CN111018740B - Synthesis method of 4-bromo-2-cyano-5-fluorobenzoic acid methyl ester - Google Patents
Synthesis method of 4-bromo-2-cyano-5-fluorobenzoic acid methyl ester Download PDFInfo
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- CN111018740B CN111018740B CN201911321662.8A CN201911321662A CN111018740B CN 111018740 B CN111018740 B CN 111018740B CN 201911321662 A CN201911321662 A CN 201911321662A CN 111018740 B CN111018740 B CN 111018740B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/14—Preparation of carboxylic acid nitriles by reaction of cyanides with halogen-containing compounds with replacement of halogen atoms by cyano groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
Abstract
The invention discloses a synthesis method of 4-bromo-2-cyano-5-fluorobenzoic acid methyl ester, belonging to the field of organic chemical synthesis. The method comprises the following steps: adding 2-amino-4-bromo-5-fluorobenzoic acid methyl ester into acid, and reacting with sodium nitrite and iodide to obtain 4-bromo-5-fluoro-2-iodobenzoic acid methyl ester; dissolving 4-bromo-5-fluoro-2-iodobenzoic acid methyl ester in an organic solvent, and reacting with cyanide under the protection of nitrogen to obtain a target product, namely 4-bromo-2-cyano-5-fluorobenzoic acid methyl ester. The method has the advantages of simple synthesis operation, short process route, easy realization and higher yield of the obtained product.
Description
Technical Field
The invention relates to the field of organic chemical synthesis, in particular to a synthesis method of 4-bromo-2-cyano-5-fluorobenzoic acid methyl ester.
Background
The fluorine-containing compound has the advantages of good fat solubility, high drug effect, strong metabolic capability and the like, and is widely applied to the fields of pesticides, medicines and the like. China is a large country with fluorine resources, and the reserve of fluorite accounts for one third of the total reserve of the world, so that favorable conditions are provided for the development of organic fluorine industry in China.
Among the fluorine-containing compounds, the fluorine-containing benzene compounds are a large class, and have various varieties and wide application. The fluorine-containing benzene compound is an organic chemical raw material with development prospect, is also an important pesticide and medical intermediate, and is widely applied to synthesis of pesticides and medicines. With the rapid development of the pesticide and medicine industries and the continuous creation and innovation of new process technologies, the demand of the fluorine-containing benzene compounds is gradually increased. Therefore, the research on the synthetic method of the fluorine-containing benzene compound has important significance.
Disclosure of Invention
The invention aims to provide a synthesis method of 4-bromo-2-cyano-5-fluorobenzoic acid methyl ester. The method takes 2-amino-4-bromo-5-fluorobenzoic acid methyl ester as a raw material, and can obtain a target product through two-step reaction, and the method is short in process route and easy to implement.
In order to achieve the above purpose, the invention provides the following technical scheme:
a synthetic method of 4-bromo-2-cyano-5-fluorobenzoic acid methyl ester comprises the following steps:
the synthesis method is realized by the following steps:
(1) adding 2-amino-4-bromo-5-fluorobenzoic acid methyl ester into acid, and reacting with sodium nitrite and iodide to obtain 4-bromo-5-fluoro-2-iodobenzoic acid methyl ester;
(2) dissolving 4-bromo-5-fluoro-2-iodobenzoic acid methyl ester in an organic solvent, and reacting with cyanide under the protection of nitrogen to obtain 4-bromo-2-cyano-5-fluorobenzoic acid methyl ester.
Preferably, the reaction temperature in the step (1) is 0-5 ℃, and the reaction time is 1-5 hours.
Preferably, the molar amount of sodium nitrite and iodide in step (1) is more than that of methyl 2-amino-4-bromo-5-fluorobenzoate.
Preferably, the molar ratio of methyl 2-amino-4-bromo-5-fluorobenzoate, sodium nitrite and iodide in step (1) is 1: 1.2: 2.
preferably, in step (1), the iodide is potassium iodide or sodium iodide.
Preferably, the acid in step (1) is 20% by mass of sulfuric acid.
Preferably, the organic solvent in the step (2) is N-methylpyrrolidone or N, N-dimethylformamide, the reaction temperature is 60-120 ℃, and the reaction time is 2-10 hours.
Preferably, the molar amount of cyanide in step (2) is greater than the molar amount of methyl 4-bromo-5-fluoro-2-iodobenzoate.
Preferably, the molar ratio of the methyl 4-bromo-5-fluoro-2-iodobenzoate to the cyanide in the step (2) is 1: 1.5.
preferably, the cyanide in step (2) is cuprous cyanide or zinc cyanide.
The invention has the beneficial effects that:
a. the invention provides a synthesis method of 4-bromo-2-cyano-5-fluorobenzoic acid methyl ester for the first time, and provides a synthesis route for preparing 4-bromo-2-cyano-5-fluorobenzoic acid methyl ester;
b. the invention has simple synthesis operation, short process route and easy realization;
c. the product obtained by the method has high yield.
Detailed Description
The invention is further illustrated by the following examples, without restricting its scope to these examples. Numerous other changes and modifications can be made by those skilled in the art without departing from the spirit and scope of the invention. In particular, certain agents which are both chemically and structurally related may be substituted for the agents described herein to achieve the same or similar results, and reactions may be carried out under conditions outside the preferred ranges, albeit less than optimally. Accordingly, such obvious substitutions and modifications are intended to be included within the scope of the appended claims.
Example 1
Methyl 2-amino-4-bromo-5-fluorobenzoate (24.8g, 100mmol, 1eq.) was added to 400ml of 20% by mass sulfuric acid, cooled to 2 ℃ and sodium nitrite (8.3g, 120mmol, 1.2eq.) was added portionwise. Potassium iodide (33.2g, 200mmol, 2eq.) was dissolved in 100ml of water and added dropwise to the above reaction system, and reacted at that temperature for 3 hours.
After the reaction is finished, ethyl acetate is added for extraction, sodium sulfite solution with the mass fraction of 10% and saturated sodium chloride solution are sequentially used for washing, and then column chromatography purification is carried out to obtain 31.2g of white solid methyl 4-bromo-5-fluoro-2-iodobenzoate, wherein the yield is 87%.
Methyl 4-bromo-5-fluoro-2-iodobenzoate (31.2g, 87mmol, 1eq.) was dissolved in 260ml of N-methylpyrrolidone, cuprous cyanide (11.7g, 130.5mmol, 1.5eq.) was added, and the temperature was raised to 80 ℃ under nitrogen protection, and the reaction was maintained for 5 hours.
After the reaction was completed, the reaction solution was cooled. The reaction solution was added to a mixture (volume ratio 1: 1) of ammonium chloride and aqueous ammonia in an ice-water bath, and extracted with ethyl acetate. The organic phase was washed with a mixture of ammonium chloride and aqueous ammonia (volume ratio 1: 1) and a saturated sodium chloride solution, concentrated and purified by column chromatography to give 20.4g of methyl 4-bromo-2-cyano-5-fluorobenzoate as a white solid in a yield of 91%.
1H NMR(d6-DMSO):8.56(d,J＝6.4Hz,1H),8.03(d,J＝8.9Hz,1H),3.92(s,3H)。
Example 2
Methyl 2-amino-4-bromo-5-fluorobenzoate (19.8g, 80mmol, 1eq.) was added to 320ml of 20% by mass sulfuric acid, cooled to 0 ℃ and sodium nitrite (6.6g, 96mmol, 1.2eq.) was added portionwise. Sodium iodide (24g, 160mmol, 2eq.) was dissolved in 80ml of water and added dropwise to the above reaction system, and reacted at that temperature for 5 hours.
After the reaction is finished, ethyl acetate is added for extraction, sodium sulfite solution with the mass fraction of 10% and saturated sodium chloride solution are sequentially used for washing, and then 23g of white solid methyl 4-bromo-5-fluoro-2-iodobenzoate is obtained through column chromatography purification, wherein the yield is 80%.
Methyl 4-bromo-5-fluoro-2-iodobenzoate (23g, 64mmol, 1eq.) was dissolved in 200ml of N-methylpyrrolidone, zinc cyanide (11.3g, 96mmol, 1.5eq.) was added, the temperature was raised to 120 ℃ under nitrogen protection, and the reaction was maintained for 2 hours.
After the reaction was completed, the reaction solution was cooled. The reaction solution was added to a mixture (volume ratio 1: 1) of ammonium chloride and aqueous ammonia in an ice-water bath, and extracted with ethyl acetate. The organic phase was washed with a mixture of ammonium chloride and aqueous ammonia (volume ratio 1: 1) and a saturated sodium chloride solution, concentrated and purified by column chromatography to give 13.5g of methyl 4-bromo-2-cyano-5-fluorobenzoate as a white solid in a yield of 82%.
1H NMR(d6-DMSO):8.56(d,J＝6.4Hz,1H),8.03(d,J＝8.9Hz,1H),3.92(s,3H)。
Example 3
Methyl 2-amino-4-bromo-5-fluorobenzoate (29.8g, 120mmol, 1eq.) was added to 480ml of 20% by mass sulfuric acid, cooled to 5 ℃ and sodium nitrite (9.9g, 144mmol, 1.2eq.) was added portionwise. Potassium iodide (39.8g, 240mmol, 2eq.) was dissolved in 130ml of water and added dropwise to the above reaction system, and reacted at that temperature for 1 hour.
After the reaction is finished, ethyl acetate is added for extraction, sodium sulfite solution with the mass fraction of 10% and saturated sodium chloride solution are sequentially used for washing, and then 31g of white solid methyl 4-bromo-5-fluoro-2-iodobenzoate is obtained through column chromatography purification, wherein the yield is 72%.
Methyl 4-bromo-5-fluoro-2-iodobenzoate (31g, 86.4mmol, 1eq.) was dissolved in 250ml of N, N-dimethylformamide, cuprous cyanide (11.6g, 129.6mmol, 1.5eq.) was added, and the temperature was raised to 60 ℃ under nitrogen protection, and the reaction was maintained for 10 hours.
After the reaction was completed, the reaction solution was cooled. The reaction solution was added to a mixture (volume ratio 1: 1) of ammonium chloride and aqueous ammonia in an ice-water bath, and extracted with ethyl acetate. The organic phase was washed with a mixture of ammonium chloride and aqueous ammonia (volume ratio 1: 1) and a saturated sodium chloride solution, concentrated and purified by column chromatography to give 19.6g of methyl 4-bromo-2-cyano-5-fluorobenzoate as a white solid in 88% yield.
1H NMR(d6-DMSO):8.56(d,J＝6.4Hz,1H),8.03(d,J＝8.9Hz,1H),3.92(s,3H)。
Claims (10)
1. A synthetic method of 4-bromo-2-cyano-5-fluorobenzoic acid methyl ester is characterized by comprising the following steps:
(1) adding 2-amino-4-bromo-5-fluorobenzoic acid methyl ester into acid, and reacting with sodium nitrite and iodide to obtain 4-bromo-5-fluoro-2-iodobenzoic acid methyl ester;
(2) dissolving 4-bromo-5-fluoro-2-iodobenzoic acid methyl ester in an organic solvent, and reacting with cyanide under the protection of nitrogen to obtain 4-bromo-2-cyano-5-fluorobenzoic acid methyl ester.
2. The synthesis method of methyl 4-bromo-2-cyano-5-fluorobenzoate according to claim 1, wherein the reaction temperature in the step (1) is 0-5 ℃ and the reaction time is 1-5 hours.
3. The method for synthesizing methyl 4-bromo-2-cyano-5-fluorobenzoate according to claim 1, wherein the molar amounts of sodium nitrite and iodide in step (1) are both greater than the molar amount of methyl 2-amino-4-bromo-5-fluorobenzoate.
4. The method for synthesizing methyl 4-bromo-2-cyano-5-fluorobenzoate according to claim 3, wherein the molar ratio of methyl 2-amino-4-bromo-5-fluorobenzoate, sodium nitrite and iodide in step (1) is 1: 1.2: 2.
5. the method for synthesizing methyl 4-bromo-2-cyano-5-fluorobenzoate according to any one of claims 1 to 4, wherein the iodide in the step (1) is potassium iodide or sodium iodide.
6. The method for synthesizing methyl 4-bromo-2-cyano-5-fluorobenzoate according to any one of claims 1 to 4, wherein the acid in the step (1) is sulfuric acid with a mass fraction of 20%.
7. The synthesis method of methyl 4-bromo-2-cyano-5-fluorobenzoate according to claim 1, wherein the organic solvent in the step (2) is N-methylpyrrolidone or N, N-dimethylformamide, the reaction temperature is 60-120 ℃, and the reaction time is 2-10 hours.
8. The method for synthesizing methyl 4-bromo-2-cyano-5-fluorobenzoate according to claim 1, wherein the molar amount of cyanide in the step (2) is larger than that of methyl 4-bromo-5-fluoro-2-iodobenzoate.
9. The method for synthesizing methyl 4-bromo-2-cyano-5-fluorobenzoate according to claim 8, wherein the molar ratio of methyl 4-bromo-5-fluoro-2-iodobenzoate to cyanide in the step (2) is 1: 1.5.
10. the process for synthesizing methyl 4-bromo-2-cyano-5-fluorobenzoate according to any one of claims 1, 7, 8 and 9, wherein the cyanide in the step (2) is cuprous cyanide or zinc cyanide.
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| CN111646922B (en) * | 2020-07-21 | 2022-03-11 | 阿里生物新材料（常州）有限公司 | Synthetic method of 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid |
| CN111848446B (en) * | 2020-08-21 | 2022-03-11 | 阿里生物新材料（常州）有限公司 | Synthesis method of 2-bromo-5-cyano-4-fluorobenzoic acid methyl ester |
| CN112250599B (en) * | 2020-11-24 | 2022-03-11 | 阿里生物新材料（常州）有限公司 | Synthesis method of 4-bromo-2-cyano-3-fluorobenzoic acid methyl ester |
| CN114790139A (en) * | 2021-01-26 | 2022-07-26 | 江苏中旗科技股份有限公司 | Method for synthesizing 2-chloro-4-fluorobenzoic acid by taking 2-chloro-4-amino bromobenzene as raw material |
| CN112707831A (en) * | 2021-02-05 | 2021-04-27 | 阿里生物新材料（常州）有限公司 | Synthetic method of 3- (1-aminocyclopropyl) methyl benzoate |
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