Preparation method of remetirol

Abstract

The invention belongs to the field of medicine synthesis, and particularly relates to a preparation method of Remetirom (Remetirom). The preparation method comprises the following steps: reacting 2, 3, 6-dichloropyridazine, isobutyric acid, a catalyst, acid and a free radical initiator in a solvent to obtain an intermediate I; reacting the intermediate I with 4-amino-2, 6-dichlorophenol under the conditions of inert gas protection, catalyst and alkalinity to obtain an intermediate II; reacting the intermediate II with nitrous acid ester and N-cyanoacetyl ethyl carbamate under an acidic condition to obtain an intermediate III; and the intermediate III is subjected to a one-pot self-reaction in a carboxylate-carboxylic acid solvent to obtain the remetirol. The method provided by the invention has the advantages of short steps, low cost, mild reaction conditions, high total yield, suitability for industrial production and the like.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of Resmetirom. Background Art

[0002] Resmetirom (MGL-3196) is an oral small molecule agonist of the thyroid hormone receptor β subtype (THR-β) developed by Madrigal Pharmaceuticals INC. Resmetirom received marketing approval from the U.S. FDA on March 14, 2024, for the treatment of adult patients with nonalcoholic steatohepatitis (NASH) associated with liver fibrosis. Its chemical structure is shown below:

[0003]

[0004] Existing patents report the preparation method of Remetirol:

[0005] WO2007009913A1 is the original patent for remedirol. The reported method (Method 1) involves a side reaction of aminoacetylation during the hydrolysis of intermediate 2, necessitating further hydrolysis to remove the acetyl group and produce intermediate 4. The coupling reaction of intermediate 4 with ethyl N-cyanoacetylcarbamate requires the initial preparation of the diazonium salt, a cumbersome procedure. This method consists of six steps, with an overall yield of only 8.9%.

[0006] Method 1:

[0007]

[0008] Patent WO2014043706A1 (Method 2), reported by Madrigal Pharmaceutical, the developer of Remetirazole, involves multiple steps (eight). The use of isopropenylmagnesium bromide in the synthesis of intermediate 4 generates significant heat, increasing the risk of the reaction. Furthermore, this route involves the use of expensive reagents such as cesium carbonate and isopropenylmagnesium bromide, resulting in high production costs.

[0009] Method 2:

[0010]

[0011] Therefore, there is still a need to develop a more efficient, low-cost and mild method for preparing resmifentanil. Summary of the Invention

[0012] The object of the present invention is to provide a preparation method of Resmetirom.

[0013] To achieve the above purpose, the present invention adopts the following technical solutions:

[0014] A preparation method of Remetirol: the reaction formula is

[0015]

[0016] (1) 3,6-dichloropyridazine, isobutyric acid, a catalyst, an acid, and a free radical initiator react in a solvent to obtain intermediate I;

[0017] (2) Under inert gas protection, catalyst and alkaline conditions, intermediate I reacts with 4-amino-2,6-dichlorophenol to obtain intermediate II;

[0018] (3) Intermediate II reacts with nitrite and N-cyanoacetylcarbamate under acidic conditions to obtain intermediate III;

[0019] (4) Intermediate III undergoes a one-pot self-reaction in a carboxylate-carboxylic acid solvent to obtain remdesivir.

[0020] In the step (1), 3,6-dichloropyridazine, isobutyric acid, a catalyst, an acid and a free radical initiator are added to a solvent, reacted at 40-90° C. for 0.5-6 hours, cooled after the reaction, extracted, dried, and concentrated under reduced pressure to obtain an intermediate I; wherein the molar ratio of 3,6-dichloropyridazine, isobutyric acid, the catalyst, the acid and the free radical initiator is 1:(1-1.5):(0.1-0.5):(0.2-3):(1-5).

[0021] In the step (1), the catalyst is silver nitrate, ferrous sulfate or manganese acetate catalyst;

[0022] The acid is one or more of sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, formic acid, acetic acid or propionic acid; preferably, the acid is sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, formic acid, acetic acid or propionic acid;

[0023] The free radical initiator is one or more of ammonium persulfate, sodium persulfate, potassium persulfate, hydrogen peroxide, tert-butyl hydroperoxide, tert-amyl hydroperoxide, diisopropylbenzene hydroperoxide, acetyl peroxide, benzoyl peroxide, 3,5,5-trimethylhexanoyl peroxide, dilauroyl peroxide, m-chloroperbenzoic acid, peracetic acid, cyclohexanone peroxide, diisopropylbenzene peroxide or di-tert-butyl peroxide; preferably, the free radical initiator is ammonium persulfate, sodium persulfate, potassium persulfate or hydrogen peroxide.

[0024] The solvent is one or more of water, methanol, ethanol, n-butanol, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, toluene, acetone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, and 1,4-dioxane. Preferably, the solvent is water, chloroform, dichloroethane, tetrahydrofuran, or 2-methyltetrahydrofuran.

[0025] In the step (2), the intermediate I, 4-amino-2,6-dichlorophenol, a base and a catalyst are added to a solvent, protected by inert gas, and reacted at a temperature of 70 to 120° C. for 12 to 36 hours. After the reaction is completed, the mixture is cooled, the pH is adjusted, filtered, extracted, dried, concentrated under reduced pressure, pulped, filtered, and dried to obtain the intermediate II; wherein the molar ratio of the intermediate I, 4-amino-2,6-dichlorophenol, the catalyst and the base is 1:(0.8-1.4):(0-1):(1.5-5);

[0026] In the step (2), the catalyst is one of cuprous iodide, potassium iodide or sodium iodide;

[0027] The base is one of potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, triethylamine, or N,N-diisopropylethylamine; preferably, the base is potassium carbonate, sodium carbonate, or cesium carbonate; the solvent is one of N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, toluene, acetonitrile, N-methylpyrrolidone, or dimethyl sulfoxide; preferably, the solvent is N,N-dimethylacetamide, N,N-dimethylformamide, N-methylpyrrolidone, or dimethyl sulfoxide.

[0028] In the step (3), intermediate II, N-cyanoacetyl ethyl carbamate, and acid are added to a solvent, the mixture is stirred under controlled temperature, nitrite is added, and the mixture is reacted at a controlled temperature of -5 to 5°C for 0.5 to 6 hours. After the reaction is completed, water is added, the mixture is filtered, pulped, filtered, and dried to obtain intermediate III; wherein the molar ratio of intermediate II, N-cyanoacetyl ethyl carbamate, and nitrite is 1:(1-1.5):(1-1.5).

[0029] The acid is one or more of formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid or hydrobromic acid;

[0030] The solvent is one or more of water, acetonitrile, acetone, 1,4-dioxane, tetrahydrofuran or 2-methyltetrahydrofuran;

[0031] The nitrite is butyl nitrite, isobutyl nitrite, tert-butyl nitrite, amyl nitrite, isoamyl nitrite or hexyl nitrite.

[0032] In the step (4), the intermediate III and the carboxylate are added to a carboxylic acid solvent, and the reaction is carried out at a temperature of 80 to 118° C. for 12 to 48 hours. After the reaction is completed, the mixture is cooled, water is added, filtered, decolorized, concentrated, pulped, filtered, and dried to obtain Remetirol; wherein the molar ratio of the intermediate III to the carboxylate is 1:(2-8).

[0033] In the step (4), the carboxylate is one of potassium formate, potassium acetate, sodium formate or sodium acetate; and the carboxylic acid solvent is one of formic acid, acetic acid or propionic acid.

[0034] Advantages of the present invention

[0035] 1. After completion of each step of the synthesis route of the present invention, only conventional post-treatment is required and no chromatography column purification is required, resulting in fewer and controllable impurities;

[0036] 2. The synthetic route of the present invention integrates the hydrolysis and aromatic cyclization of the 2-chloropyridazine ring into one step, avoiding the amino protection-deprotection operation and simplifying the preparation process;

[0037] 3. The synthetic route of the present invention has only four reaction steps, high atom economy, mild reaction conditions, a total yield of up to 45.0%, and the raw materials used are low in cost. It is an economical method for synthesizing Resmetirom and is worthy of industrial promotion. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] Figure 1 This is the NMR spectrum of the intermediate III provided in the embodiment of the present invention.

[0039] Figure 2 This is the nuclear magnetic resonance spectrum of Resmetirom provided in an embodiment of the present invention. DETAILED DESCRIPTION

[0040] Unless otherwise specified, the raw materials, reagents, methods, etc. used in the examples are conventional raw materials, reagents, and methods in the art.

[0041] Example 1

[0042] (1) Preparation of 3,6-dichloro-4-isopropylpyridazine (Intermediate I):

[0043] 3,6-Dichloropyrazine (30.0 g, 203 mmol), isobutyric acid (18.8 g, 213 mmol), silver nitrate (3.4 g, 20 mmol), 100 mL of water, and trifluoroacetic acid (11.6 g, 101 mmol) were added to 150 mL of dichloroethane and stirred at 55°C to dissolve. 69.4 g (304 mmol) of an aqueous solution of ammonium persulfate was added dropwise to the reaction mixture, which was heated to 70°C for 4 hours and then cooled to room temperature. The mixture was quenched by adding saturated sodium bicarbonate solution, extracted with dichloromethane, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain 35.4 g of a slightly yellow, transparent oil with a yield of 92% and an HPLC purity of 91%.

[0044] 1 H NMR (400MHz, DMSO-d6) δ7.99 (s, 1H), 3.16 (hept, J = 6.8Hz, 1H), 1.26 (d, J = 6.9Hz, 6H). MS (ESI) m / z: 191.0 [MH] ﹣ .

[0045] (2) Preparation of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline (Intermediate II):

[0046] Intermediate I (32.0 g, 168 mmol) and 4-amino-2,6-dichlorophenol (35.8 g, 202 mmol) were dissolved in 120 mL of N,N-dimethylacetamide. Potassium carbonate (68.9 g, 505 mmol) and cuprous iodide (16.1 g, 84 mmol) were added. The mixture was degassed with nitrogen for 10 min, incubated at 90°C for 24 h, and then cooled to room temperature. The reaction mixture was poured into 1.5 L of water, and the pH was adjusted to 8 with 1N hydrochloric acid. 1.0 L of ethyl acetate was added, stirred, and filtered. The aqueous phase was extracted with ethyl acetate, washed sequentially with water, 5% lithium chloride solution, and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The mixture was slurried with a mixed solvent of ether and n-heptane (3:2, v:v), filtered, and dried to obtain 45.2 g of a white solid with an 81% yield and 90% HPLC purity.

[0047] 1 H NMR (400MHz, DMSO-d6) δ7.67(s,1H),6.72(s,2H),5.69(s,2H),3.16(hept,J=6.8Hz,1H),1.28(d,J=6.9Hz,6H).MS(ESI)m / z:330.0[MH] - .

[0048] (3) Preparation of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)yl)phenyl)hydrazinocarbonyl)carbamate (Intermediate III):

[0049] Intermediate II (20.0 g, 60 mmol) and ethyl N-cyanoacetylcarbamate (10.4 g, 66 mmol) were dissolved in a mixed solution of 100 mL of acetonitrile and 100 mL of acetic acid. The mixture was stirred for 5 min under ice bath conditions, tert-butyl nitrite (7.5 g, 73 mmol) was added and reacted for 3 hours. 1 L of water was added to the mixture and filtered. The crude product was slurried with an acetonitrile-water mixed solvent (3:10, V:V), filtered, washed with water and petroleum ether in sequence, and dried to obtain 25.5 g of a yellow solid (see Figure 1 ), the yield was 85%, and the HPLC purity was 97%.

[0050] 1 H NMR(400MHz,DMSO-d6)δ12.16(s,1H),10.92(s,1H),8.04(s,2H),7.81(s,1H),4.2 1(q,J=7.1Hz,2H),3.24-3.13(m,1H),1.40-1.24(m,9H).MS(ESI)m / z:520.9[M+Na] + .

[0051] (4) Preparation of Resmetirom:

[0052] Intermediate III (15.2 g, 31 mmol) and potassium acetate (15.0 g, 153 mmol) were added to 200 mL of acetic acid, reacted at 100 ° C for 48 h, and cooled to 0 ° C. Diluted with 1 L of cold water and stirred for 30 minutes. Filtered, the filter cake was washed with water, 50% ethanol solution and petroleum ether in sequence. The filter cake was dissolved in 1.5 L of acetonitrile, decolorized with activated carbon, and filtered. The filtrate was concentrated under reduced pressure and then added with water for pulping, filtered, washed with water and petroleum ether, and dried to obtain 9.4 g of light yellow solid Remetirol (see Figure 2 ), the yield was 71% and the HPLC purity was 99%.

[0053] 1 H NMR (400MHz, DMSO-d6) δ13.28(s,1H),12.24(s,1H),7.79(s,2H),7.45(s,1H),3.12-2.99(m,1H),1.20(d,J=6.9Hz,6H). 13C NMR(101MHz,DMSO)δ160.03,155.04,154.44,151.61,147.42,145.78,137.76, 128.85,127.14,123.34,119.78,112.58,28.22,20.94.MS(ESI)m / z:433.0[MH] - .

[0054] Example 2

[0055] (1) Preparation of 3,6-dichloro-4-isopropylpyridazine (Intermediate I):

[0056] 3,6-Dichloropyrazine (30.0 g, 203 mmol), isobutyric acid (18.8 g, 213 mmol), silver nitrate (6.8 g, 40 mmol), 100 mL of water, and trifluoroacetic acid (69.4 g, 608 mmol) were added to 150 mL of dichloroethane and stirred at 55°C to dissolve. 164.4 g (608 mmol) of potassium persulfate solution was added dropwise to the reaction mixture, heated to 80°C for 2 h, and cooled to room temperature. Saturated sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with dichloromethane. The mixture was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain 34.7 g of a slightly yellow, transparent oily product with a yield of 90% and an HPLC purity of 90%.

[0057] (2) Preparation of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline (Intermediate II):

[0058] Intermediate I (32.0 g, 168 mmol) and 4-amino-2,6-dichlorophenol (38.7 g, 219 mmol) were dissolved in 120 mL of N,N-dimethylacetamide, and cesium carbonate (82.3 g, 253 mmol) and cuprous iodide (16.1 g, 84 mmol) were added. The mixture was degassed with nitrogen for 10 min, incubated at 90°C for 24 h, and then cooled to room temperature. The reaction mixture was poured into 1.5 L of water, and the pH was adjusted to 8 with 1N hydrochloric acid. 1.0 L of ethyl acetate was added, stirred, and filtered. The aqueous phase was extracted with ethyl acetate, washed sequentially with water, 5% lithium chloride solution, and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The mixture was slurried with a mixed solvent of ether and n-heptane (3:2, v:v), filtered, and dried to obtain 44.6 g of a white solid with an 80% yield and 90% HPLC purity.

[0059] (3) Preparation of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)yl)phenyl)hydrazinocarbonyl)carbamate (Intermediate III):

[0060] Intermediate II (20.0 g, 60 mmol) and ethyl N-cyanoacetylcarbamate (10.4 g, 66 mmol) were dissolved in a mixture of 100 mL of acetonitrile and 100 mL of propionic acid. The mixture was stirred for 5 min in an ice bath, and tert-butyl nitrite (9.3 g, 90 mmol) was added and reacted for 4 hours. 1 L of water was added to the mixture and the mixture was filtered. The crude product was slurried with an acetonitrile-water mixture (3:10, v:v), filtered, washed sequentially with water and petroleum ether, and dried to obtain 25.3 g of a yellow solid with a yield of 84% and an HPLC purity of 97%.

[0061] (4) Preparation of Resmetirom:

[0062] Intermediate III (15.2 g, 31 mmol) and sodium acetate (12.5 g, 153 mmol) were added to 200 mL of acetic acid, reacted at 110 ° C for 36 h, and cooled to 0 ° C. Diluted with 1 L of cold water and stirred for 30 minutes. Filtered, the filter cake was washed with water, 50% ethanol solution and petroleum ether in sequence. The filter cake was dissolved in 1.5 L of acetonitrile, decolorized with activated carbon, and filtered. The filtrate was concentrated under reduced pressure and then added with water for pulping, filtered, washed with water and petroleum ether, and dried to obtain 9.4 g of light orange solid Remetirol, with a yield of 71% and an HPLC purity of 99%.

[0063] Example 3

[0064] (1) Preparation of 3,6-dichloro-4-isopropylpyridazine (Intermediate I):

[0065] 3,6-Dichloropyrazine (30.0 g, 203 mmol), isobutyric acid (18.8 g, 213 mmol), silver nitrate (17.2 g, 101 mmol), 300 mL of water, and concentrated sulfuric acid (4.0 g, 40 mmol) were added to 150 mL of dichloroethane and stirred at 55°C to dissolve. 138.8 g (608 mmol) of an aqueous solution of ammonium persulfate was added dropwise to the reaction mixture, which was heated to 70°C and allowed to react for 2 h before cooling to room temperature. The mixture was quenched by adding saturated sodium bicarbonate solution, extracted with dichloromethane, washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to obtain 35.1 g of a slightly yellow, transparent oily product with a yield of 91% and an HPLC purity of 90%.

[0066] (2) Preparation of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)oxy)aniline (Intermediate II):

[0067] Intermediate I (32.0 g, 168 mmol) and subsequently 4-amino-2,6-dichlorophenol (35.8 g, 202 mmol) were dissolved in 120 mL of N-methylpyrrolidone. Potassium carbonate (68.9 g, 505 mmol) and cuprous iodide (32.2 g, 168 mmol) were added sequentially. The mixture was degassed with nitrogen for 10 min, incubated at 90°C for 30 h, and then cooled to room temperature. The reaction mixture was poured into 1.5 L of water, and the pH was adjusted to 8 with 1N hydrochloric acid. 1.0 L of ethyl acetate was added, stirred, and filtered. The aqueous phase was extracted with ethyl acetate, washed sequentially with water, 5% lithium chloride solution, and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The mixture was slurried with a mixed solvent of ether and n-heptane (3:2, v:v), filtered, and dried to yield 45.2 g of a slightly yellow solid with an 81% yield and 89% HPLC purity.

[0068] (3) Preparation of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl)yl)phenyl)hydrazinocarbonyl)carbamate (Intermediate III):

[0069] Intermediate II (20.0 g, 60 mmol) and ethyl N-cyanoacetylcarbamate (12.3 g, 78 mmol) were dissolved in a mixture of 100 mL of acetonitrile and 100 mL of acetic acid. The mixture was stirred for 5 min under ice-bath conditions, and tert-butyl nitrite (8.1 g, 79 mmol) was added and reacted for 2 h. 1 L of water was added to the mixture and filtered. The crude product was slurried with an acetonitrile-water mixture (3:10, v:v), filtered, washed sequentially with water and petroleum ether, and dried to obtain 25.2 g of a yellow solid with an 84% yield and 97% HPLC purity.

[0070] (4) Preparation of Resmetirom:

[0071] Intermediate III (15.2 g, 31 mmol) and sodium acetate (7.5 g, 92 mmol) were added to 200 mL of acetic acid, reacted at 118 ° C for 24 h, and cooled to 0 ° C. Diluted with 1 L of cold water and stirred for 30 minutes. Filtered, the filter cake was washed with water, 50% ethanol solution and petroleum ether. The filter cake was dissolved in 1.5 L of acetonitrile, decolorized with activated carbon, and filtered. After the filtrate was decompressed, water was added to make a pulp, filtered, washed with water and petroleum ether, and dried to obtain 9.3 g of light orange solid Remetirol, with a yield of 70% and an HPLC purity of 99%.

[0072] Although the embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and are not to be construed as limiting the present invention. A person skilled in the art may make several modifications and improvements without departing from the concept of the present application, and these modifications and improvements shall fall within the scope of protection of the present application.

Claims

1. A method for preparing resmetirole, characterized in that: The reaction formula is (1) 3,6-dichloropyridazine, isobutyric acid, a catalyst, an acid, and a free radical initiator react in a solvent to obtain intermediate I; (2) Under inert gas protection, catalyst and alkaline conditions, intermediate I reacts with 4-amino-2,6-dichlorophenol to obtain intermediate II; (3) Intermediate II reacts with nitrite and N-cyanoacetylcarbamate under acidic conditions to obtain intermediate III; (4) Intermediate III undergoes a one-pot self-reaction in a carboxylate-carboxylic acid solvent to obtain remdesivir.

2. The method according to claim 1, wherein: In the step (1), 3,6-dichloropyridazine, isobutyric acid, a catalyst, an acid and a free radical initiator are added to a solvent, reacted at 40-90° C. for 0.5-6 hours, cooled after the reaction, extracted, dried, and concentrated under reduced pressure to obtain an intermediate I; wherein the molar ratio of 3,6-dichloropyridazine, isobutyric acid, the catalyst, the acid and the free radical initiator is 1:(1-1.5):(0.1-0.5):(0.2-3):(1-5).

3. The method according to claim 1 or 2, characterized in that: In the step (1), the catalyst is silver nitrate, ferrous sulfate or manganese acetate catalyst; The acid is one or more of sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, formic acid, acetic acid or propionic acid; The free radical initiator is one or more of ammonium persulfate, sodium persulfate, potassium persulfate, hydrogen peroxide, tert-butyl hydroperoxide, tert-amyl hydroperoxide, diisopropylbenzene hydroperoxide, acetyl peroxide, benzoyl peroxide, 3,5,5-trimethylhexanoyl peroxide, dilauroyl peroxide, m-chloroperbenzoic acid, peracetic acid, cyclohexanone peroxide, diisopropylbenzene peroxide or di-tert-butyl peroxide; The solvent is one or more of water, methanol, ethanol, n-butanol, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, chloroform, carbon tetrachloride, dichloroethane, toluene, acetone, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, and 1,4-dioxane.

4. The method according to claim 1, wherein: In the step (2), the intermediate I, 4-amino-2,6-dichlorophenol, a base and a catalyst are added to a solvent, protected by inert gas, and reacted at a temperature of 70 to 120° C. for 12 to 36 hours. After the reaction is completed, the reaction is cooled, the pH is adjusted, the reaction is filtered, extracted, dried, concentrated under reduced pressure, pulped, filtered, and dried to obtain the intermediate II; wherein the molar ratio of the intermediate I, 4-amino-2,6-dichlorophenol, the catalyst and the base is 1:(0.8-1.4):(0-1):(1.5-5).

5. The method according to claim 1 or 4, characterized in that: In the step (2), the catalyst is one of cuprous iodide, potassium iodide or sodium iodide; The base is one of potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, triethylamine or N,N-diisopropylethylamine; The solvent is one of N,N-dimethylacetamide, N,N-dimethylformamide, 1,4-dioxane, toluene, acetonitrile, N-methylpyrrolidone or dimethyl sulfoxide.

6. The method according to claim 1, wherein: In the step (3), intermediate II, N-cyanoacetyl ethyl carbamate, and acid are added to a solvent, the mixture is stirred under controlled temperature, nitrite is added, and the mixture is reacted at a controlled temperature of -5 to 5°C for 0.5 to 6 hours. After the reaction is completed, water is added, the mixture is filtered, pulped, filtered, and dried to obtain intermediate III; wherein the molar ratio of intermediate II, N-cyanoacetyl ethyl carbamate, and nitrite is 1:(1-1.5):(1-1.5).

7. The method according to claim 1 or 6, characterized in that: In the step (3), the acid is one or more of formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid or hydrobromic acid; the solvent is one or more of water, acetonitrile, acetone, 1,4-dioxane, tetrahydrofuran or 2-methyltetrahydrofuran; and the nitrite is butyl nitrite, isobutyl nitrite, tert-butyl nitrite, amyl nitrite, isoamyl nitrite or hexyl nitrite.

8. The method according to claim 1, wherein: In the step (4), the intermediate III and the carboxylate are added to a carboxylic acid solvent, and the reaction is carried out at a temperature of 80 to 118° C. for 12 to 48 hours. After the reaction is completed, the mixture is cooled, water is added, filtered, decolorized, concentrated, pulped, filtered, and dried to obtain Remetirol; wherein the molar ratio of the intermediate III to the carboxylate is 1:(2-8).

9. The method according to claim 1, wherein: In the step (4), the carboxylate is one of potassium formate, potassium acetate, sodium formate or sodium acetate; and the carboxylic acid solvent is one of formic acid, acetic acid or propionic acid.

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