CN115894211A - Preparation method of 3-hydroxy-4-methylbenzoic acid - Google Patents

Abstract

The present invention relates to a process for the preparation of 3-hydroxy-4-alkylbenzoic acids, said 3-hydroxy-4-alkylbenzoic acids having the following general formula (I):

wherein R is C1-C20 alkyl; the preparation method comprises the step of mixing 3-halogeno-4-alkylbenzoic acid, alkali and a polar solvent for reaction. The preparation method has relatively low requirements on equipment, low raw material cost, no need of other catalysts, few reaction steps, simple and convenient operation, short total time consumption and little three wastes, and can obtain the 3-hydroxy-4-alkylbenzoic acid with high yield and high purity.

Description

A kind of preparation method of 3-hydroxy-4-methylbenzoic acid

technical field

The invention belongs to the field of organic compound synthesis, and in particular relates to a preparation method of 3-hydroxy-4-alkylbenzoic acid.

Background technique

Hydroxy-4-methylbenzoic acid is an important intermediate in organic synthesis, widely used in medicine, agriculture, organic cutting, etc., especially in new pharmaceutical fields.

In the previous preparation methods, if the benzene ring has a halogen atom, such as bromobenzene, if it reacts with an alkaline substance such as sodium hydroxide, not only high temperature and high pressure conditions are required, but also metals such as Cu are required as catalysts for the substitution reaction to occur; The existing synthetic method of hydroxy-4-methylbenzoic acid, for example, cited literature 1, uses 3-methoxy-4-methylbenzoic acid methyl ester to first demethylate and then hydrolyze to obtain 3-hydroxy-4-methyl Benzoic acid, but this preparation method raw material cost is relatively high, and the reaction path of this method is as follows:

Citation 2 uses p-toluic acid to be sulfonated and then hydrolyzed to obtain 3-hydroxy 4-methylbenzoic acid. The cost of the raw materials for this preparation method is relatively high, and the sulfonation reaction step requires a high temperature of 150 degrees, and produces a large amount of Wastewater, the reaction path of this method is as follows:

Citation:

Citation 1: WO2015161011

Citation 2: The cis-and trans-Modifications of 1-Methyl-cyclohexan-2-ol-carboxylic Acid and their Conversion into 1-Methyl-△ ¹ -cyclohexene-4-carboxylic Acid, 1908, 93(1416-1428)

Contents of the invention

The problem to be solved by the invention

In view of the problems existing in the prior art as mentioned above, it is urgent to develop a method with few reaction steps, no catalyst, easy operation, short overall time consumption, low raw material cost, high product purity and yield, and three wastes produced. Process for the preparation of minor 3-hydroxy-4-alkylbenzoic acids.

solutions to problems

Specifically, the present invention provides the following technical solutions:

[1] A preparation method for 3-hydroxyl-4-alkylbenzoic acid, characterized in that, said 3-hydroxyl-4-alkylbenzoic acid has the following general formula (I):

Wherein, R is a C1-C20 alkyl group;

Moreover, the preparation method includes the step of mixing and reacting 3-halogeno-4-alkylbenzoic acid with alkali and polar solvent.

[2] The preparation method according to [1], wherein the preparation method further comprises:

The step of raising the temperature of the reaction system to carry out the reaction, the step of adjusting the pH value of the reaction system,

And the step of post-processing the reaction system to obtain 3-hydroxyl-4-alkylbenzoic acid.

[3] The production method according to [1] or [2], wherein,

The R is selected from any one of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

[4] The preparation method according to any one of [1] to [3], wherein,

The alkali is selected from any one of alkali metal hydroxides, alkali metal salts, alkaline earth metal hydroxides, alkali metal salts, and ammonia;

The polar solvent is selected from any one of water, tetrahydrofuran and dioxane.

[5] The preparation method according to any one of [1] to [4], wherein,

The molar ratio of the 3-halo-4-alkylbenzoic acid to the base is 1:(2.0-3.0).

[6] The preparation method according to any one of [1] to [5], wherein,

The amount of the polar solvent used is 1 to 20 times the mass of the 3-halo-4-methylbenzoic acid.

[7] The preparation method according to any one of [1] to [6], wherein,

Said raising the temperature of the reaction system refers to raising the temperature to 50-180°C;

The time for the reaction is 1-10 hours.

[8] The preparation method according to any one of [1] to [7], wherein,

The step of adjusting the pH value of the reaction system is to adjust the pH value to 4-6.5.

[9] The preparation method according to any one of [1] to [8], characterized in that,

The post-processing includes filtering, washing and drying.

[10] The preparation method according to any one of [1] to [9], wherein,

The 3-halogenated-4-alkylbenzoic acid is obtained by mixing and heating p-alkylbenzoic acid, nitric acid and a halogenating agent before post-processing;

Wherein, the halogenating reagent is selected from one or more of hydrogen chloride, sodium chloride, potassium chloride, hydrogen bromide, sodium bromide, potassium bromide, hydroiodic acid, sodium iodide, potassium iodide or its aqueous solution ;

Further, the concentration of the nitric acid is 30%-85%;

Furthermore, the molar ratio of the p-alkylbenzoic acid to the halogenating agent is 1:(1.0-3.0).

The effect of the invention

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

1. The preparation method of the present invention has relatively low requirements on equipment, does not need to use a catalyst, has few reaction steps, is easy to operate, takes a short time overall, and produces little three wastes;

2. The cost of raw materials used in the preparation method of the present invention is low, and the reaction time is significantly shortened without using a catalyst, and the target product can be obtained with high yield and high purity.

3. In some preferred embodiments of the present invention, the raw material 3-halo-4-alkylbenzoic acid used in the present invention can be obtained by mixing p-alkylbenzoic acid, nitric acid and a halogenating reagent, and the method does not use Expensive halogen simple substance, low raw material cost, no complex operation steps such as adding catalyst, and the dilute nitric acid after use can be recycled and reused, and the three wastes generated are very small.

It should be noted that the above descriptions do not disclose all the embodiments of the present invention and all advantages of the present invention.

Description of drawings

Fig. 1: the nuclear magnetic spectrum of the 3-chloro-4-methylbenzoic acid that preparation example 1 obtains

Fig. 2: the nuclear magnetic spectrum of the 3-bromo-4-methylbenzoic acid that preparation example 2 obtains

Fig. 3: The nuclear magnetic spectrum of the 3-hydroxyl-4-methylbenzoic acid that embodiment 2 obtains

Fig. 4: the liquid chromatogram of the 3-hydroxyl-4-methylbenzoic acid that embodiment 2 obtains

Detailed ways

Embodiments of the present invention will be described below, but the present invention is not limited thereto. The present invention is not limited to the configurations described below, and various changes can be made within the scope of the claims for protection of the invention. Embodiments and examples obtained by appropriately combining the technical means disclosed in different embodiments and examples are also included in this document. within the technical scope of the invention. In addition, all the documents described in this specification are referred in this specification as a reference document.

Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

In this specification, the numerical range represented by "numerical value A - numerical value B" means the range which includes numerical value A and B of an end point.

In this specification, the numerical range represented by "above" or "below" means a numerical range including the number.

In this specification, "room temperature" refers to an operation without temperature control, and generally refers to 20°C to 30°C.

In this specification, the meaning expressed by "may" includes the meaning of performing certain processing and not performing certain processing.

In this specification, the use of "optional" or "optional" means that certain substances, components, execution steps, application conditions and other factors are used or not used.

In this specification, the names of units used are the names of international standard units, and if there is no special statement, the used "%" means weight or mass percentage.

The terms "comprising" and any variations thereof in the description and claims of the present invention are intended to cover a non-exclusive inclusion. For example, a process, method or system, product or device comprising a series of steps or units is not limited to the listed steps or units, but optionally also includes steps or units not listed, or optionally further includes Other steps or units inherent in these processes, methods, products or apparatus.

In this specification, references to "preferred embodiments", "embodiments" and the like mean that specific elements (eg, features, structures, properties, and/or characteristics) described in relation to the embodiments are included herein In at least one embodiment described, and may or may not be present in other embodiments. In addition, it is to be understood that the described elements may be combined in any suitable manner in the various embodiments.

In this specification, a polar solvent refers to a solvent whose solvent molecule is a polar molecule.

In the present specification, the molar ratio of 3-halo-4-alkylbenzoic acid to the base is calculated based on the number of moles of the base in the solution.

The invention provides a preparation method of 3-hydroxyl-4-alkylbenzoic acid, which comprises the step of mixing and reacting 3-halogenated-4-alkylbenzoic acid with a base and a polar solvent.

The following will describe each of the above steps one by one.

3-hydroxyl-4-alkylbenzoic acid of the present invention has following general formula (I):

Wherein, R is a C1-C20 alkyl group, and in some specific embodiments of the present invention, it can be selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert Any of butyl, in some preferred embodiments of the invention, R is methyl.

<mixing steps>

The mixing step refers to mixing the 3-halo-4-alkylbenzoic acid with the ammonia solution.

3-Halo-4-alkylbenzoic acid

In the previous preparation method of 3-halo-4-alkylbenzoic acid, the alkyl substituted benzoic acid and water are generally added to the reaction vessel, and halogen simple substance (chlorine and bromine, etc.) is added for heating reaction , but in the actual use process, it is difficult to control the amount of chlorine gas, which will easily cause the reaction substrate to be incompletely reacted or replaced by too much chlorine, and the price of bromine is relatively expensive. Before, it was necessary to add a certain amount of quaternary ammonium salt phase transfer catalyst, and the cost of raw materials required for the reaction was relatively high, which was not suitable for large-scale industrial production. In addition, some synthetic reactions also use hydrogen peroxide as an oxidizing agent, but this may increase the risk of explosion and reduce the safety factor in industrial production.

In some preferred embodiments of the present invention, the 3-halogenated-4-alkylbenzoic acid can be obtained by post-processing after mixing p-alkylbenzoic acid, nitric acid and a halogenating reagent, heating and reacting.

Wherein, the equation involved in the reaction is:

Wherein, R is a C1-C20 alkyl group, and in some specific embodiments of the present invention, it can be selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert Any of butyl, in some preferred embodiments of the invention, R is methyl.

X is halogen and can be chlorine, bromine or iodine. In some preferred embodiments of the present invention, X is chlorine or bromine, more preferably, it can be bromine.

The halogenating reagent (HX or MX) described in the application can be selected from hydrogen chloride, sodium chloride, potassium chloride, hydrogen bromide, sodium bromide, potassium bromide, hydroiodic acid, sodium iodide, potassium iodide or its aqueous solution one or more of. Wherein, the aqueous solution of the halogenated reagent can be hydrochloric acid (aqueous solution of hydrogen chloride), hydrobromic acid (aqueous solution of hydrogen bromide), etc., and the concentration of the aqueous solution of the halogenated reagent can be 25% to 60%, preferably 30% to 50%, for example, the concentration of hydrochloric acid is preferably 31%, and the concentration of hydrobromic acid is preferably 48%. If the concentration of the aqueous solution is too high, it will cause a waste of resources, and other by-products may be produced to affect the yield and purity of the target product; if the concentration of the aqueous solution is too low, it may be difficult for the substitution reaction to occur, resulting in the yield of the target product. too low. Based on the reactivity of halogen, in some specific embodiments of the present invention, the halogenating reagent or its aqueous solution is preferably hydrochloric acid, hydrobromic acid, or sodium bromide.

In the mixing step, the concentration of the nitric acid may be 30%-85%, preferably 35%-65%, more preferably 37%-60%, more preferably 40%-50%. If the concentration of nitric acid is too low, the oxidation effect will not be strong, making it difficult for halogen to replace benzene ring, which will affect the final yield of the product; if the concentration of nitric acid is too high, the risk of operation will increase. Smoke may be emitted due to volatilization, which makes the reaction difficult to carry out and becomes an obstacle to obtaining the target product with high purity and high yield.

There is no special limitation on the amount of nitric acid. In some specific embodiments, 700-1400 mL of nitric acid with a concentration of 35%-45% can be added to 1 mol of p-alkylbenzoic acid. Considering from the perspective of saving raw materials and ensuring the yield , preferably 800-1200mL of nitric acid with a concentration of 35% to 45% is added to 1mol of p-alkylbenzoic acid, and more preferably 850-1000mL of nitric acid is added to 1mol of p-alkylbenzoic acid at a concentration of 35% to 45%. of nitric acid.

In some specific embodiments, the molar ratio of the added p-alkylbenzoic acid to the halogenating agent is 1:(1.0～3.0), preferably 1:(1.05～2.7), more preferably 1:(1.2 ~2.3). Adding an appropriate amount of halogenating reagent can make it substituted at the 3-position to the greatest extent, and while obtaining the target product in high yield, it will not cause waste of the reaction substrate. If the amount of halogenated reagent added is small, the time required for the reaction may be significantly longer, as long as 3 to 4 days, and the conversion rate and yield will also become lower; if more halogenated reagents are added, not only does not meet the requirements The principle of economy may also affect the purity and yield of the reaction product.

In addition, there is no particular limitation on the order in which the three reactants are added. In some specific embodiments, p-alkylbenzoic acid can be added to nitric acid, and then a halogenating reagent can be added; p-alkylene can also be added to nitric acid. Base benzoic acid and then add halogenation reagent. Mixing p-alkylbenzoic acid and nitric acid first, and then adding the halogenating reagent can make the reaction easier and minimize the generation of by-products.

In some specific embodiments, the heating reaction refers to heating the reaction system to 50-110°C, further to 60-100°C. The temperature has a certain influence on the halogenation reaction on the benzene ring. If the heating temperature is too high, it may cause a large loss of nitric acid volatilization and increase the safety risk. If the heating temperature is too low, the reaction may not be complete. , the reaction yield decreases, and the halogen atom is easy to replace at the 2 position, resulting in the reaction to produce other isomers. There is no particular limitation on the maintenance time of the heating, usually, the temperature of the reaction system can be raised until reflux occurs, and then the temperature can be maintained to allow the reaction system to react.

There is no particular limitation on the method of heating and raising the temperature, and indirect heating methods such as air bath and water bath may be used.

In some specific embodiments, the reaction time is 2.5-8 hours, preferably 3-6 hours, more preferably 4 hours.

In other specific embodiments, a cooling step may be included before the post-treatment step, preferably, the reaction system is cooled to room temperature.

In some specific embodiments, after cooling the reaction system to room temperature, the reaction system is post-treated, wherein the post-treatment steps include filtering, washing and drying.

The filtration can be carried out by solid-liquid separation, and the separation method is not particularly limited, and suction filtration can be used. After filtering, the unreacted (or remaining) nitric acid can be collected, and the concentration can be adjusted by adding nitric acid with a higher concentration (such as more than 50%), so as to be used again in the preparation method of 3-halogenated-4-alkylbenzoic acid The reaction substrate is reacted, thereby realizing recycling, improving the utilization rate of reaction raw materials, saving costs, and greatly reducing the generation of waste liquid. For the concentration of nitric acid added, it is preferably 60% to 85% nitric acid, and further 60% to 70% nitric acid. For the volume of nitric acid added, it is preferred to measure the volume of unreacted nitric acid after collecting unreacted nitric acid. volume, calculate the difference between it and the original nitric acid volume, add higher concentration of nitric acid to make up the volume to the original nitric acid volume, and react it again as the reaction raw material of 3-halogenated-4-alkylbenzoic acid. In the reaction process, it can be judged whether p-alkylbenzoic acid has reacted completely by conventional analytical means in organic chemistry, such as thin-layer chromatography (spot plate) or high-performance liquid chromatography (HPLC). If it has not reacted completely, it can continue Add a small amount of nitric acid with higher concentration to promote the reaction to complete.

After filtering, there is a washing step, and the obtained solid can be washed with clear water. Then dry to obtain 3-halo-4-alkylbenzoic acid, wherein the drying method can preferably use heating and vacuum drying, and weigh after drying.

The above-mentioned reaction to obtain 3-halogenated-4-alkylbenzoic acid adopts the benzoic acid substituted in the para-position (4-position) by the alkyl group as the initial reactant, adds nitric acid with oxidation and then adds the halogenating reagent to provide the halogen group Elements, generate positive halide ions to attack the benzene ring, so as to obtain the target product. Since the alkyl positioning group is in the ortho-para position, the carboxylic acid positioning group is in the meta position, and the 2-position is a passivated position, which will not be substituted, so the halogen of the basic reaction will not be carried out at a position other than the 3-position Halogenation reaction, so a variety of positional isomers will not be generated, and the purity and yield of the product obtained are high.

alkali

The alkali of the present invention is selected from any one of hydroxides of alkali metals, alkali metal salts, hydroxides of alkaline earth metals, alkali metal salts, and ammonia, or the aqueous solution of the above-mentioned alkalis, which can be enumerated as hydroxide Sodium, potassium hydroxide, calcium hydroxide, etc. In some specific embodiments of the present invention, the alkali is preferably potassium hydroxide or its aqueous solution. Wherein, based on the mass of the solution, the mass fraction of the alkali aqueous solution is 60%-95%, preferably 70-93%, more preferably 80%-91%. If the mass fraction of the aqueous base solution is too low, it will make it difficult for the hydroxyl group to be substituted with the benzene ring, affecting the final yield of the product; if the mass fraction of the base is too high, it will cause waste of reaction raw materials.

There is no particular limitation on the amount of alkali used in this application. In some specific embodiments of this application, 1 mol of 3-chloro-4-methylbenzoic acid can correspond to 5 to 11 g of 80% to 95% of the added mass fraction. Potassium hydroxide; from the perspective of saving raw materials and ensuring the yield, preferably 1mol of 3-chloro-4-methylbenzoic acid can be correspondingly added with 6～10g of potassium hydroxide with a mass fraction of 82%～93%; More preferably, 7-9.5 g of potassium hydroxide with a mass fraction of 80%-91% may be added corresponding to 1 mol of 3-chloro-4-methylbenzoic acid.

In some specific embodiments of the present application, the molar ratio of the added 3-halo-4-alkylbenzoic acid to the base is 1:(2.0～3.0), preferably 1:(2.1～2.8), more preferably is 1:(2.3～2.7). Adding an appropriate amount of base as defined in this application can make it possible to replace the halogen atom with a hydroxyl group at the 3-position to the greatest extent, so as to obtain a high yield of the target product without causing waste of the reaction substrate. If the amount of alkali added is less, the time required for the reaction may be significantly longer, and the conversion rate and yield will also become lower; if more alkali is added, not only does not meet the principle of economical saving, but it may also affect the reaction product. purity and yield.

solvent

The preparation method of the present application is not particularly limited to the choice of solvent, usually can be selected the polar solvent with high boiling point, does not destroy alkalinity after mixing, can enumerate have water, tetrahydrofuran, dioxane etc., in some specific examples of the present invention In some embodiments, the solvent is water. The present application has no particular limitation on the amount of solvent used. In some specific embodiments of the present invention, the amount of the solvent used can be 1 to 20 times the mass of 3-halogenated-4-methylbenzoic acid, preferably 5 to 20 times the mass of benzoic acid. 15 times, more preferably 6 to 10 times; too much will cause the concentration of the alkali to be too low, which will cause the reaction to fail and cause waste; if the dosage is too small, the alkali will not be completely dissolved, and the reaction will not proceed.

mix

The present application has no special limitation on the conditions of the mixing reaction, and in some specific embodiments of the present invention, the reaction is preferably carried out under high pressure. Wherein, the high pressure refers to a pressure of 1 MPa-10 MPa, and further may be 2-5 MPa. The reaction vessel to be used is not particularly limited, and it is preferable to use an autoclave, a high-pressure tank, etc. commonly used in this field. The capacity of the reaction container is also not particularly limited.

<Procedure for raising the temperature of the reaction system to carry out the reaction>

heat up

In some specific embodiments of the present invention, when the reaction is carried out under high pressure, the temperature of the reaction system is raised to 50-180°C, further to 60-160°C; in some specific embodiments of the present invention, 3-halo- When the halogen in 4-alkylbenzoic acid is chlorine element, since chlorine element is relatively inactive, it is preferably carried out under high pressure, and the reaction temperature is preferably 100-180°C. When the reaction is carried out under normal pressure, the temperature of the reaction system is raised to 90-110°C, further to 95-105°C; in some specific embodiments of the present invention, the halogen in 3-halo-4-alkylbenzoic acid is In the case of bromine element, since bromine element is relatively active, the reaction can be carried out under normal pressure, and the temperature at this time is preferably 100-105°C. The temperature has a certain influence on the substitution reaction of the hydroxyl group on the benzene ring. If the heating temperature is too high, the safety risk may be increased. If the heating temperature is too low, the reaction may be incomplete and the reaction yield may decrease. If the temperature is too high, it may cause excessive pressure during the reaction, which is dangerous and may cause waste of energy.

There is no particular limitation on the method of temperature rise in this application. In some specific embodiments of the present invention, it can be electric heating, heat conduction oil electric heating, or steam heating by using saturated steam or high-pressure superheated steam to raise the temperature of the reaction system. The method can be open or closed; in some specific embodiments of the present invention, the heating treatment is carried out by means of heat conduction oil electric heating.

reaction

The reaction time of the present application is related to the reaction conditions. If the reaction conditions are high temperature and high pressure, the reaction time is significantly shortened. In some specific embodiments of the present invention, it is 1 to 3 hours; if the reaction does not use high pressure, only increase the temperature , in some specific embodiments of the present invention, it is 6-10h.

The equation for the reaction is as follows:

X is selected from fluorine, chlorine, bromine, iodine

Wherein, R is a C1-C20 alkyl group, and in some specific embodiments of the present invention, it can be selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert Any of butyl, in some preferred embodiments of the invention, R is methyl.

X is halogen, which can be fluorine, chlorine, bromine or iodine. In some preferred embodiments of the present invention, X is chlorine or bromine.

In some other specific embodiments of the present application, a cooling step may also be included before the post-treatment step, preferably, the reaction system is cooled to room temperature.

<Adjust the pH value of the reaction system>

In some specific embodiments of the present invention, after the reaction system is cooled to room temperature, the step of adjusting the pH value of the reaction system is performed. Wherein, the step of adjusting the pH value of the reaction system includes adding one or more of hydrochloric acid, malic acid, citric acid, tartaric acid, and lactic acid to the reaction system, wherein, preferably, hydrogen chloride with a mass fraction of 30% to 35% can be added Hydrochloric acid, more preferably conventional commercially available hydrochloric acid with a concentration of 31%; adjust the pH value of the reaction system to 4-6.5, preferably to 4.5-6.

<Post-processing steps>

In some specific embodiments of the present invention, after cooling the reaction system to room temperature, the reaction system is post-treated, wherein the steps of post-treatment include filtering, washing and drying.

The filtration can be carried out by solid-liquid separation, and the separation method is not particularly limited, and suction filtration can be used.

After filtering, there is a washing step, and the obtained solid can be washed with clear water. Then dry to obtain the target product 3-hydroxyl-4-alkylbenzoic acid, wherein the drying method can preferably use heating and vacuum drying, weigh after drying, and pass the target product (actual) generation amount/the theoretical generation amount of the target product× 100% calculated yield.

In some preferred embodiments of the present application, nitric acid with oxidation is added to p-alkylbenzoic acid, and then a halogenating reagent is added to provide halogen elements, and positive halide ions are generated to attack the benzene ring. position, the carboxylic acid positioning group is the meta-position, the 2-position is the passivated position, and will not be substituted, so the halogen of the basic reaction will not undergo a halogenation reaction at a position other than the 3-position, thereby obtaining a 3-halogen Substituted-4-alkylbenzoic acid. Then mix 3-halo-4-alkylbenzoic acid with alkali and polar solvent, raise the temperature, adjust the pH value of the reaction system to acidity, and then perform post-treatment. Due to the electric absorption effect of the carboxyl group, the halogen on the benzene ring The atom is activated, which reduces the halogen activation energy, so the reaction can be carried out without using a catalyst, and the target product 3-hydroxyl-4-alkylbenzoic acid with high yield can be obtained.

The invention is further illustrated, but not limited, by the following examples.

Example

Preparation Example 1

P-toluic acid (5 grams) was joined in 40% nitric acid (30 milliliters), hydrochloric acid (31% concentration, 5.2 grams) was added, the temperature was raised to 100° C., and the reaction was carried out for 3 hours, the monitoring reaction was complete, cooling, and solid pumping Filter, wash with water, and dry to obtain the product 3-chloro-4-methylbenzoic acid (5.9 grams), purity: 97.9%, yield: 94%. See Figure 1 for the NMR image of the product.

Preparation example 2

P-toluic acid (5 grams) is joined in the nitric acid (30 milliliters) of 40%, adds hydrobromic acid (48% concentration, 7.5 grams), is warming up to 100 ℃, reacts 2.5 hours, monitors the completion of reaction, cooling, The solid was filtered with suction, washed with water, and dried to obtain the product 3-bromo-4-methylbenzoic acid (7.4 g), purity: 98.2%, yield: 94%. See Figure 2 for the NMR image of the product.

Preparation example 3

In the filtration recovery nitric acid (26 milliliters) of Preparation Example 1, add 4 milliliters of 65% nitric acid, then add p-toluic acid (5 grams), hydrochloric acid (31% concentration, 5 grams), be warming up to 100 ℃, react After 3 hours, monitor the completion of the reaction, cool, filter the solid with suction, wash with water, and dry to obtain the product 3-chloro-4-methylbenzoic acid (5.92 g), purity: 97.7%, yield: 94%.

Example 1

Add 3-chloro-4-methylbenzoic acid (10 grams), potassium hydroxide (mass fraction is 90%, 9.1 grams), water (80 grams) in 200 milliliters of high-pressure tanks, close the high-pressure tanks, and heat up to 160 degrees , reacted for 8 hours, monitored the completion of the reaction, cooled, and the reaction solution was adjusted to pH 5 with concentrated hydrochloric acid in an ice bath, and the solid was suction filtered, washed with clear water, and dried to obtain product 3-hydroxyl-4-methylbenzoic acid (8.35 grams ). Purity: 98.7%, Yield: 93%.

Example 2

Add 3-bromo-4-methylbenzoic acid (10 grams), potassium hydroxide (mass fraction is 90%, 6.4 grams), water (80 grams) in 200 milliliters of high-pressure tanks, close the high-pressure tanks, and heat up to 100 degrees , reacted for 3 hours, monitored the completion of the reaction, cooled, and the reaction solution was adjusted to pH 5 with concentrated hydrochloric acid in an ice bath, and the solid was filtered with suction, washed with clear water, and dried to obtain product 3-hydroxyl-4-methylbenzoic acid (6.86 grams ). Purity: 99%, yield: 97%, NMR and liquid chromatographic characterization of the obtained product, the results are shown in Figure 3 and Figure 4.

Example 3

Add 3-bromo-4-methylbenzoic acid (10 grams), potassium hydroxide (mass fraction is 90%, 6.4 grams), water (80 grams) in 250 milliliters one-mouth bottle, connect reflux tube, be heated up to 100 degree, reacted for 3 hours, monitored the completion of the reaction, cooled, the reaction solution was adjusted to pH 5 with concentrated hydrochloric acid, and the ice bath was used for suction filtration of the solid, washed with clear water, and dried to obtain the product 3-hydroxyl-4-methylbenzoic acid (6.83 gram). Purity: 98.7%, Yield: 97%.

Example 4

Add 3-bromo-4-methylbenzoic acid (10 grams), potassium hydroxide (mass fraction is 90%, 6.4 grams), water (80 grams) in 200 milliliters of high-pressure tanks, close the high-pressure tanks, and heat up to 160 degrees , reacted for 1 hour, monitored the completion of the reaction, cooled, and the reaction solution was adjusted to pH 5 with concentrated hydrochloric acid in an ice bath, and the solid was filtered with suction, washed with clear water, and dried to obtain product 3-hydroxyl-4-methylbenzoic acid (6.81 grams ). Purity: 99%, Yield: 98%.

It can be seen from the above examples that the preparation method of 3-hydroxy-4-alkylbenzoic acid of the present application is simple to operate, the product yield reaches more than 93%, and the purity reaches more than 98.7%. Compared with the preparation method in the prior art, the reaction conditions of the present application require less equipment, simple reaction steps, low raw material cost, very little three wastes, and high product yield and purity.

The above examples are only used to illustrate several embodiments of the present invention, and the description thereof is relatively specific and detailed, but should not be construed as any limitation to the scope of the present invention. It should be clear that for those skilled in the art, several modifications and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention.

Industrial availability

The preparation method of the present invention can be widely used in the preparation of industrial 3-hydroxyl-4-alkylbenzoic acid.

Claims (10)

1. A process for the preparation of 3-hydroxy-4-alkylbenzoic acids, characterized in that the 3-hydroxy-4-alkylbenzoic acid has the following general formula (I):

wherein R is C1-C20 alkyl;

and the preparation method comprises the step of mixing and reacting the 3-halogenated-4-alkylbenzoic acid with alkali and a polar solvent.

2. The method of manufacturing according to claim 1, further comprising:

heating the reaction system for reaction, adjusting the pH value of the reaction system,

And a step of subjecting the reaction system to a post-treatment to obtain 3-hydroxy-4-alkylbenzoic acid.

3. The production method according to claim 1 or 2,

and R is selected from any one of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

4. The production method according to any one of claims 1 to 3,

the alkali is selected from any one of hydroxides of alkali metals, alkali metal salts, hydroxides of alkaline earth metals, alkali metal salts and ammonia water;

the polar solvent is any one of water, tetrahydrofuran and dioxane.

5. The production method according to any one of claims 1 to 4,

the molar ratio of the 3-halogeno-4-alkylbenzoic acid to the alkali is 1 (2.0-3.0).

6. The production method according to any one of claims 1 to 5,

the dosage of the polar solvent is 1 to 20 times of the mass of the 3-halogenated-4-methylbenzoic acid.

7. The production method according to any one of claims 1 to 6,

the step of heating the reaction system refers to heating the reaction system to 50-180 ℃;

the reaction time is 1-10 h.

8. The production method according to any one of claims 1 to 7,

the step of adjusting the pH value of the reaction system is to adjust the pH value to 4-6.5.

9. The production method according to any one of claims 1 to 8,

the post-treatment comprises filtration, washing and drying.

10. The production method according to any one of claims 1 to 9,

the 3-halogenated-4-alkylbenzoic acid is obtained by mixing and heating p-alkylbenzoic acid, nitric acid and a halogenated reagent and then carrying out post-treatment;

wherein the halogenating agent is selected from one or more of hydrogen chloride, sodium chloride, potassium chloride, hydrogen bromide, sodium bromide, potassium bromide, hydroiodic acid, sodium iodide, potassium iodide or aqueous solution thereof;

further, the concentration of the nitric acid is 30-85%;

furthermore, the molar ratio of the p-alkylbenzoic acid to the halogenating reagent is 1 (1.0-3.0).

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