A process for the preparation of 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline

Abstract

This invention relates to the field of pharmaceutical synthesis technology, specifically to a method for preparing 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline. The method comprises the following steps: a compound of formula IX undergoes a substitution reaction to obtain a compound of formula VIII; compound VIII is acylated and then condensed with compound VII to obtain a compound of formula VI; compound VI is deprotected from its Boc protecting group to obtain compound V; compound V reacts with potassium thiocyanate to obtain compound IV; compound IV undergoes intramolecular cyclization to obtain compound III; compound III is reduced to obtain compound II; and compound II is further reduced to obtain compound I. This invention offers advantages such as high yield, high purity, readily available and conventional starting materials, low cost, suitability for industrial production, and environmental friendliness, making it suitable for large-scale industrial production and possessing excellent application prospects.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical synthesis technology, and specifically relates to a preparation method of 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline. Background Art

[0002] Deucravacitinib (Chinese name: deuterium depatitinib or deucravacitinib) is the world's first marketed oral selective tyrosine kinase 2 (TYK2) allosteric inhibitor, and also the first original deuterated new drug. It was approved by the U.S. Food and Drug Administration (FDA) on September 9, 2022 for use in adult patients with moderate-to-severe plaque psoriasis who are suitable for systemic therapy or phototherapy. At present, the National Medical Products Administration of China has accepted its marketing application on July 15, 2022. The CAS number of Deucravacitinib is 1609392-27-9, the molecular weight is 425.47, and the molecular formula is C 20 H 19 D3N8O3, the structural formula of which is as follows,

[0003]

[0004] 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline is a key intermediate for the synthesis of Deucravacitinib, with a CAS number of 1609394-10-6, a molecular weight of 204.23, and a molecular formula of C 10 H 12 N4O, the structural formula of which is as follows,

[0005]

[0006] Patent WO2014074661 and CN116490501 reported the following synthetic route: 2-hydroxy-3-nitrobenzoic acid methyl ester is used as the starting material, 2-methoxy-3-nitrobenzamide is obtained through substitution and amine-ester exchange reaction, then formylated with DMFDMA and subsequently cyclized with hydrazine hydrate to obtain 3-(2-methoxy-3-nitrophenyl)-1H-1,2,4-triazole, then methylated with methyl iodide, and finally the nitro group is reduced to obtain 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline. In this route, the material methyl iodide used is expensive and highly toxic, the isomer by-product produced in the methylation reaction is difficult to purify, and the production cost is relatively high.

[0007]

[0008] CN112236425, WO2021180072, and WO2023023322 report the following synthetic route, which uses 5-chloro-2-methoxybenzonitrile as the starting material and cyclizes it with N-methylformylhydrazine to obtain 3-(5-chloro-2-methoxyphenyl)-1-methyl-1H-1,2,4-triazole. Then, a nitration reaction occurs to give 3-(5-chloro-2-methoxy-3-nitrophenyl)-1-methyl-1H-1,2,4-triazole, which is finally reduced on palladium on carbon to obtain the target intermediate. This route uses N-methylformylhydrazine, a raw material that is difficult to obtain and expensive, and requires a nitration reaction. The final step, which simultaneously reduces the nitro group and chlorine on the benzene ring, requires a large amount of catalyst, resulting in a high cost.

[0009]

[0010] CN114989103 reports the following synthetic route: starting with 3-bromo-2-methoxybenzonitrile and N-methylformylhydrazine, cyclization yields 3-(3-bromo-2-methoxyphenyl)-1-methyl-1H-1,2,4-triazole, which then undergoes amination under a catalyst to obtain the target intermediate. The N-methylformylhydrazine used in this route is expensive and requires an organopalladium catalyst.

[0011]

[0012] CN115724830 reports the following synthetic route: 3-bromo-2-methoxyaniline is used as the starting material, coupled with pinacol diboronate to obtain an arylboronic ester, which is then subjected to a Suzuki coupling reaction with 3-bromo-1-methyl-1H-1,2,4-triazole to obtain the target intermediate. However, the starting materials, pinacol diboronate, bromotriazole intermediate, and organopalladium catalyst used in this route are expensive, and the yield is low, making the cost too high for large-scale production.

[0013]

[0014] In general, these routes involve expensive raw materials, catalysts, and other components, resulting in high costs and limited competitiveness for large-scale production. Therefore, it is of great significance to study a new synthetic method for 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline that is high in yield, high in purity, uses readily available starting materials, is low in cost, suitable for industrial production, and is environmentally friendly. Summary of the Invention

[0015] To address the problems of the prior art, the present invention aims to provide a method for preparing 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline.

[0016] A method for preparing 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline, comprising the following steps:

[0017]

[0018] Step 1: Compound IX undergoes a substitution reaction to give compound VIII;

[0019] Step 2: Compound VIII undergoes an acylation reaction with oxalyl chloride to obtain acyl chloride, which is then condensed with compound VII to obtain compound VI.

[0020] Step 3: The Boc protecting group of compound VI is removed to obtain compound V;

[0021] Step 4: Compound V reacts with potassium thiocyanate to obtain compound IV;

[0022] Step 5: Compound IV undergoes intramolecular cyclization to obtain compound III;

[0023] Step 6: Compound III is reduced to obtain compound II;

[0024] Step 7: Compound II is further reduced to obtain compound I.

[0025] Preferably, in step 1, the substitution reaction is carried out under the action of a base, and the base is selected from sodium methoxide;

[0026] And / or, the solvent for the substitution reaction is selected from methanol;

[0027] And / or, the reaction temperature of the substitution reaction is 40-60°C;

[0028] And / or, the molar ratio of the compound of formula IX to the base is 1:(2-3).

[0029] Preferably, in step 2, the solvent for the acylation reaction is selected from at least one of dichloromethane, 1,2-dichloroethane, or chloroform;

[0030] And / or, the acylation reaction is carried out in the presence of a catalyst selected from N,N-dimethylformamide;

[0031] And / or, the molar ratio of the compound of formula VIII to oxalyl chloride is 1:(1.05 to 1.3).

[0032] Preferably, in step 2, the solvent for condensation is selected from at least one of dichloromethane, 1,2-dichloroethane, or chloroform;

[0033] And / or, the condensation is carried out under the action of a base, the base being selected from at least one of N,N-diisopropylethylamine or triethylamine;

[0034] And / or, the condensation reaction temperature is 0-20°C;

[0035] And / or, the molar ratio of the compound of formula VIII to the compound of formula VII is 1:(1 to 1.2);

[0036] And / or, the ratio of the compound of formula VIII to the base is 1:(2-3).

[0037] Preferably, in step 3, the solvent for removing the Boc protecting group is isopropyl acetate;

[0038] And / or, the process of removing the Boc protecting group is carried out under the action of an acid, wherein the acid is selected from HCl;

[0039] And / or, the reaction temperature for removing the Boc protecting group is 20-30°C;

[0040] And / or, the molar ratio of the compound of formula VI to the acid is 1:(4-6).

[0041] Preferably, in step 4, the solvent for the reaction is methanol;

[0042] And / or, the reaction temperature is 60-70°C;

[0043] And / or, the molar ratio of the compound of formula V to potassium thiocyanate is 1:(1-2).

[0044] Preferably, in step 5, the solvent for intramolecular cyclization is methanol;

[0045] And / or, the intramolecular cyclization process is carried out under the action of a base, the base being selected from sodium methoxide.

[0046] Preferably, in step 6, the solvent for reduction is methanol;

[0047] And / or, the reduction is carried out in the presence of an acid, selected from nitric acid;

[0048] And / or, the reduction reaction temperature is 40-60℃.

[0049] Preferably, in step 7, the solvent for reduction is at least one of methanol or ethanol;

[0050] And / or, the reducing agent for the reduction is selected from hydrogen;

[0051] And / or, the reduction is carried out in the presence of a catalyst selected from 10% palladium on carbon;

[0052] And / or, the reduction reaction temperature is 20-30°C;

[0053] And / or, the ratio of the compound of formula II to the catalyst is 1:(0.05 to 0.1) by mass.

[0054] Preferably, in step 1, the substitution reaction is carried out under the action of a base, which is selected from sodium methoxide; the solvent for the substitution reaction is selected from methanol; the reaction temperature of the substitution reaction is 40-60℃; and the molar ratio of the compound of formula IX to the base is 1:2.5.

[0055] In step 2, the solvent for the acylation reaction is selected from dichloromethane; the acylation reaction is carried out under the action of a catalyst, which is selected from N,N-dimethylformamide; the molar ratio of compound VIII to oxaloyl chloride is 1:1.1; the solvent for the condensation is selected from dichloromethane; the condensation is carried out under the action of a base, which is selected from N,N-diisopropylethylamine; the reaction temperature for the condensation is 0-20℃; the molar ratio of compound VIII to compound VII is 1:1; during the condensation process, the molar ratio of compound VIII to base is 1:2.

[0056] In step 3, the solvent for removing the Boc protecting group is isopropyl acetate; the process of removing the Boc protecting group is carried out under the action of an acid, which is selected from HCl; the reaction temperature for removing the Boc protecting group is 20-30℃; and the molar ratio of the compound of formula VI to the acid is 1:4.

[0057] In step 4, the solvent for the reaction is methanol; the reaction temperature is 60-70℃; and the molar ratio of compound V to potassium thiocyanate is 1:1.5.

[0058] In step 5, the solvent for the intramolecular cyclization is methanol; the intramolecular cyclization process is carried out under the action of a base, which is selected from sodium methoxide.

[0059] In step 6, the solvent for reduction is methanol; the reduction is carried out under the action of an acid, which is selected from nitric acid; the reaction temperature for reduction is 40-60℃.

[0060] In step 7, the solvent for reduction is methanol; the reducing agent for reduction is selected from hydrogen; the reduction is carried out under the action of a catalyst, which is selected from 10% palladium on carbon; the reaction temperature for reduction is 20-30℃; and the mass ratio of the compound of formula II to the catalyst is 1:0.1.

[0061] This invention presents a novel synthetic route for the preparation of 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline, an intermediate of deuterocelexitinib, and optimizes the process conditions for each reaction step. The synthetic route of this invention offers advantages such as high yield, high purity, readily available starting materials, low cost, suitability for industrial production, and environmental friendliness, making it more suitable for large-scale industrial production compared to existing synthetic routes. Therefore, this invention has excellent application prospects.

[0062] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0063] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Attached Figure Description

[0064] Figure 1 The image shows the nuclear magnetic resonance spectrum of the product prepared in Example 1 of this invention. Detailed Implementation

[0065] The reagents and raw materials used in the following examples are all commercially available products.

[0066] Example 1:

[0067] Step 1: Preparation of Compound VIII

[0068]

[0069] Compound IX (475 g, 2.566 mol) was dissolved in methanol (5 L), heated to 50 °C, and sodium methoxide methanol solution (1.2 L, wt. 30%) was added dropwise. After the addition was complete, the mixture was stirred at 50 °C for 4 hours. The reaction was monitored by TLC, and the starting material was basically reacted. The reaction solution was cooled to below 20 °C, and dilute hydrochloric acid was slowly added to adjust the pH to 2-3, resulting in the precipitation of a large amount of solid. The solid was filtered, the filter cake was washed with water, and the obtained filter cake was vacuum dried at 50 °C for 48 hours to obtain 485.6 g of compound VIII, a white solid with a yield of 96%. MS (ESI) + )m / z198[M+H] + .

[0070] Step 2: Preparation of Compound VI

[0071]

[0072] Add compound VIII (300 g, 1.52 mol), dichloromethane (3 L), and N,N-dimethylformamide (10 mL) to a reaction flask, stir, cool to 5 °C, and add oxaloyl chloride (212.5 g, 1.67 mol) dropwise. After stirring at room temperature for 1 h, monitor the reaction by TLC. When the starting material has basically reacted, stop the reaction and concentrate to dryness under reduced pressure at 40 °C for later use. Add compound VII (227 g, 1.52 mol), dichloromethane (1.5 L), and N,N-diisopropylethylamine (393.4 g, 3.04 mol) to another reaction flask, stir, and cool to 5 °C. Dissolve the acyl chloride of compound VIII in dichloromethane (1.5 L) and add it dropwise to the reaction solution. After the addition is complete, stir the reaction at room temperature for about 1 h. Monitor the reaction by TLC. When the starting material has basically reacted, stop the reaction. Add water (100 mL) to the reaction solution and stir for 10 minutes. Then add dilute hydrochloric acid (1 M, 1.5 L) for extraction and separation. Wash once with saturated sodium bicarbonate (500 mL), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give 484 g of compound VI, with a molar yield of 98%. MS (ESI) + )m / z 326[M+H] + .

[0073] Step 3: Preparation of compound V

[0074]

[0075] Compound VI (484 g, 1.489 mol) was dissolved in isopropyl acetate (3 L), stirred, and then 1050 mL of hydrogen chloride methanol solution (25%) was added. The reaction was carried out at room temperature for 8 h, and the reaction was monitored by TLC. The reaction of the starting material was basically completed. The mixture was then filtered, and the filter cake was washed with isopropyl acetate and dried under vacuum at 50 °C to obtain 384.9 g of compound V, with a molar yield of 99%. MS (ESI) + )m / z 226[M+H] + .

[0076] Step 4: Preparation of Formula IV Compounds

[0077]

[0078] Compound V (100 g, 0.383 mol), anhydrous methanol (1 L), and potassium thiocyanate (55.8 g, 0.5745 mol) were added to a reaction flask. The mixture was heated to reflux and stirred for approximately 20 h. The reaction was monitored by TLC, and the reactants were found to have largely reacted. The reaction solution was then cooled to 40 °C, water (1 L) was added, and the mixture was further cooled to 5 °C. The mixture was filtered, washed with water, and the filter cake was dried under vacuum at 50 °C for approximately 24 h to obtain 92.6 g of compound IV as a yellow solid, with a molar yield of 85%. MS (ESI) + )m / z 285[M+H]+

[0079] Step 5: Preparation of Compound III

[0080]

[0081] Compound IV (100 g, 0.352 mol) and anhydrous methanol (1 L) were added to a reaction flask and stirred. Then, sodium methoxide methanol solution (125.3 g, wt. 30%) was slowly added to the reaction solution. After the addition was complete, the mixture was heated to reflux. The reaction was stirred for 8 h, and the reaction was monitored by TLC until the reactants had essentially reacted completely. The reaction solution was then cooled to room temperature, and the pH was adjusted to 2-3 with dilute hydrochloric acid to precipitate a solid. The solid was filtered, the filter cake was washed with water, and then dried under vacuum at 50 °C for 12 h to obtain 79.7 g of compound III, a yellow solid, with a molar yield of 85%. MS (ESI) + )m / z267[M+H] + .

[0082] Step 6: Preparation of Compound II

[0083]

[0084] Nitric acid (550 mL) and anhydrous methanol (220 mL) were added to the reaction flask, stirred, and heated to 50 °C. Then, 110 g (0.413 mol) of solid compound III was slowly added in portions to the reaction solution. After the addition was complete, the reaction was stirred for approximately 0.5 h. The reaction was monitored by TLC, indicating that the reactants had largely reacted. The reaction solution was cooled to room temperature, and the pH was adjusted to 9–10 with saturated sodium carbonate. The aqueous phase was extracted with isopropyl acetate (0.9 L × 2). The combined organic phases were washed once with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 45 °C until a large amount of solid precipitated. Isopropyl acetate (1.1 L) was added again to dissolve the solid, and concentrated sulfuric acid (37.2 g) was added dropwise to form a salt and precipitate the solid. The solid was filtered, and the filter cake was washed with isopropyl acetate to obtain the sulfate of compound III. The sulfate of compound III was suspended in isopropyl acetate (1.1 L), and the pH was adjusted to 9–10 with saturated sodium carbonate solution (temperature controlled not to exceed 30 °C). The liquid was separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated until a large amount of solid precipitated. Heptane (550 mL) was added and the mixture was stirred, filtered, and the filter cake was dried under vacuum at 50 °C for 12 h to obtain 87 g of compound II, a pale yellow solid, with a molar yield of 90%; HPLC purity of 99.5%; MS (ESI) + )m / z 235[M+H] + .

[0085] Step 7: Preparation of Compound I

[0086]

[0087] Compound II (100 g, 0.427 mol) was dissolved in anhydrous methanol (1000 mL), and palladium on carbon (10 g, 10%, 50% wet) was added. The mixture was purged three times with nitrogen, followed by three purgings with hydrogen. The reaction mixture was stirred at room temperature for 16 h under hydrogen (20–30 psi), and the reaction was monitored for completion by TLC. The mixture was filtered through diatomaceous earth, and the filtrate was washed with methanol (100 mL). 10 g of activated carbon (to remove palladium) was added, and the mixture was stirred for 2 h. The mixture was filtered, concentrated to remove most of the methanol, and then slurried with isopropyl ether (500 mL). The filtrate was filtered again, and the filter cake was dried at 45 °C to give 82.8 g of compound I as a white solid, with a molar yield of 95% and an HPLC purity of 99.6%. Figure 1 As shown, 1 HNMR(400MHz,Chloroform-d)δ8.08(s,1H),7.34(dd,J=7.6,1.6Hz,1H),6.99(t,J=7 .6Hz,1H),6.81(dd,J=7.6,1.6Hz,1H),3.99(s,3H),3.77(s,2H),3.59(s,3H);MS(ESI + )m / z 205[M+H] + .

[0088] Example 2: Scale-up Production

[0089] Step 1: Preparation of Compound VIII

[0090]

[0091] Compound IX (3.8 kg, 20.54 mol) was dissolved in methanol (38 L), heated to 50 °C, and sodium methoxide methanol solution (9.5 L, wt. 30%) was added dropwise. After the addition was complete, the mixture was stirred at 50 °C for 4 hours. The reaction was monitored by TLC, and the starting material was basically reacted. The reaction solution was cooled to below 20 °C, and dilute hydrochloric acid was slowly added to adjust the pH to 2-3, resulting in the precipitation of a large amount of solid. The solid was filtered, the filter cake was washed with water, and the obtained filter cake was vacuum dried at 50 °C for 48 hours to obtain 3.88 kg of off-white solid of compound VIII, with a yield of 95.8%. MS (ESI) + )m / z198[M+H] + .

[0092] Step 2: Preparation of Compound VI

[0093]

[0094] Add compound VIII (3 kg, 15.2 mol), dichloromethane (30 L), and N,N-dimethylformamide (100 mL) to a reaction vessel, stir, cool to 5 °C, and add oxaloyl chloride (2.1 kg, 16.7 mol) dropwise. After stirring at room temperature for 1 h, monitor the reaction by TLC. When the reactants have basically reacted, stop the reaction and concentrate to dryness under reduced pressure at 40 °C for later use. Add compound VII (2.3 kg, 1.52 mol), dichloromethane (15 L), and N,N-diisopropylethylamine (3.9 kg, 30.4 mol) to another reaction flask, stir, and cool to 5 °C. Dissolve the acyl chloride of compound VIII in dichloromethane (15 L) and add it dropwise to the reaction solution. After the addition is complete, stir the reaction at room temperature for about 2 h. Monitor the reaction by TLC. When the reactants have basically reacted, stop the reaction. Add water (1 L) to the reaction solution and stir for 10 min. Then add dilute hydrochloric acid (1 M, 15 L) for extraction and separation. Wash once with saturated sodium bicarbonate (5 L), dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to give 4.8 kg of compound VI, with a molar yield of 97%. MS (ESI) + )m / z 326[M+H] + .

[0095] Step 3: Preparation of compound V

[0096]

[0097] Compound VI (4.8 kg, 14.7 mol) was dissolved in isopropyl acetate (30 L), stirred, and then 10 L (25%) of hydrogen chloride methanol solution was added. The reaction was carried out at room temperature for 8 h, and the reaction was monitored by TLC. The reaction of the starting material was basically completed. The mixture was then filtered, and the filter cake was washed with isopropyl acetate and dried under vacuum at 50 °C to obtain 3.8 kg of compound V, with a molar yield of 99%. MS (ESI) + )m / z 226[M+H] + .

[0098] Step 4: Preparation of Formula IV Compounds

[0099]

[0100] Compound V (2 kg, 7.66 mol), anhydrous methanol (20 L), and potassium thiocyanate (1.1 kg, 11.5 mol) were added to a reaction flask. The mixture was heated to reflux and stirred for approximately 20 h. The reaction was monitored by TLC, and the reactants were found to have largely reacted. The reaction solution was then cooled to 40 °C, water (20 L) was added, and the mixture was further cooled to 5 °C. The mixture was filtered, washed with water, and the filter cake was dried under vacuum at 50 °C for approximately 24 h to obtain 1.89 kg of compound IV as a yellow solid, with a molar yield of 87%. MS (ESI) + )m / z 285[M+H] +

[0101] Step 5: Preparation of Compound III

[0102]

[0103] Compound IV (2 kg, 7.035 mol) and anhydrous methanol (20 L) were added to a reaction flask and stirred. Then, a sodium methoxide methanol solution (2.5 kg, wt. 30%) was slowly added to the reaction mixture. After the addition was complete, the mixture was heated to reflux. The reaction was stirred for 8 h, and the reaction was monitored by TLC until the reactants had largely reacted. The reaction mixture was then cooled to room temperature, and the pH was adjusted to 2-3 with dilute hydrochloric acid to precipitate a solid. The solid was filtered, the filter cake was washed with water, and then dried under vacuum at 50 °C for 12 h to obtain 1.6 kg of compound III as a yellow solid, with a molar yield of 86%. MS (ESI) + )m / z267[M+H] + .

[0104] Step 6: Preparation of Compound II

[0105]

[0106] Nitric acid (11 L) and anhydrous methanol (4 L) were added to the reaction flask, stirred, and heated to 50 °C. Then, 2.2 kg (8.26 mol) of solid compound III was slowly added in portions to the reaction solution. After the addition was complete, the reaction was stirred for about 1 hour, and the reaction was monitored by TLC until the reactants had largely reacted. The reaction solution was cooled to room temperature, and the pH was adjusted to 9–10 with saturated sodium carbonate. The aqueous phase was extracted with isopropyl acetate (20 L × 2). The combined organic phases were washed once with saturated brine (4 L), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure at 45 °C until a large amount of solid precipitated. Isopropyl acetate (22 L) was added again to dissolve the solid, and concentrated sulfuric acid (744 g) was added dropwise to form a salt and precipitate the solid. The solid was filtered, and the filter cake was washed with isopropyl acetate to obtain the sulfate of compound III. The sulfate of compound III was suspended in isopropyl acetate (1.1 L), and the pH was adjusted to 9–10 with saturated sodium carbonate solution (temperature controlled not to exceed 30 °C). The liquid was separated, the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated until a large amount of solid precipitated. Heptane (11 L) was added and the mixture was stirred, filtered, and the filter cake was dried under vacuum at 50 °C for 12 h to obtain 1.78 kg of compound II, a pale yellow solid, with a molar yield of 92%; HPLC purity of 99.2%; MS (ESI) purity of 99.2%. + )m / z235[M+H] + .

[0107] Step 7: Preparation of Compound I

[0108]

[0109] Compound II (1.5 kg, 6.4 mol) was dissolved in anhydrous methanol (15 L), and palladium on carbon (150 g, 10%, 50% wet) was added. The mixture was purged three times with nitrogen, followed by three purgings with hydrogen. The reaction mixture was stirred at room temperature for 16 h under hydrogen (20–30 psi), and the reaction was monitored for completion by TLC. The mixture was filtered through diatomaceous earth, and the filtrate was washed with methanol (1 L). 150 g of activated carbon (to remove palladium) was added, and the mixture was stirred for 2 h. The mixture was filtered, concentrated to remove most of the methanol, and then slurried with isopropyl ether (7.5 L). The filtrate was filtered, and the filter cake was dried at 45 °C to give 1.25 kg of compound I as a white solid, with a molar yield of 96%; HPLC purity of 99.5%; MS (ESI) purity of 99.5%. + )m / z205[M+H] + .

[0110] The technical solution of the present invention will be further illustrated by the following experiments.

[0111] Optimization of process conditions in experimental examples

[0112] This invention provides several comparative experimental groups. In these comparative experimental groups, some process parameters or raw materials are changed based on Example 1, while other experimental steps and process parameters not specifically described are the same as in Example 1.

[0113] The specific conditions and their impact on the reaction results are shown in the table below:

[0114] Table 1 shows the optimal process conditions for the first step reaction.

[0115] Example 1 2.5eq Sodium methoxide methanol solution 96％ \ Comparative experimental group 1 2.0eq Sodium methoxide methanol solution 65％ \ Comparative experimental group 2 3.0eq Sodium methoxide methanol solution 85％ \

[0116] Table 2 shows the optimal process conditions for the second step reaction.

[0117] Example 1 2.0eq N,N-Diisopropylethylamine 98％ \ Comparative experimental group 3 2.0eq Triethylamine 65％ \ Comparative experimental group 4 1.5eq N,N-Diisopropylethylamine 72％ \

[0118] Table 3 shows the optimal process conditions for the third step reaction.

[0119] Example 1 4.0eq Hydrogen chloride methanol solution 99％ \ Comparative experimental group 7 4.0eq Ethyl hydrochloride solution 76％ \ Comparison Experimental Group 8 4.0eq 1,4-dioxane hydrogen chloride solution 55％ \

[0120] Table 4 shows the optimal process conditions for the fourth step reaction.

[0121] Example 1 1.5eq Potassium thiocyanate 85％ \ Comparative experimental group 10 1.0eq Potassium thiocyanate 55％ \ Comparative experimental group 11 1.2eq Potassium thiocyanate 65％ \ Comparative experimental group 11 2.0eq Potassium thiocyanate 75％ \

[0122] Table 5 shows the optimal process conditions for the fifth step reaction.

[0123] Example 1 2.0eq Sodium methoxide methanol solution 86％ \ Comparative experimental group 12 1.5eq Sodium methoxide methanol solution 56％ \ Comparative experimental group 13 3.0eq Sodium methoxide methanol solution 36％ \

[0124] Table 6 shows the optimal process conditions for the seventh step reaction.

[0125] Example 1 0.1 methanol 95％ 99.6％ Comparative experimental group 14 0.05 methanol 82％ 97.8％ Comparative experimental group 15 0.05 ethanol 80％ 98.7％

[0126] As can be seen from the data in the table above, the process parameters and raw materials used in Example 1 can achieve the best molar yield and product purity.

[0127] As can be seen from the above embodiments and experimental examples, the method for preparing 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline provided by the present invention has the advantages of high yield, high purity, readily available starting materials, low cost, suitability for industrial production, and environmental friendliness. It is suitable for large-scale industrial production and has a good application prospect.

Claims

1. A method for preparing 2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)aniline, characterized in that, Includes the following steps: Step 1: Compound IX undergoes a substitution reaction to give compound VIII; Step 2: Compound VIII undergoes an acylation reaction with oxalyl chloride to obtain acyl chloride, which is then condensed with compound VII to obtain compound VI. Step 3: The compound of formula VI is deprotected by the Boc protecting group to obtain the compound of formula V; the deprotection process is carried out under the action of an acid, which is selected from a hydrogen chloride methanol solution; Step 4: Compound V reacts with potassium thiocyanate to obtain compound IV; Step 5: Compound IV undergoes intramolecular cyclization to obtain compound III; the intramolecular cyclization process is carried out under the action of a base, the base being selected from sodium methoxide, and the amount of sodium methoxide used is 2.0 eq; Step 6: Compound III is reduced to obtain compound II; Step 7: Compound II is further reduced to obtain compound I.

2. The preparation method according to claim 1, characterized in that: In step 1, the substitution reaction is carried out under the action of a base, which is selected from sodium methoxide; And / or, the solvent for the substitution reaction is selected from methanol; And / or, the reaction temperature of the substitution reaction is 40-60°C; And / or, the molar ratio of the compound of formula IX to the base is 1:2~3.

3. The preparation method according to claim 1, characterized in that: In step 2, the solvent for the acylation reaction is selected from at least one of dichloromethane, 1,2-dichloroethane, or chloroform; And / or, the acylation reaction is carried out in the presence of a catalyst selected from... N,N -Dimethylformamide; And / or, the molar ratio of the compound of formula VIII to oxalyl chloride is 1:1.05~1.

3.

4. The preparation method according to claim 1, characterized in that: In step 2, the solvent for condensation is selected from at least one of dichloromethane, 1,2-dichloroethane, or chloroform; And / or, the condensation is carried out under the action of a base, the base being selected from... N , N -At least one of diisopropylethylamine or triethylamine; And / or, the condensation reaction temperature is 0-20°C; And / or, the molar ratio of compound VIII to compound VII is 1:1 to 1.2; And / or, the ratio of the compound of formula VIII to the base is 1:2~3.

5. The preparation method according to claim 1, characterized in that: In step 3, the solvent for removing the Boc protecting group is isopropyl acetate; And / or, the reaction temperature for removing the Boc protecting group is 20-30°C; And / or, the molar ratio of the compound of formula VI to the acid is 1:4~6.

6. The preparation method according to claim 1, characterized in that: In step 4, the solvent for the reaction is methanol; And / or, the reaction temperature is 60-70°C; And / or, the molar ratio of the compound of formula V to potassium thiocyanate is 1:1~2.

7. The preparation method according to claim 1, characterized in that: In step 5, the solvent for intramolecular cyclization is methanol.

8. The preparation method according to claim 1, characterized in that: In step 6, the solvent used for reduction is methanol; And / or, the reduction is carried out in the presence of an acid, selected from nitric acid; And / or, the reduction reaction temperature is 40-60℃.

9. The preparation method according to claim 1, characterized in that: In step 7, the solvent used for reduction is at least one of methanol or ethanol; And / or, the reducing agent for the reduction is selected from hydrogen; And / or, the reduction is carried out in the presence of a catalyst selected from 10% palladium on carbon; And / or, the reduction reaction temperature is 20-30°C; And / or, the mass ratio of the compound of formula II to the catalyst is 1:0.05~0.

1.

10. The preparation method according to any one of claims 1-9, characterized in that: In step 1, the substitution reaction is carried out under the action of a base, which is selected from sodium methoxide; the solvent for the substitution reaction is selected from methanol; the reaction temperature for the substitution reaction is 40-60℃; and the molar ratio of the compound of formula IX to the base is 1:2.

5. In step 2, the solvent for the acylation reaction is selected from dichloromethane; the acylation reaction is carried out in the presence of a catalyst, which is selected from... N,N -Dimethylformamide; the molar ratio of the compound of formula VIII to oxaloyl chloride is 1:1.1; the solvent for the condensation is selected from dichloromethane; the condensation is carried out under the action of a base, the base being selected from... N , N -Diisopropylethylamine; the condensation reaction temperature is 0-20℃; the molar ratio of compound VIII to compound VII is 1:1; during the condensation process, the molar ratio of compound VIII to base is 1:2; In step 3, the solvent for removing the Boc protecting group is isopropyl acetate; the process of removing the Boc protecting group is carried out under the action of an acid, which is selected from HCl; the reaction temperature for removing the Boc protecting group is 20-30℃; and the molar ratio of the compound of formula VI to the acid is 1:

4. In step 4, the solvent for the reaction is methanol; the reaction temperature is 60-70℃; and the molar ratio of compound V to potassium thiocyanate is 1:1.

5. In step 5, the solvent for the intramolecular cyclization is methanol; the intramolecular cyclization process is carried out under the action of a base, which is selected from sodium methoxide. In step 6, the solvent for reduction is methanol; the reduction is carried out under the action of an acid, which is selected from nitric acid; the reaction temperature for reduction is 40-60℃. In step 7, the solvent for reduction is methanol; the reducing agent for reduction is selected from hydrogen; the reduction is carried out under the action of a catalyst, which is selected from 10% palladium on carbon; the reaction temperature for reduction is 20-30℃; and the mass ratio of the compound of formula II to the catalyst is 1:0.1.

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