CN109678741B - Preparation method of 4-amino-3-fluorobenzoic acid - Google Patents

Preparation method of 4-amino-3-fluorobenzoic acid Download PDF

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CN109678741B
CN109678741B CN201910085012.1A CN201910085012A CN109678741B CN 109678741 B CN109678741 B CN 109678741B CN 201910085012 A CN201910085012 A CN 201910085012A CN 109678741 B CN109678741 B CN 109678741B
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difluorobenzonitrile
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aminobenzonitrile
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water
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CN109678741A (en
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杨小格
王永灿
王秀英
姜志鹏
张金鑫
宋桐集
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Jinkai Liaoning Life Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/26—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing carboxyl groups by reaction with HCN, or a salt thereof, and amines, or from aminonitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/38—Separation; Purification; Stabilisation; Use of additives
    • C07C227/40—Separation; Purification

Abstract

The invention relates to a preparation method of 4-amino-3-fluorobenzoic acid, which is characterized by being prepared by taking 3, 4-difluorobenzonitrile as a raw material, and preferably comprising the following steps: (1) reacting 3, 4-difluorobenzonitrile with ammonia gas to obtain an intermediate 3-fluoro-4-aminobenzonitrile; (2) and (3) carrying out hydrolysis reaction on the intermediate 3-fluoro-4-aminobenzonitrile under alkaline conditions to obtain the 4-amino-3-fluorobenzoic acid. The method takes cheap 3, 4-difluorobenzonitrile as a main raw material, synthesizes the 4-amino-3-fluorobenzoic acid with high yield and high purity through two steps of ammoniation and hydrolysis, has the advantages of convenient operation, economic price and small environmental pollution, and can realize large-scale industrial production.

Description

Preparation method of 4-amino-3-fluorobenzoic acid
Technical Field
The invention relates to the technical field of compound preparation, and particularly relates to a preparation method of 4-amino-3-fluorobenzoic acid.
Background
The existing method for synthesizing 4-amino-3-fluorobenzoic acid comprises the following three methods: 1) 4-nitro-3-fluorotoluene is used as a raw material and is oxidized by a strong oxidant such as potassium permanganate (US 20080139619; US20090270372), potassium dichromate (j.med.chem.2005,48(6), 729; PCT2009130481) or sodium dichromate (bio.med.chem.lett.2007,17(4), 1043; bio.med.chem.lett.2009,19(5),1386) oxidation to produce 4-nitro-3-fluorobenzoic acid followed by Pd/C catalytic hydrogenation of the nitro group for reduction (bio.med.chem.2016, 24(12), 2697; PCT2000016769) to prepare 4-amino-3-fluorobenzoic acid. Wherein the raw material 4-nitro-3-fluorotoluene is prepared by nitration of 3-fluorotoluene (dye and dye: 2004,41(5), 271; journal of the college of academy of sciences: 2006,26(3), 49). 2) 4-nitro-3-fluorotoluene is also used as raw material, and is undergone the processes of free radical bromination reaction to produce benzyl bromide, hydrolysis to obtain benzyl alcohol and treatment by using NaClO or NaClO2Oxidizing benzyl alcohol to acid, and finally, carrying out Pd/C catalytic reduction to prepare the catalyst (PCT 2004058764; PCT 2003037898). 3) The o-fluoronitrobenzene is taken as a raw material to prepare 2-fluoro-4-alkyl nitrobenzene (Tetrahedron,2001, 57(22), 4753; chem.2002,67(2),394), and synthesized by the same procedure as in method (1).
Method1：
Figure BDA0001961491690000011
Method2：
Figure BDA0001961491690000021
Method3：
Figure BDA0001961491690000022
Disclosure of Invention
The technical problem solved by the invention is as follows: in the prior art, the first method generates two isomers, the selectivity of the target product is lower than 20%, so that the raw materials are high in price, the nitration step and the oxidation step belong to strong exothermic reactions, potential safety hazards are high, a large amount of acidic wastewater and manganese-containing or chromium-containing wastewater are generated, and environmental pollution is high. The reduction step needs expensive noble metal catalyst palladium Pd, so the cost is high; the second method, while avoiding the use of expensive chromium/manganese salts, significantly increases the number of reaction steps; the third method, like the first two methods, has the disadvantages of expensive raw materials, long synthesis steps, high cost, troublesome operation, high safety risk and great environmental pollution.
In order to solve the technical problems, the invention provides a method for preparing 4-amino-3-fluorobenzoic acid. Cheap 3, 4-difluorobenzonitrile is used as a main raw material, and the 4-amino-3-fluorobenzoic acid is synthesized with high yield and high purity through two steps of ammoniation and hydrolysis, so that the method has the advantages of convenience in operation, low price and low environmental pollution, and can realize large-scale industrial production.
Specifically, aiming at the defects of the prior art, the invention provides the following technical scheme:
a preparation method of 4-amino-3-fluorobenzoic acid is characterized by taking 3, 4-difluorobenzonitrile as a raw material.
Preferably, in the above preparation method, the 4-amino-3-fluorobenzoic acid is prepared from a raw material containing 3, 4-difluorobenzonitrile.
In the preparation method, 3, 4-difluorobenzonitrile is used as a parent compound participating in the reaction.
Preferably, the preparation method comprises the following steps:
(1) reacting 3, 4-difluorobenzonitrile with ammonia gas to obtain an intermediate 3-fluoro-4-aminobenzonitrile;
(2) and (3) carrying out hydrolysis reaction on the intermediate 3-fluoro-4-aminobenzonitrile under alkaline conditions to obtain the 4-amino-3-fluorobenzoic acid.
Preferably, in the above preparation method, the molar ratio of the 3, 4-difluorobenzonitrile to the ammonia gas is 1: (2-10), preferably 1: (4-10).
Preferably, in the above preparation method, the reaction temperature of the 3, 4-difluorobenzonitrile and ammonia gas is 60 to 150 ℃, preferably 90 to 110 ℃.
Preferably, in the above preparation method, the reaction time of the 3, 4-difluorobenzonitrile and ammonia gas is 20-40 h.
Preferably, in the above preparation method, the step (1) comprises the steps of:
reacting 3, 4-difluorobenzonitrile with ammonia gas, adjusting the temperature to 10-35 ℃, and recrystallizing the obtained material to obtain an intermediate 3-fluoro-4-aminobenzonitrile.
Preferably, in the above preparation method, before the recrystallization process, a process of extracting the material with water and an organic extraction solvent or washing the material to remove salts and obtain an organic phase is further included.
Preferably, in the above preparation method, before the recrystallization process, the method further comprises the following steps: directly adding a weight crystallization solvent, heating to dissolve, then cooling to crystallize, filtering, washing a filter cake with water, and drying to obtain a pure product of the 3-fluoro-4-aminobenzonitrile.
Preferably, in the above preparation method, the extraction process comprises the following steps: and mixing water and an organic extraction solvent, and extracting the material, wherein the mass ratio of the water to the organic extraction solvent to the 3, 4-difluorobenzonitrile is preferably (5-15): 2-6): 1.
Preferably, in the above preparation method, the washing and desalting process comprises the following steps:
adding an organic extraction solvent into the materials, discharging after dissolving, adding water for washing, removing salt, and separating an organic phase.
Preferably, in the above preparation method, the organic extraction solvent is one or more selected from the group consisting of methyl tert-butyl ether, 2-methyltetrahydrofuran, ethyl acetate and dichloromethane.
Preferably, in the above preparation method, the recrystallization process comprises the following steps: adding a recrystallization solvent into the obtained material, heating to 60-80 ℃, and then cooling to 0-5 ℃.
Preferably, in the above preparation method, the recrystallization solvent is one or more selected from benzene, toluene, and xylene. Preferably, the above preparation method further comprises a step of adding a reaction solvent to the 3, 4-difluorobenzonitrile before the step of reacting the 3, 4-difluorobenzonitrile with ammonia gas; the reaction solvent is one or more than two of toluene, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, 2-methyltetrahydrofuran, N-dimethylformamide or dimethyl sulfoxide, and preferably, the reaction solvent comprises diethylene glycol dimethyl ether.
Preferably, in the above production method, when the reaction solvent is insoluble in water, the step (1) comprises the steps of: adding 3, 4-difluorobenzonitrile into a reaction solvent, reacting with ammonia gas, washing the obtained material with water, separating an organic phase, concentrating to obtain a crude product, and recrystallizing to obtain an intermediate 3-fluoro-4-aminobenzonitrile, wherein the water-insoluble reaction solvent is selected from toluene or 2-methyltetrahydrofuran;
when the reaction solvent is a low boiling point solvent dissolved in water, the step (1) comprises the steps of: adding 3, 4-difluorobenzonitrile into a reaction solvent, reacting with ammonia gas, concentrating the obtained material until no fraction is produced, shuffling with water, and recrystallizing to obtain an intermediate 3-fluoro-4-aminobenzonitrile; the low boiling point solvent dissolved in water is preferably ethylene glycol dimethyl ether;
when the reaction solvent is a high boiling point solvent dissolved in water, the step (1) comprises the steps of: adding 3, 4-difluorobenzonitrile into a reaction solvent, reacting with ammonia gas, extracting the material with a mixture of water and an organic extraction solvent to obtain an organic phase, and performing a recrystallization process to obtain an intermediate 3-fluoro-4-aminobenzonitrile; the water-soluble high-boiling-point solvent is selected from one or more of diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, N-dimethylformamide or dimethyl sulfoxide, and preferably, the water-soluble high-boiling-point solvent comprises diethylene glycol dimethyl ether.
Preferably, in the above preparation method, the molar concentration of the 3, 4-difluorobenzonitrile in the reaction solvent is greater than 0.5mol/L, preferably 1 to 5 mol/L.
Preferably, in the above preparation method, the recrystallization process further includes a filtration process.
Preferably, in the above preparation method, the step (2) comprises the steps of:
and mixing the intermediate 3-fluoro-4-aminobenzonitrile with an alkaline aqueous solution, performing hydrolysis reaction, and adding acid to adjust the pH value to obtain the 4-amino-3-fluorobenzoic acid.
Preferably, in the above preparation method, the temperature of the hydrolysis reaction in the step (2) is 50 to 100 ℃. The reaction time is 1-10 h.
Preferably, in the above preparation method, the molar ratio of the 3-fluoro-4-aminobenzonitrile to the base is 1: (1-5), preferably 1: (1-3).
Preferably, in the above preparation method, the pH is 1.0 to 4.0, preferably 2.0 to 3.0.
Preferably, in the above production method, the base is selected from hydroxides or carbonates of alkali metals or alkaline earth metals, and the acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, formic acid, and acetic acid.
Preferably, in the above preparation method, the concentration of the basic aqueous solution is 5 to 30 wt%, and the concentration of the acid is 5 to 30 wt%.
The invention also provides 4-amino-3-fluorobenzoic acid which is prepared by the preparation method.
The invention also provides application of the 4-amino-3-fluorobenzoic acid in the field of medicines.
The invention has the advantages that: 1) the raw materials are easy to obtain, and the cost is low; 2) the synthesis steps are simple and easy to operate, the purity is high, the yield is high, the environmental pollution is low, and the industrial production is easy to realize.
Drawings
FIG. 1 is a liquid phase-mass spectrum of the intermediate 3-fluoro-4-aminobenzonitrile obtained in example 1.
FIG. 2 is a liquid phase-mass spectrum of 4-amino-3-fluorobenzoic acid, a product obtained in example 1.
Detailed Description
In order to solve the defects of expensive raw material price, long synthesis steps, high cost, troublesome operation, high safety risk and great environmental pollution existing in the existing preparation method of 4-amino-3-fluorobenzoic acid, the invention provides a method for preparing 4-amino-3-fluorobenzoic acid. Cheap 3, 4-difluorobenzonitrile is used as a main raw material, and the 4-amino-3-fluorobenzoic acid is synthesized with high yield and purity through two steps of ammoniation and hydrolysis, so that the method has the advantages of convenience in operation, economic price and small environmental pollution, and can realize large-scale industrial production.
In a preferred embodiment, the present invention provides a method for preparing 4-amino-3-fluorobenzoic acid, the synthetic route is shown as the following reaction formula, and the method mainly comprises the following steps:
Figure BDA0001961491690000051
(1) ammoniation: reacting 3, 4-difluorobenzonitrile with ammonia gas in an autoclave to obtain an intermediate 3-fluoro-4-aminobenzonitrile;
(2) hydrolysis: and (2) carrying out hydrolysis reaction on the intermediate 3-fluoro-4-aminobenzonitrile obtained in the step (1) under an alkaline condition to generate 4-amino-3-fluorobenzoic acid.
Preferably, the amination in the step (1) is: firstly, adding 3, 4-difluorobenzonitrile and a solvent (or not adding the solvent) into an autoclave, then introducing ammonia gas, heating to 60-150 ℃ for reaction, and taking a reaction material to perform controlled reaction in Liquid Chromatography (LC) until the reaction is complete. When the solvent exists, the temperature is reduced to 10-30 ℃, after pressure relief, the following proper mode is selected for post-treatment according to different types of solvents: 1) when the solvent is not mutually soluble with water, adding water to wash the organic phase, concentrating to obtain a crude product, and recrystallizing to obtain a pure product; 2) when the solvent is a low boiling point solvent which is mutually soluble with water, concentrating until no fraction is obtained, adding water, mixing and filtering, and recrystallizing a filter cake to obtain a pure product of 3-fluoro-4-aminobenzonitrile; 3) when the solvent is a high boiling point solvent which is mutually soluble with water, adding water and an organic extraction solvent, separating out an organic phase, adding a recrystallization solvent, cooling and crystallizing to obtain an intermediate 3-fluoro-4-aminobenzonitrile. When no solvent is reacted, after the temperature is reduced to 10-30 ℃ and the pressure is released, one of the following modes can be selected for post-treatment: 1) adding an organic solvent to dissolve and discharge materials, adding water to wash, separating out an organic phase, concentrating to obtain a crude product, and recrystallizing to obtain a pure product of 3-fluoro-4-aminobenzonitrile; 2) directly adding a weight crystallization solvent, heating to dissolve, then cooling to crystallize, filtering, washing a filter cake with water, and drying to obtain a pure product of the 3-fluoro-4-aminobenzonitrile. Wherein the organic solvent is selected from methyl tert-butyl ether, ethyl acetate, dichloromethane and water-immiscible solvents.
Preferably, the amination in the step (1): the method can be carried out under the condition of no solvent or by adding a solvent. The reaction solvent is one or more selected from toluene, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, 2-methyl tetrahydrofuran, N-dimethylformamide or dimethyl sulfoxide, wherein diethylene glycol dimethyl ether is preferred. The mass ratio of the 3, 4-difluorobenzonitrile to the solvent is 1: 0-100.
Preferably, the amination in the step (1): the molar ratio of the 3, 4-difluorobenzonitrile to the ammonia gas is 1:2-10, wherein the effect is better when the molar ratio is 1: 4-10.
Preferably, the amination in the step (1): the reaction temperature is 90-110 ℃.
Preferably, the amination in the step (1): the organic solvent (extraction solvent) is selected from methyl tert-butyl ether, ethyl acetate, dichloromethane, etc. and water-immiscible solvent.
Preferably, the amination in the step (1): the recrystallization solvent is selected from one or more of benzene, toluene or xylene.
Preferably, the reaction of 3, 4-difluorobenzonitrile and ammonia gas in the step (1) is carried out under the control of liquid chromatography until the reaction is complete, and the method for controlling the reaction is not limited to liquid chromatography, and other ways are also possible, such as: TLC, or GC.
In the invention, the organic solvent is added into the raw materials to facilitate discharging.
Preferably, the hydrolysis reaction in step (2): mixing 3-fluoro-4-aminobenzonitrile with an alkaline aqueous solution, reacting at 50-100 ℃, and controlling the reaction to be complete by liquid chromatography; and (3) dropwise adding acid to adjust the pH value to 1.0-4.0, cooling to room temperature, filtering, and mixing filter cakes with water and drying to obtain the 4-amino-3-fluorobenzoic acid.
Preferably, the hydrolysis reaction in step (2): the base is selected from hydroxides or carbonates of alkali metals or alkaline earth metals, such as sodium hydroxide and potassium hydroxide; the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, formic acid or acetic acid.
Preferably, the hydrolysis reaction in step (2): in the reaction, the molar ratio of the 3-fluoro-4-aminobenzonitrile to the alkali is 1: 1.0 to 5.0, preferably 1: 1.0-3.0; the concentration of the alkali aqueous solution is 5-30%; the concentration of the acid is 5-30%.
Preferably, the hydrolysis reaction in step (2): the optimum pH value adjusted by adding acid is 2.0-3.0.
The preparation of 4-amino-3-fluorobenzoic acid according to the invention is further illustrated by the following specific examples.
In the following examples, information on the reagents and instruments used is as follows:
3, 4-difluorobenzonitrile: zhejiang Yingxin chemical Co., Ltd., content of 99%.
Autoclave: dalianhuichang petrochemical equipment, model number: KCF-250, bearing pressure is not less than 4 Mpa.
Liquid chromatography: agilent, type: 1260.
liquid chromatography-mass spectrometer: agilent, type: 6120.
differential scanning calorimeter: shimadzu DSC-60.
Example 1
Step 1: 3, 4-difluorobenzonitrile (30g,0.22mol) was charged into a 500mL autoclave, and ammonia gas (7.5 g, 0.44mol) was purged. Then heating to 90 ℃ for reaction for 24h (the highest pressure in the reaction process is 4.0Mpa), sampling, and monitoring the reaction by liquid chromatography until the normalized content of the raw materials is less than or equal to 0.5%. Cooling to room temperature, releasing pressure, and adding methyl tert-butyl ether (90mL) to dissolve the materials; the reaction mixture was washed with water (150 mL. times.3) to remove ammonium fluoride, the organic phase was separated and concentrated under reduced pressure to a solid phase to give the crude product. Recrystallizing with toluene (120mL), cooling to 0 deg.C, filtering, leaching the filter cake with cold toluene (0-5 deg.C), and vacuum drying at 40 deg.C to obtain 8.8g of 3-fluoro-4-aminobenzonitrile (yield: 30%; purity > 99%; off-white solid, melting point 70-72 deg.C).
Wherein, the calculation formula of the yield is as follows: product mass ÷ (3, 4-difluorobenzonitrile mole number × product molecular weight) × 100%
The purity detection method comprises the following steps: agilent liquid chromatography 1260, area normalized.
The method for detecting the melting point comprises the following steps: detecting with differential scanning calorimeter.
Step 2: adding 3-fluoro-4-aminobenzonitrile (13.6g,0.1mol) and sodium hydroxide aqueous solution (0.1mol,5 wt%) at room temperature, heating to 50 ℃ for reaction for 10h, sampling, monitoring the reaction by liquid chromatography until the normalized content of the raw materials is less than or equal to 0.5%, cooling to 20 ℃, dropwise adding 15 wt% hydrochloric acid at the temperature to adjust the pH value to 2, filtering, shuffling a filter cake with water (70mL), and drying in vacuum at 50 ℃ to obtain 14.7g of 4-amino-3-fluorobenzoic acid (yield 95%, purity greater than 99%, white solid, melting point: 215-.
The detection method of the intermediate 3-fluoro-4-aminobenzonitrile and the product 4-amino-3-fluorobenzoic acid comprises the following steps: agilent liquid chromatography 1260, area normalized. Identifying the product by liquid phase mass spectrometry (LC-MS).
Wherein, the calculation formula of the yield is as follows: product mass ÷ (3-fluoro-4-aminobenzonitrile mole number × product molecular weight) × 100%
The intermediate and the product obtained in the embodiment are detected by a liquid chromatography-mass spectrometer, and the detection result of the intermediate is as follows: LC-MS (M/z) 137[ M + H]+，C7H5FN2. The detection result of the product is as follows: LC-MS (M/z) 156[ M + H]+，C7H6FNO2. Specifically, the table is shown in fig. 1-fig. 2 and table 1-table 2.
FIG. 1 is a liquid phase-mass spectrum (LC-MS diagram) of the intermediate, Table 1 is the detection result of FIG. 1, and from FIG. 1 and Table 1, it can be seen that the ion mass-to-charge ratios 137.0514, 138.054 and the corresponding molecular formula C7H5FN2Shows that the intermediate 3-fluoro-4-aminobenzonitrile is synthesized, figure 2 is a liquid phase-mass spectrogram of the product 4-amino-3-fluorobenzoic acid, table 2 is a detection result of figure 2, and as can be seen from figures 2 and table 2, the ion mass-to-charge ratios 156.0461 and 157.0491 and the corresponding molecular formula C7H6FNO2Indicating that the synthesized product is 4-amino-3-fluorobenzoic acid.
TABLE 1 detection results of intermediate LC-MS plot
Figure BDA0001961491690000081
TABLE 2 detection results of LC-MS graph of product
Figure BDA0001961491690000082
Figure BDA0001961491690000091
Example 2
Step 1: 3, 4-difluorobenzonitrile (30g,0.22mol) was charged into a 500mL autoclave, and ammonia gas (15 g, 0.88mol) was purged. Then heating to 90 ℃ for reaction for 24h (the highest pressure in the reaction process is 4.0Mpa), sampling, and monitoring the reaction by liquid chromatography until the normalized content of the raw materials is less than or equal to 0.5%. Cooling to room temperature, releasing pressure, and adding ethyl acetate (90mL) to dissolve the materials; the reaction mixture was washed with water (150 mL. times.3) to remove ammonium fluoride, the organic phase was separated and concentrated under reduced pressure to a solid phase to give the crude product. Recrystallization from toluene (120mL), filtration at 0 ℃ and filtration, rinsing the filter cake with cold toluene (0-5 ℃) once, and vacuum drying at 40 ℃ to obtain 27.9g of 3-fluoro-4-aminobenzonitrile (yield: 95%; purity > 99%; off-white solid, melting point 70-72 ℃) and, using the same method as in example 1, the intermediate was 3-fluoro-4-aminobenzonitrile.
Step 2: 3-fluoro-4-aminobenzonitrile (13.6g,0.1mol) and an aqueous solution of sodium hydroxide (0.1mol,5 wt%) were added at room temperature, then the temperature was raised to 50 ℃ for reaction for 10 hours, sampling was performed, the reaction was monitored by liquid chromatography until the normalized content of the raw material was not more than 0.5%, then the temperature was lowered to 20 ℃ and 15 wt% hydrochloric acid was added dropwise at this temperature to adjust the pH to 2, filtration was performed, the filter cake was once mixed with water (70mL), vacuum-dried at 50 ℃ to obtain 14.7g of 4-amino-3-fluorobenzoic acid (yield 95%, purity > 99%, white solid, melting point: 215-.
Example 3
Step 1: 3, 4-difluorobenzonitrile (30g,0.22mol) was charged into a 500mL autoclave, and ammonia gas (37.4 g, 2.2mol) was purged. Then heating to 110 ℃ for reaction for 24h, sampling, and monitoring the reaction by liquid chromatography until the normalized content of the raw materials is less than or equal to 0.5%. After the temperature was decreased to room temperature and the pressure was released, toluene (120mL) was added, the temperature was raised to 60 ℃ and the temperature was maintained for 0.5h, then the temperature was decreased to 0 ℃ and the mixture was filtered, the filter cake was shuffled with water (150 mL. times.3), the filter was filtered, and the filter cake was dried under vacuum at 40 ℃ to obtain 27.9g of 3-fluoro-4-aminobenzonitrile (yield 95%; purity > 99%, off-white solid, melting point 70-72 ℃) and 3-fluoro-4-aminobenzonitrile was detected as an intermediate by the same method as in example 1.
Step 2: 3-fluoro-4-aminobenzonitrile (13.6g,0.1mol), sodium hydroxide (0.18mol,10 wt%) and water were added at room temperature, then the temperature was raised to 100 ℃ to react for 1.5h, sampling was performed, the reaction was monitored by liquid chromatography until the normalized content of the raw materials was not more than 0.5%, then the temperature was lowered to 30 ℃ and 15 wt% hydrochloric acid was added dropwise at this temperature to adjust the pH to 2, filtration was performed, the filter cake was once mixed with water (70mL), vacuum drying was performed at 55 ℃ to obtain 15.2g of 4-amino-3-fluorobenzoic acid (yield 98%, purity > 99%, white solid, melting point: 215-.
Example 4
Step 1: 3, 4-difluorobenzonitrile (30g,0.22mol) was charged into a 500mL autoclave, and ammonia gas (15 g, 0.88mol) was purged. Then heating to 110 ℃ for reaction for 24h, sampling, and monitoring the reaction by liquid chromatography until the normalized content of the raw materials is less than or equal to 0.5%. After the temperature was decreased to room temperature and the pressure was released, toluene (120mL) was added, the temperature was increased to 80 ℃ and the temperature was maintained for 0.5h, then the temperature was decreased to 0 ℃ and the mixture was filtered, the filter cake was shuffled with water (150 mL. times.3), the filter was filtered, and the filter cake was dried under vacuum at 40 ℃ to obtain 27.3g of 3-fluoro-4-aminobenzonitrile (yield 93%; purity > 99%, off-white solid, melting point 70-72 ℃) and 3-fluoro-4-aminobenzonitrile was detected as an intermediate by the same method as in example 1.
Step 2: 3-fluoro-4-aminobenzonitrile (13.6g,0.1mol), sodium hydroxide (0.18mol,10 wt%) and water were added at room temperature, then the temperature was raised to 100 ℃ to react for 1.5h, sampling was performed, the reaction was monitored by liquid chromatography until the normalized content of the raw materials was not more than 0.5%, then the temperature was lowered to 30 ℃ and 15 wt% hydrochloric acid was added dropwise at this temperature to adjust the pH to 2, filtration was performed, the filter cake was once mixed with water (70mL), vacuum drying was performed at 55 ℃ to obtain 15.2g of 4-amino-3-fluorobenzoic acid (yield 98%, purity > 99%, white solid, melting point: 215-.
Example 5
Step 1: 3, 4-difluorobenzonitrile (30g,0.22mol) and diethylene glycol dimethyl ether (150mL) were charged to a 500mL autoclave, and ammonia gas (22.5 g, 1.32mol) was purged. Then heating to 100 ℃ for reaction for 24h, sampling, and monitoring the reaction by liquid chromatography until the normalized content of the raw materials is less than or equal to 0.5%. After the temperature was decreased to room temperature and the pressure was released, water (180mL,180g) was added, extraction was performed with ethyl acetate (60 g. times.3), the organic phases were combined, concentrated under reduced pressure to a non-flowing liquid, the residue in the kettle was recrystallized with toluene (120mL), filtered at 5 ℃ and the filter cake was rinsed once with toluene (5 ℃) and dried under vacuum at 40 ℃ to give 26.4g of 3-fluoro-4-aminobenzonitrile (yield 90%; off-white solid with purity > 99%, melting point 70-72 ℃) and the intermediate was detected to be 3-fluoro-4-aminobenzonitrile by the same method as in example 1.
Step 2: 3-fluoro-4-aminobenzonitrile (13.6g,0.1mol), sodium hydroxide (0.18mol,20 wt%) and water were added at room temperature, then the temperature was raised to 90 ℃ for reaction for 2h, sampling was performed, the reaction was monitored by liquid chromatography until the normalized content of the raw material was not more than 0.5%, then the temperature was lowered to 30 ℃ and 15 wt% sulfuric acid was added dropwise at this temperature to adjust the pH to 2, filtration was performed, the filter cake was once mixed with water (70mL), vacuum drying was performed at 55 ℃ to obtain 14.7g of 4-amino-3-fluorobenzoic acid (yield 95%, purity > 99%, white solid, melting point: 215-.
Example 6
Step 1: 3, 4-difluorobenzonitrile (30g,0.22mol) and diethylene glycol dimethyl ether (150mL) were charged to a 500mL autoclave, and ammonia gas (22.5 g, 1.32mol) was purged. Then heating to 100 ℃ for reaction for 24h, sampling, and monitoring the reaction by liquid chromatography until the normalized content of the raw materials is less than or equal to 0.5%. After the temperature was decreased to room temperature and the pressure was released, water (150mL,150g) was added, methylene chloride was used for extraction (20 g. times.3), the organic phases were combined, concentrated under reduced pressure to a non-flowing liquid, the residue in the kettle was recrystallized from toluene (120mL), filtered at 5 ℃ and the filter cake was rinsed once with toluene (5 ℃) and dried under vacuum at 40 ℃ to give 26.4g of 3-fluoro-4-aminobenzonitrile (yield 90%; off-white solid with purity > 99%, melting point 70-72 ℃) and the intermediate was detected to be 3-fluoro-4-aminobenzonitrile by the same method as in example 1.
Step 2: 3-fluoro-4-aminobenzonitrile (13.6g,0.1mol), sodium hydroxide (0.5mol,20 wt%) and water were added at room temperature, then the temperature was raised to 90 ℃ for reaction for 2h, sampling was performed, the reaction was monitored by liquid chromatography until the normalized content of the raw material was not more than 0.5%, then the temperature was lowered to 30 ℃ and 15 wt% sulfuric acid was added dropwise at this temperature to adjust the pH to 1, filtration was performed, the filter cake was once mixed with water (70mL), vacuum drying was performed at 55 ℃ to obtain 12.4g of 4-amino-3-fluorobenzoic acid (yield 80%, purity > 99%, white solid, melting point: 215-.
Example 7
Step 1: 3, 4-difluorobenzonitrile (30g,0.22mol) and 2-methyltetrahydrofuran (150mL) were charged to a 500mL autoclave, and ammonia gas (15.0 g, 0.88mol) was purged. Then heating to 60 ℃ for reaction for 40h, and controlling the reaction to be complete by liquid chromatography. After the temperature was decreased to room temperature and the pressure was released, the reaction mixture was washed with water (150 mL. times.3), the organic phase was separated, concentrated under reduced pressure to a non-flowing liquid, recrystallized with benzene (120mL), filtered by cooling to 5 ℃ and the filter cake was rinsed once with toluene (5 ℃ C.), dried under vacuum at 40 ℃ to obtain 21.0g of 3-fluoro-4-aminobenzonitrile (yield: 70%; purity > 99%; off-white solid, melting point 70-72 ℃ C.), and the intermediate was detected to be 3-fluoro-4-aminobenzonitrile by the same method as in example 1.
Step 2: 3-fluoro-4-aminobenzonitrile (13.6g,0.1mol) and an aqueous solution of sodium hydroxide (0.3mol,30 wt%) were added at room temperature, and then the mixture was heated to 60 ℃ to react for 6 hours, then cooled to 20 ℃ and then 10 wt% hydrochloric acid was added dropwise thereto to adjust the pH to 3, followed by filtration, and the filter cake was mixed with water (70mL) once and dried under vacuum at 50 ℃ to obtain 14.3g of 4-amino-3-fluorobenzoic acid (yield 92%, purity > 99%, white solid, melting point: 215 and 216 ℃ C.), and the product was detected as 4-amino-3-fluorobenzoic acid by the same method as in example 1.
Example 8
Step 1: 3, 4-difluorobenzonitrile (30g,0.22mol) and ethylene glycol dimethyl ether (150mL) were charged to a 500mL autoclave, and ammonia gas (20g, 1.18mol) was purged. Then heating to 95 ℃ for reaction for 40h, and controlling the reaction to be complete by liquid chromatography. After the temperature was decreased to room temperature and the pressure was released, the mixture was concentrated to a non-flowing liquid, the residue in the autoclave was washed with water (150 mL. times.3), the crude product obtained by filtration was recrystallized from toluene (120mL), the temperature was decreased to 5 ℃ and the filtrate was filtered, the filter cake was rinsed once with toluene (5 ℃ C.), and vacuum-dried at 40 ℃ to obtain 25.5g of 3-fluoro-4-aminobenzonitrile (yield: 85%; purity > 99%; off-white solid, melting point 70-72 ℃ C.), and the intermediate was 3-fluoro-4-aminobenzonitrile as detected by the same method as in example 1.
Step 2: 3-fluoro-4-aminobenzonitrile (13.6g,0.1mol) and an aqueous solution of sodium hydroxide (0.14mol,20 wt%) were added at room temperature, and then the mixture was heated to 60 ℃ to react for 6 hours, then cooled to 20 ℃ and then 10 wt% hydrochloric acid was added dropwise thereto to adjust the pH to 4, followed by filtration, and the filter cake was mixed with water (70mL) once and dried under vacuum at 50 ℃ to obtain 12.5g of 4-amino-3-fluorobenzoic acid (yield 80%, purity > 99%, white solid, melting point: 215 and 216 ℃ C.), and the product was detected as 4-amino-3-fluorobenzoic acid by the same method as in example 1.
Example 9
Step 1: 3, 4-difluorobenzonitrile (30g,0.22mol) was charged into a 500mL autoclave, and ammonia gas (45 g, 2.7mol) was purged. Then heating to 150 ℃ for reaction for 24h, sampling, and monitoring the reaction by liquid chromatography until the normalized content of the raw materials is less than or equal to 0.5%. After the temperature was decreased to room temperature and the pressure was released, xylene (120mL) was added, the mixture was warmed to 80 ℃ and kept at that temperature for 0.5h, then the temperature was decreased to 0 ℃ and filtered, the filter cake was shuffled with water (150 mL. times.3), filtered, and vacuum-dried at 40 ℃ to obtain 26.4g of 3-fluoro-4-aminobenzonitrile (yield 90%; purity > 99%, off-white solid, melting point 70-72 ℃) and 3-fluoro-4-aminobenzonitrile as an intermediate was detected by the same method as in example 1.
Step 2: 3-fluoro-4-aminobenzonitrile (13.6g,0.1mol), sodium hydroxide (0.8mol,10 wt%) and water were added at room temperature, then the temperature was raised to 100 ℃ to react for 1.5h, sampling was performed, the reaction was monitored by liquid chromatography until the normalized content of the raw materials was not more than 0.5%, then the temperature was lowered to 30 ℃ and 15 wt% hydrochloric acid was added dropwise at this temperature to adjust the pH to 5, filtration was performed, the filter cake was once mixed with water (70mL), vacuum drying was performed at 55 ℃ to obtain 10.9g of 4-amino-3-fluorobenzoic acid (yield 70%, purity > 99%, white solid, melting point: 215-.
In conclusion, the preparation method disclosed by the invention is low in cost, simple in steps, high in yield, low in pollution and easy for industrial production.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the technical scope of the present invention.

Claims (78)

1. A method for preparing 4-amino-3-fluorobenzoic acid, which is characterized by comprising the following steps:
(1) reacting 3, 4-difluorobenzonitrile with ammonia gas to obtain an intermediate 3-fluoro-4-aminobenzonitrile;
(2) and (3) carrying out hydrolysis reaction on the intermediate 3-fluoro-4-aminobenzonitrile under alkaline conditions to obtain the 4-amino-3-fluorobenzoic acid.
2. The preparation method according to claim 1, wherein the molar ratio of the 3, 4-difluorobenzonitrile to the ammonia gas is 1: (2-10).
3. The preparation method according to claim 1, wherein the molar ratio of the 3, 4-difluorobenzonitrile to the ammonia gas is 1: (4-10).
4. The preparation method according to claim 1, wherein the reaction temperature of the 3, 4-difluorobenzonitrile and the ammonia gas is 60-150 ℃.
5. The preparation method according to claim 2, wherein the reaction temperature of the 3, 4-difluorobenzonitrile and the ammonia gas is 60-150 ℃.
6. The preparation method according to claim 3, wherein the reaction temperature of the 3, 4-difluorobenzonitrile with ammonia gas is 60-150 ℃.
7. The preparation method according to claim 1, wherein the reaction temperature of the 3, 4-difluorobenzonitrile and the ammonia gas is 90-110 ℃.
8. The preparation method according to claim 2, wherein the reaction temperature of the 3, 4-difluorobenzonitrile and the ammonia gas is 90-110 ℃.
9. The preparation method according to claim 3, wherein the reaction temperature of the 3, 4-difluorobenzonitrile and the ammonia gas is 90-110 ℃.
10. The production method according to claim 1, wherein the step (1) comprises the steps of:
reacting 3, 4-difluorobenzonitrile with ammonia gas, adjusting the temperature to 10-35 ℃, and recrystallizing the obtained material to obtain an intermediate 3-fluoro-4-aminobenzonitrile.
11. The production method according to claim 2, wherein the step (1) comprises the steps of:
reacting 3, 4-difluorobenzonitrile with ammonia gas, adjusting the temperature to 10-35 ℃, and recrystallizing the obtained material to obtain an intermediate 3-fluoro-4-aminobenzonitrile.
12. The production method according to claim 4, wherein the step (1) comprises the steps of:
reacting 3, 4-difluorobenzonitrile with ammonia gas, adjusting the temperature to 10-35 ℃, and recrystallizing the obtained material to obtain an intermediate 3-fluoro-4-aminobenzonitrile.
13. The production method according to claim 7, wherein the step (1) comprises the steps of:
reacting 3, 4-difluorobenzonitrile with ammonia gas, adjusting the temperature to 10-35 ℃, and recrystallizing the obtained material to obtain an intermediate 3-fluoro-4-aminobenzonitrile.
14. The preparation method of claim 10, wherein the recrystallization process further comprises a step of extracting the material with water and an organic extraction solvent or washing the material to remove salt to obtain an organic phase.
15. The method according to claim 11, wherein the recrystallization process further comprises a step of extracting the material with water and an organic extraction solvent or washing the material to remove salts to obtain an organic phase.
16. The preparation method of claim 12, wherein the recrystallization process further comprises a step of extracting the material with water and an organic extraction solvent or washing the material to remove salt to obtain an organic phase.
17. The method according to claim 13, wherein the recrystallization process further comprises a step of extracting the material with water and an organic extraction solvent or washing the material to remove salts to obtain an organic phase.
18. The method of claim 14, wherein the extraction process comprises the steps of: and mixing water and an organic extraction solvent, and extracting the material, wherein the mass ratio of the water to the organic extraction solvent to the 3, 4-difluorobenzonitrile is preferably (5-15): 2-6): 1.
19. The method of claim 15, wherein the extraction process comprises the steps of: and mixing water and an organic extraction solvent, and extracting the material, wherein the mass ratio of the water to the organic extraction solvent to the 3, 4-difluorobenzonitrile is preferably (5-15): 2-6): 1.
20. The method of claim 16, wherein the extraction process comprises the steps of: and mixing water and an organic extraction solvent, and extracting the material, wherein the mass ratio of the water to the organic extraction solvent to the 3, 4-difluorobenzonitrile is preferably (5-15): 2-6): 1.
21. The method of claim 17, wherein the extraction process comprises the steps of: and mixing water and an organic extraction solvent, and extracting the material, wherein the mass ratio of the water to the organic extraction solvent to the 3, 4-difluorobenzonitrile is preferably (5-15): 2-6): 1.
22. The method of claim 14, wherein the washing and desalting process comprises the steps of:
adding an organic extraction solvent into the materials, discharging after dissolving, adding water for washing, removing salt, and separating an organic phase.
23. The method of claim 15, wherein the washing and desalting process comprises the following steps:
adding an organic extraction solvent into the materials, discharging after dissolving, adding water for washing, removing salt, and separating an organic phase.
24. The method of claim 16, wherein the washing and desalting process comprises the following steps:
adding an organic extraction solvent into the materials, discharging after dissolving, adding water for washing, removing salt, and separating an organic phase.
25. The method of claim 17, wherein the washing and desalting process comprises the following steps:
adding an organic extraction solvent into the materials, discharging after dissolving, adding water for washing, removing salt, and separating an organic phase.
26. The method according to claim 14, wherein the organic extraction solvent is one or more selected from the group consisting of methyl tert-butyl ether, 2-methyltetrahydrofuran, ethyl acetate, and dichloromethane.
27. The method according to claim 18, wherein the organic extraction solvent is one or more selected from the group consisting of methyl tert-butyl ether, 2-methyltetrahydrofuran, ethyl acetate, and dichloromethane.
28. The method according to claim 22, wherein the organic extraction solvent is one or more selected from the group consisting of methyl tert-butyl ether, 2-methyltetrahydrofuran, ethyl acetate, and dichloromethane.
29. The method of claim 10, wherein the recrystallization process comprises the steps of: adding a recrystallization solvent into the obtained material, heating to 60-80 ℃, and then cooling to 0-5 ℃.
30. The method of claim 14, wherein the recrystallization process comprises the steps of: adding a recrystallization solvent into the obtained material, heating to 60-80 ℃, and then cooling to 0-5 ℃.
31. The method of claim 18, wherein the recrystallization process comprises the steps of: adding a recrystallization solvent into the obtained material, heating to 60-80 ℃, and then cooling to 0-5 ℃.
32. The method of claim 22, wherein the recrystallization process comprises the steps of: adding a recrystallization solvent into the obtained material, heating to 60-80 ℃, and then cooling to 0-5 ℃.
33. The production method according to claim 29, wherein the recrystallization solvent is one or two or more selected from benzene, toluene, and xylene.
34. The production method according to claim 30, wherein the recrystallization solvent is one or two or more selected from benzene, toluene, and xylene.
35. The production method according to claim 31, wherein the recrystallization solvent is one or two or more selected from benzene, toluene, and xylene.
36. The production method according to claim 32, wherein the recrystallization solvent is one or two or more selected from benzene, toluene, and xylene.
37. The production method according to any one of claims 1 to 36, further comprising a step of adding a reaction solvent to the 3, 4-difluorobenzonitrile before the step of reacting the 3, 4-difluorobenzonitrile with ammonia gas; the reaction solvent is one or more than two of toluene, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, 2-methyltetrahydrofuran, N-dimethylformamide or dimethyl sulfoxide.
38. The production method according to claim 37, wherein the reaction solvent is diethylene glycol dimethyl ether.
39. The method according to claim 37, wherein,
when the reaction solvent is insoluble in water, the step (1) comprises the steps of: adding 3, 4-difluorobenzonitrile into a reaction solvent, reacting with ammonia gas, washing the obtained material with water, separating an organic phase, concentrating to obtain a crude product, and recrystallizing to obtain an intermediate 3-fluoro-4-aminobenzonitrile; the water-insoluble reaction solvent is selected from toluene or 2-methyltetrahydrofuran;
when the reaction solvent is a low boiling point solvent dissolved in water, the step (1) comprises the steps of: adding 3, 4-difluorobenzonitrile into a reaction solvent, reacting with ammonia gas, concentrating the obtained material until no fraction is produced, shuffling with water, and recrystallizing to obtain an intermediate 3-fluoro-4-aminobenzonitrile; the low boiling point solvent dissolved in water is preferably ethylene glycol dimethyl ether;
when the reaction solvent is a high boiling point solvent dissolved in water, the step (1) comprises the steps of: adding 3, 4-difluorobenzonitrile into a reaction solvent, reacting with ammonia gas, extracting the material with a mixture of water and an organic extraction solvent to obtain an organic phase, and performing a recrystallization process to obtain an intermediate 3-fluoro-4-aminobenzonitrile; the high boiling point solvent dissolved in water is one or more than two of diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, N-dimethylformamide or dimethyl sulfoxide.
40. The production method according to claim 39, wherein the water-soluble high-boiling solvent is diethylene glycol dimethyl ether.
41. The preparation method according to claim 37, wherein the molar concentration of the 3, 4-difluorobenzonitrile in the reaction solvent is more than 0.5 mol/L.
42. The preparation method according to claim 38, wherein the molar concentration of the 3, 4-difluorobenzonitrile in the reaction solvent is more than 0.5 mol/L.
43. The preparation method according to claim 39, wherein the molar concentration of the 3, 4-difluorobenzonitrile in the reaction solvent is more than 0.5 mol/L.
44. The preparation method according to claim 37, wherein the molar concentration of the 3, 4-difluorobenzonitrile in the reaction solvent is 1 to 5 mol/L.
45. The preparation method according to claim 38, wherein the molar concentration of the 3, 4-difluorobenzonitrile in the reaction solvent is 1 to 5 mol/L.
46. The production method according to claim 39, wherein the molar concentration of the 3, 4-difluorobenzonitrile in the reaction solvent is 1 to 5 mol/L.
47. The production method according to any one of claims 1 to 36, wherein the step (2) comprises the steps of:
and mixing the intermediate 3-fluoro-4-aminobenzonitrile with an alkaline aqueous solution, performing hydrolysis reaction, and adding acid to adjust the pH value to obtain the 4-amino-3-fluorobenzoic acid.
48. The method of claim 37, wherein the step (2) comprises the steps of:
and mixing the intermediate 3-fluoro-4-aminobenzonitrile with an alkaline aqueous solution, performing hydrolysis reaction, and adding acid to adjust the pH value to obtain the 4-amino-3-fluorobenzoic acid.
49. The production method according to any one of claims 38 to 46, wherein the step (2) comprises the steps of:
and mixing the intermediate 3-fluoro-4-aminobenzonitrile with an alkaline aqueous solution, performing hydrolysis reaction, and adding acid to adjust the pH value to obtain the 4-amino-3-fluorobenzoic acid.
50. The production method according to any one of claims 1 to 36, wherein the temperature of the hydrolysis reaction in the step (2) is 50 to 100 ℃.
51. The method according to claim 37, wherein the hydrolysis reaction in the step (2) is carried out at a temperature of 50 to 100 ℃.
52. The production method according to any one of claims 38 to 46, wherein the temperature of the hydrolysis reaction in the step (2) is 50 to 100 ℃.
53. The method according to claim 47, wherein the hydrolysis reaction in the step (2) is carried out at a temperature of 50 to 100 ℃.
54. The method according to claim 48, wherein the hydrolysis reaction in the step (2) is carried out at a temperature of 50 to 100 ℃.
55. The method according to claim 49, wherein the hydrolysis reaction in the step (2) is carried out at a temperature of 50 to 100 ℃.
56. The production method according to any one of claims 1 to 36, wherein the molar ratio of the 3-fluoro-4-aminobenzonitrile to the base is 1: (1-5).
57. The method of claim 37, wherein the molar ratio of 3-fluoro-4-aminobenzonitrile to base is 1: (1-5).
58. The production method according to any one of claims 38 to 46, wherein the molar ratio of the 3-fluoro-4-aminobenzonitrile to the base is 1: (1-5).
59. The production method according to claim 47, wherein the molar ratio of the 3-fluoro-4-aminobenzonitrile to the base is 1: (1-5).
60. The production method according to claim 48, wherein the molar ratio of the 3-fluoro-4-aminobenzonitrile to the base is 1: (1-5).
61. The production method according to claim 49, wherein the molar ratio of the 3-fluoro-4-aminobenzonitrile to the base is 1: (1-5).
62. The method of claim 50, wherein the molar ratio of 3-fluoro-4-aminobenzonitrile to base is 1: (1-5).
63. The production method according to claim 51, wherein the molar ratio of the 3-fluoro-4-aminobenzonitrile to the base is 1: (1-5).
64. The method of claim 52, wherein the molar ratio of 3-fluoro-4-aminobenzonitrile to base is 1: (1-5).
65. The method of claim 53, wherein the molar ratio of 3-fluoro-4-aminobenzonitrile to base is 1: (1-5).
66. The production method according to claim 54, wherein the molar ratio of the 3-fluoro-4-aminobenzonitrile to the base is 1: (1-5).
67. The method of claim 55, wherein the molar ratio of 3-fluoro-4-aminobenzonitrile to base is 1: (1-5).
68. The production method according to any one of claims 1 to 36, wherein the molar ratio of the 3-fluoro-4-aminobenzonitrile to the base is 1: (1-3).
69. The method of claim 47, wherein the pH is 1.0-4.0.
70. The method of claim 48, wherein the pH is 1.0-4.0.
71. The method of claim 49, wherein the pH is 1.0-4.0.
72. The method of any one of claims 53 to 55, wherein the pH is from 1.0 to 4.0.
73. The method of any one of claims 59-61, wherein the pH is 1.0-4.0.
74. The method of claim 47, wherein the pH is 2.0-3.0.
75. The method of claim 48, wherein the pH is 2.0-3.0.
76. The method of claim 49, wherein the pH is 2.0-3.0.
77. The method of any one of claims 53 to 55, wherein the pH is from 2.0 to 3.0.
78. The method of any one of claims 59-61, wherein the pH is 2.0-3.0.
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