A method for preparing a key intermediate of Ensetivir

Abstract

The present invention provides a method for synthesizing 1-methyl-3-hydroxymethyl-1,2,4-triazole, a key intermediate of an anti-new coronavirus drug Ensetwei. It includes a two-step reaction. In the first step, 1,2,4-triazole-3-methyl formate and paraformaldehyde are added to a solvent in a certain proportion, a certain amount of catalyst is added after mixing evenly, and the reaction is stirred at a certain temperature until the raw material is completely converted. The reaction solution is cooled, concentrated under reduced pressure to remove part of the solvent, and then filtered to obtain a hydroxymethylated intermediate. In the second step, a solid catalyst precursor is loaded into a fixed bed reactor, and hydrogen is introduced after nitrogen replacement and heating, and in-situ reduction is performed to obtain a catalyst for catalytic hydrogenation. The product of the first step reaction is dissolved in a solvent and then introduced into the reactor at a certain flow rate. The reaction solution flowing out of the end of the reactor is cooled, concentrated under reduced pressure to remove the solvent, and purified to obtain the target product 1-methyl-3-hydroxymethyl-1,2,4-triazole. The present invention has the characteristics of high product yield, good quality, and low environmental pollution, and meets the requirements of industrial clean production.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug intermediate preparation, and specifically relates to a method for preparing an anti-new coronavirus drug intermediate 1-methyl-3-hydroxymethyl-1,2,4-triazole. Background Art

[0002] Ensitrelvir is a small molecule 3CL protease inhibitor newly developed by Shionogi Co., Ltd. of Japan. 1-Methyl-3-hydroxymethyl-1,2,4-triazole is a key intermediate for synthesizing the hydrophilic structure of the drug and plays an important role in the activity of the drug.

[0003] The currently reported synthesis method of 1-methyl-3-hydroxymethyl-1,2,4-triazole is a two-step synthesis through the selective alkylation reaction of 1,2,4-triazole-3-carboxylate and the ester reduction reaction. In the alkylation process, methyl iodide and dimethyl sulfate are commonly used as methylating agents. These methylating agents are highly toxic and have poor chemical selectivity, and are prone to produce ortho-methylated byproducts.

[0004] During the ester reduction process, DIBAL-H, lithium aluminum tetrahydride, and sodium borohydride are required as reducing agents. These reducing agents inevitably use water as a quenching agent during the post-reaction treatment process; since the product has excellent water solubility, it brings great difficulties to the purification of the product, and ultimately affects the quality and yield of the product.

[0005] Therefore, there is an urgent need for a new method for synthesizing 1-methyl-3-hydroxymethyl-1,2,4-triazole with good selectivity, simple operation process and high product quality. Summary of the invention

[0006] Aiming at the problems of poor chemical selectivity, difficulty in product purification and unstable product quality in the existing 1-methyl-3-hydroxymethyl-1,2,4-triazole preparation process, the present invention provides a new method for synthesizing 1-methyl-3-hydroxymethyl-1,2,4-triazole, which has the advantages of good selectivity, simple operation process and high product quality.

[0007] The technical solution of the present invention comprises a two-step reaction:

[0008] The first step is the selective hydroxymethylation reaction:

[0009] The chemical reaction equation is as follows:

[0010]

[0011] Mix 1,2,4-triazole-3-carboxylic acid methyl ester and paraformaldehyde in a certain proportion and add them to a reactor. Add a solvent and stir evenly, then add a catalyst. Stir for a certain time at a certain temperature to allow 1,2,4-triazole-3-carboxylic acid methyl ester to react completely. Cool the reaction liquid, concentrate under reduced pressure to remove part of the solvent, filter the resulting solid compound, wash it, and dry it to obtain 1-hydroxymethyl-1,2,4-triazole-3-carboxylic acid methyl ester;

[0012] Preferably, in the first step reaction, the molar ratio of 1,2,4-triazole-3-carboxylic acid methyl ester to formaldehyde is 1:1-1:8.

[0013] Preferably, the solvent in the first step reaction is at least one of methanol, ethanol, isopropanol and tert-butanol.

[0014] Preferably, the catalyst in the first step reaction is at least one of sodium hydroxide, sodium acetate, sodium carbonate, triethylamine, triethylenediamine, and diethylamine.

[0015] Preferably, the reaction temperature in the first step reaction is room temperature to 80° C., and the reaction time is 10 to 24 hours.

[0016] The second step is catalytic hydrogenation reaction:

[0017] The chemical reaction equation is as follows:

[0018]

[0019] The supported catalyst precursor is loaded into a fixed bed reactor, and nitrogen is introduced for replacement, and then hydrogen is introduced for heating and in-situ reduction to obtain a catalyst for catalytic hydrogenation. The product of the first step reaction is dissolved and introduced into the reactor at a certain flow rate. The reaction liquid flowing out from the end of the reactor is cooled, concentrated under reduced pressure to remove the solvent, and purified to obtain the target product 1-methyl-3-hydroxymethyl-1,2,4-triazole.

[0020] Preferably, the supported catalyst in the second step reaction is γ-Al 2 O 3 The invention relates to a supported catalyst with Cu, Co, Zn, Fe and Ni as carrier and at least one of Cu, Co, Zn, Fe and Ni as active component, and the supported amount is 10-30%.

[0021] The preparation method of the catalytic hydrogenation solid catalyst is as follows: dissolving metal nitrate, obtaining a catalyst precursor through impregnation, drying and calcination, and then reducing it in situ with hydrogen.

[0022] With 20% Cu / γ-Al catalyst 2 O 3 For example, the preparation method is as follows: 24.1g Cu(NO 3 )2 ·3H 2 O was dissolved in 300 mL of deionized water to prepare solution a. 21.7 g of Na 2 CO 3 Solution b was prepared by dissolving in 300 mL of deionized water. At room temperature, solution a and solution b were slowly added dropwise to 300 mL of deionized water while stirring vigorously. During the addition, the pH value was strictly controlled to be between 7 and 8. After the addition, the mixture was aged for 1 h, filtered, washed with deionized water, and the filter cake was dried at 120 ° C for 6 h. The obtained solid was fully mixed and ground with 30.30 g of pseudo-boehmite and 50 mL of deionized water, and then filled into a molding machine (diameter 3 mm) for extrusion molding. The molded catalyst was dried at 100 ° C for 8 h, and then calcined at 500 ° C in a muffle furnace for 6 h, and then the catalyst was cut into small sections of 3 to 5 mm. Before use, the catalyst must be reduced at 360 ° C for 3 h in a hydrogen atmosphere.

[0023] Preferably, the loading amount of the active component in the second step reaction is 10-30%.

[0024] Preferably, the feed rate in the second step reaction is 0.5-3.0 mL / min, the hydrogen pressure is 2.0-7.0 MPa, and the reaction temperature is 60-160°C.

[0025] Preferably, the purification method in the second step reaction is recrystallization.

[0026] Preferably, the recrystallization solvent in the second step reaction is methanol, ethanol, isopropanol, tert-butanol, methyl tert-butyl ether, n-hexane, or n-heptane.

[0027] The invention provides a two-step method for preparing 1-methyl-3-hydroxymethyl-1,2,4-triazole, wherein 1-methyl-3-hydroxymethyl-1,2,4-triazole is completely reacted to generate 1-hydroxymethyl-1,2,4-triazole-3-methyl carboxylate, and then catalytic hydrogenolysis is performed to obtain 1-methyl-3-hydroxymethyl-1,2,4-triazole.

[0028] The reaction process of the present invention uses a cheap supported catalyst, which is simple to prepare, economical and environmentally friendly, has high activity, and meets the requirements of industrial clean production. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 The H NMR spectrum of 1-hydroxymethyl-1,2,4-triazole-3-carboxylic acid methyl ester

[0030] Figure 2 It is the H NMR spectrum of 1-methyl-3-hydroxymethyl-1,2,4-triazole DETAILED DESCRIPTION

[0031] The present invention will be further described below in conjunction with specific embodiments.

[0032] The following examples may enable those skilled in the art to better understand the present invention. However, the contents described in the examples are only used to illustrate the present invention, and should not and will not limit the present invention in any way.

[0033] Example 1

[0034] A method for preparing a key intermediate of Ensetivir comprises the following two steps:

[0035] Step 1: Selective N-hydroxymethylation

[0036] 127g of 1,2,4-triazole-3-carboxylic acid methyl ester, 60g of paraformaldehyde, 40g of sodium hydroxide, and 500mL of ethanol were added to a 1L four-necked bottle, and the reaction was stirred at room temperature for 24 hours. When the solution became homogeneous, TLC was used to detect the reaction, and the raw material 1,2,4-triazole-3-carboxylic acid methyl ester was completely converted. The reaction solution was cooled and concentrated under reduced pressure to remove 300mL of ethanol. 150g of 1-hydroxymethyl-1,2,4-triazole-3-carboxylic acid methyl ester intermediate was obtained by filtration, with a yield of 96%.

[0037] Step 2: Catalytic hydrogenation

[0038] 24.1 g Cu(NO 3 ) 2 ·3H 2 O was dissolved in 300 mL of deionized water to prepare solution a. 21.7 g of Na 2 CO 3 Solution b was prepared by dissolving in 300 mL of deionized water. At room temperature, solution a and solution b were slowly added dropwise to 300 mL of deionized water while stirring vigorously. During the addition process, the pH value was strictly controlled to be between 7 and 8. After the addition, the mixture was aged for 1 hour, filtered, washed with deionized water, and the filter cake was dried at 120°C for 6 hours. The obtained solid was fully mixed and ground with 30.30 g of pseudo-boehmite and 50 mL of deionized water, and then filled into a molding machine (3 mm in diameter) for extrusion molding. The molded catalyst was dried at 100°C for 8 hours, and then calcined at 500°C in a muffle furnace for 6 hours, and then the catalyst was cut into small sections of 3 to 5 mm. Before use, the catalyst must be reduced at 360°C for 3 hours in a hydrogen atmosphere. 2 O 3 The fixed bed reactor has an inner diameter of 15 mm, a length of 650 mm, and a constant temperature zone of 200 mm. 40 mL of the catalyst oxide is loaded into the fixed bed tubular reactor, and then N 2 The air in the fixed bed reactor was exhausted and H 2 Exhaust N2 . The reactor was heated to 360°C and kept warm for 3 hours to obtain a reduced catalyst. Then the temperature of the tubular reactor was adjusted to 120°C, and the hydrogen pressure of the reactor was adjusted to 4.0MPa. The intermediate obtained in the first step was diluted with 400mL of ethanol and continuously passed into the fixed bed reactor at a feed rate of 0.6mL / min using a horizontal flow pump. The reaction liquid continued to flow out from the lower end of the fixed bed reactor, and the reaction liquid flowing out after the condensation section was collected. The reaction liquid was concentrated to obtain a white solid compound, and the white solid was recrystallized using 200mL of ethanol to obtain 111.5g of pure product with a yield of 98.6%.

[0039] Example 2

[0040] A method for preparing a key intermediate of Ensetivir comprises the following two steps:

[0041] Step 1: Selective N-hydroxymethylation

[0042] 127g of 1,2,4-triazole-3-carboxylic acid methyl ester, 80g of paraformaldehyde, 101g of triethylamine, and 400mL of methanol were added to a 1L four-necked bottle, and stirred at 50°C for 12 hours. When the solution became homogeneous, TLC was used to detect the reaction, and the raw material 1,2,4-triazole-3-carboxylic acid methyl ester was completely converted. The reaction solution was cooled and concentrated under reduced pressure to remove 300mL of ethanol. 152g of 1-hydroxymethyl-1,2,4-triazole-3-carboxylic acid methyl ester intermediate was obtained by filtration, with a yield of 97%.

[0043] Step 2: Catalytic hydrogenation

[0044] Put 29.0gNi(NO 3 ) 2 6H 2 O was dissolved in 300 mL of deionized water to prepare solution a. 21.7 g of Na 2 CO 3 Solution b was prepared by dissolving in 300 mL of deionized water. At room temperature, solution a and solution b were slowly added dropwise to 300 mL of deionized water while stirring vigorously. During the addition process, the pH value was strictly controlled to be between 7 and 8. After the addition, the mixture was aged for 1 hour, filtered, washed with deionized water, and the filter cake was dried at 120°C for 6 hours. The obtained solid was fully mixed and ground with 30.30 g of pseudo-boehmite and 50 mL of deionized water, and then filled into a molding machine (3 mm in diameter) for extrusion molding. The molded catalyst was dried at 100°C for 8 hours, and then calcined at 500°C in a muffle furnace for 6 hours, and then the catalyst was cut into small sections of 3 to 5 mm. Before use, the catalyst must be reduced at 360°C for 3 hours in a hydrogen atmosphere. NiO / γ-Al 2 O 3The fixed bed reactor has an inner diameter of 15 mm, a length of 650 mm, and a constant temperature zone of 200 mm. 40 mL of the catalyst oxide is loaded into the fixed bed tubular reactor, and then N 2 To exhaust the air in the fixed bed reactor, H 2 Exhaust N 2 . The reactor was heated to 360°C and kept warm for 3 hours to obtain a reduced catalyst. Then the tubular reactor was adjusted to 150°C, and the hydrogen pressure of the reactor was adjusted to 3.6MPa. The intermediate obtained in the first step was diluted with 300mL of methanol and continuously passed into the fixed bed reactor at a feed rate of 0.6mL / min using a horizontal flow pump. The reaction liquid continued to flow out from the lower end of the fixed bed reactor, and the reaction liquid flowing out after the condensation section was collected. The reaction liquid was concentrated to obtain a white solid compound, and the white solid was recrystallized using 100mL of methanol to obtain 110g of pure product with a yield of 97.3%.

[0045] Example 3

[0046] A method for preparing a key intermediate of Ensetivir comprises the following two steps:

[0047] Step 1: Selective N-hydroxymethylation

[0048] 127g of 1,2,4-triazole-3-carboxylic acid methyl ester, 70g of polyformaldehyde, 112g of triethylenediamine, and 500mL of methanol were added to a 1L four-necked bottle, and stirred at room temperature for 18 hours. When the solution became homogeneous, TLC was used to detect the reaction, and the raw material 1,2,4-triazole-3-carboxylic acid methyl ester was completely converted. The reaction solution was cooled and concentrated under reduced pressure to remove 300mL of methanol. 149g of 1-hydroxymethyl-1,2,4-triazole-3-carboxylic acid methyl ester intermediate was obtained by filtration, with a yield of 95.3%.

[0049] Step 2: Catalytic hydrogenation

[0050] 29.1 g Co(NO 3 ) 2 6H 2 O was dissolved in 300 mL of deionized water to prepare solution a. 21.7 g of Na 2 CO 3Solution b was prepared by dissolving in 300 mL of deionized water. At room temperature, solution a and solution b were slowly added dropwise to 300 mL of deionized water while stirring vigorously. During the addition process, the pH value was strictly controlled to be between 7 and 8. After the addition, the mixture was aged for 1 hour, filtered, washed with deionized water, and the filter cake was dried at 120°C for 6 hours. The obtained solid was fully mixed and ground with 30.30 g of pseudo-boehmite and 50 mL of deionized water, and then filled into a molding machine (3 mm in diameter) for extrusion molding. The molded catalyst was dried at 100°C for 8 hours, and then calcined at 500°C in a muffle furnace for 6 hours, and then the catalyst was cut into small sections of 3 to 5 mm. Before use, the catalyst must be reduced at 360°C for 3 hours in a hydrogen atmosphere. CoO / γ-Al 2 O 3 The fixed bed reactor has an inner diameter of 15 mm, a length of 650 mm, and a constant temperature zone of 200 mm. 40 mL of the catalyst oxide is loaded into the fixed bed tubular reactor, and then N 2 To exhaust the air in the fixed bed reactor, H 2 Exhaust N 2 . The reactor was heated to 360°C and kept warm for 3 hours to obtain a reduced catalyst. Then the tubular reactor was adjusted to 130°C, and the hydrogen pressure of the reactor was adjusted to 5.0MPa. The intermediate obtained in the first step was diluted with 400mL of ethanol and continuously passed into the fixed bed reactor at a feed rate of 0.6mL / min using a horizontal flow pump. The reaction liquid continued to flow out from the lower end of the fixed bed reactor, and the reaction liquid flowing out after the condensation section was collected. The reaction liquid was concentrated to obtain a white solid compound, and the white solid was recrystallized using 200mL of ethanol to obtain 107.4g of pure product with a yield of 95%.

[0051] Example 4

[0052] A method for preparing a key intermediate of Ensetivir comprises the following two steps:

[0053] Step 1: Selective N-hydroxymethylation

[0054] 127g of 1,2,4-triazole-3-carboxylic acid methyl ester, 60g of paraformaldehyde, 40g of sodium hydroxide, and 500mL of ethanol were added to a 1L four-necked bottle, and the reaction was stirred at room temperature for 24 hours. When the solution became homogeneous, TLC was used to detect the reaction, and the raw material 1,2,4-triazole-3-carboxylic acid methyl ester was completely converted. The reaction solution was cooled and concentrated under reduced pressure to remove 300mL of ethanol. 150g of 1-hydroxymethyl-1,2,4-triazole-3-carboxylic acid methyl ester intermediate was obtained by filtration, with a yield of 96%.

[0055] Step 2: Catalytic hydrogenation

[0056] 43.0 g Zr(NO 3 )4 ·5H 2 O was dissolved in 300 mL of deionized water to prepare solution a. 43.4 g of Na 2 CO 3 Solution b was prepared by dissolving in 300 mL of deionized water. At room temperature, solution a and solution b were slowly added dropwise to 300 mL of deionized water while stirring vigorously. During the addition process, the pH value was strictly controlled to be between 7 and 8. After the addition, the mixture was aged for 1 hour, filtered, washed with deionized water, and the filter cake was dried at 120°C for 6 hours. The obtained solid was fully mixed and ground with 30.30 g of pseudo-boehmite and 50 mL of deionized water, and then filled into a molding machine (3 mm in diameter) for extrusion molding. The molded catalyst was dried at 100°C for 8 hours, and then calcined at 500°C in a muffle furnace for 6 hours, and then the catalyst was cut into small sections of 3 to 5 mm. Before use, the catalyst must be reduced at 360°C for 3 hours in a hydrogen atmosphere. ZrO / γ-Al 2 O 3 The fixed bed reactor has an inner diameter of 15 mm, a length of 650 mm, and a constant temperature zone of 200 mm. 40 mL of the catalyst oxide is loaded into the fixed bed tubular reactor, and then N 2 To exhaust the air in the fixed bed reactor, H 2 Exhaust N 2 . The reactor was heated to 360°C and kept warm for 3 hours to obtain a reduced catalyst. Then the tubular reactor was adjusted to 160°C, and the hydrogen pressure of the reactor was adjusted to 7.0 MPa. The intermediate obtained in the first step was diluted with 400 mL of ethanol and continuously passed into the fixed bed reactor at a feed rate of 1.2 mL / min using a horizontal flow pump. The reaction liquid continued to flow out from the lower end of the fixed bed reactor, and the reaction liquid flowing out after the condensation section was collected. The reaction liquid was concentrated to obtain a white solid compound, and the white solid was recrystallized using 200 mL of ethanol to obtain 109 g of pure product with a yield of 96.4%.

[0057] Example 5

[0058] A method for preparing a key intermediate of Ensetivir comprises the following two steps:

[0059] Step 1: Selective N-hydroxymethylation

[0060] 127g of 1,2,4-triazole-3-carboxylic acid methyl ester, 60g of paraformaldehyde, 40g of sodium hydroxide, and 500mL of ethanol were added to a 1L four-necked bottle, and the reaction was stirred at room temperature for 24 hours. When the solution became homogeneous, TLC was used to detect the reaction, and the raw material 1,2,4-triazole-3-carboxylic acid methyl ester was completely converted. The reaction solution was cooled and concentrated under reduced pressure to remove 300mL of ethanol. 150g of 1-hydroxymethyl-1,2,4-triazole-3-carboxylic acid methyl ester intermediate was obtained by filtration, with a yield of 96%.

[0061] Step 2: Catalytic hydrogenation

[0062] 20.1 g Fe(NO 3 ) 3 9H 2 O, 16.1 g Co(NO 3 ) 2 6H 2 O was dissolved in 300 mL of deionized water to prepare solution a. 72.9 g of Na 2 CO 3 Solution b was prepared by dissolving in 300 mL of deionized water. At room temperature, solution a and solution b were slowly added dropwise to 300 mL of deionized water while stirring vigorously. During the addition process, the pH value was strictly controlled to be between 7 and 8. After the addition, the mixture was aged for 1 hour, filtered, washed with deionized water, and the filter cake was dried at 120°C for 6 hours. The obtained solid was fully mixed and ground with 30.30 g of pseudo-boehmite and 50 mL of deionized water, and then filled into a molding machine (3 mm in diameter) for extrusion molding. The molded catalyst was dried at 100°C for 8 hours, and then calcined at 500°C in a muffle furnace for 6 hours, and then the catalyst was cut into small sections of 3 to 5 mm. Before use, the catalyst must be reduced at 360°C for 3 hours in a hydrogen atmosphere. 2 O 3 The fixed bed reactor has an inner diameter of 15 mm, a length of 650 mm, and a constant temperature zone of 200 mm. 40 mL of the catalyst oxide is loaded into the fixed bed tubular reactor, and then N 2 To exhaust the air in the fixed bed reactor, H 2 Exhaust N 2 . The reactor was heated to 360°C and kept warm for 3 hours to obtain a reduced catalyst. Then the tubular reactor was adjusted to 110°C, and the hydrogen pressure of the reactor was adjusted to 5.0 MPa. The intermediate obtained in the first step was diluted with 400 mL of ethanol and continuously fed into the fixed bed reactor at a feed rate of 2.0 mL / min using a horizontal flow pump. The reaction liquid continued to flow out from the lower end of the fixed bed reactor, and the reaction liquid flowing out after the condensation section was collected. The reaction liquid was concentrated to obtain a white solid compound, and the white solid was recrystallized using 200 mL of ethanol to obtain 106 g of pure product with a yield of 93.7%.

[0063] Example 6

[0064] A method for preparing a key intermediate of Ensetivir comprises the following two steps:

[0065] Step 1: Selective N-hydroxymethylation

[0066] 127g of 1,2,4-triazole-3-carboxylic acid methyl ester, 60g of paraformaldehyde, 40g of sodium hydroxide, and 500mL of ethanol were added to a 1L four-necked bottle, and the reaction was stirred at room temperature for 24 hours. When the solution became homogeneous, TLC was used to detect the reaction, and the raw material 1,2,4-triazole-3-carboxylic acid methyl ester was completely converted. The reaction solution was cooled and concentrated under reduced pressure to remove 300mL of ethanol. 150g of 1-hydroxymethyl-1,2,4-triazole-3-carboxylic acid methyl ester intermediate was obtained by filtration, with a yield of 96%.

[0067] Step 2: Catalytic hydrogenation

[0068] 17.4 g Ni(NO 3 ) 2 6H 2 O, 14.6 g Cu(NO 3 ) 2 ·3H 2 O, 16.3 g Co(NO 3 ) 2 6H 2 O was dissolved in 300 mL of deionized water to prepare solution a. 90.5 g of Na 2 CO 3 Dissolve in 300 mL of deionized water to prepare solution b. At room temperature, solution a and solution b are slowly added dropwise to 300 mL of deionized water while stirring vigorously. During the addition process, the pH value is strictly controlled to be between 7 and 8. After the addition is completed, age for 1 hour, filter, wash with deionized water, and dry the filter cake at 120°C for 6 hours. The obtained solid is fully mixed and ground with 30.30 g of pseudo-boehmite and 50 mL of deionized water, and then filled into a molding machine (diameter 3.0 mm) for extrusion molding. The molded catalyst is dried at 100°C for 8 hours, then calcined at 500°C in a muffle furnace for 6 hours, and then the catalyst is cut into small sections of 3 to 5 mm. Before use, the catalyst must be reduced at 360°C for 3 hours in a hydrogen atmosphere. NiO / CuO / CoO / γ-Al 2 O 3 The fixed bed reactor has an inner diameter of 15 mm, a length of 650 mm, and a constant temperature zone of 200 mm. 40 mL of the catalyst oxide is loaded into the fixed bed tubular reactor, and then N 2 To exhaust the air in the fixed bed reactor, H 2 Exhaust N 2. The reactor was heated to 360°C and kept warm for 3 hours to obtain a reduced catalyst. Then the tubular reactor was adjusted to 110°C, and the hydrogen pressure of the reactor was adjusted to 5.0 MPa. The intermediate obtained in the first step was diluted with 400 mL of ethanol and continuously fed into the fixed bed reactor at a feed rate of 1.6 mL / min using a horizontal flow pump. The reaction liquid continued to flow out from the lower end of the fixed bed reactor, and the reaction liquid flowing out after the condensation section was collected. The reaction liquid was concentrated to obtain a white solid compound, and the white solid was recrystallized using 200 mL of ethanol to obtain 112 g of pure product with a yield of 99%.

[0069] NMR spectrum of 1-hydroxymethyl-1,2,4-triazole-3-carboxylic acid methyl ester:

[0070] 1 HNMR(400MHz,DMSO-d6)δ8.79(s,1H),7.27(s,0H),5.54(s,0H),3.86(s,0H).

[0071] NMR spectrum of 1-methyl-1,2,4-triazole-3-carboxylic acid methyl ester:

[0072] 1 H NMR (400MHz, DMSO-d6) δ8.36 (s, 1H), 5.22-5.21 (m, 1H), 4.39 (d, J = 5.8Hz, 2H), 3.82 (s, 3H).

Claims

1. A synthetic method of the key intermediate of ensitrelvir, 1-methyl-3-hydroxymethyl-1,2,4-triazole, characterized in that, it comprises the following two-step reactions: The first step: Selective N-hydroxymethylation reaction. Methyl 1,2,4-triazole-3-carboxylate and paraformaldehyde are added to a reaction kettle in a certain proportion, a solvent and a catalyst are added, and the reaction is stirred at a certain temperature until the raw materials are completely converted. The reaction solution is cooled, the solvent is removed by reduced pressure concentration, and the obtained solid compound is filtered, washed, and dried to obtain the intermediate product of selective hydroxymethylation; in the first-step reaction, the catalyst is at least one of sodium hydroxide, sodium acetate, sodium carbonate, triethylamine, triethylenediamine, and diethylamine; The second step: selective catalytic hydrogenation reaction, the catalyst precursor is loaded into a fixed bed reactor, nitrogen is introduced for replacement, hydrogen is introduced for heating, and in-situ reduction is performed to obtain a solid catalyst for catalytic hydrogenation; the product of the first step reaction is dissolved and introduced into the reactor at a certain flow rate, and the reaction liquid flowing out of the end of the reactor is cooled, concentrated under reduced pressure to remove the solvent, and purified to obtain the target product 1-methyl-3-hydroxymethyl-1,2,4-triazole; the solid catalyst for catalytic hydrogenation in the second step reaction is γ-Al 2 O 3 The invention discloses a supported catalyst with Cu, Zn, Fe and Ni as carrier and at least one of them as active component, and the loading amount is 10-30%. The preparation method of the catalytic hydrogenation solid catalyst is as follows: dissolving metal nitrate, obtaining a catalyst precursor by impregnation, drying and roasting, and then reducing it in situ by hydrogen.

2. The synthetic method of the intermediate 1-methyl-3-hydroxymethyl-1,2,4-triazole according to claim 1, characterized in that, in the first-step reaction, the molar ratio of methyl 1,2,4-triazole-3-carboxylate to paraformaldehyde is 1:1 - 1:

8.

3. The synthetic method of the intermediate 1-methyl-3-hydroxymethyl-1,2,4-triazole according to claim 1, characterized in that, in the first-step reaction, the solvent is at least one of methanol, ethanol, isopropanol, and tert-butanol.

4. The synthetic method of the intermediate 1-methyl-3-hydroxymethyl-1,2,4-triazole according to claim 1, characterized in that, in the first-step reaction, the reaction temperature is room temperature - 80 °C, and the reaction time is 10 - 24 hours.

5. The synthetic method of the intermediate 1-methyl-3-hydroxymethyl-1,2,4-triazole according to claim 1, characterized in that, in the second-step reaction, the feeding rate is 0.5 - 3.0 mL / min, the hydrogen pressure is 2.0 - 7.0 MPa, and the reaction temperature is 60 - 160 °C.

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