Synthesis method of 4-substituted-1H-pyrazole-3-methyl formate

Abstract

The invention belongs to the technical field of organic chemical synthesis, and provides a synthesis method of 4-substituted-1H-pyrazole-3-methyl formate. The method comprises the following steps: by utilizing the characteristic of thermodynamic stability of molecules, firstly introducing carboxyl to the 5-site of a pyrazole ring, and then carrying out deprotection along with intramolecular rearrangement and interconversion, so as to obtain 4-site functional group substituted 3-pyrazolecarboxylic acid, and automatically generating corresponding carboxylic acid methyl ester under the conditions of an acidic compound and methanol. The synthesis of the 4-substituted-1H-pyrazole-3-methyl formate is completed by taking various commercially available 4-substituted pyrazoles as initial raw materials through amino functional group protection, organic alkali hydrogen exchange, carbon dioxide carboxylation, deprotection, isomerization and esterification. The synthesis method disclosed by the invention is high in yield.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis technology, and in particular to a method for synthesizing methyl 4-substituted-1H-pyrazole-3-carboxylate. Background Technology

[0002] 4-Substituted-1H-pyrazole-3-carboxylic acid methyl ester, as an important organic synthesis building block, plays a vital role in many fields, including medicine, pesticides, and materials. Its unique chemical structure and properties provide broad prospects for the development of related technologies.

[0003] The pyrazole ring structure endows it with a certain degree of stability and a unique electron cloud distribution, while the introduction of the carboxyl functional group greatly enriches its chemical reactivity, enabling it to participate as an important intermediate in the construction of complex organic molecules and creating conditions for the synthesis of derivatives with specific functions.

[0004] Currently, the main methods for synthesizing methyl 4-substituted-1H-pyrazole-3-carboxylate are:

[0005] The first method, using 4-substituted-3-methylpyrazole as the starting material, is a more classic synthetic route, and the reaction formula is as follows:

[0006]

[0007] The specific process is as follows: First, using 4-substituted-3-methylpyrazole as the starting material, a strong oxidant such as potassium permanganate or potassium dichromate is used to oxidize the 3-methyl group to a carboxyl group under acidic conditions. This reaction is usually carried out under heating conditions. By controlling the reaction temperature and time, the reaction is ensured to occur fully. Subsequently, after a series of separation and purification steps, such as extraction and crystallization, 4-substituted-1H-pyrazole-3-carboxylic acid is obtained. This method uses relatively readily available raw materials, but the reaction conditions are quite harsh, the separation and purification of intermediate products is cumbersome, and the oxidation step may produce many byproducts, affecting the yield and purity. More importantly, the oxidant has relatively poor safety, chromium reagent is highly toxic, and the solid waste after the reaction is difficult to treat.

[0008] The second method uses 1H-pyrazole-3-carboxylic acid esters as starting materials, and the reaction formula is as follows:

[0009]

[0010] The specific process is as follows: using 1H-pyrazole-3-carboxylic acid esters as raw materials, 4-substituted-1H-pyrazole-3-carboxylic acid methyl esters are synthesized by functionalizing the carboxyl group at the ortho position. Although the reaction conditions are not as harsh as those of oxidation reactions, the types of functionalization reactions are relatively limited. Generally, only simple halogenation or nitration can be carried out, and there are regioselectivity issues. The yield and derivatization are not high, making it unsuitable for the development of a series of products.

[0011] Therefore, it is urgent to develop a high-yield methyl 4-substituted-1H-pyrazole-3-carboxylate. Summary of the Invention

[0012] In view of this, the object of the present invention is to provide a method for synthesizing methyl 4-substituted-1H-pyrazole-3-carboxylate. The synthesis method provided by the present invention has a high yield.

[0013] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0014] This invention provides a method for synthesizing methyl 4-substituted-1H-pyrazole-3-carboxylate, comprising the following steps:

[0015] Mixing 4-substituted-1H-pyrazole, 3,4-dihydro-2H-pyran, and p-toluenesulfonic acid with the structure shown in Formula I and protecting the amino functional group yields the first intermediate with the structure shown in Formula II.

[0016] The first intermediate, an organic base, and a polar aprotic solvent are mixed and subjected to hydrogen abstraction to obtain a hydrogen abstraction system; the hydrogen abstraction system is then carboxylated under the condition of carbon dioxide purging to obtain a second intermediate with the structure shown in Formula III.

[0017] The second intermediate, the acidic compound, and methanol were mixed and subjected to deprotection-isomerization-esterification to obtain the methyl 4-substituted-1H-pyrazole-3-carboxylate.

[0018]

[0019] In formulas I to III, R is -CH3, -Br, -F, -Cl, -OCH3, -NO2, -CF3, - i Pr or - t Bu.

[0020] Preferably, the molar ratio of the 4-substituted-1H-pyrazole to the 3,4-dihydro-2H-pyran is 1:1.1;

[0021] The molar ratio of the 4-substituted-1H-pyrazole to p-toluenesulfonic acid is 1:0.1 to 0.5.

[0022] Preferably, the medium protected by the amino functional group is an organic solvent, including dichloromethane;

[0023] The mixing of 4-substituted-1H-pyrazole, 3,4-dihydro-2H-pyran, and p-toluenesulfonic acid with the structure shown in Formula I includes the following steps:

[0024] Mix 4-substituted-1H-pyrazole, p-toluenesulfonic acid, and a medium protected by amino functional groups, and then add 3,4-dihydro-2H-pyran dropwise.

[0025] Preferably, the amino functional group is protected at a temperature of 20–40°C for a time of 10–60 min.

[0026] Preferably, the organic base includes one or more of n-butyllithium, bis(trimethylsilyl)aminopotassium, bis(trimethylsilyl)aminosodium, diisopropylaminolithium, and diisopropylaminosodium;

[0027] The polar aprotic solvent includes tetrahydrofuran and / or diethyl ether;

[0028] The molar ratio of the first intermediate to the organic base is 1 to 1.5:1.5.

[0029] Preferably, the first intermediate, an organic base, and a polar aprotic solvent are mixed and subjected to hydrogen abstraction to obtain a hydrogen abstraction system; the hydrogen abstraction system undergoes carboxylation under the condition of carbon dioxide introduction, comprising:

[0030] The first intermediate is mixed with a polar aprotic solvent to obtain a solution of the first intermediate;

[0031] After the first intermediate solution is cooled to -50 to -90°C, a polar aprotic solvent solution of an organic base is added to the cooled first intermediate solution, and hydrogen is extracted by keeping it at the temperature to obtain a hydrogen extraction system.

[0032] Carbon dioxide is introduced into the hydrogen capture system to carry out carboxylation.

[0033] Preferably, the hydrogen capture temperature is -50 to -90°C and the time is 0.5 to 3 hours.

[0034] Preferably, the carboxylation includes performing a first reaction and a second reaction sequentially, wherein the temperature of the first reaction is -50 to -90°C and the time is 0.5 to 3 hours; and the temperature of the second reaction is 20 to 40°C and the time is 1 to 3 hours.

[0035] Preferably, the acidic compound comprises an inorganic acidic compound and / or an organic acidic compound, wherein the inorganic acidic compound comprises hydrochloric acid and / or sulfuric acid, and the organic acidic compound comprises one or more of p-toluenesulfonic acid, benzoic acid, and acetic acid;

[0036] The molar ratio of the second intermediate to the acidic compound is 1:1 to 10.

[0037] Preferably, the deprotection-isomerization-esterification temperature is 60-90°C and the time is 12-24 hours.

[0038] This invention provides a method for synthesizing methyl 4-substituted-1H-pyrazole-3-carboxylate.

[0039] Beneficial effects

[0040] The synthetic method of this invention changes the previous strategy of methyl oxidation to carboxylic acid or functionalization at the ortho position of carboxylic acid. This invention utilizes the thermodynamic stability of the molecule, first introducing a carboxyl group into the 5-position of the pyrazole ring, followed by deprotection and intramolecular rearrangement tautomerism to obtain 4-functionalized 3-pyrazolecarboxylic acid, which spontaneously generates the corresponding methyl carboxylic acid under acidic compound and methanol conditions. Using various commercially available 4-substituted pyrazoles as starting materials, the synthesis of 4-substituted-1H-pyrazole-3-carboxylic acid methyl ester is achieved through amino functional group protection, organic base hydrogen abstraction, carbon dioxide carboxylation, deprotection-isomerization-esterification. The synthetic method of this invention avoids the conventional strategies of methyl oxidation to carboxylic acid (often using potassium permanganate, which is a vigorous reaction, generates a lot of solid and liquid waste, has low yield, and many side reactions) or ortho-functionalization of carboxylic acid (often position-selective, with low yield and limited types of functionalization). The synthetic method of this invention is simple to operate, has a high yield, and has the potential for industrial scale-up.

[0041] It is worth noting that, in the presence of a protecting group, the pyrazole ring configuration is fixed, and the carboxyl group is introduced to the more reactive pyrazole 5-position. However, as the protecting group is removed under acidic conditions, the pyrazole ring undergoes tautomerism, and the position of the carboxyl group changes to the pyrazole ring 3-position. The ingenious implementation of this strategy provides new ideas and methods for constructing this type of special heterocyclic molecule. Detailed Implementation

[0042] This invention provides a method for synthesizing methyl 4-substituted-1H-pyrazole-3-carboxylate, comprising the following steps:

[0043] Mixing 4-substituted-1H-pyrazole with the structure shown in Formula I, 3,4-dihydro-2H-pyran (DHP), and p-toluenesulfonic acid, and protecting the amino functional group, yields the first intermediate with the structure shown in Formula II.

[0044] The first intermediate, an organic base, and a polar aprotic solvent are mixed and subjected to hydrogen abstraction to obtain a hydrogen abstraction system; the hydrogen abstraction system is then carboxylated under the condition of carbon dioxide purging to obtain a second intermediate with the structure shown in Formula III.

[0045] The second intermediate, the acidic compound, and methanol were mixed and subjected to deprotection-isomerization-esterification to obtain the methyl 4-substituted-1H-pyrazole-3-carboxylate.

[0046]

[0047] In formulas I to III, R is -CH3, -Br, -F, -Cl, -OCH3, -NO2, -CF3, - i Pr or - t Bu.

[0048] Unless otherwise specified, the raw materials used in this invention are preferably commercially available products.

[0049] In this invention, 4-substituted-1H-pyrazole, 3,4-dihydro-2H-pyran, and p-toluenesulfonic acid of the structure shown in Formula I are mixed and protected with amino functional groups to obtain the first intermediate of the structure shown in Formula II.

[0050] In this invention, in formula I, R is -CH3, -Br, -F, -Cl, -OCH3, -NO2, -CF3, - i Pr or - t Bu.

[0051] In this invention, the structural formula of the 3,4-dihydro-2H-pyran is as follows:

[0052] In this invention, the p-toluenesulfonic acid is preferably p-toluenesulfonic acid monohydrate.

[0053] In this invention, the medium protected by the amino functional group is preferably an organic solvent, and the organic solvent preferably includes dichloromethane (DCM).

[0054] In this invention, the molar ratio of the 4-substituted-1H-pyrazole and the 3,4-dihydro-2H-pyran is preferably 1:1.1.

[0055] In this invention, the molar ratio of the 4-substituted-1H-pyrazole to p-toluenesulfonic acid (TsOH) is preferably 1:0.1 to 0.5, and more preferably 1:0.1, 1:0.2, 1:0.3, 1:0.4 or 1:0.5.

[0056] In this invention, the mixing of 4-substituted-1H-pyrazole, 3,4-dihydro-2H-pyran, and p-toluenesulfonic acid of Formula I preferably includes the following steps:

[0057] 4-substituted-1H-pyrazole, p-toluenesulfonic acid, and an amino-functionalized protected medium are mixed, and then 3,4-dihydro-2H-pyran is added dropwise. In this invention, the mixing of 4-substituted-1H-pyrazole, p-toluenesulfonic acid, and the amino-functionalized protected medium is preferably carried out with stirring at room temperature.

[0058] In this invention, the preferred temperature for amino functional group protection is 20–40°C, and the preferred time is 10–60 min, specifically 10 min, 20 min, 30 min, 40 min, 50 min, or 60 min. In this invention, the protection time for the amino functional group preferably begins after the complete addition of the 3,4-dihydro-2H-pyran. In this invention, the amino functional group protection is preferably carried out under stirring conditions. In this invention, the amino functional group protection process is preferably monitored using LCMS.

[0059] After the amino functional group is protected, the present invention preferably further includes: sequentially washing, separating, concentrating, and drying the obtained amino functional group protected solution to obtain the first intermediate. In the present invention, the washing reagent is preferably a saturated sodium carbonate aqueous solution.

[0060] After obtaining the first intermediate with the structure shown in Formula II, the present invention mixes the first intermediate, an organic base and a polar aprotic solvent to perform hydrogen abstraction to obtain a hydrogen abstraction system; the hydrogen abstraction system is carboxylated under the condition of carbon dioxide introduction to obtain the second intermediate with the structure shown in Formula III.

[0061] In this invention, the organic base preferably includes one or more of n-butyllithium, bis(trimethylsilyl)aminopotassium, bis(trimethylsilyl)aminosodium, diisopropylaminolithium, and diisopropylaminosodium, and more preferably diisopropylaminolithium (LDA).

[0062] In this invention, the polar aprotic solvent preferably includes tetrahydrofuran and / or diethyl ether, and more preferably tetrahydrofuran (TFH).

[0063] In this invention, the molar ratio of the first intermediate to the organic base is preferably 1 to 1.5:1.5, and more preferably 1:1.5, 1.1:1.5, 1.2:1.5, 1.3:1.5, 1.4:1.5 or 1.5:1.5.

[0064] In this invention, the first intermediate, an organic base, and a polar aprotic solvent are mixed and subjected to hydrogen abstraction to obtain a hydrogen abstraction system; the carboxylation process of the hydrogen abstraction system under the condition of carbon dioxide introduction preferably includes:

[0065] The first intermediate is mixed with a polar aprotic solvent to obtain a solution of the first intermediate;

[0066] After the first intermediate solution is cooled to -50 to -90°C, a polar aprotic solvent solution of an organic base is added to the cooled first intermediate solution, and hydrogen is extracted by keeping it at the temperature to obtain a hydrogen extraction system.

[0067] Carbon dioxide is introduced into the hydrogen capture system to carry out carboxylation.

[0068] In this invention, the cooling to -50 to -90°C is preferably achieved by placing the first intermediate solution in a dry ice bath; the dry ice bath is preferably obtained by adding dry ice to ethanol or ethyl acetate, and more preferably by adding dry ice to ethanol. In this invention, after cooling the first intermediate solution to -50 to -90°C, stirring for 5 to 10 minutes is also preferred.

[0069] In this invention, the concentration of the polar aprotic solvent solution of the organic base is preferably 2 mol / L.

[0070] In this invention, the hydrogen capture temperature is preferably -50 to -90°C, specifically -50°C, -60°C, -70°C, -80°C or -90°C; the time is preferably 0.5 to 3 hours, specifically 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours or 3 hours, and the hydrogen capture is preferably carried out under stirring conditions.

[0071] In this invention, the carboxylation preferably includes sequentially performing a first reaction and a second reaction. The temperature of the first reaction is preferably -50 to -90°C, specifically -50°C, -60°C, -70°C, -80°C, or -90°C; the time is preferably 0.5 to 3 hours, specifically 0.5 hours, 1 hour, 1.5 hours, 2 hours, 2.5 hours, or 3 hours. The temperature of the second reaction is preferably 20 to 40°C, specifically 20°C, 25°C, 30°C, 35°C, or 40°C; the time is preferably 1 to 3 hours, specifically 1 hour, 1.5 hours, 2 hours, 2.5 hours, or 3 hours. The carboxylation is preferably carried out under stirring conditions. In this invention, during the second reaction, it is preferable to monitor whether the reaction is complete using TLC.

[0072] Following the carboxylation, the present invention preferably further includes: quenching the carboxylation with water, rotary evaporating the resulting reaction solution to obtain an aqueous phase; adding water to the aqueous phase, then adding methyl tert-butyl ether to extract impurities to obtain a pure aqueous phase; adjusting the pH of the pure aqueous phase to 4-5, adding ethyl acetate for extraction, and combining the extracts to obtain an ethyl acetate phase; concentrating and drying the ethyl acetate phase to obtain the second intermediate. In the present invention, the reagent used to adjust the pH of the pure aqueous phase to 4-5 is preferably an aqueous hydrochloric acid solution, and the concentration of the aqueous hydrochloric acid solution is preferably 0.5 ml / L.

[0073] After obtaining the second intermediate with the structure shown in Formula III, the present invention mixes the second intermediate, an acidic compound, and methanol, and performs deprotection-isomerization-esterification to obtain the methyl 4-substituted-1H-pyrazole-3-carboxylate.

[0074] In this invention, the acidic compound preferably comprises inorganic acidic compounds and / or organic acidic compounds, more preferably inorganic acidic compounds. In this invention, the inorganic acidic compound preferably comprises hydrochloric acid and / or sulfuric acid, more preferably sulfuric acid. In this invention, the organic acidic compound preferably comprises one or more of p-toluenesulfonic acid, benzoic acid, and acetic acid.

[0075] In this invention, the methanol is more preferably anhydrous methanol.

[0076] In this invention, the molar ratio of the second intermediate to the acidic compound is preferably 1:1 to 10, and more preferably 1:1, 1:1.45, 1:1.6, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 or 1:10.

[0077] In this invention, the temperature for deprotection-isomerization-esterification is preferably 60–90°C, specifically 60°C, 70°C, 80°C, or 90°C, and the time is preferably 12–24 hours, specifically 12 hours, 18 hours, or 24 hours. The deprotection-isomerization-esterification is preferably carried out under air atmosphere, stirring, and reflux conditions. In this invention, the completeness of the reaction is preferably monitored by TLC during the deprotection-isomerization process.

[0078] Following the deprotection-isomerization-esterification process, the present invention preferably further includes: evaporating the medium from the resulting reaction solution, sequentially adding a saturated sodium bicarbonate aqueous solution and ethyl acetate for extraction, and combining the ethyl acetate phases; concentrating and drying the ethyl acetate phase to obtain a concentrate; and purifying the concentrate by column chromatography to obtain the methyl 4-substituted-1H-pyrazole-3-carboxylate. In this invention, the eluent for column chromatography purification is preferably a petroleum ether-ethyl acetate system, wherein the volume ratio of petroleum ether to ethyl acetate in the petroleum ether-ethyl acetate system is preferably 50:1 to 3:1, specifically preferably 50:1 to 5:1, 20:1 to 5:1, 30:1 to 4:1, 20:1 to 3:1, 10:1 to 3:1, or 30:1 to 6:1.

[0079] In this invention, during the deprotection-isomerization-esterification process, while removing the protecting group, the carboxyl group is tautomerized to the 3-position of the pyrazole ring, and esterification is catalyzed to form methyl 4-substituted-1H-pyrazole-3-carboxylate.

[0080] In this invention, the reaction formula for synthesizing methyl 4-substituted-1H-pyrazole-3-carboxylate is as follows:

[0081]

[0082] The following detailed description of the synthesis method of methyl 4-substituted-1H-pyrazole-3-carboxylate provided by the present invention, with reference to the embodiments, should not be construed as limiting the scope of protection of the present invention.

[0083] Example 1

[0084]

[0085] Add 1-1 (164 mg, 2.0 mmol), p-toluenesulfonic acid monohydrate (38 mg, 0.2 mmol), and dichloromethane (10.0 mL) to the reaction flask, stir at room temperature, and then add DHP (185.0 mg, 2.2 mmol) dropwise. After the addition is complete, stir for 10 minutes. LC-MS showed that the reaction was complete. The reaction solution was washed with saturated sodium carbonate aqueous solution (5 mL), separated, concentrated, and dried to obtain 1-2, which was used for the next step.

[0086] Take a dry 50 mL three-necked flask equipped with a three-way valve for a carbon dioxide balloon. Under vacuum conditions, dry the flask thoroughly with a high-temperature gun. Dilute the previously obtained intermediate 1-2 (332 mg, 2.0 mmol) with 5 mL of dry tetrahydrofuran. Slowly inject the solution into the flask using a 5 mL syringe. Cool the solution to -70°C in a dry ice bath and stir for 5–10 min to dissolve and clarify. At this temperature, 1 mL of LDA (2 mol / LinTHF, 2 mmol) was slowly added using a 1 mL syringe, and the mixture was kept at -70°C and stirred for 1 hour to obtain a pale yellow clear liquid. The three-way valve was turned on to introduce carbon dioxide gas into the reaction flask, and the mixture was stirred at -70°C for 30 min. After half an hour, the dry ice bath was removed, and the mixture was slowly raised to room temperature and stirred for 1.5 hours until the liquid turned pale yellow. The sample was taken, and the reaction was monitored by TLC to ensure complete reaction. 2 mL of water was added to quench the reaction, and the reaction solution was transferred to a 50 mL round-bottom flask. The tetrahydrofuran reaction solution was removed by vortexing, leaving only the aqueous phase. 3 mL of water was added, and impurities were extracted with 5 mL × 3 of methyl tert-butyl ether. The pH was adjusted to about 5-4 with 0.5 mol / L hydrochloric acid aqueous solution, followed by extraction with ethyl acetate three times (10 mL × 3). The organic phases were combined and about 30 mL were dried and concentrated to obtain 385 mg (1.83 mmol) of a pale yellow oily substance, with a molar yield of 91.5%, which was directly used in the next step.

[0087] In a 100 mL round-bottom reaction flask containing 1-3 (385 mg, 1.83 mmol), 7 mL of anhydrous methanol and 285 mg (2.9 mmol) of concentrated sulfuric acid were added. The flask was fitted with a reflux condenser and protected with a three-way air bulb. The mixture was stirred at 70 °C for 18 hours. After the reaction was complete as monitored by TLC, most of the methanol was removed by rotary evaporation. The mixture was neutralized with 10 mL of saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (10 mL × 3). No product was observed on the aqueous phase TLC. The organic phases were combined, dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 50:1 to 5:1) to give 1-4, 238 mg (1.7 mmol), a white solid, in a molar yield of 85%. ¹H NMR (400 MHz, CDCl₃): δ 2.31 (s, 3H), 3.92 (s, 3H), 7.44 (s, 1H), 12.0 (br s, 1H).

[0088] Example 2

[0089]

[0090] Add 2-1 (294 mg, 2.0 mmol), p-toluenesulfonic acid monohydrate (38 mg, 0.2 mmol), and dichloromethane (10.0 mL) to the reaction flask, stir at room temperature, and then add DHP (185.0 mg, 2.2 mmol) dropwise. After the addition is complete, stir for 10 minutes. LC-MS showed that the reaction was complete. The reaction solution was washed with saturated sodium carbonate aqueous solution (5 mL), concentrated to dryness, and used as 2-2 for the next step.

[0091] Take a dry 50 mL three-necked flask equipped with a three-way valve for a carbon dioxide balloon. Under vacuum conditions, dry the flask thoroughly with a high-temperature gun. Dilute the previously obtained intermediate 2-2 (462 mg, 2.0 mmol) with 5 mL of dry tetrahydrofuran. Slowly inject the solution into the flask using a 5 mL syringe. Cool the solution to -70°C in a dry ice bath and stir for 5–10 min to dissolve and clarify. At this temperature, 1 mL of LDA (2 mol / L in THF, 2.0 mmol) was slowly added using a 1 mL syringe, and the mixture was kept at -70°C with stirring for 1 hour. Then, a three-way valve was opened to introduce carbon dioxide gas into the reaction flask, and the mixture was stirred at -70°C for 30 minutes. After half an hour, the dry ice bath was removed, and the mixture was slowly brought to room temperature with stirring for 1.5 hours. A sample was taken, and TLC was used to monitor the reaction until complete. 2 mL of water was added to quench the reaction, and the reaction solution was transferred to a 50 mL round-bottom flask. The tetrahydrofuran reaction solution was removed by rotary evaporation, leaving only the aqueous phase. 3 mL of water was added, and impurities were extracted with 5 mL × 3 of methyl tert-butyl ether. The pH was adjusted to approximately 5–4 with 0.5 M hydrochloric acid aqueous solution, followed by extraction three times with ethyl acetate (10 mL × 3). The organic phases were combined (approximately 30 mL), dried, and concentrated to obtain 495.7 mg (1.83 mmol) of a pale yellow oil, with a molar yield of 91.5%, which was directly used in the next step.

[0092] In a 100 mL round-bottom flask containing 2-3 (495.7 mg, 1.83 mmol), 7 mL of anhydrous methanol and 285 mg (2.9 mmol) of concentrated sulfuric acid were added. The flask was fitted with a reflux condenser and protected with a three-way air bulb. The mixture was stirred at 70 °C for 18 hours. After the reaction was complete as monitored by TLC, most of the methanol was removed by rotary evaporation. The mixture was neutralized with 10 mL of saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (10 mL × 3). No product was observed on the aqueous phase TLC. The organic phases were combined, dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 5:1) to give a white solid 2-4, 356.7 mg, 1.74 mmol, with a molar yield of 87%. ¹H NMR (400 MHz, DMSO-D6): δ 3.85 (s, 3H), 8.0 (s, 1H), 14.0 (brs, 1H).

[0093] Example 3

[0094]

[0095] Add 3-1 (172 mg, 2.0 mmol), p-toluenesulfonic acid monohydrate (38 mg, 0.2 mmol), and dichloromethane (10.0 mL) to the reaction flask, stir at room temperature, and then add DHP (185.0 mg, 2.2 mmol) dropwise. After the addition is complete, stir for 10 minutes. LC-MS showed that the reaction was complete. The reaction solution was washed with saturated sodium carbonate aqueous solution (5 mL), concentrated to dryness, and used as 3-2 for the next step.

[0096] Take a dry 50 mL three-necked flask equipped with a three-way valve for a carbon dioxide balloon. Under vacuum conditions, dry the flask thoroughly with a high-temperature gun. Dilute the previously obtained intermediate 3-2 (340 mg, 2.0 mmol) with 5 mL of dry tetrahydrofuran. Slowly inject the solution into the flask using a 5 mL syringe. Cool the solution to -70°C in a dry ice bath and stir for 5–10 min to dissolve and clarify. At this temperature, 1 mL of LDA (2 mol / L inTHF, 2.0 mmol) was slowly added using a 1 mL syringe, and the mixture was kept at -70°C with stirring for 1 hour. Then, a three-way valve was opened to introduce carbon dioxide gas into the reaction flask, and the mixture was stirred at -70°C for 30 min. After half an hour, the dry ice bath was removed, and the mixture was slowly brought to room temperature with stirring for 1.5 hours. A sample was taken, and TLC was used to monitor the reaction until complete. 2 mL of water was added to quench the reaction, and the reaction solution was transferred to a 50 mL round-bottom flask. The tetrahydrofuran reaction solution was removed by rotary evaporation, leaving only the aqueous phase. 3 mL of water was added, and impurities were extracted with 5 mL × 3 of methyl tert-butyl ether. The pH was adjusted to approximately 5–4 with 0.5 M hydrochloric acid aqueous solution, followed by extraction three times with ethyl acetate (10 mL × 3). The organic phases were combined (approximately 30 mL), dried, and concentrated to obtain a pale yellow oily substance of 394.1 mg (1.84 mmol), with a molar yield of 92.0%, which was directly used in the next step.

[0097] In a 100 mL round-bottom reaction flask containing 3-3 (394.1 mg, 1.84 mmol), 7 mL of anhydrous methanol and 285 mg (2.9 mmol) of concentrated sulfuric acid were added. The flask was fitted with a reflux condenser and protected with a three-way air bulb. The mixture was stirred at 70 °C for 18 hours. After the reaction was complete as monitored by TLC, most of the methanol was removed by rotary evaporation. The mixture was neutralized with 10 mL of saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (10 mL × 3). No product was observed on the aqueous phase TLC. The organic phases were combined, dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 5:1) to give a brown solid 3-4, 236.3 mg (1.64 mmol), with a molar yield of 82%. ¹H NMR (400 MHz, DMSO-D6): 12.51 (l H, brs), 8.15 (l H, m), 3.81 (s, 3H).

[0098] Example 4

[0099]

[0100] Add 4-1 (205 mg, 2.0 mmol), p-toluenesulfonic acid monohydrate (38 mg, 0.2 mmol), and dichloromethane (10.0 mL) to the reaction flask, stir at room temperature, and then add DHP (185.0 mg, 2.2 mmol) dropwise. After the addition is complete, stir for 10 minutes. LC-MS showed that the reaction was complete. The reaction solution was washed with saturated sodium carbonate aqueous solution (5 mL), concentrated to dryness, and used as 4-2 for the next step.

[0101] Take a dry 50 mL three-necked flask equipped with a three-way valve for a carbon dioxide balloon. Under vacuum conditions, dry the flask thoroughly with a high-temperature gun. Dilute the previously obtained intermediate 4-2 (372 mg, 2.0 mmol) with 5 mL of dry tetrahydrofuran. Slowly inject the solution into the flask using a 5 mL syringe. Cool the solution to -70°C in a dry ice bath and stir for 5–10 min to dissolve and clarify. At this temperature, 1 mL of LDA (2 mol / L inTHF, 2.0 mmol) was slowly added using a 1 mL syringe, and the mixture was kept at -70°C with stirring for 1 hour. Then, the three-way valve was opened to introduce carbon dioxide gas into the reaction flask, and the mixture was stirred at -70°C for 30 min. After half an hour, the dry ice bath was removed, and the mixture was slowly raised to room temperature with stirring for 1.5 hours. A sample was taken, and the reaction was monitored by TLC to ensure complete reaction. 2 mL of water was added to quench the reaction, and the reaction solution was transferred to a 50 mL round-bottom flask. The tetrahydrofuran reaction solution was removed by rotary evaporation, leaving only the aqueous phase. 3 mL of water was added, and impurities were extracted with 5 mL × 3 of methyl tert-butyl ether. The pH was adjusted to approximately 5–4 with 0.5 M hydrochloric acid aqueous solution, followed by extraction three times with ethyl acetate (10 mL × 3). The organic phases were combined (approximately 30 mL), dried, and concentrated to obtain 395.6 mg (1.72 mmol) of a pale yellow oily substance, with a molar yield of 86%, which was directly used in the next step.

[0102] In a 100 mL round-bottom flask containing 4-3 (395.6 mg, 1.72 mmol), 7 mL of anhydrous methanol and 300 mg (3.06 mmol) of concentrated sulfuric acid were added. The flask was fitted with a reflux condenser and protected with a three-way air bulb. The mixture was stirred at 70 °C for 18 hours. After the reaction was complete as monitored by TLC, most of the methanol was removed by rotary evaporation. The mixture was neutralized with 10 mL of saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (10 mL × 3). No product was observed on the aqueous phase TLC. The organic phases were combined, dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 30:1 to 4:1) to give a brown solid 4-4, 257.9 mg (1.61 mmol), with a molar yield of 80.5%. ¹H NMR (400 MHz, DMSO-D6): 13.8 (l H, brs), 7.95 (l H, m), 3.90 (s, 3H).

[0103] Example 5

[0104]

[0105] Add 5-1 (196 mg, 2.0 mmol), p-toluenesulfonic acid monohydrate (38 mg, 0.2 mmol), and dichloromethane (10.0 mL) to the reaction flask, stir at room temperature, and then add DHP (185.0 mg, 2.2 mmol) dropwise. After the addition is complete, stir for 10 minutes. LC-MS showed that the reaction was complete. The reaction solution was washed with saturated sodium carbonate aqueous solution (5 mL), concentrated to dryness, and used as 5-2 for the next step.

[0106] Take a dry 50 mL three-necked flask equipped with a three-way valve for a carbon dioxide balloon. Under vacuum conditions, dry the flask thoroughly with a high-temperature gun. Dilute the previously obtained intermediate 5-2 (364 mg, 2.0 mmol) with 5 mL of dry tetrahydrofuran. Slowly inject the solution into the flask using a 5 mL syringe. Cool the solution to -70°C in a dry ice bath and stir for 5–10 min to dissolve and clarify. At this temperature, 1 mL of LDA (2 mol / L inTHF, 2.0 mmol) was slowly added using a 1 mL syringe, and the mixture was kept at -70°C with stirring for 1 hour. Then, the three-way valve was opened to introduce carbon dioxide gas into the reaction flask, and the mixture was stirred at -70°C for 30 minutes. After half an hour, the dry ice bath was removed, and the mixture was slowly brought to room temperature with stirring for 1.5 hours. A sample was taken, and the reaction was monitored by TLC to ensure complete reaction. 2 mL of water was added to quench the reaction, and the reaction solution was transferred to a 50 mL round-bottom flask. The tetrahydrofuran reaction solution was removed by rotary evaporation, leaving only the aqueous phase. 3 mL of water was added, and impurities were extracted with 5 mL × 3 of methyl tert-butyl ether. The pH was adjusted to approximately 5–4 with 0.5 M hydrochloric acid aqueous solution, followed by extraction three times with ethyl acetate (10 mL × 3). The organic phases were combined (approximately 30 mL), dried, and concentrated to obtain 339 mg (1.50 mmol) of a pale yellow oily substance (5-3), with a molar yield of 75%, which was directly used in the next step.

[0107] In a 100 mL round-bottom flask containing 5-3 (339 mg, 1.5 mmol), 7 mL of anhydrous methanol and 300 mg (3.06 mmol) of concentrated sulfuric acid were added. The flask was fitted with a reflux condenser and protected with a three-way air bulb. The mixture was stirred at 70 °C for 18 hours. After the reaction was complete as monitored by TLC, most of the methanol was removed by rotary evaporation. The mixture was neutralized with 10 mL of saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (10 mL × 3). No product was observed on the aqueous phase TLC. The organic phases were combined, dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 20:1 to 3:1) to give a white solid 5-4, 218.7 mg (1.40 mmol), with a molar yield of 70.0%. ¹H NMR (400 MHz, DMSO-D6): 12.51 (l H, brs), 8.14 (l H, m), 3.83 (s, 3H), 3.81 (s, 3H).

[0108] Example 6

[0109]

[0110] Add 6-1 (226 mg, 2.0 mmol), p-toluenesulfonic acid monohydrate (38 mg, 0.2 mmol), and dichloromethane (10.0 mL) to the reaction flask, stir at room temperature, and then add DHP (185.0 mg, 2.2 mmol) dropwise. After the addition is complete, stir for 10 minutes. LC-MS showed that the reaction was complete. The reaction solution was washed with saturated sodium carbonate aqueous solution (5 mL), concentrated to dryness, and used as 6-2 for the next step.

[0111] Take a dry 50 mL three-necked flask equipped with a three-way valve for a carbon dioxide balloon. Under vacuum conditions, dry the flask thoroughly with a high-temperature gun. Dilute the previously obtained intermediate 6-2 (394 mg, 2.0 mmol) with 5 mL of dry tetrahydrofuran. Slowly inject the solution into the flask using a 5 mL syringe. Cool the solution to -70°C in a dry ice bath and stir for 5–10 min to dissolve and clarify. At this temperature, 1 mL of LDA (2 mol / L inTHF, 2.0 mmol) was slowly added using a 1 mL syringe, and the mixture was kept at -70 °C with stirring for 1 hour. Then, the three-way valve was turned on to introduce carbon dioxide gas into the reaction flask, and the mixture was stirred at -70 °C for 30 min. After half an hour, the dry ice bath was removed, and the mixture was slowly raised to room temperature with stirring for 1.5 hours. The sample was taken, and the reaction was monitored by TLC to ensure complete reaction. 2 mL of water was added to quench the reaction, and the reaction solution was transferred to a 50 mL round-bottom flask. The tetrahydrofuran reaction solution was removed by rotary evaporation, leaving only the aqueous phase. 3 mL of water was added, and impurities were extracted with 5 mL × 3 of methyl tert-butyl ether. The pH was adjusted to approximately 5–4 with 0.5 M hydrochloric acid aqueous solution, followed by extraction three times with ethyl acetate (10 mL × 3). The organic phases were combined (approximately 30 mL), dried, and concentrated to obtain 6-3, 406 mg, 1.68 mmol, with a molar yield of 84%, which was directly used in the next step.

[0112] In a 100 mL round-bottom flask containing 6-3 (406 mg, 1.68 mmol), 7 mL of anhydrous methanol and 300 mg (3.06 mmol) of concentrated sulfuric acid were added. The flask was fitted with a reflux condenser and protected with a three-way air bulb. The mixture was stirred at 70 °C for 18 hours. After the reaction was complete as monitored by TLC, most of the methanol was removed by rotary evaporation. The mixture was neutralized with 10 mL of saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (10 mL × 3). No product was observed on the aqueous phase TLC. The organic phases were combined, dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 3:1) to give a white solid 6-4, 270 mg (1.58 mmol), with a molar yield of 79.0%. ¹H NMR (400 MHz, DMSO-D6): 14.39 (br s, 1H), 9.98 (s, 1H), 3.90 (s, 3H).

[0113] Example 7

[0114]

[0115] Add 7-1 (272 mg, 2.0 mmol), p-toluenesulfonic acid monohydrate (38 mg, 0.2 mmol), and dichloromethane (10.0 mL) to the reaction flask, stir at room temperature, and then add DHP (185.0 mg, 2.2 mmol) dropwise. After the addition is complete, stir for 10 minutes. LC-MS showed that the reaction was complete. The reaction solution was washed with saturated sodium carbonate aqueous solution (5 mL), concentrated to dryness, and used as 7-2 for the next step.

[0116] Take a dry 50 mL three-necked flask equipped with a three-way valve for a carbon dioxide balloon. Under vacuum conditions, dry the flask thoroughly with a high-temperature gun. Dilute the previously obtained intermediate 7-2 (440 mg, 2.0 mmol) with 5 mL of dry tetrahydrofuran. Slowly inject the solution into the flask using a 5 mL syringe. Cool the solution to -70°C in a dry ice bath and stir for 5–10 min to dissolve and clarify. At this temperature, 1 mL of LDA (2 mol / L inTHF, 2.0 mmol) was slowly added using a 1 mL syringe, and the mixture was kept at -70°C with stirring for 1 hour. Then, the three-way valve was opened to introduce carbon dioxide gas into the reaction flask, and the mixture was stirred at -70°C for 30 min. After half an hour, the dry ice bath was removed, and the mixture was slowly brought to room temperature with stirring for 1.5 hours. A sample was taken, and the reaction was monitored by TLC to ensure complete reaction. 2 mL of water was added to quench the reaction, and the reaction solution was transferred to a 50 mL round-bottom flask. The tetrahydrofuran reaction solution was removed by rotary evaporation, leaving only the aqueous phase. 3 mL of water was added, and impurities were extracted with 5 mL × 3 of methyl tert-butyl ether. The pH was adjusted to approximately 5–4 with 0.5 M hydrochloric acid aqueous solution, followed by extraction three times with ethyl acetate (10 mL × 3). The organic phases were combined (approximately 30 mL), dried, and concentrated to obtain 7-3, 433 mg 1.64 mmol, with a molar yield of 82%, which was directly used in the next step.

[0117] 7 mL of anhydrous methanol and 300 mg (3.06 mmol) of concentrated sulfuric acid were added to a 100 mL round-bottom flask containing 7-4 (433 mg, 1.64 mmol). The flask was fitted with a reflux condenser and protected with a three-way air bulb. The mixture was stirred at 70 °C for 18 hours. After the reaction was complete as monitored by TLC, most of the methanol was removed by rotary evaporation. The mixture was neutralized with 10 mL of saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (10 mL × 3). No product was observed on the aqueous phase TLC. The organic phases were combined, dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 10:1 to 3:1) to give a white solid 7-4, 292 mg (1.50 mmol), with a molar yield of 75.0%. ¹H NMR (400 MHz, CDCl₃): 4.20 (s, 3H), 8.35 (s, 1H), 12.35 (s, 1H).

[0118] Example 8

[0119]

[0120] Add 8-1 (220 mg, 2.0 mmol), p-toluenesulfonic acid monohydrate (38 mg, 0.2 mmol), and dichloromethane (10.0 mL) to the reaction flask, stir at room temperature, and then add DHP (185.0 mg, 2.2 mmol) dropwise. After the addition is complete, stir for 10 minutes. LC-MS showed that the reaction was complete. The reaction solution was washed with saturated sodium carbonate aqueous solution (5 mL), concentrated to dryness, and used as 8-2 for the next step.

[0121] Take a dry 50 mL three-necked flask equipped with a three-way valve for a carbon dioxide balloon. Under vacuum conditions, dry the flask thoroughly with a high-temperature gun. Dilute the previously obtained intermediate 8-2 (388 mg, 2.0 mmol) with 5 mL of dry tetrahydrofuran. Slowly inject the solution into the flask using a 5 mL syringe. Cool the solution to -70°C in a dry ice bath and stir for 5–10 min to dissolve and clarify. At this temperature, 1 mL of LDA (2 mol / L inTHF, 2.0 mmol) was slowly added using a 1 mL syringe, and the mixture was kept at -70°C with stirring for 1 hour. Then, a three-way valve was opened to introduce carbon dioxide gas into the reaction flask, and the mixture was stirred at -70°C for 30 minutes. After half an hour, the dry ice bath was removed, and the mixture was slowly brought to room temperature with stirring for 1.5 hours. A sample was taken, and the reaction was monitored by TLC to ensure complete reaction. 2 mL of water was added to quench the reaction, and the reaction solution was transferred to a 50 mL round-bottom flask. The tetrahydrofuran reaction solution was removed by rotary evaporation, leaving only the aqueous phase. 3 mL of water was added, and impurities were extracted with 5 mL × 3 of methyl tert-butyl ether. The pH was adjusted to approximately 5–4 with 0.5 M hydrochloric acid aqueous solution, followed by extraction three times with ethyl acetate (10 mL × 3). The organic phases were combined (approximately 30 mL), dried, and concentrated to obtain 8-3, 343 mg 1.44 mmol, with a molar yield of 72%, which was directly used in the next step.

[0122] 7 mL of anhydrous methanol and 300 mg (3.06 mmol) of concentrated sulfuric acid were added to a 100 mL round-bottom flask containing 8-3 (343 mg, 1.44 mmol). The flask was fitted with a reflux condenser and protected with a three-way air bulb. The mixture was stirred at 70 °C for 18 hours. After the reaction was complete as monitored by TLC, most of the methanol was removed by rotary evaporation. The mixture was neutralized with 10 mL of saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (10 mL × 3). No product was observed on the aqueous phase TLC. The organic phases were combined, dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 30:1 to 6:1) to give a white solid 8-4, 228.8 mg (1.36 mmol), with a molar yield of 68.0%. ¹H NMR (400 MHz, DMSO-D6): 1.27 (d, 6H, J = 6.9 Hz), 3.45 (m, 1H), 3.96 (s, 3H); 7.56 (s, 1H).

[0123] Example 9

[0124]

[0125] Add 9-1 (248 mg, 2.0 mmol), p-toluenesulfonic acid monohydrate (38 mg, 0.2 mmol), and dichloromethane (10.0 mL) to the reaction flask, stir at room temperature, and then add DHP (185.0 mg, 2.2 mmol) dropwise. After the addition is complete, stir for 10 minutes. LC-MS showed that the reaction was complete. The reaction solution was washed with saturated sodium carbonate aqueous solution (5 mL), concentrated to dryness, and used as 9-2 for the next step.

[0126] Take a dry 50 mL three-necked flask equipped with a three-way valve for a carbon dioxide balloon. Under vacuum conditions, dry the flask thoroughly with a high-temperature gun. Dilute the previously obtained intermediate 9-2 (416 mg, 2.0 mmol) with 5 mL of dry tetrahydrofuran. Slowly inject the solution into the flask using a 5 mL syringe. Cool the solution to -70°C in a dry ice bath and stir for 5–10 min to dissolve and clarify. At this temperature, 1 mL of LDA (2 mol / L inTHF, 2.0 mmol) was slowly added using a 1 mL syringe, and the mixture was kept at -70°C with stirring for 1 hour. Then, the three-way valve was opened to introduce carbon dioxide gas into the reaction flask, and the mixture was stirred at -70°C for 30 min. After half an hour, the dry ice bath was removed, and the mixture was slowly brought to room temperature with stirring for 1.5 hours. A sample was taken, and the reaction was monitored by TLC to ensure complete reaction. 2 mL of water was added to quench the reaction, and the reaction solution was transferred to a 50 mL round-bottom flask. The tetrahydrofuran reaction solution was removed by rotary evaporation, leaving only the aqueous phase. 3 mL of water was added, and impurities were extracted with 5 mL × 3 of methyl tert-butyl ether. The pH was adjusted to approximately 5–4 with 0.5 M hydrochloric acid aqueous solution, followed by extraction three times with ethyl acetate (10 mL × 3). The organic phases were combined (approximately 30 mL), dried, and concentrated to obtain 9-3, 357.8 mg (1.42 mmol), with a molar yield of 71%, which was directly used in the next step.

[0127] In a 100 mL round-bottom flask containing 9-3 (357.8 mg, 1.42 mmol), 7 mL of anhydrous methanol and 300 mg (3.06 mmol) of concentrated sulfuric acid were added. The flask was fitted with a reflux condenser and protected with a three-way air bulb. The mixture was stirred at 70 °C for 18 hours. After the reaction was complete as monitored by TLC, most of the methanol was removed by rotary evaporation. The mixture was neutralized with 10 mL of saturated sodium bicarbonate aqueous solution and extracted with ethyl acetate (10 mL × 3). No product was observed on the aqueous phase TLC. The organic phases were combined, dried, concentrated, and purified by column chromatography (petroleum ether:ethyl acetate = 30:1 to 6:1) to give a white solid 9-4, 221.7 mg (1.22 mmol), with a molar yield of 61.0%. ¹H NMR (400 MHz, DMSO-D6): 1.35 (s, 9H), 3.81 (s, 3H); 7.81 (s, 1H), 12.51 (brs, 1H).

[0128] This invention uses various commercially available 4-substituted pyrazoles as starting materials, and synthesizes 4-substituted-1H-pyrazole-3-carboxylic acid methyl esters through amino functional group protection, organic base hydrogen abstraction, carbon dioxide carboxylation, deprotection-isomerization-esterification. This invention successfully constructs a series of 3-carboxylic acid methyl ester pyrazole compounds (instead of 5-carboxylic acid methyl esters), pioneering a new method and strategy for the synthesis of such compounds. The synthetic method of this invention avoids the previous strategies of methyl oxidation to carboxylic acid (often using potassium permanganate, which is a vigorous reaction, produces a lot of solid and liquid waste, has low yields, and many side reactions) or ortho-functionalization of carboxylic acid (often position-selective, with low yields and limited types of functionalization). It is worth noting that, in the presence of a protecting group, the pyrazole ring configuration is fixed, and the carboxyl group is introduced to the more reactive pyrazole 5-position. However, as the protecting group is removed under acidic conditions, the pyrazole ring undergoes tautomerism, and the position of the carboxyl group changes to the pyrazole ring 3-position. The ingenious implementation of this strategy provides new ideas and methods for constructing this type of special heterocyclic molecule.

[0129] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for synthesizing methyl 4-substituted-1H-pyrazole-3-carboxylate, characterized in that, Includes the following steps: Mixing 4-substituted-1H-pyrazole, 3,4-dihydro-2H-pyran, and p-toluenesulfonic acid with the structure shown in Formula I and protecting the amino functional group yields the first intermediate with the structure shown in Formula II. The first intermediate, an organic base, and a polar aprotic solvent are mixed and subjected to hydrogen abstraction to obtain a hydrogen abstraction system; the hydrogen abstraction system is then carboxylated under the condition of carbon dioxide purging to obtain a second intermediate with the structure shown in Formula III. The second intermediate, the acidic compound, and methanol were mixed and subjected to deprotection-isomerization-esterification to obtain the methyl 4-substituted-1H-pyrazole-3-carboxylate. In formulas I to III, R is -CH3, -Br, -F, -Cl, -OCH3, -NO2, -CF3, - i Pr or - t Bu.

2. The synthesis method according to claim 1, characterized in that, The molar ratio of the 4-substituted-1H-pyrazole to the 3,4-dihydro-2H-pyran is 1:1.1; The molar ratio of the 4-substituted-1H-pyrazole to p-toluenesulfonic acid is 1:0.1 to 0.

5.

3. The synthesis method according to claim 1, characterized in that, The medium protected by the amino functional group is an organic solvent, including dichloromethane; The mixing of 4-substituted-1H-pyrazole, 3,4-dihydro-2H-pyran, and p-toluenesulfonic acid with the structure shown in Formula I includes the following steps: Mix 4-substituted-1H-pyrazole, p-toluenesulfonic acid, and a medium protected by amino functional groups, and then add 3,4-dihydro-2H-pyran dropwise.

4. The synthesis method according to claim 1, 2, or 3, characterized in that, The amino functional group is protected at a temperature of 20–40°C for a time of 10–60 min.

5. The synthesis method according to claim 1, characterized in that, The organic base includes one or more of n-butyllithium, potassium bis(trimethylsilyl)amino, sodium bis(trimethylsilyl)amino, lithium diisopropylamino, and sodium diisopropylamino. The polar aprotic solvent includes tetrahydrofuran and / or diethyl ether; The molar ratio of the first intermediate to the organic base is 1 to 1.5:1.

5.

6. The synthesis method according to claim 1, characterized in that, The first intermediate, an organic base, and a polar aprotic solvent are mixed and subjected to hydrogen abstraction to obtain a hydrogen abstraction system; the hydrogen abstraction system undergoes carboxylation under carbon dioxide purging conditions, including the following processes: The first intermediate is mixed with a polar aprotic solvent to obtain a solution of the first intermediate; After the first intermediate solution is cooled to -50 to -90°C, a polar aprotic solvent solution of an organic base is added to the cooled first intermediate solution, and hydrogen is extracted by keeping it at the temperature to obtain a hydrogen extraction system. Carbon dioxide is introduced into the hydrogen capture system to carry out carboxylation.

7. The synthesis method according to claim 1, 5, or 6, characterized in that, The hydrogen capture temperature is -50 to -90°C, and the time is 0.5 to 3 hours.

8. The synthesis method according to claim 1, 5, or 6, characterized in that, The carboxylation includes sequentially performing a first reaction and a second reaction. The temperature of the first reaction is -50 to -90°C, and the time is 0.5 to 3 hours. The temperature of the second reaction is 20 to 40°C, and the time is 1 to 3 hours.

9. The synthesis method according to claim 1, characterized in that, The acidic compound includes inorganic acidic compounds and / or organic acidic compounds, wherein the inorganic acidic compound includes hydrochloric acid and / or sulfuric acid, and the organic acidic compound includes one or more of p-toluenesulfonic acid, benzoic acid, and acetic acid; The molar ratio of the second intermediate to the acidic compound is 1:1 to 10.

10. The synthesis method according to claim 1 or 9, characterized in that, The deprotection-isomerization-esterification process takes place at a temperature of 60–90°C for 12–24 hours.

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