Synthesis process of 3-bromo-1-(3-chloro-2-pyridinyl)-1h-pyrazole-5-carboxylic acid

Abstract

The application belongs to the technical field of organic synthesis, and particularly relates to a synthesis process of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid. The synthesis process takes maleic anhydride as a starting material, and 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid is obtained after esterification, bromination, acyl chlorination, cyclization, NBS bromination, DDQ oxidation, ester hydrolysis, acidification and refining, the atomic utilization rate is sufficient, and the product quality is excellent. In addition, the synthesis process has the advantages of strong stability, excellent bromination selectivity, mild and efficient oxidation reaction, industrialization friendliness, simple and controllable operation, low three-waste discharge, and is suitable for industrialized continuous production, and can be further popularized to the preparation of halogenated pyridyl pyrazole carboxylic acid compounds.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a synthesis process of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid. Background Technology

[0002] 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-carboxylic acid is a core intermediate in diamide insecticides such as chlorantraniliprole and broflanilide. In existing technologies, the synthesis of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-carboxylic acid mainly includes the following three routes: (1) The target product was prepared by three steps: bromination, coupling with 2,3-dichloropyridine, and introduction of a carboxyl group, using N,N-dimethylaminosulfonylpyrazole as the starting material. This process requires special reagents such as LDA (lithium diisopropylamino) and TFA (trifluoroacetic acid), resulting in high raw material costs and limited sources. Furthermore, the reaction must be carried out at a low temperature of -75°C, which is demanding and makes industrial production difficult.

[0003] (2) Using 2,3-dichloropyridine as a raw material, 3-chloro-2-hydrazinopyridine is obtained by hydrazinolysis, and then cyclized with diethyl maleate in a sodium metal / anhydrous ethanol system. The product is then obtained by bromination, oxidation, and hydrolysis. This route is simple to operate, but the use of sodium metal poses a safety risk, and the yield of the cyclization step is low, making it unsuitable for industrial application.

[0004] (3) Patent CN110615780A describes the following synthesis method: after bromination and acylation of monomethyl maleate, it is reacted with 3-chloro-2-hydrazinopyridine in an acetonitrile / sodium bicarbonate system at 0°C, followed by cyclization and hydrolysis to obtain the target compound. This method has readily available raw materials, mild conditions, and excellent yield, but it has drawbacks such as a long procedure and strict requirements for the quality of raw materials.

[0005] In summary, it is of great significance to develop a simpler, more economical, and safer process for the synthesis of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid. Summary of the Invention

[0006] The objective of this invention is to provide a synthetic process for 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid. This 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid has high atom utilization and excellent product quality, making it suitable for industrial production.

[0007] The synthesis process of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid according to the present invention consists of the following steps: (1) Preparation of monoisopropyl maleate solution Under nitrogen protection, a solution of monoisopropyl maleate was prepared by esterification reaction of sodium isopropoxide with isopropanol as solvent and maleic anhydride as raw material. (2) Preparation of isopropyl 2-bromo-4-oxobutyrate The monoisopropyl maleate solution prepared in step (1) was cooled to 0-5℃, and a hydrogen bromide-isopropanol solution was added dropwise to carry out a bromination reaction to prepare isopropyl 2-bromo-4-oxobutyrate. After the reaction was completed, the solution was distilled under reduced pressure, cooled to 20-25℃, and dichloromethane was added. The solution was stirred evenly to carry out solvent replacement and obtain a dichloromethane solution of isopropyl 2-bromo-4-oxobutyrate. (3) Preparation of isopropyl 2-bromo-4-chloro-4-oxobutyrate The dichloromethane solution of isopropyl 2-bromo-4-oxobutyrate prepared in step (2) was cooled to 0-5℃, and thionyl chloride was added dropwise. After the addition was complete, the solution was kept warm and stirred to carry out the acyl chloride reaction. After the reaction was completed, dry nitrogen gas was purged to remove acid, and then the solution was cooled to -5℃~0℃. Triethylamine was added dropwise to adjust the pH of the system to 6.5-7.0, thus preparing the dichloromethane system of isopropyl 2-bromo-4-chloro-4-oxobutyrate. (4) Preparation of 3-hydroxy-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester Triethylamine was added to the dichloromethane system of 2-bromo-4-chloro-4-oxobutyrate isopropyl ester prepared in step (3), the mixture was stirred evenly and cooled to -5~0℃, and a 10% mass concentration of 3-chloro-2-hydrazylpyridine dichloromethane solution was added dropwise. After the addition was completed, the temperature was raised to 40-45℃, and the mixture was kept warm and stirred to carry out a homogeneous cyclization reaction to obtain 3-hydroxy-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester. (5) Preparation of 3-bromo-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester The 3-hydroxy-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester reaction system prepared in step (4) was cooled to 0-5℃, and azobisisobutyronitrile (AIBN) was added and stirred to dissolve. Then, a 10% mass concentration of dichloromethane solution of N-bromosuccinimide (NBS) was added dropwise. After the addition was completed, the temperature was raised to 20-40℃ and stirred to carry out the bromination reaction. (6) Preparation of isopropyl 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid Add 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) to the 3-bromo-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester reaction system prepared in step (5), heat to 40-50℃, keep warm and stir to carry out oxidation reaction. After the reaction is completed, add sodium thiosulfate aqueous solution and stir for 20 min. Let stand and separate the liquid. Wash the organic phase once with sodium thiosulfate aqueous solution of the same concentration. Add sodium carbonate aqueous solution to the washed organic phase and stir for 15 min. Let stand and separate the liquid. Wash the organic phase with pure water until the pH of the aqueous phase is 7.0. After standing and separating the liquid, retain the organic phase. (7) Preparation of sodium 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylate Add an aqueous solution of sodium hydroxide to the organic phase of isopropyl 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate obtained in step (6), heat to 50-55℃, keep warm and stir to carry out alkaline ester hydrolysis reaction, maintain the pH of the reaction system at 10-12, after the reaction is completed, let stand and separate the layers, recover and reuse the organic layer, and the aqueous phase is the sodium solution of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate; (8) Preparation of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid The sodium 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate solution obtained in step (7) was cooled to 25-30℃, and dilute hydrochloric acid was added dropwise to adjust the pH of the system to 2-3. The mixture was stirred for 30 min, then cooled to 1-5℃ and filtered to obtain crude 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid. The crude 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid was then post-treated to prepare high-purity 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid.

[0008] In step (1), the molar ratio of maleic anhydride to sodium isopropoxide is 1:1.03-1.27, and the molar ratio of isopropanol to maleic anhydride is 2.61-13.06:1.

[0009] In step (1), the esterification reaction temperature is 55-65℃ and the esterification reaction time is 2-5h.

[0010] In step (2), the molar ratio of hydrogen bromide to maleic anhydride monoisopropyl ester is 1.2-1.3:1, and the molar ratio of isopropanol to maleic anhydride monoisopropyl ester is 2-10:1.

[0011] In step (2), the time for adding hydrogen bromide-isopropanol solution is 2 hours, and the bromination reaction time is 2-3 hours.

[0012] The pressure of vacuum distillation in step (2) is 0.08-0.09 MPa and the temperature of vacuum distillation is 40-60℃.

[0013] In step (2), the molar ratio of dichloromethane to isopropanol is 0.5-5:1.

[0014] After the reaction in step (2) is completed, isopropanol and residual hydrogen bromide are removed by vacuum distillation.

[0015] In step (3), the molar ratio of thionyl chloride to isopropyl 2-bromo-4-oxobutyrate is 1.05-1.5:1.

[0016] In step (3), the thionyl chloride is added over a period of 0.5-3 hours. During the addition process, room temperature water is used to cool and control the reaction temperature to 30-50°C.

[0017] The acyl chloride reaction in step (3) takes 2.5-3 hours.

[0018] In step (3), the flow rate of nitrogen is 0.5-1.0 L / min, and the purging time is 30-40 min.

[0019] In step (4), the molar ratio of triethylamine to isopropyl 2-bromo-4-chloro-4-oxobutyrate is 1.05-1.25:1, and the molar ratio of 3-chloro-2-hydrazinopyridine to isopropyl 2-bromo-4-chloro-4-oxobutyrate is 1.02-1.2:1.

[0020] In step (4), the dichloromethane solution of 3-chloro-2-hydrazylpyridine is added dropwise over a period of 1-2 hours.

[0021] The homogeneous cyclization reaction in step (4) takes 7-8 hours.

[0022] In step (5), the molar ratio of azobisisobutyronitrile, N-bromosuccinimide and 3-hydroxy-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester is 0.01~0.03 : 1.05~1.2 : 1.

[0023] The bromination reaction time in step (5) is 2-4 hours.

[0024] The bromination step in step (5) and the cyclization step in step (4) are carried out in the same dichloromethane system, without the need to change the solvent.

[0025] In step (6), the mass concentration of sodium thiosulfate aqueous solution is 5-10%, and the mass concentration of sodium carbonate aqueous solution is 5%.

[0026] In step (6), the organic phase is washed once with an aqueous solution of sodium thiosulfate of the same concentration to thoroughly remove excess bromine and DDQ residue.

[0027] In step (6), add sodium carbonate aqueous solution and stir for 15 minutes. Let stand and separate the liquid to remove impurities from the system.

[0028] In step (6), the molar ratio of 2,3-dichloro-5,6-dicyanobenzoquinone to 3-bromo-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester is 1.05-1.2:1.

[0029] The oxidation reaction in step (6) takes 3-5 hours.

[0030] In step (7), the mass concentration of sodium hydroxide solution is 20-40%, and the molar ratio of sodium hydroxide to isopropyl 3-bromo-1-(3-chloropyridin-2-yl)-1Hpyrazole-5-carboxylic acid is 2.5-3.5:1.

[0031] The time for the alkaline ester hydrolysis reaction in step (7) is 3-4 hours.

[0032] In step (8), the mass concentration of dilute hydrochloric acid is 10-15%.

[0033] The post-treatment described in step (8) involves dissolving crude 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid in hot water at 80°C, removing insoluble impurities by hot filtration, and recrystallizing the filtrate at 1-5°C for 2-3 hours. After filtration, the filter cake is washed 2-3 times with distilled water at 10°C. The washed filter cake is then vacuum dried at 45-50°C and 0.070-0.08 MPa for 8-10 hours to obtain the target product 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid.

[0034] The chemical equations involved in the synthesis process of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid described in this invention are as follows: Compared with the prior art, the present invention has the following advantages: (1) The synthesis process of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid described in this invention uses maleic anhydride as the starting material, and proceeds through esterification, bromination, acylation, cyclization, NBS bromination, DDQ oxidation, esterification, and acidification, followed by purification to obtain 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid. This process achieves high atom utilization and produces a product of excellent quality. Furthermore, this synthesis process exhibits strong stability, excellent bromination selectivity, mild and efficient oxidation reaction, industrial friendliness, simple and controllable operation, low waste emissions, and suitability for continuous industrial production. It can be further extended to the preparation of halopyridinylpyrazolecarboxylic acid compounds.

[0035] (2) The synthesis process of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid described in this invention uses the synergistic effect of isopropanol and sodium isopropoxide. The steric hindrance of maleic acid monoisopropyl ester is large, which significantly improves the directional selectivity of the cyclization reaction, reduces ring-opening impurities, and the isopropyl ester has high structural stability, avoiding the loss of bromine and chlorine atoms. The process has strong stability and good reproducibility.

[0036] (3) The synthesis process of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid described in this invention has excellent selectivity of bromination reaction, avoids excessive bromination to generate impurities, and achieves directional bromination, which greatly reduces the content of sterically hindered isomer impurities, resulting in a lighter product color and significantly improved purity.

[0037] (4) The synthesis process of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid described in this invention has a mild and efficient oxidation reaction. DDQ is used as the oxidant to replace the traditional strong corrosive oxidant. There is no strong corrosion or degradation side reaction. It does not destroy the structure of the pyridine ring and pyrazole ring. The oxidation efficiency is high and the by-products are few.

[0038] (5) The synthesis process of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid described in this invention is a homogeneous reaction throughout the process, with few solvent changes, mild reaction conditions (no need for ultra-low temperature and high pressure), simple and controllable operation, low emissions of three wastes, and is suitable for industrial continuous production. Detailed Implementation

[0039] The present invention will be further described in detail below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto. All reagents used in the embodiments are industrial grade or analytical grade; unless otherwise specified, they are operated according to conventional methods. Example 1

[0040] The synthesis process of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid described in Example 1 consists of the following steps: (1) Preparation of monoisopropyl maleate Under nitrogen protection, isopropanol (400g, 6.65mol, molar ratio of isopropanol to maleic anhydride 6.5:1) was added to the reactor, followed by maleic anhydride (100g, 1.02mol). After stirring evenly, sodium isopropoxide (88.7g, 1.08mol, molar ratio of maleic anhydride to sodium isopropoxide 1:1.06) was slowly added. The temperature was raised to 60℃, and the reaction was carried out with stirring for 4 hours to obtain a monoisopropyl maleate isopropanol solution.

[0041] (2) Preparation of isopropyl 2-bromo-4-oxobutyrate The isopropanol solution of monoisopropyl maleate obtained in step (1) was cooled to 3°C, and a hydrogen bromide-isopropanol solution (containing 132.6 g of hydrogen bromide, 1.64 mol of hydrogen bromide, a molar ratio of hydrogen bromide to monoisopropyl maleate of 1.25:1, and a mass concentration of 40% of the hydrogen bromide-isopropanol solution) was slowly added dropwise over a period of 2 h. After the addition was complete, the solution was kept warm and stirred for 2.5 h for bromination. After the reaction was complete, isopropanol and residual hydrogen bromide were removed by vacuum distillation at a pressure of 0.085 MPa and a distillation temperature of 50°C. After cooling, dichloromethane (200 g) was added and stirred evenly to replace the solvent, resulting in a dichloromethane solution of isopropyl 2-bromo-4-oxobutyrate.

[0042] (3) Preparation of isopropyl 2-bromo-4-chloro-4-oxobutyrate The system obtained in step (2) was cooled to 3°C, and thionyl chloride (145.2 g, 1.22 mol, with a molar ratio of thionyl chloride to isopropyl 2-bromo-4-oxobutyrate of 1.2:1) was slowly added dropwise over a period of 1.5 h. The reaction temperature was controlled at 35°C by cooling with room temperature water. After the addition was complete, the system was kept at this temperature and stirred for 3 h to carry out the acyl chlorination reaction. After the reaction was completed, dry nitrogen gas (flow rate 0.8 L / min) was purged for 35 min to remove acid. The system was then cooled to -3°C, and triethylamine was added dropwise to adjust the pH of the system to 6.8, resulting in a dichloromethane system of isopropyl 2-bromo-4-chloro-4-oxobutyrate.

[0043] (4) Preparation of 3-hydroxy-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester Triethylamine (114.3 g, 1.13 mol, with a molar ratio of triethylamine to isopropyl 2-bromo-4-chloro-4-oxobutyrate of 1.12:1) was added to the system in step (3). The mixture was stirred until homogeneous and cooled to -3°C. A 10% solution of 3-chloro-2-hydrazylpyridine dichloromethane (containing 170.3 g, 1.19 mol of 3-chloro-2-hydrazylpyridine, with a molar ratio of 3-chloro-2-hydrazylpyridine to isopropyl 2-bromo-4-chloro-4-oxobutyrate of 1.1:1) was slowly added dropwise over a time of 1.5 h. After the addition was complete, the temperature was raised to 42°C and kept warm while stirring to carry out a homogeneous cyclization reaction for 7.5 h to obtain isopropyl 3-hydroxy-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid.

[0044] (5) Preparation of 3-bromo-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester The reaction system of step (4) was cooled to 3°C, and AIBN (0.51 g, 0.0031 mol, with a molar ratio of AIBN to 3-hydroxy-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester = 0.02:1) was added. After stirring and dissolving, a 10% concentration of NBS dichloromethane solution (containing 228.3 g of NBS, 1.28 mol, with a molar ratio of NBS to 3-hydroxy-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester = 1.1:1) was slowly added dropwise. After the addition was completed, the temperature was raised to 30°C, and the bromination reaction was carried out by stirring for 3 h. This step and the cyclization step were carried out in the same dichloromethane system, and there was no need to change the solvent.

[0045] (6) Preparation of isopropyl 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid Add DDQ (288.7 g, 1.27 mol, molar ratio of 2,3-dichloro-5,6-dicyanobenzoquinone to 3-bromo-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester of 1.1:1) to the bromination reaction system in step (5), heat to 45 °C, and maintain the temperature with stirring for 4 h for oxidation reaction. After the reaction is complete, add 200 g of 8% sodium thiosulfate aqueous solution, stir for 20 min, let stand and separate the liquids. Wash the organic phase once with the same concentration of sodium thiosulfate aqueous solution. Then add 150 g of 5% sodium carbonate aqueous solution to the organic phase, stir for 15 min, let stand and separate the liquids. Wash the organic phase with pure water until the pH of the aqueous phase is 7.0. After standing and separating the liquids, retain the organic phase.

[0046] (7) Preparation of sodium 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylate Add 136.8 g, 1.02 mol of 30% sodium hydroxide aqueous solution (molar ratio of sodium hydroxide to isopropyl 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate 3.0:1) to the organic phase obtained in step (6), heat to 52 °C, and carry out alkaline ester hydrolysis reaction for 3.5 h with stirring, maintaining the pH of the reaction system at 11. After the reaction is completed, allow the mixture to stand and separate into layers. The organic layer is recovered and reused, and the aqueous phase is the sodium 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate solution.

[0047] (8) Preparation of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid The aqueous phase obtained in step (7) was cooled to 28°C, and 12% dilute hydrochloric acid was added dropwise to adjust the pH of the system to 2.5. After stirring for 30 min, the system was cooled to 3°C and filtered to obtain the crude product. The crude product was dissolved in 80°C hot water, and insoluble impurities were removed by hot filtration. The filtrate was cooled to 3°C and recrystallized for 2.5 h. After filtration, the filter cake was washed twice with 10°C distilled water. The washed filter cake was placed in a vacuum dryer at 48°C and 0.075 MPa for 9 h to obtain 272.7 g of the target product 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid. The purity was 99.4% as determined by high performance liquid chromatography, and the total yield was 87.9%. Example 2

[0048] The synthesis process of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid described in Example 2 consists of the following steps: (1) Preparation of monoisopropyl maleate Under nitrogen protection, isopropanol (160g, 2.66mol, molar ratio of isopropanol to maleic anhydride 2.61:1) was added to the reactor, followed by maleic anhydride (100g, 1.02mol). After stirring evenly, sodium isopropoxide (86.2g, 1.05mol, molar ratio of maleic anhydride to sodium isopropoxide 1:1.03) was slowly added. The temperature was raised to 55℃, and the reaction was carried out with stirring for 2 hours to obtain a monoisopropyl maleate isopropanol solution.

[0049] (2) Preparation of isopropyl 2-bromo-4-oxobutyrate The isopropanol solution of monoisopropyl maleate obtained in step (1) was cooled to 0°C, and a hydrogen bromide-isopropanol solution (containing 127.2 g of hydrogen bromide, 1.57 mol of hydrogen bromide, a molar ratio of hydrogen bromide to monoisopropyl maleate of 1.2:1, and a mass concentration of 30%) was slowly added dropwise over a period of 2 h. After the addition was complete, the solution was kept warm and stirred for 2 h for bromination. After the reaction was complete, isopropanol and residual hydrogen bromide were removed by vacuum distillation at a pressure of 0.08 MPa and a distillation temperature of 40°C. After cooling, dichloromethane (300 g) was added and stirred evenly to replace the solvent, resulting in a dichloromethane solution of isopropyl 2-bromo-4-oxobutyrate.

[0050] (3) Preparation of isopropyl 2-bromo-4-chloro-4-oxobutyrate The system obtained in step (2) was cooled to 0℃, and thionyl chloride (120.3 g, 1.01 mol, with a molar ratio of thionyl chloride to isopropyl 2-bromo-4-oxobutyrate of 1.05:1) was slowly added dropwise over a period of 0.5 h. The reaction temperature was controlled at 40℃ by cooling with room temperature water. After the addition was complete, the system was kept at this temperature and stirred for 2.5 h for acyl chlorination. After the reaction was complete, dry nitrogen gas (flow rate 0.5 L / min) was introduced to purge the system for 30 min to remove acid. The system was then cooled to -5℃, and triethylamine was added dropwise to adjust the pH of the system to 6.5, resulting in a dichloromethane system of isopropyl 2-bromo-4-chloro-4-oxobutyrate.

[0051] (4) Preparation of 3-hydroxy-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester Add triethylamine (106.2 g, 1.05 mol, the molar ratio of triethylamine to isopropyl 2-bromo-4-chloro-4-oxobutyrate is 1.05:1) to the system in step (3), stir evenly and cool to -5℃; slowly add 10% concentration of 3-chloro-2-hydrazylpyridine dichloromethane solution (containing 155.3 g, 1.08 mol of 3-chloro-2-hydrazylpyridine, the molar ratio of 3-chloro-2-hydrazylpyridine to isopropyl 2-bromo-4-chloro-4-oxobutyrate is 1.02:1), the addition time is controlled to 1 h, after the addition is completed, raise the temperature to 40℃, keep warm and stir to carry out homogeneous cyclization reaction for 7 h, and obtain 3-hydroxy-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester.

[0052] (5) Preparation of 3-bromo-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester Cool the reaction system of step (4) to 0℃, add AIBN (0.26g, 0.0016mol, molar ratio of AIBN to 3-hydroxy-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester = 0.01:1), stir to dissolve, and slowly add 10% NBS dichloromethane solution (containing 207.5g NBS, 1.17mol, molar ratio of NBS to 3-hydroxy-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester = 1.05:1). After the addition is complete, heat to 20℃ and keep warm and stir to carry out the bromination reaction for 2h. This step and the cyclization step are carried out in the same dichloromethane system, and there is no need to change the solvent.

[0053] (6) Preparation of isopropyl 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid Add DDQ (263.3 g, 1.16 mol, molar ratio of 2,3-dichloro-5,6-dicyanobenzoquinone to 3-bromo-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester of 1.05:1) to the bromination reaction system in step (5), heat to 40 °C, and maintain the temperature with stirring for 3 h for oxidation reaction. After the reaction is complete, add 200 g of 5% sodium thiosulfate aqueous solution, stir for 20 min, let stand and separate the liquids, and wash the organic phase once with the same concentration of sodium thiosulfate aqueous solution; then add 150 g of 5% sodium carbonate aqueous solution to the organic phase, stir for 15 min, let stand and separate the liquids, wash the organic phase with pure water until the pH of the aqueous phase is 7.0, let stand and separate the liquids, and retain the organic phase.

[0054] (7) Preparation of sodium 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylate Add 114.0 g (0.57 mol) of 20% sodium hydroxide aqueous solution (the molar ratio of sodium hydroxide to isopropyl 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate is 2.5:1) to the organic phase obtained in step (6). Heat to 50 °C and stir for 3.0 h to carry out alkaline ester hydrolysis reaction, maintaining the pH of the reaction system at 10. After the reaction is complete, allow the mixture to stand and separate into layers. The organic layer is recovered and reused, and the aqueous phase is the sodium 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate solution.

[0055] (8) Preparation of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid The aqueous phase obtained in step (7) was cooled to 25°C, and 10% dilute hydrochloric acid was added dropwise to adjust the pH of the system to 2.0. After stirring for 30 min, the system was cooled to 1°C and filtered to obtain the crude product. The crude product was dissolved in 80°C hot water, and insoluble impurities were removed by hot filtration. The filtrate was cooled to 1°C and recrystallized for 2 h. After filtration, the filter cake was washed twice with 10°C distilled water. The washed filter cake was placed in a vacuum dryer at 45°C and 0.07 MPa for 8 h to obtain 269.1 g of the target product 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid. The purity was 99.1% as determined by high performance liquid chromatography, and the total yield was 86.4%. Example 3

[0056] The synthesis process of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid described in Example 3 consists of the following steps: (1) Preparation of monoisopropyl maleate Under nitrogen protection, isopropanol (800g, 13.32mol, molar ratio of isopropanol to maleic anhydride 13.06:1) was added to the reactor, followed by maleic anhydride (100g, 1.02mol). After stirring evenly, sodium isopropoxide (106.3g, 1.30mol, molar ratio of maleic anhydride to sodium isopropoxide 1:1.27) was slowly added. The temperature was raised to 65℃, and the esterification reaction was carried out with stirring for 5 hours to obtain a monoisopropyl maleate isopropanol solution.

[0057] (2) Preparation of isopropyl 2-bromo-4-oxobutyrate The isopropanol solution of monoisopropyl maleate obtained in step (1) was cooled to 5°C, and a hydrogen bromide-isopropanol solution (containing 138.0 g of hydrogen bromide, 1.71 mol, a molar ratio of hydrogen bromide to monoisopropyl maleate of 1.3:1, and a mass and concentration of 20% of the hydrogen bromide-isopropanol solution) was slowly added dropwise over a period of 2 h. After the addition was complete, the solution was kept warm and stirred for 3 h for bromination. After the reaction was complete, isopropanol and residual hydrogen bromide were removed by vacuum distillation at a pressure of 0.09 MPa and a distillation temperature of 60°C. After cooling, dichloromethane (500 g) was added and stirred evenly to replace the solvent, resulting in a dichloromethane solution of isopropyl 2-bromo-4-oxobutyrate.

[0058] (3) Preparation of isopropyl 2-bromo-4-chloro-4-oxobutyrate The system obtained in step (2) was cooled to 5°C, and thionyl chloride (185.8 g, 1.56 mol, with a molar ratio of thionyl chloride to isopropyl 2-bromo-4-oxobutyrate of 1.5:1) was slowly added dropwise over a period of 3 h. The reaction temperature was controlled at 45°C by cooling with room temperature water. After the addition was complete, the system was kept at this temperature and stirred for 3 h to carry out the acyl chlorination reaction. After the reaction was completed, dry nitrogen gas (flow rate 1.0 L / min) was introduced to purge for 40 min to remove acid. The system was then cooled to 0°C, and triethylamine was added dropwise to adjust the pH of the system to 7.0, resulting in a dichloromethane system of isopropyl 2-bromo-4-chloro-4-oxobutyrate.

[0059] (4) Preparation of 3-hydroxy-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester Triethylamine (127.6 g, 1.26 mol, with a molar ratio of triethylamine to isopropyl 2-bromo-4-chloro-4-oxobutyrate of 1.25:1) was added to the system in step (3). A 10% concentration of 3-chloro-2-hydrazylpyridine dichloromethane solution (containing 183.7 g, 1.28 mol of 3-chloro-2-hydrazylpyridine, with a molar ratio of 3-chloro-2-hydrazylpyridine to isopropyl 2-bromo-4-chloro-4-oxobutyrate of 1.2:1) was slowly added dropwise at 0°C for 2 h. After the addition was complete, the temperature was raised to 45°C and kept warm with stirring to carry out a homogeneous cyclization reaction for 8 h to obtain 3-hydroxy-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester.

[0060] (5) Preparation of 3-bromo-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester The reaction system of step (4) was cooled to 5°C, and AIBN (0.77 g, 0.0047 mol, with a molar ratio of AIBN to 3-hydroxy-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester = 0.03:1) was added. After stirring and dissolving, a 10% concentration of NBS dichloromethane solution (containing 249.0 g, 1.40 mol of NBS, with a molar ratio of NBS to 3-hydroxy-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester = 1.2:1) was slowly added dropwise. After the addition was completed, the temperature was raised to 40°C, and the bromination reaction was carried out by stirring for 4 h.

[0061] (6) Preparation of isopropyl 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid Add DDQ (314.1 g, 1.38 mol, molar ratio of 2,3-dichloro-5,6-dicyanobenzoquinone to 3-bromo-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester of 1.2:1) to the bromination reaction system in step (5), heat to 50 °C, and maintain the temperature with stirring for 5 h for oxidation reaction. After the reaction is complete, add 200 g of 10% sodium thiosulfate aqueous solution, stir for 20 min, let stand and separate the liquids, and wash the organic phase once with the same concentration of sodium thiosulfate aqueous solution; then add 150 g of 5% sodium carbonate aqueous solution to the organic phase, stir for 15 min, let stand and separate the liquids, wash the organic phase with pure water until the pH of the aqueous phase is 7.0, let stand and separate the liquids, and retain the organic phase.

[0062] (7) Preparation of sodium 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylate Add 152.0 g (1.52 mol) of 40% sodium hydroxide aqueous solution (the molar ratio of sodium hydroxide to isopropyl 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate is 3.5:1) to the organic phase obtained in step (6). Heat to 55°C and maintain the temperature with stirring for 4.0 h to carry out alkaline ester hydrolysis reaction, keeping the pH of the reaction system at 12. After the reaction is complete, allow the mixture to stand and separate into layers. The organic layer is recovered and reused, and the aqueous phase is the sodium 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate solution.

[0063] (8) Preparation of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid The aqueous phase obtained in step (7) was cooled to 30°C, and 15% dilute hydrochloric acid was added dropwise to adjust the pH of the system to 3.0. After stirring for 30 min, the system was cooled to 5°C and filtered to obtain the crude product. The crude product was dissolved in 80°C hot water, and insoluble impurities were removed by hot filtration. The filtrate was cooled to 5°C and recrystallized for 3 h. After filtration, the filter cake was washed three times with 10°C distilled water. The washed filter cake was placed in a vacuum dryer at 50°C and 0.08 MPa for 10 h to obtain 279.3 g of the target product 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid. The purity was 99.5% as determined by high performance liquid chromatography, and the total yield was 90.1%.

[0064] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-disclosed technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.

Claims

1. A process for synthesizing 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid, characterized in that: It consists of the following steps: (1) Preparation of monoisopropyl maleate solution Under nitrogen protection, a solution of monoisopropyl maleate was prepared by esterification reaction of sodium isopropoxide with isopropanol as solvent and maleic anhydride as raw material. (2) Preparation of isopropyl 2-bromo-4-oxobutyrate The monoisopropyl maleate solution prepared in step (1) was cooled to 0-5℃, and a hydrogen bromide-isopropanol solution was added dropwise to carry out a bromination reaction to prepare isopropyl 2-bromo-4-oxobutyrate. After the reaction was completed, the solution was distilled under reduced pressure, cooled to 20-25℃, and dichloromethane was added. The solution was stirred evenly to carry out solvent replacement and obtain a dichloromethane solution of isopropyl 2-bromo-4-oxobutyrate. (3) Preparation of isopropyl 2-bromo-4-chloro-4-oxobutyrate The dichloromethane solution of isopropyl 2-bromo-4-oxobutyrate prepared in step (2) was cooled to 0-5℃, and thionyl chloride was added dropwise. After the addition was complete, the solution was kept warm and stirred to carry out the acyl chloride reaction. After the reaction was completed, dry nitrogen gas was purged to remove acid, and then the solution was cooled to -5℃~0℃. Triethylamine was added dropwise to adjust the pH of the system to 6.5-7.0, thus preparing the dichloromethane system of isopropyl 2-bromo-4-chloro-4-oxobutyrate. (4) Preparation of 3-hydroxy-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester Triethylamine was added to the dichloromethane system of 2-bromo-4-chloro-4-oxobutyrate isopropyl ester prepared in step (3), the mixture was stirred evenly and cooled to -5~0℃, and a 10% mass concentration of 3-chloro-2-hydrazylpyridine dichloromethane solution was added dropwise. After the addition was completed, the temperature was raised to 40-45℃, and the mixture was kept warm and stirred to carry out a homogeneous cyclization reaction to obtain 3-hydroxy-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester. (5) Preparation of 3-bromo-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester The 3-hydroxy-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester reaction system prepared in step (4) was cooled to 0-5℃, and azobisisobutyronitrile was added and stirred to dissolve. Then, a 10% mass concentration of N-bromosuccinimide in dichloromethane solution was added dropwise. After the addition was completed, the temperature was raised to 20-40℃ and stirred to carry out the bromination reaction. (6) Preparation of isopropyl 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid Add 2,3-dichloro-5,6-dicyanobenzoquinone to the 3-bromo-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester reaction system prepared in step (5), heat to 40-50℃, keep warm and stir to carry out oxidation reaction. After the reaction is completed, add sodium thiosulfate aqueous solution and stir for 20 min. Let stand and separate the liquid. Wash the organic phase once with sodium thiosulfate aqueous solution of the same concentration. Add sodium carbonate aqueous solution to the washed organic phase and stir for 15 min. Let stand and separate the liquid. Wash the organic phase with pure water until the pH of the aqueous phase is 7.

0. After standing and separating the liquid, retain the organic phase. (7) Preparation of sodium 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylate Add an aqueous solution of sodium hydroxide to the organic phase of isopropyl 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate obtained in step (6), heat to 50-55℃, keep warm and stir to carry out alkaline ester hydrolysis reaction, maintain the pH of the reaction system at 10-12, after the reaction is completed, let stand and separate the layers, recover and reuse the organic layer, and the aqueous phase is the sodium solution of 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate; (8) Preparation of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid The sodium 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate solution obtained in step (7) was cooled to 25-30℃, and dilute hydrochloric acid was added dropwise to adjust the pH of the system to 2-3. The mixture was stirred for 30 min, then cooled to 1-5℃ and filtered to obtain crude 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid. The crude 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid was then post-treated to prepare high-purity 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid.

2. The synthesis process of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid according to claim 1, characterized in that: In step (1), the molar ratio of maleic anhydride to sodium isopropoxide is 1:1.03-1.27, and the molar ratio of isopropanol to maleic anhydride is 2.61-13.06:

1. In step (1), the esterification reaction temperature is 55-65℃ and the esterification reaction time is 2-5h.

3. The synthesis process of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid according to claim 1, characterized in that: In step (2), the molar ratio of hydrogen bromide to maleic anhydride monoisopropyl ester is 1.2-1.3:1, and the molar ratio of isopropanol to maleic anhydride monoisopropyl ester is 2-10:

1. In step (2), the time for adding the hydrogen bromide-isopropanol solution is 2 hours, and the bromination reaction time is 2-3 hours. The pressure of vacuum distillation in step (2) is 0.08-0.09 MPa and the temperature of vacuum distillation is 40-60℃; In step (2), the molar ratio of dichloromethane to isopropanol is 0.5-5:

1.

4. The synthesis process of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid according to claim 1, characterized in that: In step (3), the molar ratio of thionyl chloride to isopropyl 2-bromo-4-oxobutyrate is 1.05-1.5:1; In step (3), the thionyl chloride is added over a period of 0.5-3 hours, and the reaction temperature is controlled at 30-50°C by cooling with room temperature water during the addition process. The acyl chloride reaction in step (3) takes 2.5-3 hours; In step (3), the flow rate of nitrogen is 0.5-1.0 L / min, and the purging time is 30-40 min.

5. The synthesis process of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid according to claim 1, characterized in that: In step (4), the molar ratio of triethylamine to isopropyl 2-bromo-4-chloro-4-oxobutyrate is 1.05-1.25:1, and the molar ratio of 3-chloro-2-hydrazinopyridine to isopropyl 2-bromo-4-chloro-4-oxobutyrate is 1.02-1.2:

1. In step (4), the dichloromethane solution of 3-chloro-2-hydrazinopyridine is added dropwise over a period of 1-2 hours. The homogeneous cyclization reaction in step (4) takes 7-8 hours.

6. The synthesis process of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid according to claim 1, characterized in that: In step (5), the molar ratio of azobisisobutyronitrile, N-bromosuccinimide, and 3-hydroxy-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester is 0.01~0.03 : 1.05~1.2 : 1; The bromination reaction time in step (5) is 2-4 hours.

7. The synthesis process of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid according to claim 1, characterized in that: In step (6), the mass concentration of the sodium thiosulfate aqueous solution is 5-10%, and the mass concentration of the sodium carbonate aqueous solution is 5%. In step (6), the molar ratio of 2,3-dichloro-5,6-dicyanobenzoquinone to 3-bromo-1-(3-chloro-2-pyridyl)-4,5-dihydro-1H-pyrazole-5-carboxylic acid isopropyl ester is 1.05-1.2:1; The oxidation reaction in step (6) takes 3-5 hours.

8. The synthesis process of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid according to claim 1, characterized in that: In step (7), the mass concentration of the sodium hydroxide solution is 20-40%, and the molar ratio of sodium hydroxide to isopropyl 3-bromo-1-(3-chloropyridin-2-yl)-1Hpyrazole-5-carboxylic acid is 2.5-3.5:1; The time for the alkaline ester hydrolysis reaction in step (7) is 3-4 hours.

9. The synthesis process of 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid according to claim 1, characterized in that: In step (8), the mass concentration of dilute hydrochloric acid is 10-15%; The post-treatment described in step (8) involves dissolving crude 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid in hot water at 80°C, removing insoluble impurities by hot filtration, and recrystallizing the filtrate at 1-5°C for 2-3 hours. After filtration, the filter cake is washed 2-3 times with distilled water at 10°C. The washed filter cake is then vacuum dried at 45-50°C and 0.070-0.08 MPa for 8-10 hours to obtain the target product 3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid.

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