A method for synthesizing 5-bromopyrimidine-4-carboxylic acid

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of 5-bromopyrimidine-4-carboxylic acid. 4-hydroxypyrimidine-6-methyl ester is used as a starting material, 5-bromo-4-hydroxypyrimidine-6-methyl ester is obtained through a bromination reaction, and then 5-bromopyrimidine-4-carboxylic acid is obtained through hydroxyl chlorination and hydrolysis dehalogenation. In the application, the problems of many by-products and great separation difficulty in the traditional synthesis process are avoided. Through accurate control of reaction conditions in each step, the reaction selectivity and product yield are effectively improved, the purity of the target product can reach more than 98%, the raw materials are easy to obtain and low in cost, the reaction conditions are mild and easy to operate, special and expensive equipment is not needed, the safety is high, the application is friendly to the environment, and the industrialized production is easy to realize.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for synthesizing 5-bromopyrimidine-4-carboxylic acid. Background Technology

[0002] Pyrimidines are important heterocyclic compounds with unique structural advantages and good biocompatibility as molecular cores, making them a commonly used and advantageous backbone in drug molecule design. Their ring structure is similar to the pyrimidine bases in nucleic acids, allowing them to specifically bind to targets in vivo. Therefore, drugs with pyrimidine cores cover multiple therapeutic areas, including antitumor, antibacterial, antihypertensive, antiviral, and immunotherapeutic applications.

[0003] 5-Bromopyrimidine-4-carboxylic acid, as an important pyrimidine derivative, is a key pharmaceutical intermediate. The bromine atom and carboxyl group in its molecule can serve as active reaction sites. It is often used in the synthesis of bioactive drug molecules such as arthritis treatment drugs and anticancer drugs. It can be further modified through reactions such as nucleophilic aromatic substitution and palladium-catalyzed cross-coupling, providing an important material basis for new drug development.

[0004] Currently, US Patent Publication No. 4110450A discloses a method for synthesizing 5-bromopyrimidine-4-carboxylic acid, the preparation process of which is as follows:

[0005] ;

[0006] While this method can prepare the target product, the yield is only 52%. Due to the competing reaction between the two bromine molecules, the product contains many impurities in low concentrations, requiring purification by column chromatography. However, column chromatography is difficult to perform and increases production costs, making it difficult to achieve efficient and economical industrial-scale preparation. Furthermore, this method requires the use of metallic sodium as a reagent, which has extremely high chemical reactivity. The feeding, quenching, and maintenance of the inert atmosphere in large-scale reactions present significant engineering challenges. Moreover, metallic sodium is flammable and explosive, posing extremely high safety risks during storage, transportation, and use, and is prone to causing accidents.

[0007] In summary, existing synthetic methods suffer from low yields, numerous impurities, difficult purification, high costs, and significant safety risks, failing to meet the demands of industrial production and new drug development. Therefore, developing a high-yield, low-impurity, simple-to-purify, safe, reliable, and cost-effective method for synthesizing 5-bromopyrimidine-4-carboxylic acid is crucial for advancing pyrimidine drug development, reducing costs, and ensuring production safety. Summary of the Invention

[0008] The purpose of this invention is to provide a method for synthesizing 5-bromopyrimidine-4-carboxylic acid to solve the above-mentioned technical problems.

[0009] To achieve the above-mentioned technical objectives, the technical solution of the present invention is as follows: A method for synthesizing 5-bromopyrimidine-4-carboxylic acid, the reaction route of which is as follows:

[0010] .

[0011] As a further improvement, the method for synthesizing the 5-bromopyrimidine-4-carboxylic acid is as follows: S1. Methyl 4-hydroxypyrimidine-6-carboxylate was dissolved in N,N-dimethylformamide. The temperature was controlled at 0-10℃. N-bromosuccinimide was added in portions, and the temperature was slowly raised to 20-30℃. The mixture was stirred for 3-5 hours. After the reaction was completed, thionyl chloride was added at 20-30℃, and the reaction was continued for 6 hours. After the reaction was completed, the reaction system was added to water at 10-20℃ to quench the reaction. The mixture was extracted three times with MTBE. The organic phases were combined, washed, dried, and concentrated under reduced pressure to obtain methyl 4-chloro-5-bromopyrimidine-6-carboxylate. The reaction equation is:

[0012] ;

[0013] S2. Methyl 4-chloro-5-bromopyrimidine-6-carboxylic acid and tetrahydrofuran were mixed evenly and cooled to 0-10°C in an ice-salt bath. Hydrazine hydrate was added dropwise, and the reaction was maintained at 0-10°C for 1-2 hours. After the reaction was completed, sodium hydroxide solution was added, and the temperature was raised to 20-30°C for 3-5 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and cooled to 20-30°C. Under nitrogen protection, sodium hypochlorite solution was slowly added dropwise. After the addition was completed, the mixture was reacted at 20-30°C for 1-2 hours. After the reaction was completed, sodium thiosulfate was added to remove excess oxidant. The mixture was stirred for 15 minutes and extracted twice with MTBE. The organic phase was discarded. The aqueous phase was acidified with hydrochloric acid to pH=1-2 and extracted three times with ethyl acetate. The organic phases were combined, washed, dried, concentrated under reduced pressure, dispersed in petroleum ether, filtered, and dried under vacuum to constant weight to obtain 5-bromopyrimidine-4-carboxylic acid. The reaction equation is:

[0014] .

[0015] As a further improvement, in step S1, the mass ratio of methyl 4-hydroxypyrimidine-6-carboxylate, N-bromosuccinimide, and thionyl chloride is 1:2.5~3.0:2.2~2.8.

[0016] As a further improvement, in step S2, the mass ratio of methyl 4-chloro-5-bromopyrimidine-6-carboxylate to hydrazine hydrate is 1:0.26~0.31, wherein the concentration of hydrazine hydrate is 70~98wt%.

[0017] As a further improvement, in step S2, the mass ratio of methyl 4-chloro-5-bromopyrimidine-6-carboxylate, sodium hydroxide solution, sodium hypochlorite solution, and sodium thiosulfate solution is 1:4.5~6.5:4.0~5.5:2.2~2.6; wherein the concentration of sodium hydroxide is 5~15wt%, the concentration of sodium hypochlorite solution is 8~13wt%, and the concentration of sodium thiosulfate solution is 5~20wt%.

[0018] Due to the adoption of the above technical solution, the beneficial effects of the present invention are as follows: This invention provides a method for synthesizing 5-bromopyrimidine-4-carboxylic acid, using methyl 4-hydroxypyrimidine-6-carboxylate as the starting material, and preparing 5-bromopyrimidine-4-carboxylic acid through a two-step reaction. Compared with existing technologies, it has significant advantages, as detailed below: I. The initial raw material methyl 4-hydroxypyrimidine-6-carboxylate has a stable market supply, which can ensure the continuity of production. Moreover, it is inexpensive, which can effectively reduce raw material costs, enhance product competitiveness, and make it suitable for large-scale industrial production.

[0019] Second, both steps of the reaction are carried out at temperatures of 0~30℃, requiring no harsh conditions and are easy to operate; moreover, no special hazardous reagents are used, avoiding safety hazards, reducing safety management costs and operational difficulty, and improving production reliability.

[0020] Third, the yield of intermediate in step S1 can reach 92-96%, the yield of product in step S2 can reach 86-89%, and the total product yield can reach 79-85%; products with a purity of over 98% can be obtained without complex purification, reducing cost input, shortening the production cycle, and solving the pain points of low yield and difficult purification in existing processes.

[0021] Fourth, the synthesis process is mild and environmentally friendly, with no highly polluting steps, reducing environmental costs; the route design is novel, solving the problems of low yield, difficult purification, high cost and high risk of existing processes, and providing direction and ideas for industrial production. Attached Figure Description

[0022] Figure 1 This is the 1H NMR spectrum of 5-bromopyrimidine-4-carboxylic acid. Detailed Implementation

[0023] The technical solution of the present invention will be clearly and completely described below with reference to specific embodiments. However, those skilled in the art will understand that the embodiments described below are some embodiments of the present invention, but not all embodiments, and are only used to illustrate the present invention, and should not be regarded as limiting the scope of the present invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. Where specific conditions are not specified in the embodiments, conventional conditions or manufacturer's conditions shall be followed. Where the manufacturers of reagents or instruments are not specified, they are all conventional products that can be purchased commercially.

[0024] Example 1 A method for synthesizing 5-bromopyrimidine-4-carboxylic acid, comprising the following steps: S1. Dissolve 154g of methyl 4-hydroxypyrimidine-6-carboxylate in 1540mL of N,N-dimethylformamide (DMF). At 5℃, add 429g of N-bromosuccinimide (NBS) in three equal portions to the methyl 4-hydroxypyrimidine-6-carboxylate solution. After the addition is complete, slowly raise the temperature to 25℃ and stir the reaction for 5h. When the methyl 4-hydroxypyrimidine-6-carboxylate content is <2% by HPLC, the reaction stage is considered to be over. This step prepares methyl 4-hydroxy-5-bromopyrimidine-6-carboxylate. S2. Add 357g of thionyl chloride to the reaction system of step S1 and continue the reaction for 6 hours. When the methyl 4-hydroxy-5-bromopyrimidine-6-carboxylate content is less than 2% by liquid chromatography, the reaction is considered to be complete. After the reaction is complete, the reaction solution is obtained. At 15°C, the reaction solution is quenched in batches in 7700ml of water while stirring. It is extracted with 1000mL of methyl tert-butyl ether (MTBE) three times. The organic phases are combined, washed with 700mL of saturated brine, and then dehydrated with anhydrous sodium sulfate (Na2SO4). After filtration, the solution is concentrated under reduced pressure at 40°C to constant weight to obtain 236.6g of yellow oily methyl 4-chloro-5-bromopyrimidine-6-carboxylate, with a yield of 94.2% and an HPLC yield of 95.1%.

[0025] S3. Mix 236.6g of methyl 4-chloro-5-bromopyrimidine-6-carboxylate and 2366ml of tetrahydrofuran until homogeneous. Cool the mixture to 5°C in an ice-salt bath. Add 70.5g of 80wt% hydrazine hydrate dropwise and maintain the reaction at 5°C for 2 hours. If the methyl 4-chloro-5-bromopyrimidine-6-carboxylate content is less than 1% by liquid phase monitoring, the reaction is considered complete. In this step, methyl 4-hydrazino-5-bromopyrimidine-6-carboxylate is prepared. S4. Add 1183 mL (1313.13 g) of [a specific ingredient] (with a density of approximately 1.1 g / cm³) to the reaction system from step S3. 3Sodium 4-hydrazino-5-bromopyrimidine-6-carboxylate was prepared by heating a sodium hydroxide solution to 25°C and reacting for 5 hours. The hydrolysis reaction endpoint was determined by monitoring the liquid phase and finding that methyl 4-hydrazino-5-bromopyrimidine-6-carboxylate was less than 1%. Sodium 4-hydrazino-5-bromopyrimidine-6-carboxylate was prepared in this step. S5. Concentrate the reaction system from step S4 under reduced pressure at 45°C to remove tetrahydrofuran. Cool to 25°C and, under nitrogen protection, slowly add 1022 mL (1210 g) of 10 wt% (density approximately 1.2 g / cm³) of [a specific chemical compound]. 3 Add sodium hypochlorite solution, and after the addition is complete, react at 25℃ for 2 hours. If the 4-hydrazino-5-bromopyrimidine-6-carboxylate sodium content is less than 1% by liquid chromatography, the reaction is considered complete. After the reaction is complete, add 475 mL (522.5 g) of 10 wt% sodium hypochlorite solution (density approximately 1.1 g / cm³). 3 The organic phase was stirred in a sodium thiosulfate solution for 15 min, and impurities were extracted twice with 300 ml of MTBE. The organic phase was discarded, and the aqueous phase was acidified to pH 1-2 with 6 mol / L hydrochloric acid. It was then extracted three times with 500 ml of ethyl acetate. The organic phases were combined and washed once with 300 ml of saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure until a large amount of solid precipitated. The solid was then dispersed in 245 ml of petroleum ether, filtered, and dried under vacuum at 35 °C to constant weight to obtain 165.2 g of 5-bromopyrimidine-4-carboxylic acid; yield 86.5%, liquid phase purity 98.3%, and overall yield 81.5%.

[0026] like Figure 1 As shown, 1 ¹H-NMR (CD₃OD) δ: 9.17 (s, ¹H), 9.12 (s, ¹H). (The last part, "by" appears to be incomplete and requires further context.) 1 H-NMR results confirmed that the reaction product was 5-bromopyrimidine-4-carboxylic acid.

[0027] Example 2 A method for synthesizing 5-bromopyrimidine-4-carboxylic acid, comprising the following steps: S1. Dissolve 154g of methyl 4-hydroxypyrimidine-6-carboxylate in 1540mL of DMF. At 0℃, add 462g of NBS in three equal portions to the methyl 4-hydroxypyrimidine-6-carboxylate solution. After the addition is complete, slowly raise the temperature to 20℃ and stir for 4h. If the methyl 4-hydroxypyrimidine-6-carboxylate content is <2% by HPLC, the reaction is considered to be complete. Methyl 4-hydroxy-5-bromopyrimidine-6-carboxylate is prepared in this step. S2. Add 431.2 g of thionyl chloride to the reaction system of step S1 and continue the reaction for 6 h. When the methyl 4-hydroxy-5-bromopyrimidine-6-carboxylate is less than 2% by liquid phase monitoring, the reaction is considered to be completed. After the reaction is completed, the reaction solution is obtained. At 10 °C, the reaction solution is quenched in batches into 7700 ml of water while stirring. It is extracted with 1000 mL of MTBE three times. The organic phases are combined, washed with 700 mL of saturated brine, dehydrated with anhydrous Na2SO4, filtered, and concentrated under reduced pressure at 35 °C to constant weight to obtain 241.3 g of yellow oily methyl 4-chloro-5-bromopyrimidine-6-carboxylate.

[0028] S3. Mix 241.3g of methyl 4-chloro-5-bromopyrimidine-6-carboxylate and 2366ml of tetrahydrofuran until homogeneous. Cool the mixture to 0℃ in an ice-salt bath. Add 73.35g of 70wt% hydrazine hydrate dropwise and maintain the reaction at 0℃ for 1.5h. If the methyl 4-chloro-5-bromopyrimidine-6-carboxylate content is less than 1% by liquid phase monitoring, the reaction is considered complete. In this step, methyl 4-hydrazino-5-bromopyrimidine-6-carboxylate is prepared. S4. Add 1569g of 5wt% sodium hydroxide solution to the reaction system in step S3, heat to 20℃ and react for 3h. The hydrolysis reaction endpoint is defined as methyl 4-hydrazino-5-bromopyrimidine-6-carboxylate <1% by liquid phase monitoring. Sodium 4-hydrazino-5-bromopyrimidine-6-carboxylate is prepared in this step. S5. The reaction system from step S4 was concentrated under reduced pressure at 40°C to remove tetrahydrofuran. The temperature was then lowered to 20°C, and under nitrogen protection, 1328 g of 8 wt% sodium hypochlorite solution was slowly added dropwise. After the addition was complete, the reaction was carried out at 20°C for 1.5 h. The liquid phase monitoring showed that the sodium 4-hydrazino-5-bromopyrimidine-6-carboxylate was <1%, which was considered the end of the stage reaction. After the reaction was complete, 628 g of 5 wt% sodium thiosulfate was added, and the mixture was stirred for 15 min. Impurities were extracted with 300 ml of MTBE twice. The organic phase was discarded. The aqueous phase was acidified with 6 mol / L hydrochloric acid to pH=1~2 and extracted with 500 ml of ethyl acetate three times. The organic phases were combined and washed once with 300 ml of saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure until a large amount of solid precipitated. The solid was then dispersed in 245 ml of petroleum ether, filtered, and dried under vacuum at 35°C to constant weight to obtain 173.4 g of 5-bromopyrimidine-4-carboxylic acid.

[0029] Example 3 A method for synthesizing 5-bromopyrimidine-4-carboxylic acid, comprising the following steps: S1. Dissolve 154g of methyl 4-hydroxypyrimidine-6-carboxylate in 1540mL of DMF. At 10℃, add 385g of NBS in three equal portions to the methyl 4-hydroxypyrimidine-6-carboxylate solution. After the addition is complete, slowly raise the temperature to 30℃ and stir for 3h. If the methyl 4-hydroxypyrimidine-6-carboxylate content is <2% by HPLC, the reaction stage is considered to be over. Methyl 4-hydroxy-5-bromopyrimidine-6-carboxylate is prepared in this step. S2. Add 338.8 g of thionyl chloride to the reaction system of step S1 and continue the reaction for 6 h. When the methyl 4-hydroxy-5-bromopyrimidine-6-carboxylate is less than 2% by liquid phase monitoring, the reaction is considered to be completed. After the reaction is completed, the reaction solution is obtained. At 20 °C, the reaction solution is quenched in batches into 7700 ml of water while stirring. It is extracted with 1000 mL of MTBE three times. The organic phases are combined, washed with 700 mL of saturated brine, dehydrated with anhydrous Na2SO4, filtered, and concentrated under reduced pressure at 45 °C to constant weight to obtain 231.3 g of yellow oily methyl 4-chloro-5-bromopyrimidine-6-carboxylate.

[0030] S3. Mix 231.3g of methyl 4-chloro-5-bromopyrimidine-6-carboxylate and 2366ml of tetrahydrofuran until homogeneous. Cool the mixture to 10°C in an ice-salt bath. Add 61.5g and 98wt% hydrazine hydrate dropwise. Maintain the reaction at 10°C for 1 hour. If the methyl 4-chloro-5-bromopyrimidine-6-carboxylate content is less than 1% by liquid phase monitoring, the reaction is considered complete. In this step, methyl 4-hydrazino-5-bromopyrimidine-6-carboxylate is prepared. S4. Add 11040g of 15wt% sodium hydroxide solution to the reaction system in step S3, heat to 30℃ and react for 3h. The hydrolysis reaction endpoint is defined as methyl 4-hydrazino-5-bromopyrimidine-6-carboxylate <1% by liquid phase monitoring. Sodium 4-hydrazino-5-bromopyrimidine-6-carboxylate is prepared in this step. S5. The reaction system from step S4 was concentrated under reduced pressure at 50°C to remove tetrahydrofuran. The temperature was then lowered to 30°C, and under nitrogen protection, 925g of a 13wt% sodium hypochlorite solution was slowly added dropwise. After the addition was complete, the reaction was carried out at 30°C for 1 hour. When the 4-hydrazino-5-bromopyrimidine-6-carboxylic acid sodium salt was less than 1%, the reaction was considered complete. After the reaction was complete, 509g of a 20wt% sodium thiosulfate solution was added, and the mixture was stirred for 15 minutes. Impurities were extracted twice with 300ml of MTBE. The organic phase was discarded. The aqueous phase was acidified to pH 1-2 with 6mol / L hydrochloric acid and extracted three times with 500ml of ethyl acetate. The organic phases were combined and washed once with 300ml of saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure until a large amount of solid precipitated. The solid was then dispersed in 245ml of petroleum ether, filtered, and dried under vacuum at 35°C to constant weight to obtain 160.6g of 5-bromopyrimidine-4-carboxylic acid.

[0031] Example 4 A method for synthesizing 5-bromopyrimidine-4-carboxylic acid, comprising the following steps: S1. Dissolve 154g of methyl 4-hydroxypyrimidine-6-carboxylate in 1540mL of N,N-dimethylformamide (DMF). At 5℃, add 445g of N-bromosuccinimide (NBS) in three equal portions to the methyl 4-hydroxypyrimidine-6-carboxylate solution. After the addition is complete, slowly raise the temperature to 25℃ and stir the reaction for 5h. When the methyl 4-hydroxypyrimidine-6-carboxylate content is <2% by HPLC, the reaction stage is considered to be over. This step prepares methyl 4-hydroxy-5-bromopyrimidine-6-carboxylate. S2. Add 410g of thionyl chloride to the reaction system of step S1 and continue the reaction for 6 hours. When the methyl 4-hydroxy-5-bromopyrimidine-6-carboxylate is less than 2% by liquid phase monitoring, the reaction is considered to be completed. After the reaction is completed, the reaction solution is obtained. At 15°C, the reaction solution is quenched in batches in 7700ml of water while stirring. It is extracted with 1000mL of methyl tert-butyl ether (MTBE) three times. The organic phases are combined, washed with 700mL of saturated brine, and then dehydrated with anhydrous sodium sulfate (Na2SO4). After filtration, it is concentrated under reduced pressure at 40°C to constant weight to obtain 238.8g of yellow oily methyl 4-chloro-5-bromopyrimidine-6-carboxylate.

[0032] S3. Mix 238.8g of methyl 4-chloro-5-bromopyrimidine-6-carboxylate and 2366ml of tetrahydrofuran until homogeneous. Cool the mixture to 5°C in an ice-salt bath. Add 73.5% and 80wt% hydrazine hydrate dropwise. Maintain the reaction at 5°C for 2 hours. If the methyl 4-chloro-5-bromopyrimidine-6-carboxylate content is less than 1% by liquid phase monitoring, the reaction is considered complete. In this step, methyl 4-hydrazino-5-bromopyrimidine-6-carboxylate is prepared. S4. Add 1314g of 10wt% sodium hydroxide solution to the reaction system in step S3, heat to 25℃ and react for 5h. The hydrolysis reaction endpoint is defined as methyl 4-hydrazino-5-bromopyrimidine-6-carboxylate <1% by liquid phase monitoring. Sodium 4-hydrazino-5-bromopyrimidine-6-carboxylate is prepared in this step. S5. The reaction system from step S4 was concentrated under reduced pressure at 45°C to remove tetrahydrofuran. The temperature was then lowered to 25°C, and under nitrogen protection, 1242 g of 10 wt% sodium hypochlorite solution was slowly added dropwise. After the addition was complete, the reaction was carried out at 25°C for 2 hours. When the 4-hydrazino-5-bromopyrimidine-6-carboxylic acid sodium salt was less than 1%, the reaction was considered complete. After the reaction was complete, 597 g of 10 wt% sodium thiosulfate was added, and the mixture was stirred for 15 minutes. Impurities were extracted with 300 ml of MTBE twice. The organic phase was discarded. The aqueous phase was acidified with 6 mol / L hydrochloric acid to pH 1-2 and extracted with 500 ml of ethyl acetate three times. The organic phases were combined and washed once with 300 ml of saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure until a large amount of solid precipitated. The solid was then dispersed in 245 ml of petroleum ether, filtered, and dried under vacuum at 35°C to constant weight to obtain 168.1 g of 5-bromopyrimidine-4-carboxylic acid.

[0033] Example 5 A method for synthesizing 5-bromopyrimidine-4-carboxylic acid, comprising the following steps: S1. Dissolve 154g of methyl 4-hydroxypyrimidine-6-carboxylate in 1540mL of N,N-dimethylformamide (DMF). At 5℃, add 400g of N-bromosuccinimide (NBS) in three equal portions to the methyl 4-hydroxypyrimidine-6-carboxylate solution. After the addition is complete, slowly raise the temperature to 25℃ and stir for 5h. When the methyl 4-hydroxypyrimidine-6-carboxylate content is <2% by HPLC, the reaction is considered to be complete. This step prepares methyl 4-hydroxy-5-bromopyrimidine-6-carboxylate. S2. Add 350g of thionyl chloride to the reaction system of step S1 and continue the reaction for 6h. When the methyl 4-hydroxy-5-bromopyrimidine-6-carboxylate is less than 2% by liquid phase monitoring, the reaction is considered to be completed. After the reaction is completed, the reaction solution is obtained. At 15℃, the reaction solution is quenched in batches in 7700ml of water while stirring. It is extracted with 1000mL of methyl tert-butyl ether (MTBE) three times. The organic phases are combined, washed with 700mL of saturated brine, and then dehydrated with anhydrous sodium sulfate (Na2SO4). After filtration, it is concentrated under reduced pressure at 40℃ to constant weight to obtain 234.8g of yellow oily methyl 4-chloro-5-bromopyrimidine-6-carboxylate.

[0034] S3. Mix 234.8g of methyl 4-chloro-5-bromopyrimidine-6-carboxylate and 2366ml of tetrahydrofuran until homogeneous. Cool the mixture to 5°C in an ice-salt bath. Add 63.5% and 80wt% hydrazine hydrate dropwise. Maintain the reaction at 5°C for 2 hours. If the methyl 4-chloro-5-bromopyrimidine-6-carboxylate content is less than 1% by liquid phase monitoring, the reaction is considered complete. In this step, methyl 4-hydrazino-5-bromopyrimidine-6-carboxylate is prepared. S4. Add 1174g of 10wt% sodium hydroxide solution to the reaction system in step S3, heat to 25℃ and react for 5h. The hydrolysis reaction endpoint is defined as methyl 4-hydrazino-5-bromopyrimidine-6-carboxylate <1% by liquid phase monitoring. Sodium 4-hydrazino-5-bromopyrimidine-6-carboxylate is prepared in this step. S5. The reaction system from step S4 was concentrated under reduced pressure at 45°C to remove tetrahydrofuran. The temperature was then lowered to 25°C, and under nitrogen protection, 1092 g of 10 wt% sodium hypochlorite solution was slowly added dropwise. After the addition was complete, the reaction was carried out at 25°C for 2 hours. When the 4-hydrazino-5-bromopyrimidine-6-carboxylic acid sodium salt was less than 1%, the reaction was considered complete. After the reaction was complete, 540 g of 10 wt% sodium thiosulfate was added, and the mixture was stirred for 15 minutes. Impurities were extracted with 300 ml of MTBE twice. The organic phase was discarded. The aqueous phase was acidified with 6 mol / L hydrochloric acid to pH 1-2 and extracted with 500 ml of ethyl acetate three times. The organic phases were combined and washed once with 300 ml of saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure until a large amount of solid precipitated. The solid was then dispersed in 245 ml of petroleum ether, filtered, and dried under vacuum at 35°C to constant weight to obtain 166.155 g of 5-bromopyrimidine-4-carboxylic acid.

[0035] The specific embodiments of the present invention described above do not constitute a limitation on the scope of protection of the present invention. Any other corresponding changes and modifications made in accordance with the technical concept of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. A method for synthesizing 5-bromopyrimidine-4-carboxylic acid, characterized in that, Its reaction route is as follows: 。 2. The method for synthesizing 5-bromopyrimidine-4-carboxylic acid according to claim 1, characterized in that, The specific steps are as follows: S1. Methyl 4-hydroxypyrimidine-6-carboxylate was dissolved in N,N-dimethylformamide. The temperature was controlled at 0-10℃. N-bromosuccinimide was added in portions, and the temperature was slowly raised to 20-30℃. The mixture was stirred for 3-5 hours. After the reaction was completed, thionyl chloride was added at 20-30℃, and the reaction was continued for 6 hours. After the reaction was completed, the reaction system was added to water at 10-20℃ to quench the reaction. The mixture was extracted three times with MTBE. The organic phases were combined, washed, dried, and concentrated under reduced pressure to obtain methyl 4-chloro-5-bromopyrimidine-6-carboxylate. S2. Methyl 4-chloro-5-bromopyrimidine-6-carboxylate and tetrahydrofuran were mixed evenly and cooled to 0-10°C in an ice-salt bath. Hydrazine hydrate was added dropwise, and the reaction was maintained at 0-10°C for 1-2 hours. After the reaction was completed, sodium hydroxide solution was added, and the temperature was raised to 20-30°C for 3-5 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and cooled to 20-30°C. Under nitrogen protection, sodium hypochlorite solution was slowly added dropwise. After the addition was completed, the mixture was reacted at 20-30°C for 1-2 hours. After the reaction was completed, sodium thiosulfate was added to remove excess oxidant. The mixture was stirred for 15 minutes and extracted twice with MTBE. The organic phase was discarded. The aqueous phase was acidified with hydrochloric acid to pH=1-2 and extracted three times with ethyl acetate. The organic phases were combined, washed, dried, concentrated under reduced pressure, dispersed in petroleum ether, filtered, and dried under vacuum to constant weight to obtain 5-bromopyrimidine-4-carboxylic acid.

3. The method for synthesizing 5-bromopyrimidine-4-carboxylic acid according to claim 2, characterized in that, In step S1, the mass ratio of methyl 4-hydroxypyrimidine-6-carboxylate, N-bromosuccinimide, and thionyl chloride is 1:2.5~3.0:2.2~2.

8.

4. The method for synthesizing 5-bromopyrimidine-4-carboxylic acid according to claim 2, characterized in that, In step S2, the mass ratio of methyl 4-chloro-5-bromopyrimidine-6-carboxylate to hydrazine hydrate is 1:0.26~0.31, wherein the concentration of hydrazine hydrate is 70~98wt%.

5. The method for synthesizing 5-bromopyrimidine-4-carboxylic acid according to claim 2, characterized in that, In step S2, the mass ratio of methyl 4-chloro-5-bromopyrimidine-6-carboxylate, sodium hydroxide solution, sodium hypochlorite solution, and sodium thiosulfate solution is 1:4.5~6.5:4.0~5.5:2.2~2.6; wherein the concentration of sodium hydroxide is 5~15wt%, the concentration of sodium hypochlorite solution is 8~13wt%, and the concentration of sodium thiosulfate solution is 5~20wt%.

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