dioxane. When acetonitrile is used in Comparative Example 1, the yield of the resmetirol intermediate of the structure shown in formula (I) is reduced from 88% in Example 3 to 75%, and the purity is reduced from 99.0% to 97.3%. It shows that Example 3 of the present invention can effectively improve the yield and purity of the target product of the resmetirol intermediate of the structure shown in formula (I) by selecting a suitable organic solvent for reaction.

[0061] Comparative Example 2

[0062] Compound 1 (20.1 g, 0.1 mol), compound 2 (13.8 g, 0.1 mol), potassium acetate (29.4 g, 0.3 mol), palladium acetate (1.12 g, 0.005 mol) and X-PHOS (2.38 g, 0.005 mol) were sequentially placed in a 1000 mL three-necked flask, and DMF (200 mL) was added and stirred evenly. The mixture was replaced with nitrogen three times, and heated to 95 ° C under nitrogen protection for 4 h. After cooling to room temperature, water (200 mL) was added to precipitate more solids, stirred for 1 h, and filtered. The filter cake was dried at 50 ° C to constant weight to obtain 25.0 g of yellow solid, with a yield of 82% and a HPLC purity of 97.8%.

[0063] Comparative Example 2 is compared with Example 3. The base used in Comparative Example 2 is potassium acetate. Under the same other reaction conditions, the base used in Example 3 is potassium carbonate. When potassium acetate is used in Comparative Example 2, the yield of the resmetirol intermediate of the structure shown in formula (I) is reduced from 88% in Example 3 to 82%, and the purity is reduced from 99.0% to 97.8%. It shows that Example 3 of the present invention can effectively improve the yield and purity of the target product of the resmetirol intermediate of the structure shown in formula (I) by selecting the appropriate type of base for reaction.

[0064] Comparative Example 3

[0065] Compound 1 (20.1 g, 0.1 mol), compound 2 (13.8 g, 0.1 mol), potassium carbonate (41.4 g, 0.3 mol), palladium acetate (1.12 g, 0.005 mol) and X-PHOS (2.38 g, 0.005 mol) were sequentially placed in a 500 mL three-necked flask, toluene (200 mL) was added and stirred evenly, nitrogen was replaced three times, and the mixture was heated to 75 ° C under nitrogen protection for 4 h. A large amount of solid was precipitated after cooling to room temperature, and the solid was filtered. The filter cake was transferred to a 500 mL three-necked flask, water (200 mL) was added, stirred for 1 h, and filtered. The filter cake was dried at 50 ° C to constant weight to obtain 25.1 g of yellow solid, with a yield of 84% and a HPLC purity of 86.4%.

[0066] Comparative Example 3 is compared with Example 1. The reaction temperature of Comparative Example 3 is 75°C. Under the same other reaction conditions, the reaction temperature in Example 1 is 100°C, while the reaction temperature in Comparative Example 3 is 75°C. The yield of the resmetirol intermediate of the structure shown in formula (I) obtained is reduced from 89% in Example 1 to 84%, and the purity is reduced from 98.5% to 86.4%. It shows that Example 1 of the present invention can effectively improve the yield and purity of the target product of the resmetirol intermediate of the structure shown in formula (I) by reasonably setting the reaction temperature.

[0067] Comparative Example 4

[0068] Compound 1 (20.1 g, 0.1 mol), compound 2 (13.8 g, 0.1 mol), cesium carbonate (32.6 g, 0.1 mol), bis(triphenylphosphine)palladium dichloride (3.5 g, 0.005 mol) and X-PHOS (2.38 g, 0.005 mol) were sequentially placed in a 1000 mL three-necked flask, and DMF (200 mL) was added and stirred evenly. The mixture was replaced with nitrogen three times, and heated to 90 ° C under nitrogen protection for 4 h. After cooling to room temperature, water (200 mL) was added to precipitate a large amount of solid, stirred for 1 h, and filtered. The filter cake was dried at 50 ° C to constant weight to obtain 23.0 g of yellow solid, with a yield of 77% and a HPLC purity of 89.7%.

[0069] Comparative Example 4 is compared with Example 5. In Comparative Example 4, the molar ratio of compound 1 to cesium carbonate is 1:1. Under the same other reaction conditions, the molar ratio of compound 1 to cesium carbonate in Example 5 is 1:2. When the molar ratio of compound 1 to cesium carbonate in Comparative Example 4 is 1:1, the yield of the resmetirol intermediate of the structure shown in formula (I) obtained is reduced from 93% in Example 5 to 77%, and the purity is reduced from 99.3% to 89.7%. It shows that by reasonably setting the molar ratio of compound 1 to the base in Example 5 of the present invention, the yield and purity of the target product of the resmetirol intermediate of the structure shown in formula (I) can be effectively improved.

[0070] From the above examples, it can be seen that the preparation method provided by the present invention uses 4-bromo-2,6-dichlorophenol and 3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile as initial raw materials, and obtains the target compound 2-(3,5-dichloro-4-hydroxyphenyl)-3,5-dioxy-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile in one step by palladium catalytic coupling in an alkaline environment. The preparation method of the resmetirol intermediate provided by the present invention avoids the safety risks brought by the diazotization reaction; at the same time, it avoids the quality risks brought by nitrosamine impurities. The method provided by the present invention has a simple synthesis process route, with only one step reaction; it does not involve the use of dangerous reactions and dangerous reagents, and has high safety; the obtained product has high quality and is suitable for industrial production.

[0071] Although the above embodiment describes the present invention in detail, it is only a part of the embodiments of the present invention, not all of the embodiments. Other embodiments can be obtained based on this embodiment without creativity, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for preparing a resmetirole intermediate, characterized in that: The following steps are involved: The compound of the structure shown in Formula 1, 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile, a base, a palladium catalyst, a ligand of the palladium catalyst and an organic solvent are mixed, and a coupling reaction is carried out in a protective gas atmosphere to obtain a resmetirol intermediate of the structure shown in Formula (I); In formula 1: R is Br or I.

2. The preparation method according to claim 1, characterized in that: The organic solvent includes one or more of N,N-dimethylformamide, toluene and dioxane.

3. The preparation method according to claim 1 or 2, characterized in that: The temperature of the coupling reaction is 90-100°C.

4. The preparation method according to claim 1, characterized in that: The molar ratio of the compound of the structure shown in Formula 1 to the 3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile is 1:

1.

5. The preparation method according to claim 1, characterized in that: The base includes an alkali metal carbonate.

6. The preparation method according to claim 1, 4 or 5, characterized in that: The molar ratio of the compound represented by the structure of Formula 1 to the base is 1:(2-3).

7. The preparation method according to claim 1, characterized in that: The palladium catalyst includes palladium acetate and / or bis(triphenylphosphine)palladium dichloride.

8. The preparation method according to claim 1, 4 or 7, characterized in that: The molar ratio of the compound with the structure shown in Formula 1 to the palladium catalyst is 1:(0.01-0.05).

9. The preparation method according to claim 1, characterized in that: The ligand of the palladium catalyst is 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl.

10. The preparation method according to claim 1, 4 or 9, characterized in that: The molar ratio of the compound having the structure shown in Formula 1 to the ligand of the palladium catalyst is 1:(0.01-0.05).

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