Preparation method of 5-bromopyridine-2-carboxylic acid methyl ester

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 5-bromopyridine-2-carboxylic acid methyl ester, which specifically comprises the following steps: 1) reacting 3-butyric acid-2-oxo-methyl ester with 2-bromoethylamine to synthesize 6-amino-5-bromo-3, 5-diene-2-ketone; (2) enabling the 6-amino-5-bromine-3, 5-diene-2-ketone prepared in the step (1) to react with glacial acetic acid, and synthesizing 5-bromine-2-methylpyridine; (3) reacting the 5-bromo-2-methylpyridine prepared in the step (2) with potassium permanganate to synthesize 5-bromopicolinic acid; 4) reacting the 5-bromopicolinic acid prepared in the step 3) with methanol and concentrated hydrochloric acid to synthesize the 5-bromopyridine-2-carboxylic acid methyl ester.The preparation method of the 5-bromopyridine-2-carboxylic acid methyl ester.The preparation method of the 5-bromopyridine-2-carboxylic acid methyl ester.The preparation method of the 5-bromopyridine-2-carboxylic acid methyl esterhas the advantages that the total reaction yield is high, the prepared 5-bromopyridine-2-carboxylic acid methyl esteris high in purity, reaction conditions are mild, cyanide does not need to participate in the reaction, and operation is easy.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a method for preparing 5-bromopyridine-2-carboxylic acid methyl ester. Background Art

[0002] 5-Bromopyridine-2-carboxylic acid methyl ester is an important intermediate for the synthesis of heterocyclic compound pesticides and medicines, with higher biological activity and lower toxicity.

[0003] In the prior art, the preparation method of 5-bromopyridine-2-carboxylic acid methyl ester usually uses 2,5-dibromopyridine as a raw material, reacts with sodium cyanide to generate 2-cyano-5-bromopyridine, and then hydrolyzes it into 5-bromo-2-pyridinecarboxylic acid, and then reacts with methanolic hydrochloric acid to generate 5-bromopyridine-2-carboxylic acid methyl ester. The preparation method of 5-bromopyridine-2-carboxylic acid methyl ester uses highly toxic sodium cyanide, which has great safety hazards in actual production, and the reaction yield and product purity are both low, and the post-processing is complicated, which is not conducive to large-scale industrial production. Therefore, it is particularly important to develop a preparation method of 5-bromopyridine-2-carboxylic acid methyl ester that does not require sodium cyanide to participate in the reaction, has high reaction yield and product purity, and is easy to operate. Summary of the invention

[0004] In view of the above problems, the present invention provides a method for preparing 5-bromopyridine-2-carboxylic acid methyl ester.

[0005] The present invention relates to a method for preparing 5-bromopyridine-2-carboxylic acid methyl ester, which specifically comprises the following steps: 1) Synthesis of 6-amino-5-bromo-3,5-dien-2-one: 3-Butyric acid-2-oxomethyl ester and 2-bromoethylamine are added to the reaction solvent in sequence, stirred and heated for reaction, and the reaction is monitored by TLC. After the reaction is completed, the reaction solution is cooled to room temperature and evaporated to dryness under reduced pressure to obtain 6-amino-5-bromo-3,5-dien-2-one; 2) Synthesis of 5-bromo-2-methylpyridine: The 6-amino-5-bromo-3,5-diene-2-one prepared in step 1) is added to the reaction solvent, glacial acetic acid is added under stirring, and the mixture is stirred and heated for reaction. The reaction is monitored by TLC. After the reaction is completed, the reaction solution is evaporated to dryness under reduced pressure, and water and dichloromethane are added for extraction. The water layer is extracted with dichloromethane again, and the dichloromethane layers of the two extractions are combined, washed with saturated sodium bicarbonate and water in turn, and evaporated to dryness under reduced pressure to obtain 5-bromo-2-methylpyridine; 3) Synthesis of 5-bromopicolinic acid: The 5-bromo-2-methylpyridine prepared in step 2) is added to the reaction solvent, and then potassium permanganate is added, stirred and heated for reaction, and the reaction is monitored by TLC. After the reaction is completed, the reaction solution is cooled to room temperature, and 3 mol / L hydrochloric acid is added to acidify the reaction solution to a pH value of 5, and the reaction solution is added with ethyl acetate for extraction twice, and the ethyl acetate layers of the two extractions are combined and evaporated to dryness under reduced pressure to obtain 5-bromopicolinic acid; 4) Synthesis of 5-bromopyridine-2-carboxylic acid methyl ester: The 5-bromopicolinic acid prepared in step 3) is added to methanol, stirred and concentrated hydrochloric acid is added, stirred and heated for reaction, and the reaction is monitored by TLC. After the reaction is completed, the reaction solution is evaporated to dryness of the solvent under reduced pressure, and water and ethyl acetate are added to extract twice, the ethyl acetate layers of the two extractions are combined, washed with saturated sodium bicarbonate and water in turn, and evaporated to dryness under reduced pressure to obtain 5-bromopyridine-2-carboxylic acid methyl ester.

[0006] Preferably, the synthetic route is as follows: .

[0007] Preferably, in the step 1), the molar ratio of the 3-oxomethyl butyrate to 2-bromoethylamine is 1:1-1.2; the reaction solvent is ethanol, methanol or N,N-dimethylformamide; the mass of the 3-oxomethyl butyrate is measured in grams, the volume of the reaction solvent is measured in milliliters, and the volume of the reaction solvent is 1-5 times the mass of the 3-oxomethyl butyrate; the heating reaction is carried out at 30-45°C for 20-25 hours.

[0008] Preferably, in the step 2), the molar ratio of the 6-amino-5-bromo-3,5-diene-2-one to glacial acetic acid is 1:1-2; the reaction solvent is anisole, acetonitrile or acetic acid; the mass of the 6-amino-5-bromo-3,5-diene-2-one is measured in grams, the volume of the reaction solvent is measured in milliliters, and the volume of the reaction solvent is 1 to 5 times the mass of the 6-amino-5-bromo-3,5-diene-2-one; and the heating reaction is carried out at 50 to 60°C for 5 to 7 hours.

[0009] Preferably, in step 2), the volume ratio of water to dichloromethane during each extraction is 1:1.

[0010] Preferably, in step 3), the molar ratio of 5-bromo-2-methylpyridine to potassium permanganate is 1:1-2; the reaction solvent is water; the mass of 5-bromo-2-methylpyridine is in grams, the volume of the reaction solvent is in milliliters, and the volume of the reaction solvent is 1 to 5 times the mass of 5-bromo-2-methylpyridine; the heating reaction is carried out at 20 to 40°C for 6 to 10 hours.

[0011] Preferably, in the step 3), the volume ratio of the reaction solution to ethyl acetate is 5:3 during each extraction.

[0012] Preferably, in step 4), the molar ratio of the 5-bromopicolinic acid to concentrated hydrochloric acid is 1:1-2; the mass of the 5-bromopicolinic acid is measured in grams, the volume of the methanol is measured in milliliters, and the volume of the methanol is 1-5 times the mass of the 5-bromopicolinic acid; and the heating reaction is carried out at 30-50°C for 1-2 hours.

[0013] Preferably, in step 4), the volume ratio of water to ethyl acetate is 1:1 during each extraction.

[0014] Preferably, the total yield of the four-step reaction is greater than 80%; and the purity of the 5-bromopyridine-2-carboxylic acid methyl ester is greater than 98.5%.

[0015] Compared with the prior art, the advantages and positive effects of the present invention are: (1) The method for preparing 5-bromopyridine-2-carboxylic acid methyl ester has a high total reaction yield, reduces production costs, improves the utilization efficiency of raw materials, and thus improves economic benefits. The obtained 5-bromopyridine-2-carboxylic acid methyl ester has high purity, which improves market competitiveness. No complicated subsequent purification process is required, thereby reducing costs and time consumption. (2) The preparation method of 5-bromopyridine-2-carboxylic acid methyl ester has mild reaction conditions, so that the reaction process is more stable, making the production process safer and easier to control, and the reaction performance will not be affected when it is scaled up to industrial production; (3) The preparation method of 5-bromopyridine-2-carboxylic acid methyl ester does not require cyanide to participate in the reaction, thereby avoiding the danger of cyanide to the safety of workers during the production process and reducing the harm to the environment; (4) The preparation method of 5-bromopyridine-2-carboxylic acid methyl ester is simple to operate and has a short reaction time, which reduces labor costs and improves the stability and reliability of large-scale production. DETAILED DESCRIPTION

[0016] In order to more clearly understand the above-mentioned objects, features and advantages of the present invention, the present invention is further described below in conjunction with embodiments.

[0017] In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention may also be implemented in other ways than those described herein. Therefore, the present invention is not limited to the specific embodiments of the following disclosure.

[0018] Example 1 A method for preparing 5-bromopyridine-2-carboxylic acid methyl ester, specifically comprising the following steps: 1) Synthesis of 6-amino-5-bromo-3,5-dien-2-one: 10.0 g of 2-oxomethyl 3-butyrate and 12.0 g of 2-bromoethylamine were added to 30 ml of ethanol in sequence, stirred and reacted at 35°C for 24 h, and the reaction was monitored by TLC. After the reaction was completed, the reaction solution was cooled to room temperature and evaporated under reduced pressure at 45°C to obtain 15.2 g of 6-amino-5-bromo-3,5-diene-2-one, and the reaction yield was 90%.

[0019] 2) Synthesis of 5-bromo-2-methylpyridine: 15.2 g of 6-amino-5-bromo-3,5-diene-2-one prepared in step 1) was added to 45.6 ml of anisole, and 9.6 g of glacial acetic acid was added under stirring, and the mixture was stirred and reacted at 60° C. for 6 h; the reaction was monitored by TLC. After the reaction was completed, the reaction solution was evaporated to dryness under reduced pressure at 50° C., and then 50 ml of dichloromethane and 50 ml of water were added for extraction. The water layer was extracted again with 50 ml of dichloromethane, and the dichloromethane layers extracted twice were combined, and washed with 50 ml of saturated sodium bicarbonate and 50 ml of water in turn, and then evaporated to dryness under reduced pressure at 50° C. to obtain 13.0 g of 5-bromo-2-methylpyridine, and the reaction yield was 95%.

[0020] 3) Synthesis of 5-bromopicolinic acid: 13.0 g of 5-bromo-2-methylpyridine prepared in step 2) was added to 65 ml of water, and 23.9 g of potassium permanganate was added under stirring. The mixture was stirred and reacted at 30° C. for 8 h. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was cooled to room temperature, 3 mol / L hydrochloric acid was added to acidify the reaction solution to a pH value of 5, 39 ml of ethyl acetate was added to the reaction solution, and the mixture was extracted twice. The ethyl acetate layers of the two extractions were combined and evaporated to dryness under reduced pressure at 45° C. to obtain 14.5 g of 5-bromopicolinic acid. The reaction yield was 95%.

[0021] 4) Synthesis of 5-bromopyridine-2-carboxylic acid methyl ester: 14.5 g of 5-bromopicolinic acid prepared in step 3) was added to 72.5 ml of methanol, and 8.0 g of hydrochloric acid with a mass concentration of 36% was added under stirring. The reaction was reacted at 40° C. for 2 h. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was evaporated to dryness under reduced pressure at 50° C., 43.5 ml of water and 43.5 ml of ethyl acetate were added and extracted twice. The ethyl acetate layers of the two extractions were combined, washed with 43.5 ml of saturated sodium bicarbonate and 43.5 ml of water in turn, and evaporated to dryness under reduced pressure at 50° C. to obtain 15.2 g of 5-bromopyridine-2-carboxylic acid methyl ester with a purity of 98.7% and a reaction yield of 98%.

[0022] Example 2 A method for preparing 5-bromopyridine-2-carboxylic acid methyl ester, specifically comprising the following steps: 1) Synthesis of 6-amino-5-bromo-3,5-dien-2-one: 30.0 g of 2-oxomethyl 3-butyrate and 44.3 g of 2-bromoethylamine were added to 150 ml of methanol in sequence, stirred and reacted at 40° C. for 20 h. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was cooled to room temperature and evaporated under reduced pressure at 45° C. to obtain 46.5 g of 6-amino-5-bromo-3,5-diene-2-one. The reaction yield was 92%.

[0023] 2) Synthesis of 5-bromo-2-methylpyridine: 46.5 g of 6-amino-5-bromo-3,5-diene-2-one prepared in step 1) was added to 186 ml of acetonitrile, and 26.6 g of glacial acetic acid was added under stirring, and the mixture was stirred and reacted at 50° C. for 7 h. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was evaporated to dryness under reduced pressure at 50° C., and then 150 ml of dichloromethane and 150 ml of water were added for extraction. The water layer was extracted again with 150 ml of dichloromethane, and the two extracted dichloromethane layers were combined, washed with 150 ml of saturated sodium bicarbonate and 150 ml of water in turn, and then evaporated to dryness under reduced pressure at 50° C. to obtain 41.1 g of 5-bromo-2-methylpyridine. The reaction yield was 97%.

[0024] 3) Synthesis of 5-bromopicolinic acid: 41.1 g of 5-bromo-2-methylpyridine prepared in step 2) was added to 160 ml of water, and 68.0 g of potassium permanganate was added under stirring. The mixture was stirred and reacted at 40° C. for 6 h. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was cooled to room temperature, 3 mol / L hydrochloric acid was added to acidify the reaction solution to a pH value of 5, 96 ml of ethyl acetate was added to the reaction solution, and the mixture was extracted twice. The ethyl acetate layers of the two extractions were combined and evaporated to dryness under reduced pressure at 45° C. to obtain 45.4 g of 5-bromopicolinic acid. The reaction yield was 94%.

[0025] 4) Synthesis of 5-bromopyridine-2-carboxylic acid methyl ester: 45.4 g of 5-bromopicolinic acid prepared in step 3) was added to 140 ml of methanol, and 22.8 g of hydrochloric acid with a mass concentration of 36% was added under stirring, and the mixture was stirred and reacted at 50° C. for 1 h. The reaction was monitored by TLC. After the reaction was completed, the reaction solution was evaporated to dryness under reduced pressure at 50° C., and 150 ml of water and 150 ml of ethyl acetate were added and extracted twice. The ethyl acetate layers of the two extractions were combined, and the mixture was washed with 150 ml of saturated sodium bicarbonate and 150 ml of water in turn, and then evaporated to dryness under reduced pressure at 50° C. to obtain 46.6 g of 5-bromopyridine-2-carboxylic acid methyl ester with a purity of 98.5% and a reaction yield of 96%.

[0026] The above description is only a preferred embodiment of the present invention and does not limit the present invention in other forms. Any technician familiar with the profession may use the technical content disclosed above to change or modify it into an equivalent embodiment with equivalent changes for application in other fields. However, any simple modification or equivalent change made to the above embodiment based on the technical essence of the present invention without departing from the content of the technical solution of the present invention still falls within the protection scope of the technical solution of the present invention.

Claims

1. A method for preparing 5-bromopyridine-2-carboxylic acid methyl ester, characterized in that: The specific steps include: 1) Synthesis of 6-amino-5-bromo-3,5-dien-2-one: 3-Butyric acid-2-oxomethyl ester and 2-bromoethylamine are added to the reaction solvent in sequence, stirred and heated for reaction, and the reaction is monitored by TLC. After the reaction is completed, the reaction solution is cooled to room temperature and evaporated to dryness under reduced pressure to obtain 6-amino-5-bromo-3,5-diene-2-one; 2) Synthesis of 5-bromo-2-methylpyridine: The 6-amino-5-bromo-3,5-diene-2-one prepared in step 1) is added to the reaction solvent, glacial acetic acid is added under stirring, and the mixture is stirred and heated for reaction. The reaction is monitored by TLC. After the reaction is completed, the reaction solution is evaporated to dryness under reduced pressure, and water and dichloromethane are added for extraction. The water layer is extracted with dichloromethane again, and the dichloromethane layers of the two extractions are combined, washed with saturated sodium bicarbonate and water in turn, and evaporated to dryness under reduced pressure to obtain 5-bromo-2-methylpyridine; 3) Synthesis of 5-bromopicolinic acid: The 5-bromo-2-methylpyridine prepared in step 2) is added to the reaction solvent, and then potassium permanganate is added, stirred and heated for reaction, and the reaction is monitored by TLC. After the reaction is completed, the reaction solution is cooled to room temperature, and 3 mol / L hydrochloric acid is added to acidify the reaction solution to a pH value of 5, and the reaction solution is added with ethyl acetate for extraction twice, and the ethyl acetate layers of the two extractions are combined and evaporated to dryness under reduced pressure to obtain 5-bromopicolinic acid; 4) Synthesis of 5-bromopyridine-2-carboxylic acid methyl ester: The 5-bromopicolinic acid prepared in step 3) is added to methanol, and concentrated hydrochloric acid is added under stirring, and the mixture is stirred and heated for reaction. The reaction is monitored by TLC. After the reaction is completed, the reaction solution is evaporated to dryness of the solvent under reduced pressure, and water and ethyl acetate are added to extract twice. The ethyl acetate layers of the two extractions are combined, and the mixture is washed with saturated sodium bicarbonate and water in turn, and evaporated to dryness under reduced pressure to obtain 5-bromopyridine-2-carboxylic acid methyl ester.

2. The method for preparing 5-bromopyridine-2-carboxylic acid methyl ester according to claim 1, characterized in that: The synthetic route is as follows: 。 3. The method for preparing 5-bromopyridine-2-carboxylic acid methyl ester according to claim 2, characterized in that: In the step 1), the molar ratio of 3-butyric acid 2-oxomethyl ester to 2-bromoethylamine is 1:1-1.2; the reaction solvent is ethanol, methanol or N,N-dimethylformamide; the mass of 3-butyric acid 2-oxomethyl ester is measured in grams, the volume of the reaction solvent is measured in milliliters, and the volume of the reaction solvent is 1-5 times the mass of 3-butyric acid 2-oxomethyl ester; the heating reaction is carried out at 30-45° C. for 20-25 hours.

4. The method for preparing 5-bromopyridine-2-carboxylic acid methyl ester according to claim 3, characterized in that: In the step 2), the molar ratio of the 6-amino-5-bromo-3,5-diene-2-one to glacial acetic acid is 1:1-2; the reaction solvent is anisole, acetonitrile or acetic acid; the mass of the 6-amino-5-bromo-3,5-diene-2-one is measured in grams, the volume of the reaction solvent is measured in milliliters, and the volume of the reaction solvent is 1 to 5 times the mass of the 6-amino-5-bromo-3,5-diene-2-one; the heating reaction is carried out at 50 to 60° C. for 5 to 7 hours.

5. The method for preparing 5-bromopyridine-2-carboxylic acid methyl ester according to claim 4, characterized in that: In the step 2), the volume ratio of water to dichloromethane is 1:1 during each extraction.

6. The method for preparing 5-bromopyridine-2-carboxylic acid methyl ester according to claim 5, characterized in that: In the step 3), the molar ratio of the 5-bromo-2-methylpyridine to potassium permanganate is 1:1-2; the reaction solvent is water; the mass of the 5-bromo-2-methylpyridine is in grams, the volume of the reaction solvent is in milliliters, and the volume of the reaction solvent is 1 to 5 times the mass of the 5-bromo-2-methylpyridine; the heating reaction is carried out at 20 to 40° C. for 6 to 10 hours.

7. The method for preparing 5-bromopyridine-2-carboxylic acid methyl ester according to claim 6, characterized in that: In the step 3), the volume ratio of the reaction solution to ethyl acetate is 5:3 during each extraction.

8. The method for preparing 5-bromopyridine-2-carboxylic acid methyl ester according to claim 7, characterized in that: In the step 4), the molar ratio of the 5-bromopicolinic acid to concentrated hydrochloric acid is 1:1-2; the mass of the 5-bromopicolinic acid is in grams, the volume of the methanol is in milliliters, and the volume of the methanol is 1-5 times the mass of the 5-bromopicolinic acid; the heating reaction is carried out at 30-50°C for 1-2 hours.

9. The method for preparing 5-bromopyridine-2-carboxylic acid methyl ester according to claim 8, characterized in that: In the step 4), the volume ratio of water to ethyl acetate is 1:1 during each extraction.

10. The method for preparing 5-bromopyridine-2-carboxylic acid methyl ester according to claim 9, characterized in that: The total yield of the four-step reaction is greater than 80%; the purity of the 5-bromopyridine-2-carboxylic acid methyl ester is greater than 98.5%.

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