CN115894211A - Preparation method of 3-hydroxy-4-methylbenzoic acid - Google Patents
Preparation method of 3-hydroxy-4-methylbenzoic acid Download PDFInfo
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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
Technical Field
The invention belongs to the field of organic compound synthesis, and particularly relates to a preparation method of 3-hydroxy-4-alkylbenzoic acid.
Background
Hydroxy-4-methyl benzoic acid is an important organic synthesis intermediate, is widely used for medicines, agriculture, organic cutting and the like, and is particularly widely applied in the new pharmaceutical field.
In the prior preparation method, if a benzene ring carries halogen atoms, such as bromobenzene, and if the bromobenzene reacts with alkaline substances such as sodium hydroxide and the like, not only high-temperature and high-pressure conditions are needed, but also metals such as Cu and the like are needed as catalysts to carry out substitution reaction; the existing synthesis method of hydroxy-4-methylbenzoic acid, for example, cited document 1, uses methyl 3-methoxy-4-methylbenzoate to prepare 3-hydroxy-4-methylbenzoic acid by first demethylating and then hydrolyzing, but the preparation method has relatively high raw material cost, and the reaction route of the method is as follows:
the cited document 2 discloses a method of obtaining 3-hydroxy-4-methylbenzoic acid by sulfonating and then hydrolyzing p-methylbenzoic acid, which has a high cost of reaction raw materials, requires a high temperature of 150 ℃ in the sulfonation step, and generates a large amount of wastewater, and the reaction route of the method is as follows:
cited documents:
cited document 1: WO2015161011
Citation 2: the cis-and trans-Modifications of1-Methyl-cyclohexan-2-ol-carboxylic Acid and their Conversion into 1-Methyl-△ 1 -cyclohexene-4-carboxylic Acid,1908,93(1416-1428)
Disclosure of Invention
Problems to be solved by the invention
In view of the above problems in the prior art, it is highly desirable to develop a method for preparing 3-hydroxy-4-alkylbenzoic acid, which has the advantages of few reaction steps, no need of catalyst, simple operation, short overall time consumption, low raw material cost, high product purity and yield, and less generation of three wastes.
Means for solving the problems
Specifically, the invention provides the following technical scheme:
[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 production method according to [1], wherein the production method further comprises:
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 process according to [1] or [2], wherein,
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 the aspects of [1] to [3], wherein,
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 selected from any one of water, tetrahydrofuran and dioxane.
[5] The production method according to any one of the above aspects 1 to 4, wherein,
the molar ratio of the 3-halogenated-4-alkylbenzoic acid to the alkali is 1 (2.0-3.0).
[6] The production method according to any one of the aspects of [1] to [5], wherein,
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 the aspects of [1] to [6], wherein,
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 the aspects 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 production method according to any one of the above-mentioned aspects 1 to 8, characterized in that,
the post-treatment comprises filtration, washing and drying.
[10] The production method according to any one of the aspects of [1] to [9], wherein,
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 agent is 1 (1.0-3.0).
ADVANTAGEOUS EFFECTS OF INVENTION
Compared with the prior art, the invention has the following beneficial effects:
1. the preparation method has relatively low requirements on equipment, does not need to use a catalyst, has few reaction steps, is simple and convenient to operate, has short total time consumption, and generates few three wastes;
2. the preparation method of the invention uses low cost raw materials, shortens reaction time remarkably without using catalyst, and can obtain target products 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 agent, the method does not use expensive halogen simple substance, has low raw material cost, does not add complex operation steps such as catalyst, etc., and the used dilute nitric acid can be recycled, and generates few three wastes.
The above description does not disclose all embodiments of the present invention and all advantages of the present invention.
Drawings
FIG. 1: nuclear magnetic spectrum of 3-chloro-4-methylbenzoic acid obtained in preparation example 1
FIG. 2: nuclear magnetic spectrum of 3-bromo-4-methylbenzoic acid obtained in preparation example 2
FIG. 3: nuclear magnetic spectrum of 3-hydroxy-4-methylbenzoic acid obtained in example 2
FIG. 4: liquid chromatogram of 3-hydroxy-4-methylbenzoic acid obtained in example 2
Detailed Description
The following describes embodiments of the present invention, but the present invention is not limited to these embodiments. The present invention is not limited to the configurations described below, and various modifications are possible within the scope of the claims, and embodiments and examples obtained by appropriately combining the technical means disclosed in the respective embodiments and examples are also included in the technical scope of the present invention. All documents described in this specification are incorporated herein by reference.
Unless defined otherwise, 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 the present specification, the numerical range represented by "numerical value a to numerical value B" means a range including the end points of numerical values a and B.
In the present specification, the numerical ranges indicated by "above" or "below" refer to numerical ranges including the number.
In the present specification, "room temperature" means an operation without temperature control, and generally means 20 ℃ to 30 ℃.
In the present specification, the term "may" includes both the case where a certain process is performed and the case where no process is performed.
As used herein, the use of "optionally" or "optional" means that certain materials, components, performance steps, application conditions, and the like are used or not used.
In the present specification, the unit names used are all international standard unit names, and "%" used means weight or mass% unless otherwise specified.
The term "comprises" and any variations thereof in the description and claims of the invention are intended to cover non-exclusive inclusions. For example, a process, method, or system, article, or apparatus that comprises a list of steps or elements is not limited to only those steps or elements listed, but may alternatively include other steps or elements not listed, or inherent to such process, method, article, or apparatus.
Reference throughout this specification to "a preferred embodiment," "an embodiment," and so forth, means that a particular element (e.g., feature, structure, property, and/or characteristic) described in connection with the embodiment is included in at least one embodiment described herein, 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 the present specification, a polar solvent refers to a solvent in which the solvent molecule is a polar molecule.
In this specification, the molar ratio of 3-halo-4-alkylbenzoic acid to base is calculated based on the number of moles of base in the solution.
The invention provides a preparation method of 3-hydroxy-4-alkylbenzoic acid, which comprises the step of mixing 3-halogeno-4-alkylbenzoic acid, alkali and a polar solvent for reaction.
The following description will be made for each of the above steps.
The 3-hydroxy-4-alkylbenzoic acid has the following general formula (I):
wherein R is a C1 to C20 alkyl group, and in some embodiments of the present invention, may be selected from any one of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl, and in some preferred embodiments of the present invention, R is methyl.
< step of mixing >
The step of mixing means mixing the 3-halo-4-alkylbenzoic acid with the ammonia solution.
3-halo-4-alkylbenzoic acids
In the prior preparation method of 3-halo-4-alkylbenzoic acid, alkyl substituted benzoic acid and water are generally added into a reaction vessel, and halogen elementary substances (chlorine, bromine and the like) are added for heating reaction, but in the actual use process, the chlorine gas is difficult to control the input amount, so that the reaction substrate is easy to react incompletely or is substituted by excessive chlorine, the price of bromine is relatively expensive, and in addition, a certain amount of quaternary ammonium salt phase transfer catalyst is required to be added before the halogen elementary substances are added in the reaction, so that the raw material cost required by the reaction is high, and the method is not suitable for large-scale industrial production. In addition, some synthesis reactions also use hydrogen peroxide and the like as an oxidizing agent, but the risk of explosion may be increased, and the safety factor in industrial production may be reduced.
In some preferred embodiments of the present invention, the 3-halo-4-alkylbenzoic acid may be obtained by mixing p-alkylbenzoic acid, nitric acid and a halogenating agent, heating, reacting, and then performing post-treatment.
Wherein the reaction involves the following equation:
wherein R is a C1 to C20 alkyl group, and in some embodiments of the present invention, may be selected from any one of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl, and in some preferred embodiments of the present invention, R is methyl.
X is halogen and may be chlorine, bromine or iodine, and in some preferred embodiments of the invention, X is chlorine, bromine, and more preferably may be bromine.
The halogenating agent (HX or MX) described herein may be 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 solutions thereof. The aqueous solution of the halogenating agent may be hydrochloric acid (aqueous solution of hydrogen chloride), hydrobromic acid (aqueous solution of hydrogen bromide) or the like, and the concentration of the aqueous solution of the halogenating agent may 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, the waste of resources is caused, and other byproducts are possibly generated to influence the yield and the purity of the target product; if the concentration of the aqueous solution is too low, the substitution reaction may be difficult to occur, and the yield of the target product may be too low. Based on the reactivity of the halogen, in some particular embodiments of the invention, the halogenating agent or aqueous solution thereof is preferably hydrochloric acid, hydrobromic acid, sodium bromide.
In the mixing step, the concentration of the nitric acid may be 30% to 85%, preferably 35% to 65%, more preferably 37% to 60%, and still more preferably 40% to 50%. If the concentration of the nitric acid is too low, the generated oxidation effect is not strong, so that halogen is difficult to substitute a benzene ring, and the final yield of the product is influenced; if the concentration of nitric acid is too high, the operational risk increases, and the nitric acid may volatilize and smoke during the heating reaction, making the reaction difficult to proceed, which may hinder the production of a high-purity and high-yield target product.
The amount of the nitric acid is not particularly limited, and in some specific embodiments, 700 to 1400mL of 35 to 45% nitric acid may be added to 1mol of p-alkylbenzoic acid, and from the viewpoint of saving raw materials and ensuring the yield, 800 to 1200mL of 35 to 45% nitric acid is preferably added to 1mol of p-alkylbenzoic acid, and 850 to 1000mL of 35 to 45% nitric acid may be more preferably added to 1mol of p-alkylbenzoic acid.
In some embodiments, the molar ratio of p-alkylbenzoic acid to halogenating agent added is 1 (1.0 to 3.0), preferably 1 (1.05 to 2.7), more preferably 1 (1.2 to 2.3). The appropriate amount of the halogenating reagent is added, so that the halogenating reagent can be substituted on the 3-position to the maximum extent, the target product with high yield is obtained, and simultaneously, the waste of reaction substrates is not caused. If the amount of the halogenating agent added is small, the time required for the reaction may be significantly long, in many cases 3 to 4 days, and the conversion rate and yield may be low; if more halogenating agent is added, the economic principle is not met, and the purity and yield of the reaction product can be influenced.
In addition, the order of addition of the three reactants is not particularly limited, and in some specific embodiments, the p-alkylbenzoic acid may be added to the nitric acid, followed by the addition of the halogenating agent; the p-alkylbenzoic acid can also be added into the nitric acid, and then the halogenating reagent is added. The p-alkyl benzoic acid is mixed with the nitric acid, and the halogenated reagent is added to enable the reaction to be easier, so that the generation of byproducts is reduced to the maximum extent.
In some embodiments, the heating reaction refers to heating the reaction system to 50 to 110 ℃, and further 60 to 100 ℃. The temperature has certain influence on the halogenation reaction on the benzene ring, if the heating temperature is too high, the volatilization loss of nitric acid can be caused to be large, and the safety risk is increased, if the heating temperature is too low, the reaction can be incomplete, the reaction yield is reduced, and the halogen atom is easy to be substituted at the 2-position, so that other isomers are generated in the reaction. The duration of heating is not particularly limited, and the reaction system may be heated to reflux and then kept at that temperature to allow the reaction system to proceed.
The heating temperature is not particularly limited, and may be an indirect heating system such as an air bath or a water bath.
The reaction time is in some embodiments from 2.5 to 8 hours, preferably from 3 to 6 hours, more preferably 4 hours.
In other specific embodiments, the post-treatment step may be preceded by a cooling step, preferably, the reaction system is cooled to room temperature.
In some embodiments, the reaction system is post-treated after cooling to room temperature, wherein the post-treatment step comprises filtering, washing and drying.
Wherein the filtration may be carried out by solid-liquid separation, wherein the method of separation is not particularly limited, and suction filtration may be used. Unreacted (or residual) nitric acid can be collected after filtration, and the concentration is adjusted by supplementing nitric acid with higher concentration (for example, more than 50 percent) so as to be used as a reaction substrate in the preparation method of the 3-halogeno-4-alkylbenzoic acid for reaction again, thereby realizing cyclic utilization, improving the utilization rate of reaction raw materials, saving the cost and reducing the generation of waste liquid to a great extent. The concentration of the supplemented nitric acid is preferably 60-85% of nitric acid, and further 60-70% of nitric acid, and the volume of the supplemented nitric acid is preferably measured after unreacted nitric acid is collected, the volume difference between the unreacted nitric acid and the original nitric acid is calculated, the volume is supplemented to the original nitric acid volume by adding nitric acid with higher concentration, and the nitric acid is used as the reaction raw material of the 3-halo-4-alkylbenzoic acid for reaction again. During the reaction, whether the p-alkylbenzoic acid is completely reacted or not can be judged by a conventional analytical means in organic chemistry, such as thin layer chromatography (dot plate) or High Performance Liquid Chromatography (HPLC), if the p-alkylbenzoic acid is not completely reacted, a small amount of nitric acid with higher concentration can be continuously supplemented to promote the reaction to be completely carried out.
Filtration is followed by a washing step, which may be washing the resulting solid with clear water. And then dried to obtain the 3-halo-4-alkylbenzoic acid, wherein the method of drying preferably may use heating vacuum drying, and weighing after drying.
In the reaction for obtaining the 3-halogeno-4-alkylbenzoic acid, benzoic acid with alkyl substituted at para position (4 position) is used as an initial reactant, nitric acid with oxidation is added, and a halogenating reagent is added to provide halogen elements, so that halogen positive ions are generated to attack a benzene ring, and a target product is obtained. Because 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 and cannot be substituted, the halogen in the basic reaction cannot be halogenated in the positions except the 3 position, so that various positional isomers cannot be generated, and the purity and the yield of the obtained product are high.
Alkali
The base 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 aqueous ammonia, or an aqueous solution of the above-mentioned base may be selected, and sodium hydroxide, potassium hydroxide, calcium hydroxide, and the like are exemplified. Wherein the mass fraction of the aqueous alkali solution is 60 to 95%, preferably 70 to 93%, more preferably 80 to 91%, based on the mass of the solution. If the mass fraction of the aqueous solution of the alkali is too low, hydroxyl is difficult to replace a benzene ring, so that the final yield of the product is influenced; if the mass fraction of the base is too high, the reaction raw material is wasted.
The amount of the base is not particularly limited, and in some specific embodiments, 1mol of 3-chloro-4-methylbenzoic acid may correspond to 5 to 11g of potassium hydroxide added in a mass fraction of 80 to 95%; from the viewpoint of saving raw materials and ensuring yield, preferably 1mol of 3-chloro-4-methylbenzoic acid can be correspondingly added with 6 to 10g of 82 to 93 percent of potassium hydroxide by mass fraction; more preferably, 1mol of 3-chloro-4-methylbenzoic acid is added with 7 to 9.5g of potassium hydroxide with the mass fraction of 80 to 91 percent.
In some embodiments of the present application, the molar ratio of 3-halo-4-alkylbenzoic acid to base added is 1 (2.0-3.0), preferably 1 (2.1-2.8), more preferably 1 (2.3-2.7). The addition of an appropriate amount of base as defined herein can maximally substitute the halogen atom with hydroxyl group at the 3-position, and can obtain a high yield of the target product without wasting the reaction substrate. If the amount of the base added is small, the time required for the reaction may be significantly long, and the conversion and yield may be low; if more alkali is added, the economic principle is not met, and the purity and yield of the reaction product can be influenced.
Solvent(s)
The solvent used in the preparation method of the present invention is not particularly limited, and a polar solvent having a high boiling point and not causing deterioration of the basicity after mixing can be usually used, and water, tetrahydrofuran, dioxane, and the like can be exemplified. The amount of the solvent used herein is not particularly limited, and in some specific embodiments of the present invention, the amount of the solvent may be 1 to 20 times, preferably 5 to 15 times, and more preferably 6 to 10 times, the mass of the 3-halo-4-methylbenzoic acid; too much usage can cause too low concentration of alkali to cause the reaction to be unable to proceed, and waste can be caused; if the amount is too small, the alkali cannot be completely dissolved, and the reaction cannot proceed.
Mixing
The conditions for the mixing reaction are not particularly limited in the present application, and in some specific embodiments of the present invention, it is preferred to carry out the reaction under high pressure. Wherein the high pressure means a pressure of 1MPa to 10MPa, and further 2 MPa to 5MPa. The reaction vessel to be used is not particularly limited, and an autoclave/autoclave or the like commonly used in the art is preferably used. The volume of the reaction vessel is not particularly limited.
< step of raising the temperature of the reaction System to carry out the reaction >
Temperature rise
In some embodiments of the invention, the reaction is carried out at elevated pressure, the reaction system is warmed to 50 to 180 ℃, further 60 to 160 ℃; in some embodiments of the present invention, when the halogen in the 3-halo-4-alkylbenzoic acid is chlorine, it is preferably carried out under high pressure because chlorine is relatively inactive, and the reaction temperature is preferably 100 to 180 ℃. When the reaction is carried out under normal pressure, the temperature of a reaction system is raised to 90-110 ℃, and further 95-105 ℃; in some embodiments of the present invention, when the halogen in the 3-halo-4-alkylbenzoic acid is bromine, the reaction can be carried out at normal pressure, and the temperature is preferably 100 to 105 ℃. The temperature has a certain influence on the substitution reaction of hydroxyl groups on the benzene ring, and if the heating temperature is too high, the safety risk may be increased, if the heating temperature is too low, the reaction may not be completely performed, the reaction yield may be reduced, and if the heating temperature is too high, the pressure may be too high during the reaction, the risk may be high, and energy may be wasted.
The temperature raising mode is not particularly limited in the present application, and in some specific embodiments of the present invention, the temperature raising mode may be an electric heating mode, a heat transfer oil electric heating mode, or a steam temperature raising mode in which saturated steam or high-pressure superheated steam is used to raise the temperature of the reaction system, and the steam temperature raising mode may be an open type or a closed type; in some embodiments of the present invention, the temperature raising process is performed by electrically heating the heat transfer oil.
Reaction(s) of
The reaction time is related to the reaction conditions, and if the reaction conditions are high temperature and high pressure, the reaction time is significantly shortened, and in some specific embodiments of the present invention, is 1 to 3 hours; if the reaction is not carried out at elevated pressure, the temperature is merely increased, in some embodiments of the invention, to between 6 and 10 hours.
The equation for the reaction is as follows:
x is selected from fluorine, chlorine, bromine and iodine
Wherein R is a C1 to C20 alkyl group, and in some embodiments of the present invention, may be selected from any one of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl, and in some preferred embodiments of the present invention, R is methyl.
X is halogen and may be fluorine, chlorine, bromine or iodine, and in some preferred embodiments of the invention, X is chlorine, bromine.
In other embodiments of the present invention, a cooling step may be included before the post-treatment step, and preferably, the reaction system is cooled to room temperature.
< adjustment of pH value of reaction System >
In some embodiments of the present invention, the step of adjusting the pH of the reaction system is performed after cooling the reaction system to room temperature. Wherein the step of adjusting the pH value of the reaction system comprises adding one or more of hydrochloric acid, malic acid, citric acid, tartaric acid and lactic acid into the reaction system, wherein the hydrochloric acid with the hydrogen chloride mass fraction of 30-35% can be preferably added, and the hydrochloric acid with the conventional commercial concentration of 31% is more preferably added; the pH value of the reaction system is adjusted to 4 to 6.5, preferably 4.5 to 6.
< post-treatment step >
In some embodiments of the present invention, the reaction system is post-treated after cooling to room temperature, wherein the post-treatment comprises filtering, washing and drying.
Wherein the filtration may be carried out by solid-liquid separation, wherein the method of separation is not particularly limited, and suction filtration may be used.
Filtration is followed by a washing step, which may be washing the resulting solid with clear water. And then dried to obtain the target product 3-hydroxy-4-alkylbenzoic acid, wherein the drying method preferably can use heating vacuum drying, weighing after drying, and calculating the yield by the (actual) production amount of the target product/theoretical production amount of the target product x 100%.
In some preferred embodiments of the present application, the addition of nitric acid with an oxidizing effect to the p-alkylbenzoic acid and the addition of a halogenating reagent provides a halogen element that generates a halogen cation to attack the benzene ring, and since the alkyl directing group is in the ortho-para position, the carboxylic acid directing group is in the meta-position and the 2-position is in a passivated position and is not substituted, the essentially reactive halogen does not undergo a halogenation reaction at a position other than the 3-position to provide a 3-halo-4-alkylbenzoic acid. And then mixing the 3-halogeno-4-alkylbenzoic acid with alkali and a polar solvent, heating, adjusting the pH value of a reaction system to acidity, and then carrying out aftertreatment, wherein due to the electricity absorption effect of carboxyl, halogen atoms on a benzene ring are activated, and the halogen activation energy is reduced, so that the reaction can be carried out without using a catalyst, and the target product 3-hydroxy-4-alkylbenzoic acid with high yield can be obtained.
The invention is further illustrated, but not limited, by the following examples.
Examples
Preparation example 1
Adding p-toluic acid (5 g) into 40% nitric acid (30 ml), adding hydrochloric acid (31% concentration, 5.2 g), heating to 100 ℃, reacting for 3 hours, monitoring the reaction completion, cooling, carrying out solid suction filtration, washing with clear water, and drying to obtain a product, namely 3-chloro-4-toluic acid (5.9 g), wherein the purity is: 97.9% yield: 94 percent. The nuclear magnetic pattern of the product is shown in FIG. 1.
Preparation example 2
Adding p-toluic acid (5 g) into 40% nitric acid (30 ml), adding hydrobromic acid (48% concentration, 7.5 g), heating to 100 ℃, reacting for 2.5 hours, monitoring the reaction completion, cooling, carrying out solid suction filtration, washing with clear water, and drying to obtain a product, namely 3-bromo-4-toluic acid (7.4 g), wherein the purity is: 98.2% yield: 94 percent. The nuclear magnetic picture of the product is shown in FIG. 2.
Preparation example 3
To the filtered and recovered nitric acid (26 ml) of preparation example 1, 4 ml of 65% nitric acid was added, then p-toluic acid (5 g) and hydrochloric acid (31% concentration, 5 g) were added, the temperature was raised to 100 ℃, the reaction was carried out for 3 hours, the reaction was monitored to be completed, the reaction was cooled, the solid was filtered, washed with clear water, and dried to obtain a product, 3-chloro-4-toluic acid (5.92 g), purity: 97.7% yield: 94 percent.
Example 1
Adding 10g of 3-chloro-4-methylbenzoic acid, 9.1 g of potassium hydroxide and 80 g of water into a 200ml high-pressure tank, sealing the high-pressure tank, heating to 160 ℃, reacting for 8 hours, monitoring the reaction, cooling, adjusting the pH value of the reaction solution to 5 by using concentrated hydrochloric acid and an ice bath, carrying out suction filtration on solids, washing by using clear water, and drying to obtain a product of 3-hydroxy-4-methylbenzoic acid (8.35 g). Purity: 98.7%, yield: 93 percent.
Example 2
Adding 10g of 3-bromo-4-methylbenzoic acid, 6.4 g of potassium hydroxide and 80 g of water into a 200ml high-pressure tank, sealing the high-pressure tank, heating to 100 ℃, reacting for 3 hours, monitoring the reaction, cooling, adjusting the pH value of the reaction solution to 5 by using concentrated hydrochloric acid and an ice bath, carrying out solid suction filtration, washing by using clear water, and drying to obtain a product of 3-hydroxy-4-methylbenzoic acid (6.86 g). Purity: 99%, yield: 97%, the product obtained was characterized by nuclear magnetic and liquid chromatography, the results of which are shown in FIGS. 3 and 4.
Example 3
Adding 10g of 3-bromo-4-methylbenzoic acid, 6.4 g of potassium hydroxide and 80 g of water into a 250 ml single-neck bottle, connecting a reflux pipe, heating to 100 ℃, reacting for 3 hours, monitoring the reaction, cooling, adjusting the pH value of the reaction solution to 5 by using concentrated hydrochloric acid and ice bath, carrying out solid suction filtration, washing by using clear water, and drying to obtain a product of 3-hydroxy-4-methylbenzoic acid (6.83 g). Purity: 98.7%, yield: 97 percent.
Example 4
Adding 10g of 3-bromo-4-methylbenzoic acid, 6.4 g of potassium hydroxide and 80 g of water into a 200ml high-pressure tank, sealing the high-pressure tank, heating to 160 ℃, reacting for 1 hour, monitoring the reaction, cooling, adjusting the pH value of a reaction solution to 5 by using concentrated hydrochloric acid and an ice bath, performing suction filtration on a solid, washing by using clear water, and drying to obtain a product, namely 6.81 g of 3-hydroxy-4-methylbenzoic acid. Purity: 99%, yield: 98 percent.
The above examples show that the preparation method of 3-hydroxy-4-alkylbenzoic acid has simple operation, 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 preparation method has the advantages of low requirements on equipment for reaction conditions, simple reaction steps, low raw material cost, few three wastes, and high product yield and purity.
The above examples are intended only to illustrate several embodiments of the present invention, which are described in more detail and detail, but are not to be construed as imposing any limitation on the scope of the present invention. It should be clear that a person skilled in the art can make several variations and modifications without departing from the inventive concept, which fall within the scope of protection of the present invention.
Industrial applicability
The preparation method of the invention can be widely used for preparing industrial 3-hydroxy-4-alkyl benzoic 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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