CN112745239A

CN112745239A - Preparation method of 4-aminobenzoic acid and derivatives thereof

Info

Publication number: CN112745239A
Application number: CN202011614690.1A
Authority: CN
Inventors: 王植源
Original assignee: Individual
Current assignee: Individual
Priority date: 2020-12-30
Filing date: 2020-12-30
Publication date: 2021-05-04

Abstract

The invention discloses a preparation method of 4-aminobenzoic acid and derivatives thereof, which comprises the following steps: step (1): reacting an acid ester raw material, namely 1, 4-phthalic acid monoester or 1, 4-phthalic acid diester or 1, 4-phthalic acid monoester monoamide with hydroxylamine to respectively obtain 4-carboxyl benzoyl hydroxamic acid inorganic salt, 4-alkoxy acyl benzoyl hydroxamic acid inorganic salt and 4-carbamoyl benzoyl hydroxamic acid inorganic salt; step (2): the 4-carboxybenzoyl hydroxamic acid inorganic salt, the 4-alkoxybenzoyl hydroxamic acid inorganic salt or the 4-carbamoylbenzoyl hydroxamic acid inorganic salt is subjected to rearrangement reaction to obtain the 4-aminobenzoate, the 4-aminobenzoate and the 4-aminobenzamide; and acidifying the 4-aminobenzoic acid salt to obtain the 4-aminobenzoic acid. The invention does not use nitration and reduction reaction, and eliminates the hidden trouble of waste acid pollution and polynitrobenzene explosion.

Description

Preparation method of 4-aminobenzoic acid and derivatives thereof

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 4-aminobenzoic acid and derivatives thereof.

Background

4-aminobenzoic acid is an important raw material and an intermediate of dyes, pigments and medicines and is used for producing reactive red M-80, M-10B and reactive red purple X-2R dyes, pigment yellow 181 and the like. 4-Aminobenzoic acid is also used to prepare an excellent sunscreen agent, octyl p-dimethylaminobenzoate. It is common in industry to prepare p-aminobenzoic acid by oxidation and reduction from p-nitrotoluene as a raw material. In another process route, p-methylaniline is used as a raw material and is prepared by acetylation, oxidation and deacylation. Currently, the preparation of p-aminobenzoic acid by nitro reduction is the predominant method, and the reduction methods include the ammonium thiosulfate method (CN103980138A), the metal catalytic hydrogenation method in a microwave reactor (CN101381323A), and the metal catalytic hydrogenation method using a co-catalyst (CN 109456213A).

To avoid the use of nitration and reduction reactions, a Hofmann rearrangement reaction can be employed. U.S. Pat. No. 3931210 discloses a process for preparing 4-aminobenzoic acid using 1, 4-benzenedicarboxylic acid monomethyl ester as a starting material. The method comprises the steps of firstly reacting 1, 4-phthalic acid monomethyl ester with ammonia to generate a monoamide compound, and then converting the monoamide compound into p-aminobenzoic acid through Hofmann reaction. Chinese patent CN100427457C also discloses a method for preparing 4-aminobenzoic acid by taking 4-formylbenzoic acid methyl ester as a raw material through Hofmann rearrangement reaction. The method avoids the mixed acid nitration process, but still faces the problem of safe use of a large amount of sodium hypochlorite oxidant and highly toxic chlorine.

4-aminobenzamide or as haematochrome DB-70, CAS number 2835-68-9, as a white to pale tan powder with melting point 181-. The 4-aminobenzamide is used for manufacturing organic pigment intermediates, is mainly used for printing, dyeing and manufacturing organic pigments of cotton, artificial cotton and hemp fibers, and is used for coloring printing ink and pigment printing paste. The existing preparation method generally adopts p-nitrobenzoic acid as a raw material and is prepared by acyl chloride reaction, ammonolysis reaction and reduction reaction. The method disclosed in Chinese patent publication No. CN 104193646A: 4-nitrobenzoic acid is taken as a raw material and reacts with thionyl chloride to generate 4-nitrobenzoyl chloride, then the 4-nitrobenzoyl chloride reacts with ammonia water to generate 4-nitrobenzamide, and finally, iron powder is used for reduction reaction to generate the 4-aminobenzamide. However, in the acyl chlorination reaction, the used thionyl chloride is fuming liquid with high toxicity, strong corrosivity and strong irritation, the using amount of the thionyl chloride is 5 times of that of 4-aminobenzoic acid, the production condition is poor, the using amount is large, the reaction time is long, the recovery difficulty of thionyl chloride is large, the equipment cost is high, and the environmental pollution is large. In addition, in the reduction reaction, a large amount of high-quality iron powder is consumed for reduction by using iron powder, the large-scale production is limited by collection and transportation of the iron powder, and the treatment of three wastes is difficult due to the fact that a large amount of waste water and iron mud are discharged in the production. Chinese patent publication No. CN109867604A discloses an improved method, which still uses 4-nitrobenzoic acid as raw material to prepare 4-aminobenzamide by esterification, ammonolysis and hydrogenation reduction in a one-pot method. The process solves the problems of environmental protection and the like caused by using thionyl chloride, but the preparation of the raw materials still needs nitration reaction, and the hidden troubles of waste acid pollution and polynitrobenzene explosion are not thoroughly eliminated.

Disclosure of Invention

The invention aims to overcome the defects and defects of the prior art, and aims to provide a preparation method of 4-aminobenzoic acid and derivatives thereof, wherein the derivatives comprise 4-aminobenzoate, amide derivatives and the like. The method is safe, clean and efficient, does not use nitration and reduction reaction, and can eliminate the hidden troubles of waste acid pollution and polynitrobenzene explosion.

The technical scheme adopted by the invention for solving the technical problem is as follows:

a method for preparing 4-aminobenzoic acid and derivatives thereof comprises the following steps:

step (1): reacting an acid ester raw material, namely 1, 4-phthalic acid monoester or 1, 4-phthalic acid diester or 1, 4-phthalic acid monoester monoamide with hydroxylamine to respectively obtain 4-carboxyl benzoyl hydroxamic acid inorganic salt, 4-alkoxy acyl benzoyl hydroxamic acid inorganic salt and 4-carbamoyl benzoyl hydroxamic acid inorganic salt;

step (2): the 4-carboxybenzoyl hydroxamic acid inorganic salt, the 4-alkoxybenzoyl hydroxamic acid inorganic salt or the 4-carbamoylbenzoyl hydroxamic acid inorganic salt is subjected to rearrangement reaction to obtain the 4-aminobenzoate, the 4-aminobenzoate and the 4-aminobenzamide; and acidifying the 4-aminobenzoic acid salt to obtain the 4-aminobenzoic acid.

In addition, 4-aminobenzamide can also be obtained by further aminolysis of p-aminobenzoate.

In the above technical solution, as a preferred embodiment, the aliphatic group in the 1, 4-phthalic acid monoester or diester or 1, 4-phthalic acid monoester monoamide is a C1-C12 alkyl ester, preferably methyl or ethyl ester.

In the above technical solution, as a preferred embodiment, in the step (1), the hydroxylamine is prepared by neutralizing hydroxylamine hydrochloride with an inorganic base; more preferably, the inorganic base is a hydroxide of sodium, potassium, barium, cesium.

In the above technical solution, as a preferred embodiment, in the step (1), the reaction time is 2 to 24(5 hours, 8 hours, 11 hours, 14 hours, 17 hours, 20 hours, 23 hours) hours, the reaction temperature is 0 to 70 ℃ (10 ℃, 20 ℃, 30 ℃, 40 ℃, 50 ℃,60 ℃), and preferably, the reaction temperature is 0 to 55 ℃.

In the above-mentioned technical solution, as a preferred embodiment, in the step (1), the molar ratio of the acid ester raw material to hydroxylamine is 1.0:1.0 to 1.0:3.0 (e.g., 1:2), preferably 1:1 to 1: 2.

In the above technical solution, as a preferred embodiment, in the step (1), the reaction of the acid ester raw material with hydroxylamine is performed in an alcohol-water solution;

in step (1) of the present invention, after the reaction of the acid ester raw material with hydroxylamine, the solvent is directly removed, and a small amount of methanol-water is used for washing to obtain the corresponding inorganic salt of hydroxamic acid, which can be used for the reaction in step (2) without further purification.

In the above technical solution, as a preferred embodiment, in the step (1), the preparation process of the inorganic salt of 4-carboxybenzoyl hydroxamic acid, or the inorganic salt of 4-carbamoylbenzoyl hydroxamic acid is: the hydroxylamine is added dropwise to the alcohol solution of 1, 4-phthalic acid monoester or 1, 4-phthalic acid monoester monoamide at 0 to 25 ℃ respectively (preferably at a low temperature such as 0 ℃ to prevent side reactions of ester hydrolysis from occurring), and then kept at 20 to 55 ℃ (e.g., 25 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃, 50 ℃) for 1 to 24 hours (2 hours, 5 hours, 8 hours, 11 hours, 14 hours, 17 hours, 20 hours, 23 hours), preferably at 40 to 55 ℃.

In the above technical solution, as a preferred embodiment, in the step (1), the preparation process of the inorganic salt of 4-alkoxyacylbenzoyl hydroxamic acid is: dropping the hydroxylamine into an alcohol solution of 1, 4-phthalic acid diester at 0-25 ℃, and then reacting for 1-24 hours (2 hours, 5 hours, 8 hours, 11 hours, 14 hours, 17 hours, 20 hours, 23 hours); preferably, the molar ratio of hydroxylamine to 1, 4-phthalic acid diester is: 1.2:1-1.0:1.

In the above technical solution, as a preferred embodiment, in the step (2), the rearrangement reaction is a larsen rearrangement reaction; preferably, the temperature of the rearrangement reaction is 80-200 ℃ (e.g., 90 ℃, 100 ℃, 110 ℃, 120 ℃, 130 ℃, 140 ℃, 150 ℃, 160 ℃, 170 ℃, 180 ℃), preferably 100-; if the reaction temperature is too low, the reaction yield is low, and if the reaction temperature is too high, the vapor pressure in the reaction kettle is too high, and the operation is not suitable.

In the above technical solution, as a preferred embodiment, in the step (2), the time of the rearrangement reaction is 1 to 24 hours (2 hours, 5 hours, 8 hours, 11 hours, 14 hours, 17 hours, 20 hours, 23 hours), preferably 2 to 6 hours.

In the above-mentioned technical solution, as a preferred embodiment, in the step (2), the rearrangement reaction is performed in the presence of a reaction solvent.

In the above technical solution, as a preferred embodiment, in the step (2), the reaction solvent is a mixture of a nitrile compound and water, and preferably, the volume ratio of the nitrile compound to water is 10:1 to 1:10 (for example, 9:1, 7:1, 5:1, 3:1, 1:3, 1:5, 1:7, 1:9), preferably 2.5: 1; preferably, the nitrile compound is at least one of acetonitrile, butyronitrile, benzonitrile and adiponitrile, more preferably acetonitrile; the water is helpful for dissolving the raw materials and has better solubility than acetonitrile, and if the water amount is too small, the raw materials can not be fully dissolved, so the reaction is slow; nitrile compounds such as acetonitrile and the like are activators of rearrangement reaction, and if the proportion of the nitrile compounds is too low, the nitrile compounds can also cause non-reaction or too slow reaction and the like; the amount of the reaction solvent is such that activation and dissolution of the reaction substance are ensured to facilitate the reaction, and preferably, the reaction solvent is in excess, particularly, the nitrile compound is in excess in the reaction solvent. The weight volume ratio of the hydroxamate to the nitrile compound in the step (2) is 1:2-1:25, preferably 1: 3-1:16, preferably 1:9-1: 12.

The weight-to-volume ratio mentioned in the present invention is in g as a unit of weight and in mL as a unit of volume.

In the above technical solution, as a preferred embodiment, in the step (2), the rearrangement reaction is performed under a pressure condition of normal pressure to 1.0 MPa. Preferably, the rearrangement reaction is carried out at atmospheric pressure; preferably, the rearrangement reaction is performed under reflux conditions. In the above technical solution, as a preferred embodiment, the reaction equation in the step (1) is as follows:

the reaction equation in the step (2) is as follows:

in addition, the p-aminobenzamide can be prepared by using the product in the step (2), namely, the p-aminobenzoate as a raw material according to the following reaction equation.

Namely: in the above technical solution, as a preferred embodiment, the 4-aminobenzoate obtained in step (2) is subjected to an ammonolysis reaction to obtain 4-aminobenzamide; preferably, the ammonolysis is carried out by using an ammonia-alcohol solution with the mass concentration of 10-25%, preferably at least one of an ammonia-methanol solution, an ammonia-ethanol solution and an ammonia-propanol solution, and more preferably by using an ammonia-methanol solution with the mass concentration of 10%;

preferably, the molar ratio of ammonia to the 4-aminobenzoate ester in the ammonia-alcohol solution is 2:1 to 15:1 (e.g. 3:1, 5:1, 7:1, 9:1, 11:1, 13:1), preferably 5 to 8: 1;

preferably, before the ammonolysis reaction, the ammonolysis reaction kettle is filled with nitrogen to the pressure of 0.1-0.3MPa, preferably 0.2 MPa;

preferably, the temperature of the ammonolysis reaction is 20-25 ℃, and the time of the ammonolysis reaction is 18-48 hours (25 hours, 30 hours, 35 hours, 40 hours, 45 hours), preferably 24 hours.

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

(1) phthalate ester and derivatives are used as starting materials, and nitration and reduction reactions are not used, so that the hidden troubles of waste acid pollution and polynitrobenzene explosion are eliminated.

(2) The method for preparing the p-aminobenzamide does not relate to a two-step reaction process of acyl chlorination and secondary aminolysis, does not use thionyl chloride or solid phosgene for acyl chlorination, eliminates the recovery of hydrogen chloride and the treatment of waste salt, and reduces the total cost.

Drawings

FIG. 1 shows an infrared spectrum (KBr) of 4-aminobenzoic acid obtained in example 3 of the present invention.

FIG. 2 is an infrared spectrum (KBr) of potassium 4-carboxybenzoyl hydroxamate obtained in example 1 of the present invention.

Detailed Description

In order to highlight the objects, technical solutions and advantages of the present invention, the present invention is further illustrated by the following examples, which are presented by way of illustration of the present invention and are not intended to limit the present invention. The technical solution of the present invention is not limited to the specific embodiments listed below, and includes any combination of the specific embodiments.

Example 1

4-carboxyl benzoyl hydroxamic acid potassium salt synthesis:

at room temperature of 25-27 ℃, 1, 4-phthalic acid monomethyl ester (0.06mol, 10.80g) and 150 ml of methanol are put into a 250 ml three-necked flask, stirred to obtain an incompletely dissolved suspension, then the reaction flask is put into an ice-water bath, and after the suspension is cooled to 0 ℃, a prepared hydroxylamine solution [ potassium hydroxide (0.258mol, 14.53g), hydroxylamine hydrochloride (0.12mol, 8.34g), 65 ml of water ] is slowly added dropwise while stirring. After the addition, the reaction solution was heated within 2 hours, and the temperature of the reaction solution was slowly raised from 0 ℃ to 55 ℃ to obtain a clear and transparent solution, which was maintained at 55 ℃ for 14 hours. And (4) carrying out rotary evaporation on the clear and transparent reaction liquid, and removing methanol and water. The resulting white solid was oven dried at 45 ℃ for 24 hours under vacuum.

4-carbamoylbenzoyl hydroxamic acid potassium salt synthesis:

1, 4-phthalic acid monoester monoamide (0.06mol) and 150 ml of methanol were put into a 250 ml three-necked flask at room temperature of 25 to 27 ℃ and stirred to obtain an incompletely dissolved suspension, and then the flask was put into an ice-water bath, and after the suspension was cooled to 0 ℃, a previously prepared hydroxylamine solution [ potassium hydroxide (0.258mol, 14.53g), hydroxylamine hydrochloride (0.12mol, 8.34g), 65 ml of water ] was slowly added dropwise while stirring. After the addition, the reaction solution was heated within 2 hours, and the temperature of the reaction solution was slowly raised from 0 ℃ to 55 ℃ to obtain a clear and transparent solution, which was maintained at 55 ℃ for 14 hours. And after the reaction is finished, pumping the reaction solution, and washing the solid product by using a small amount of anhydrous methanol to obtain a target product which is a light yellow solid. The product obtained was used in the next reaction without further purification.

Example 2

4-Ethoxybenzoyl hydroxamic acid potassium salt synthesis:

at 20-25 ℃, 1.13g of potassium hydroxide dissolved in 5 ml of water, then adding hydroxylamine hydrochloride (0.69g, 10mol), after mixing, get the hydroxylamine solution. Then the hydroxylamine solution was slowly added dropwise to an ethanol solution (10 ml) of 1, 4-phthalic acid diethyl ester (2.22g, 10mol) at 20-25 ℃. After stirring at room temperature for 2 hours, product precipitated and the reaction was complete as indicated by thin plate chromatography (TLC) showing disappearance of starting material. Rotary evaporation of all solvents gave the product as a pale yellow-white solid: 2.40g (97.2% yield).

Example 3

4-aminobenzoic acid synthesis:

the potassium 4-carboxybenzoyl hydroxamate salt obtained in example 1 (20mmol, 5.15g) and an aqueous acetonitrile solution (70 ml, acetonitrile/water volume ratio of 2.5/1) were put into a 100-ml single-neck bottle at room temperature. The upper acetonitrile phase is clear and transparent, and the lower water phase is yellow and transparent. The reaction was heated in an oil bath to 110 ℃ and refluxed for 2 hours under normal pressure, and the progress of the reaction was followed by thin-plate chromatography to determine the end point of the reaction. And (4) cooling the reaction liquid to room temperature, and removing the solvent by rotary evaporation to obtain a yellow solid. 10ml of water was added to dissolve the solid, giving a reddish yellow solution, which was neutralized with 5% dilute hydrochloric acid (8 ml), stirred for 1 hour, concentrated by rotary evaporation, allowed to stand at room temperature to precipitate a crystalline product, filtered and dried to give 0.747g (89.8% yield) of 4-aminobenzoic acid. The thin layer chromatography analysis is a single product, no raw material residue exists, and the infrared spectrum of the product is consistent with that of a standard sample.

Example 4

Synthesis of 4-aminobenzamide: in a 50mL reaction flask, the potassium salt of 4-carbamoylbenzoyl hydroxamic acid (0.5g) obtained in example 1 and acetonitrile-water mixture (10mL, 2.5:1v/v) were placed. Then, the temperature was raised to 110 ℃ (oil bath temperature), and after 3.5 hours of reflux reaction, the yellow suspension turned into a red solution. The solvent was spun dry and the residual solid was washed with ethanol-water and dried to give a pale yellow solid (275mg, 88% yield), mp 181-. The infrared spectrum of the sample is consistent with that of the standard sample.

Example 5

Synthesis of ethyl 4-aminobenzoate: a50 mL reaction flask was charged with the potassium salt of 4-ethyloxyacylbenzoyl hydroxamic acid (0.15g) obtained in example 2 and acetonitrile-water mixture (2mL, 1.5:1 v/v). Then, the temperature was raised to 110 ℃ (oil bath temperature), and after 2.5 hours of reflux reaction, the yellow suspension turned into a red solution. The solvent was spun off and the residual solid was recrystallized from ethanol-water (90%) to give the product (90mg, 90% yield). The infrared spectrum of the sample is consistent with that of the standard sample.

Example 6

Synthesis of 4-aminobenzamide: ethyl 4-aminobenzoate (2.0g, 12.1mmol) was charged into a 100-ml autoclave, and an ammonia methanol solution (ammonia content: 10.3g,60.5mmol) having a mass concentration of 10% was added thereto, and the reaction vessel was closed, and nitrogen gas was introduced to a pressure of 0.2 MPa. Then, the internal temperature of the reaction kettle is kept at 20-25 ℃, after 24 hours, the reaction liquid is transferred to a single-mouth bottle, and liquid ammonia and methanol are removed by evaporation. The residual solid was washed with ethanol-water and dried to give the product as a pale yellow solid (1.4g, 85% yield), mp 181-. The infrared spectrum of the sample is consistent with that of the standard sample.

The foregoing embodiments illustrate the principles, principal features and advantages of the invention, and it will be understood by those skilled in the art that the invention is not limited to the foregoing embodiments, which are merely illustrative of the principles of the invention, and that various changes and modifications may be made therein without departing from the scope of the principles of the invention.

Claims

1. A preparation method of 4-aminobenzoic acid and derivatives thereof is characterized by comprising the following steps:

2. The process for the preparation of 4-aminobenzoic acid and its derivatives according to claim 1 characterized in that the aliphatic group in the 1, 4-phthalic acid mono-or diester or 1, 4-phthalic acid mono-ester monoamide is a C1-C12 alkyl ester, preferably methyl or ethyl ester.

3. The method for producing 4-aminobenzoic acid and its derivatives according to claim 1, characterized in that in the step (1), the hydroxylamine is produced by neutralizing hydroxylamine hydrochloride with an inorganic base; more preferably, the inorganic base is a hydroxide of sodium, potassium, barium, cesium.

4. The method for preparing 4-aminobenzoic acid and its derivatives according to claim 1, characterized in that in the step (1), the reaction time is 2-24 hours, the reaction temperature is 0-70 ℃, preferably, the reaction temperature is 0-55 ℃.

5. The method for producing 4-aminobenzoic acid and its derivatives according to claim 1, characterized in that in the step (1), the molar ratio of the acid ester raw material to hydroxylamine is 1.0:1.0 to 1.0:3.0, preferably 1:1 to 1: 2;

preferably, the reaction of the acid ester starting material with hydroxylamine is accomplished in an alcohol-water solution.

6. The method for preparing 4-aminobenzoic acid and its derivatives according to claim 1, characterized in that in the step (1), the inorganic salt of 4-carboxybenzoyl hydroxamic acid, or the inorganic salt of 4-carbamoylbenzoyl hydroxamic acid is prepared by: dropping the hydroxylamine into the alcohol solution of 1, 4-phthalic acid monoester or 1, 4-phthalic acid monoester monoamide at 0-25 deg.c, and maintaining at 20-55 deg.c, preferably 40-55 deg.c for 1-24 hr;

preferably, the preparation process of the inorganic salt of 4-alkoxyacylbenzoyl hydroxamic acid is as follows: dropping the hydroxylamine into the alcoholic solution of 1, 4-phthalic acid diester at 0-25 ℃, and reacting for 1-24 hours; preferably, the molar ratio of hydroxylamine to 1, 4-phthalic acid diester is: 1.2:1-1.0:1.

7. The process for producing 4-aminobenzoic acid and its derivatives according to claim 1, characterized in that in the step (2), the rearrangement reaction is a larsen rearrangement reaction; preferably, the temperature of the rearrangement reaction is 80-200 ℃, preferably 100-120 ℃;

preferably, the time of the rearrangement reaction is 1 to 24 hours, preferably 2 to 6 hours.

8. The process for producing 4-aminobenzoic acid and its derivatives according to claim 1, characterized in that, in the step (2), the rearrangement reaction is carried out in the presence of a reaction solvent; the reaction solvent is a mixture of a nitrile compound and water;

preferably, the volume ratio of the nitrile compound to water is 10: 1-1: 10, preferably 2.5: 1;

preferably, the nitrile compound is at least one of acetonitrile, butyronitrile, benzonitrile and adiponitrile, more preferably acetonitrile;

the weight-volume ratio g/mL of the hydroxamate to the nitrile compound in the step (2) is 1:2-1:25, preferably 1: 3-1:16, more preferably 1:9-1: 12.

9. The process for producing 4-aminobenzoic acid and its derivatives according to claim 1, characterized in that, in the step (2), the rearrangement reaction is carried out under a pressure condition of normal pressure to 1.0 MPa; preferably, the rearrangement reaction is carried out at atmospheric pressure; preferably, the rearrangement reaction is performed under reflux conditions.

10. The process for producing 4-aminobenzoic acid and its derivatives according to claim 1, characterized in that 4-aminobenzoic acid ester obtained in the step (2) is subjected to aminolysis reaction to obtain 4-aminobenzamide;

preferably, the ammonolysis is carried out by using an ammonia-alcohol solution with the mass concentration of 10-25%, preferably at least one of an ammonia-methanol solution, an ammonia-ethanol solution and an ammonia-propanol solution, and more preferably by using an ammonia-methanol solution with the mass concentration of 10%;

preferably, the molar ratio of ammonia to the 4-aminobenzoate ester in the ammonia-alcohol solution is 2:1 to 15:1, preferably 5 to 8: 1;

preferably, the temperature of the ammonolysis reaction is 20-25 ℃, and the time of the ammonolysis reaction is 18-48 hours, preferably 24 hours.