阅读说明：本技术 2-氟-3-硝基苯甲酸的制备方法 (Preparation method of 2-fluoro-3-nitrobenzoic acid ) 是由 张国富 韩泽伟 丁成荣 吕井辉 于 2021-10-15 设计创作，主要内容包括：本发明公开了一种2-氟-3-硝基苯甲酸(II)的制备方法,利用二异丙基氨基锂或叔丁基锂在低温条件下,2-氟硝基苯(I)经氟邻位锂化,干冰插羰反应,酸性水解,制得目标产物2-氟-3-硝基苯甲酸；本发明反应条件温和,无需过渡金属催化,选择性好,收率高,并且工艺简单高效、环保经济,适合大规模制备；(The invention discloses a preparation method of 2-fluoro-3-nitrobenzoic acid (II), which comprises the steps of carrying out fluoro ortho lithiation, dry ice carbonyl insertion reaction and acidic hydrolysis on 2-fluoronitrobenzene (I) by utilizing lithium diisopropylamide or tert-butyl lithium at low temperature to prepare a target product 2-fluoro-3-nitrobenzoic acid; the method has the advantages of mild reaction conditions, no need of transition metal catalysis, good selectivity, high yield, simple and efficient process, environmental protection and economy, and suitability for large-scale preparation;)

1. A preparation method of 2-fluoro-3-nitrobenzoic acid (II) is characterized by comprising the following steps:

dissolving a raw material 2-fluoronitrobenzene (I) in a reaction solvent, dropwise adding an alkali solution under the condition of nitrogen protection at-30 to-80 ℃, maintaining the temperature after dropwise adding, continuously reacting for 1-10 h, then quenching the reaction solution by dry ice, and performing post-treatment to obtain a product 2-fluoro-3-nitrobenzoic acid (II);

the alkali in the alkali solution is lithium diisopropylamideOr tert-butyl lithium

2. The process for producing 2-fluoro-3-nitrobenzoic acid (II) according to claim 1 wherein the reaction solvent is: tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, toluene or n-hexane.

3. The process for producing 2-fluoro-3-nitrobenzoic acid (II) according to claim 1, wherein the reaction solvent is used in an amount of 10L/mol based on the amount of the starting material 2-fluoronitrobenzene (I).

4. The process for producing 2-fluoro-3-nitrobenzoic acid (II) according to claim 1, wherein the ratio of the amounts of the starting 2-fluoronitrobenzene (I) and the base is 1: 1 to 10.

5. The process for the preparation of 2-fluoro-3-nitrobenzoic acid (II) according to claim 1, characterized in that the work-up is carried out by: and quenching the reaction liquid by dry ice, naturally returning to room temperature, evaporating under reduced pressure to remove the solvent to obtain a crude product, adding water, adjusting the pH value to 2 by using concentrated hydrochloric acid, extracting by using ethyl acetate, combining organic layers, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, performing suction filtration, concentrating and drying to obtain the product 2-fluoro-3-nitrobenzoic acid (II).

Technical Field

The invention relates to a preparation method of 2-fluoro-3-nitrobenzoic acid.

Background

The 2-fluoro-3-nitrobenzoic acid is an important synthetic intermediate raw material, is widely applied to the fields of pesticides and medicines, and can be used for synthesizing benzene sulfonamide thiazole medicines, quinolone derivatives, active biological enzymes and other medicines.

The synthesis method of 2-fluoro-3-nitrobenzoic acid reported in the literature at present mainly comprises the following steps:

(1) 2-fluoro-3-nitrotoluene is used as a raw material, and a chromium trioxide and sulfuric acid system is used for direct oxidation synthesis of 2-fluoro-3-nitrobenzoic acid. The chromium trioxide used in the method has high environmental toxicity, and is a non-environment-friendly method.

(2) The method comprises the steps of taking o-methyl phenol as a raw material, nitrifying to generate 2-methyl-6-nitrophenol, chlorinating hydroxyl to generate 2-chloro-3-nitrotoluene, then fluoro to generate 2-fluoro-3-nitrotoluene, and finally oxidizing to obtain the 2-fluoro-3-nitrobenzoic acid. The process is long, complex and not suitable for large-scale production.

(3) 2-fluorotoluene is used as a raw material, an oxidant such as chromium trioxide or potassium permanganate is used for oxidation to prepare 2-fluorobenzoic acid, and then the 2-fluoro-3-nitrobenzoic acid is synthesized through nitration reaction. The reaction has poor selectivity, other by-products appear in the nitration process, and the yield is low.

Lithium Diisopropylamide (LDA) used in the present invention is a stable organometallic compound and widely used as a non-nucleophilic base in organic synthesis, and a reaction for promoting 2-fluoronitrobenzene to synthesize 2-fluoro-3-nitrobenzoic acid using LDA has not been reported so far.

Disclosure of Invention

Aiming at the defects in the prior art, the invention provides a clean, environment-friendly, economic and efficient synthetic method of 2-fluoro-3-nitrobenzoic acid. The invention utilizes Lithium Diisopropylamide (LDA) or tert-butyl lithium to prepare a target product 2-fluoro-3-nitrobenzoic acid by carrying out fluorine ortho lithiation on 2-fluoronitrobenzene, carrying out carbon dioxide (dry ice) carbonyl insertion reaction and carrying out acidic hydrolysis under the condition of low temperature.

The reaction process is as follows:

the technical scheme of the invention is as follows:

a preparation method of 2-fluoro-3-nitrobenzoic acid (II) comprises the following steps:

dissolving a raw material 2-fluoronitrobenzene (I) in a reaction solvent, dropwise adding an alkali solution under the condition of nitrogen protection at-30 to-80 ℃, maintaining the temperature after dropwise adding, continuously reacting for 1-10 h, then quenching the reaction solution by dry ice, and performing post-treatment to obtain a product 2-fluoro-3-nitrobenzoic acid (II);

the reaction solvent is: tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, toluene or n-hexane; the volume dosage of the reaction solvent is 10L/mol based on the mass of the raw material 2-fluoronitrobenzene (I);

the alkali in the alkali solution is lithium diisopropylamideOr tert-butyl lithiumThe solvent in the alkali solution is the same as the reaction solvent; the mass ratio of the raw material 2-fluoronitrobenzene (I) to the alkali is 1: 1-10;

the post-treatment method comprises the following steps: quenching the reaction solution by dry ice, naturally returning to room temperature (20-30 ℃), evaporating under reduced pressure to remove the solvent to obtain a crude product, adding water, adjusting the pH to 2 by using concentrated hydrochloric acid (37%), extracting by using ethyl acetate, combining organic layers, washing by using saturated saline solution, drying by using anhydrous sodium sulfate, filtering, concentrating, and drying to obtain the product 2-fluoro-3-nitrobenzoic acid (II).

Compared with the prior art, the invention has the following beneficial effects:

(1) the reaction condition is mild, transition metal catalysis is not needed, and Lithium Diisopropylamide (LDA) is used for efficiently promoting 2-fluoronitrobenzene to synthesize 2-fluoro-3-nitrobenzoic acid;

(2) the selectivity is good, and the yield is high;

(3) simple process, high efficiency, environmental protection, economy and suitability for large-scale preparation.

Detailed Description

The invention is further described below by means of specific examples, without the scope of protection of the invention being limited thereto.

The first embodiment is as follows:

in a 250ml three-necked flask, 2-fluoronitrobenzene (1.41g, 0.01mol) was dissolved in 2-methyltetrahydrofuran (100ml), replaced with nitrogen atmosphere, then cooled, and when the temperature was-30 ℃, a mixed solution of lithium diisopropylamide (2.14g, 0.02mol) and 2-methyltetrahydrofuran (40ml) was added dropwise, and after completion of the dropwise addition, the reaction was continued for 6 hours, and after completion of the reaction, dry ice (2.2g, 0.05mol) was rapidly added under nitrogen atmosphere, followed by quenching and further stirring for 2 hours. The reaction mixture was then allowed to return to room temperature, the solvent was removed in vacuo, and the resulting residue was taken up in 30ml of water, the pH of the aqueous phase was adjusted to 2 with concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate (30 ml. times.3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 1.04g of 2-fluoro-3-nitrobenzoic acid with a purity of 96.12% and a yield of 54.00%.

¹H NMR(400MHz,CDCl₃)δ11.0(s,1H),8.50(s,2H),7.50(s,1H)。

Example two:

in a 250ml three-necked flask, 2-fluoronitrobenzene (1.41g, 0.01mol) was dissolved in tetrahydrofuran (100ml), replaced with nitrogen atmosphere, then cooled, and when the temperature was-80 ℃, a mixed solution of lithium diisopropylamide (8.57g, 0.08mol) and tetrahydrofuran (40ml) was added dropwise, and after completion of the dropwise addition, the reaction was continued at that temperature for 8 hours, and after completion of the reaction, dry ice (2.2g, 0.05mol) was rapidly added under nitrogen atmosphere, followed by quenching and further stirring for 2 hours. The reaction mixture was then allowed to return to room temperature, the solvent was removed in vacuo, and the resulting residue was taken up in 30ml of water, the pH of the aqueous phase was adjusted to 2 with concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate (30 ml. times.3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 1.64g of 2-fluoro-3-nitrobenzoic acid with a purity of 98.05% and a yield of 86.87%.

Example three:

in a 250ml three-necked flask, 2-fluoronitrobenzene (1.41g, 0.01mol) was dissolved in diethyl ether (100ml), replaced with nitrogen atmosphere, then cooled, and when the temperature was-80 ℃, a mixed solution of tert-butyl lithium (3.84g, 0.06mol) and diethyl ether (40ml) was added dropwise, and after completion of the dropwise addition, the reaction was continued at that temperature for 2 hours, and after completion of the reaction, dry ice (2.2g, 0.05mol) was rapidly added under nitrogen atmosphere, followed by quenching, and the stirring was continued for 2 hours. The reaction mixture was then allowed to return to room temperature, the solvent was removed in vacuo, and the resulting residue was taken up in 30ml of water, the pH of the aqueous phase was adjusted to 2 with concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate (30 ml. times.3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 0.96g of 2-fluoro-3-nitrobenzoic acid with a purity of 96.42% and a yield of 50.00%.

Example four:

in a 250ml three-necked flask, 2-fluoronitrobenzene (1.41g, 0.01mol) was dissolved in toluene (100ml), replaced with nitrogen atmosphere, then cooled, and when the temperature was-60 ℃, a mixed solution of lithium diisopropylamide (8.57g, 0.08mol) and toluene (40ml) was added dropwise, and after completion of the dropwise addition, the reaction was continued at that temperature for 9 hours, and after completion of the reaction, dry ice (2.2g, 0.05mol) was rapidly added under nitrogen atmosphere, followed by quenching and further stirring for 2 hours. The reaction mixture was then allowed to return to room temperature, the solvent was removed in vacuo, and the resulting residue was taken up in 30ml of water, the pH of the aqueous phase was adjusted to 2 with concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate (30 ml. times.3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 1.61g of 2-fluoro-3-nitrobenzoic acid with a purity of 97.78% and a yield of 85.04%.

Example five:

in a 250ml three-necked flask, 2-fluoronitrobenzene (1.41g, 0.01mol) was dissolved in n-hexane (100ml), replaced with nitrogen atmosphere, then cooled, and when the temperature was-30 ℃, a mixed solution of t-butyl lithium (3.84g, 0.06mol) and n-hexane (40ml) was added dropwise, and after completion of the dropwise addition, the reaction was continued at that temperature for 6 hours, and after completion of the reaction, dry ice (2.2g, 0.05mol) was rapidly added under nitrogen atmosphere, followed by quenching, and the stirring was continued for 2 hours. The reaction mixture was then allowed to return to room temperature, the solvent was removed in vacuo, and the resulting residue was taken up in 30ml of water, the pH of the aqueous phase was adjusted to 2 with concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate (30 ml. times.3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 1.28g of 2-fluoro-3-nitrobenzoic acid with a purity of 96.28% and a yield of 66.58%.

Example six:

in a 250ml three-necked flask, 2-fluoronitrobenzene (1.41g, 0.01mol) was dissolved in 2-methyltetrahydrofuran (100ml), replaced with nitrogen atmosphere, then cooled, and when the temperature was-80 ℃, a mixed solution of tert-butyllithium (5.77g, 0.09mol) and 2-methyltetrahydrofuran (40ml) was added dropwise, and after completion of the dropwise addition, the reaction was continued at that temperature for 10 hours, and after completion of the reaction, dry ice (2.2g, 0.05mol) was rapidly added under nitrogen atmosphere, followed by quenching, and stirring was continued for 2 hours. The reaction mixture was then allowed to return to room temperature, the solvent was removed in vacuo, and the resulting residue was taken up in 30ml of water, the pH of the aqueous phase was adjusted to 2 with concentrated hydrochloric acid, and the mixture was extracted with ethyl acetate (30 ml. times.3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 1.56g of 2-fluoro-3-nitrobenzoic acid with a purity of 96.34% and a yield of 81.19%.