A kind of preparation method of 3-amino-4-alkylbenzoic acid

Abstract

The present invention relates to a preparation method of 3-amino-4-alkylbenzoic acid, wherein the 3-amino-4-alkylbenzoic acid has the following general formula (I): wherein R is an alkyl group of C1 to C20; and the preparation method comprises the step of mixing 3-halogenated-4-alkylbenzoic acid with an ammonia solution for reaction. The preparation method of the present invention has relatively low equipment requirements, low raw material cost, does not use precious metals or other toxic substances as catalysts, has few reaction steps, is easy to operate, is short in overall time consumption, produces very little three wastes, and can obtain 3-amino-4-alkylbenzoic acid with high yield and high purity.

Description

Technical Field

[0001] The invention belongs to the field of organic compound synthesis, and specifically relates to a method for preparing 3-amino-4-alkylbenzoic acid. Background Art

[0002] Amino-4-methylbenzoic acid is an important organic synthesis intermediate, widely used in medicine, agriculture, organic cutting, etc., for example, it is used in the hypertension drug canagliflozin.

[0003] In the existing synthesis method, the amino group at the 3rd position of the benzene ring is almost completely obtained by adding a strong electron-withdrawing group nitro reduction. For example, reference 1 discloses that 8-methylquinoline-5-carboxylic acid is obtained by Skraup reaction (Skraup synthesis reaction) from 3-amino-p-toluic acid, wherein the amino group at the 3rd position of the benzene ring in 3-amino-p-toluic acid is obtained by nitro reduction; reference 2 is based on 3-nitro-4-methylbenzoic acid, and the amino group at the 3rd position is obtained by reducing the nitro group, but the amount of waste water produced by the nitration reaction is large, which is easy to cause pollution, and because the nitration reaction is a strong exothermic reaction, the reaction rate is fast, and improper control will produce the risk of explosion. In addition, the nitration reaction also requires maintaining an appropriate reaction temperature to avoid the formation of side reaction products such as polynitro compounds and oxides, so the reaction conditions are relatively harsh. In addition, reference 3 relates to a palladium-catalyzed coupling of ammonia with aryl chlorides, bromides, iodides and sulfonates, which involves precious metal palladium or tin substances with greater toxicity, and is costly and easy to cause environmental pollution problems.

[0004] References:

[0005] Citation 1: Gracheva, IN, Tochilkin, AISynthesis and bromination of 8-methylquinoline-5-carboxylic acid. Chem Heterocycl Compd 16, 275–277.

[0006] Reference 2: Uber jodirte und jodosirte ChemischeBerichte,vol.26,Issue 2,1733-1738.

[0007] Reference 3: Giang D. Vo, John F. Hartwig, J. Am. Chem. Soc. 2009, 131, 31, 11049–11061. Summary of the invention

[0008] Problem that the invention aims to solve

[0009] In view of the problems existing in the prior art as described above, it is urgent to develop a method for preparing 3-amino-4-alkylbenzoic acid with fewer reaction steps, simple operation, short overall time consumption, low raw material cost, no use of precious metals or other toxic substances as catalysts, high product purity and yield, and less generation of three wastes.

[0010] Solutions for solving problems

[0011] Specifically, the present invention provides the following technical solutions:

[0012] [1] A method for preparing 3-amino-4-alkylbenzoic acid, wherein the 3-amino-4-alkylbenzoic acid has the following general formula (I):

[0013]

[0014] Wherein, R is a C1-C20 alkyl group;

[0015] Furthermore, the preparation method comprises the step of mixing 3-halogenated-4-alkylbenzoic acid with an ammonia solution for reaction.

[0016] [2] The preparation method according to [1], characterized in that the preparation method further comprises:

[0017] The step of heating the reaction system to react, the step of adjusting the pH value of the reaction system,

[0018] And the step of post-treating the reaction system to obtain 3-amino-4-alkylbenzoic acid.

[0019] [3] The preparation method according to [1] or [2], wherein

[0020] The R is selected from any one of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

[0021] [4] The preparation method according to any one of the technical solutions [1] to [3], wherein

[0022] The ammonia solution is selected from any one of aqueous ammonia, methanol, ethanol or tetrahydrofuran solution of ammonia;

[0023] Wherein, the mass percentage of ammonia in the ammonia solution is 20% to 30%.

[0024] [5] The preparation method according to any one of the technical solutions [1] to [4], wherein

[0025] The molar ratio of the 3-halogenated-4-alkylbenzoic acid to the ammonia solution is 1:(2.0-20.0).

[0026] [6] The preparation method according to any one of the technical solutions [1] to [5], wherein

[0027] The heating of the reaction system refers to heating the temperature to 50-180°C;

[0028] The reaction time is 1 to 12 hours.

[0029] [7]. The preparation method according to any one of the technical solutions [1] to [6], wherein:

[0030] The step of adjusting the pH value of the reaction system is to adjust the pH value to 4-6.5.

[0031] [8] The preparation method according to any one of the technical solutions [1] to [7], wherein

[0032] The post-treatment includes filtration, washing and drying.

[0033] [9]. The preparation method according to any one of the technical solutions [1] to [8], wherein:

[0034] The 3-halogenated-4-alkylbenzoic acid is obtained by mixing p-alkylbenzoic acid, nitric acid and a halogenating agent, heating the mixture and then performing post-treatment.

[0035]

[10] . The preparation method according to any one of the technical solutions [1] to [9], wherein:

[0036] 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 their aqueous solutions;

[0037] Further, the concentration of the nitric acid is 30% to 85%;

[0038] Furthermore, the molar ratio of the p-alkylbenzoic acid to the halogenating agent is 1:(1.0-3.0).

[0039] Effects of the Invention

[0040] Compared with the prior art, the present invention has the following beneficial effects:

[0041] 1. The preparation method of the present invention has relatively low requirements on equipment, few reaction steps, simple operation, short overall time consumption, and little waste generated;

[0042] 2. The preparation method of the present invention does not use precious metals or other toxic substances as special catalysts, has low raw material costs, does not have the potential safety hazard of temperature explosion, and can obtain the target product with high yield and high purity.

[0043] 3. In some preferred embodiments of the present invention, the raw material 3-halogenated-4-alkylbenzoic acid used in the present invention can be obtained by mixing p-alkylbenzoic acid, nitric acid and a halogenating agent. This method does not use expensive halogen elements, has low raw material costs, does not require complex operating steps such as adding catalysts, and the used dilute nitric acid can be recycled and reused, generating very little three wastes.

[0044] It should be noted that the above description does not disclose all embodiments of the present invention and all advantages of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 : The NMR spectrum of 3-chloro-4-methylbenzoic acid obtained in Preparation Example 1

[0046] Figure 2 : The NMR spectrum of 3-bromo-4-methylbenzoic acid obtained in Preparation Example 2

[0047] Figure 3 : The NMR spectrum of 3-amino-4-methylbenzoic acid obtained in Example 2

[0048] Figure 4 : Liquid chromatogram of 3-amino-4-methylbenzoic acid obtained in Example 2 DETAILED DESCRIPTION

[0049] The following describes the embodiments of the present invention, but the present invention is not limited thereto. The present invention is not limited to the various structures described below, and various changes can be made within the scope of the invention claim, and the embodiments and embodiments obtained by appropriately combining the technical means disclosed in different embodiments and embodiments are also included in the technical scope of the present invention. In addition, all the documents recorded in this specification are cited in this specification as references.

[0050] 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.

[0051] In this specification, the numerical range expressed using "a numerical value A to a numerical value B" means a range including the endpoints A and B.

[0052] In the present specification, a numerical range expressed using "above" or "below" means a numerical range including the number.

[0053] In this specification, "room temperature" means no temperature control operation is applied, and generally refers to 20°C to 30°C.

[0054] In this specification, the word "may" means both performing a certain process and not performing a certain process.

[0055] In this specification, the use of "optionally" or "optional" indicates that certain substances, components, execution steps, application conditions and other factors are used or not used.

[0056] In this specification, the unit names used are all international standard unit names, and unless otherwise stated, the "%" used indicates weight or mass percentage.

[0057] The term "comprising" and any variations thereof in the specification and claims of the present invention are intended to cover non-exclusive inclusions. For example, a process, method, system, product or device comprising a series of steps or units is not limited to the listed steps or units, but may optionally include steps or units not listed, or may optionally include other steps or units inherent to these processes, methods, products or devices.

[0058] In this specification, the references to "preferred embodiments", "embodiments", etc., mean that the specific elements (e.g., features, structures, properties and / or characteristics) described in connection with the embodiments are included in at least one embodiment described herein, and may or may not exist in other embodiments. In addition, it should be understood that the elements may be combined in various embodiments in any suitable manner.

[0059] In this specification, the molar ratio of 3-halogeno-4-alkylbenzoic acid to ammonia solution is calculated based on the molar number of NH3 in the solution.

[0060] The invention provides a method for preparing 3-amino-4-alkylbenzoic acid. The method comprises the step of mixing 3-halogenated-4-alkylbenzoic acid with an ammonia solution for reaction.

[0061] The following will explain each of the above steps one by one.

[0062] The 3-amino-4-alkylbenzoic acid of the present invention has the following general formula (I):

[0063]

[0064] Wherein, R is a C1-C20 alkyl group, and in some specific embodiments of the present invention, it can be selected from any one of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. In some preferred embodiments of the present invention, R is methyl.

[0065] <Mixing steps>

[0066] The mixing step refers to mixing the 3-halogeno-4-alkylbenzoic acid with the ammonia solution.

[0067] 3-Halo-4-alkylbenzoic acid

[0068] In the preparation method of 3-halogen-4-alkylbenzoic acid in the past, generally adopt alkyl-substituted benzoic acid and water to be added in reaction vessel, and add halogen simple substance (chlorine and bromine etc.) to carry out heating reaction, but in actual use process, chlorine gas is more difficult to control the feeding amount, easily causes reaction substrate reaction incomplete or is replaced by too much chlorine, the price of bromine is also relatively expensive, and, this reaction, before adding halogen simple substance, also needs to add a certain amount of quaternary ammonium salt phase transfer catalyst, and the raw material cost required for reaction is higher, and for large-scale industrial production, it can not be said to be suitable. In addition, hydrogen peroxide etc. can also be adopted as oxidant in some building-up reactions, but the risk of explosion may be increased, and the safety factor is reduced in industrial production.

[0069] In some preferred embodiments of the present invention, the 3-halogenated-4-alkylbenzoic acid can be obtained by mixing p-alkylbenzoic acid, nitric acid and a halogenating agent, heating the mixture and then performing post-treatment.

[0070] Among them, the equation involved in the reaction is:

[0071]

[0072] Wherein, R is a C1-C20 alkyl group, and in some specific embodiments of the present invention, it can be selected from any one of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. In some preferred embodiments of the present invention, R is methyl.

[0073] X is a halogen, which may be chlorine, bromine or iodine. In some preferred embodiments of the present invention, X is chlorine or bromine, and more preferably, it may be bromine.

[0074] The halogenating agent (HX or MX) described in the present application can 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 their aqueous solutions. Wherein, the aqueous solution of the halogenating agent 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 halogenating agent 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 to cause a substitution reaction, resulting in a low yield of the target product. Based on the reactivity of halogen, in some specific embodiments of the present invention, the halogenating agent or its aqueous solution is preferably hydrochloric acid, hydrobromic acid, sodium bromide.

[0075] In the mixing step, the concentration of the nitric acid can be 30% to 85%, preferably 35% to 65%, more preferably 37% to 60%, and more preferably 40% to 50%. If the concentration of the nitric acid is too low, the oxidation effect is not strong, making it difficult for the halogen to replace the benzene ring, affecting the final yield of the product; if the concentration of the nitric acid is too high, the operation risk increases, and the nitric acid may volatilize and smoke during the heating reaction, making the reaction difficult to proceed, which becomes an obstacle to obtaining the target product with high purity and high yield.

[0076] There is no particular limitation on the amount of nitric acid used. In some specific embodiments, 700 to 1400 mL of 35% to 45% nitric acid can be added to 1 mol of p-alkylbenzoic acid. From the perspective of saving raw materials and ensuring yield, it is preferred that 800 to 1200 mL of 35% to 45% nitric acid be added to 1 mol of p-alkylbenzoic acid. It is more preferred that 850 to 1000 mL of 35% to 45% nitric acid be added to 1 mol of p-alkylbenzoic acid.

[0077] 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), and more preferably 1:(1.2-2.3). Adding an appropriate amount of halogenating agent can maximize the substitution at the 3-position, obtain a high yield of the target product, and not cause waste of the reaction substrate. If the amount of halogenating agent added is small, the time required for the reaction may be significantly extended, up to 3-4 days, and the conversion rate and yield will also be lower; if more halogenating agent is added, it is not only inconsistent with the principle of economic saving, but also may affect the purity and yield of the reaction product.

[0078] In addition, there is no particular limitation on the order of adding the three reactants. In some specific embodiments, p-alkylbenzoic acid can be added to nitric acid and then the halogenating agent can be added; p-alkylbenzoic acid can also be added to nitric acid and then the halogenating agent can be added. Mixing p-alkylbenzoic acid with nitric acid first and then adding the halogenating agent can make the reaction easier and minimize the generation of by-products.

[0079] In some specific embodiments, the heating reaction refers to heating the reaction system to 50-110°C, further 60-100°C. Temperature has a certain effect 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 be incomplete, the reaction yield decreases, and the halogen atom is easily substituted at the 2nd position, resulting in the reaction to produce other isomers. There is no particular limitation on the maintenance time of heating. Generally, the reaction system can be heated to reflux, and then the temperature is maintained to allow the reaction system to react.

[0080] The heating method is not particularly limited, and may be an indirect heating method such as an air bath or a water bath.

[0081] In some specific embodiments, the reaction time is 2.5 to 8 hours, preferably 3 to 6 hours, and more preferably 4 hours.

[0082] In some other specific embodiments, a cooling step may be included before the post-treatment step. Preferably, the reaction system is cooled to room temperature.

[0083] In some specific embodiments, the reaction system is cooled to room temperature and then post-treated, wherein the post-treatment steps include filtering, washing and drying.

[0084] Wherein the filtration can be carried out by solid-liquid separation, wherein the separation method is not particularly limited, and suction filtration can be used. After the filtration, the unreacted (or remaining) nitric acid can be collected, and the concentration can be adjusted by adding a higher concentration (such as more than 50%) of nitric acid to react again as a reaction substrate in the preparation method of 3-halogenated-4-alkylbenzoic acid, thereby realizing recycling, improving the utilization rate of the reaction raw materials, saving costs, and greatly reducing the generation of waste liquid. For the concentration of the nitric acid added, preferably 60% to 85% nitric acid, further 60% to 70% nitric acid, for the volume of the nitric acid added, preferably after the unreacted nitric acid is collected, its volume is measured, and the difference between it and the original nitric acid volume is calculated, and the higher concentration of nitric acid is added to make the volume up to the original nitric acid volume, and it is reacted again as the reaction raw material of 3-halogenated-4-alkylbenzoic acid. During the reaction, conventional analytical methods in organic chemistry, such as thin layer chromatography (spot plate) or high performance liquid chromatography (HPLC), can be used to determine whether the p-alkylbenzoic acid has reacted completely. If the reaction has not been completed, a small amount of nitric acid with a higher concentration can be added to promote the complete reaction.

[0085] After filtering, there is a washing step, in which the obtained solid can be washed with clean water, and then dried to obtain 3-halogenated-4-alkylbenzoic acid, wherein the drying method can preferably be heated vacuum drying, and weighed after drying.

[0086] The above reaction for obtaining 3-halogenated-4-alkylbenzoic acid uses benzoic acid substituted with an alkyl group at the para position (4 position) as a starting reactant, adds nitric acid with an oxidizing effect, and then adds a halogenating agent to provide a halogen element, generating a halide cation to attack the benzene ring, thereby obtaining the target product. Since the alkyl positioning group is at the ortho-para position, the carboxylic acid positioning group is at the meta position, and the 2 position is a passivated position and will not be substituted, the halogen in the basic reaction will not undergo a halogenation reaction at positions other than the 3 position, and thus will not generate a variety of positional isomers, and the obtained product has a high purity and yield.

[0087] Ammonia solution

[0088] The ammonia solution of the present invention is selected from any one of ammonia water, methanol, ethanol or tetrahydrofuran solution of ammonia. In some specific embodiments of the present invention, the ammonia solution is preferably ammonia water. Wherein, the mass percentage of ammonia in the ammonia solution (ammonia content) can be 20% to 30%, preferably 22% to 28%, and more preferably 24% to 26%. In some specific embodiments of the present invention, the ammonia content of ammonia water is preferably 23% to 28%, and more preferably 25%. If the ammonia content of the ammonia solution is too low, it will make it difficult for the amino group to replace the benzene ring, affecting the final yield of the product; if the concentration of the ammonia solution is too high, it will cause a waste of reaction raw materials.

[0089] The application does not particularly limit the amount of ammonia solution. In some specific embodiments of the application, 1 mol of 3-chloro-4-methylbenzoic acid can be added with 200-600 g of ammonia water with an ammonia content of 20%-30%. From the perspective of saving raw materials and ensuring yield, preferably, 1 mol of 3-chloro-4-methylbenzoic acid can be added with 300-500 g of ammonia water with an ammonia content of 20%-30%. More preferably, 1 mol of 3-chloro-4-methylbenzoic acid can be added with 350-450 g of ammonia water with an ammonia content of 20%-30%.

[0090] In some specific embodiments of the present application, the molar ratio of the added 3-halogenated-4-alkylbenzoic acid to the ammonia solution is 1:(2.0-20.0), preferably 1:(4.0-15.0), and more preferably 1:(5.0-10.0). Adding an appropriate amount of ammonia solution as defined in the present application can replace the halogen atom with an amino group at the 3-position to the maximum extent, thereby obtaining a high yield of the target product without causing a waste of the reaction substrate. If a small amount of ammonia solution is added, the time required for the reaction may be significantly prolonged, and the conversion rate and yield will also be lower; if more ammonia solution is added, it will not only fail to meet the principle of economic savings, but may also affect the purity and yield of the reaction product.

[0091] mix

[0092] The present application does not particularly limit the conditions for the mixed reaction. In some specific embodiments of the present invention, the reaction is preferably carried out under high pressure. The high pressure refers to a pressure of 1 MPa to 10 MPa, preferably 2 to 9 MPa. The reaction vessel used is not particularly limited, and it is preferred to use an autoclave / high-pressure tank commonly used in the art. There is no particular limitation on the capacity of the reaction vessel.

[0093] <Step of heating the reaction system to react>

[0094] Warming up

[0095] In some specific embodiments of the present invention, when the reaction is carried out under high pressure, the reaction system is heated to 50-180°C, further to 60-160°C; in some specific embodiments of the present invention, when the halogen in the 3-halogenated-4-alkylbenzoic acid is chlorine, since the chlorine element is less active, 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 reaction system is heated to 90-110°C, further to 95-105°C; in some specific embodiments of the present invention, when the halogen in the 3-halogenated-4-alkylbenzoic acid is bromine, since the bromine element is more active, the reaction can be carried out under normal pressure, and the temperature is preferably 100-105°C. Temperature has a certain effect on the substitution reaction of the amino group on the benzene ring. If the heating temperature is too high, it may cause a large loss of ammonia volatilization and increase safety risks. If the heating temperature is too low, the reaction may be incomplete and the reaction yield may decrease.

[0096] The present application does not specifically limit the method of heating. In some specific embodiments of the present invention, it may be electric heating, electric heating with thermal oil, or steam heating using saturated steam or high-pressure superheated steam to heat the reaction system. It may be open or closed. In some specific embodiments of the present invention, electric heating with thermal oil is used for heating.

[0097] reaction

[0098] The reaction time of the present application in some specific embodiments of the present invention is 1 to 12 hours, preferably 3 to 11 hours, and more preferably 10 hours.

[0099] The reaction equation is as follows:

[0100]

[0101] Wherein, R is a C1-C20 alkyl group, and in some specific embodiments of the present invention, it can be selected from any one of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. In some preferred embodiments of the present invention, R is methyl.

[0102] X is a halogen, which may be chlorine, bromine or iodine. In some preferred embodiments of the present invention, X is chlorine or bromine.

[0103] In some other specific embodiments of the present application, a cooling step may be included before the post-treatment step. Preferably, the reaction system is cooled to room temperature.

[0104] In some other specific embodiments of the present application, after the reaction system is cooled to room temperature, a step of bubbling an inert gas such as nitrogen into the reaction solution to drive away the remaining unreacted ammonia in the solution may be included.

[0105] <Adjusting the pH value of the reaction system>

[0106] In some specific embodiments of the present invention, after nitrogen or other inert gas is bubbled into the reaction solution to drive away the remaining unreacted ammonia, a step of adjusting the pH value of the reaction system is performed. 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 hydrochloric acid with a mass fraction of hydrogen chloride of 30% to 35% can be added, and more preferably conventional commercially available hydrochloric acid with a concentration of 31% can be added; the pH value of the reaction system is adjusted to 4 to 6.5, preferably to 4.5 to 6.

[0107] <Post-processing steps>

[0108] In some specific embodiments of the present invention, the reaction system is cooled to room temperature and then post-treated, wherein the post-treatment steps include filtering, washing and drying.

[0109] The filtration can be performed by solid-liquid separation, and the separation method is not particularly limited, and suction filtration can be used.

[0110] After filtering, there is a washing step, in which the obtained solid can be washed with clean water. Then, the solid is dried to obtain the target product 3-amino-4-alkylbenzoic acid, wherein the drying method can preferably be heated vacuum drying, and the solid is weighed after drying, and the yield is calculated by the target product (actual) generated amount / theoretical generated amount of the target product×100%.

[0111] In some preferred embodiments of the present application, nitric acid with an oxidizing effect is added to the p-alkylbenzoic acid, and then a halogenating agent is added to provide a halogen element, generating a halide cation to attack the benzene ring. 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 and will not be substituted, the halogen of the basic reaction will not undergo a halogenation reaction at positions other than the 3 position, thereby obtaining 3-halogenated-4-alkylbenzoic acid. Afterwards, the 3-halogenated-4-alkylbenzoic acid is mixed with an ammonia solution, the temperature is raised, the pH value of the reaction system is adjusted to acidic, and then post-processed. Due to the electric absorption effect of the carboxyl group, the halogen atoms on the benzene ring are activated, reducing the halogen activation energy, so the reaction can react without using a catalyst, and the target product 3-amino-4-alkylbenzoic acid with high yield and high yield can be obtained.

[0112] The present invention is further illustrated by the following examples, but is not intended to be limiting.

[0113] Example

[0114] Preparation Example 1

[0115] Add p-toluic acid (5 g) to 40% nitric acid (30 ml), add hydrochloric acid (31% concentration, 5.2 g), heat to 100°C, react for 3 hours, monitor the reaction completion, cool, filter the solid, wash with water, and dry to obtain the product 3-chloro-4-methylbenzoic acid (5.9 g), purity: 97.9% yield: 94%. See the NMR of the product for details. Figure 1 .

[0116] Preparation Example 2

[0117] Add p-toluic acid (5 g) to 40% nitric acid (30 ml), add hydrobromic acid (48% concentration, 7.5 g), heat to 100°C, react for 2.5 hours, monitor the reaction completion, cool, filter the solid, wash with water, and dry to obtain the product 3-bromo-4-methylbenzoic acid (7.4 g), purity: 98.2% yield: 94%. See the NMR of the product for details. Figure 2 .

[0118] Preparation Example 3

[0119] In the filtered nitric acid (26 ml) recovered in Preparation Example 1, add 4 ml of 65% nitric acid, then add p-toluic acid (5 g) and hydrochloric acid (31% concentration, 5 g), heat to 100°C, react for 3 hours, monitor the completion of the reaction, cool, filter the solid, wash with clean water, and dry to obtain the product 3-chloro-4-methylbenzoic acid (5.92 g), purity: 97.7%, yield: 94%.

[0120] Example 1

[0121] Add 3-chloro-4-methylbenzoic acid (10 g) obtained in Preparation Example 1 and ammonia water (25% ammonia content, 20 g) into a 100 ml autoclave, seal the autoclave, heat to 160 degrees, react for 10 hours, monitor the completion of the reaction, cool, blow nitrogen into the reaction solution to drive away most of the ammonia, adjust the pH to 6 with concentrated hydrochloric acid in an ice bath, filter the solid, wash with clean water, and dry to obtain the product 3-amino-4-methylbenzoic acid (8.25 g). Purity: 97.9%, yield: 93.4%.

[0122] Example 2

[0123] Add 3-bromo-4-methylbenzoic acid (10 g) obtained in Preparation Example 2 and ammonia water (25% ammonia, 20 g) to a 100 ml autoclave, seal the autoclave, heat to 160 degrees, react for 3 hours, monitor the completion of the reaction, cool, blow nitrogen into the reaction solution to drive away most of the ammonia, adjust the pH value to 6 with concentrated hydrochloric acid in an ice bath, filter the solid, wash with clean water, and dry to obtain the product 3-amino-4-methylbenzoic acid (6.79 g). Purity: 99%, yield: 96.7%, the obtained product was characterized by NMR and liquid chromatography, the results are shown in Figure 3 and Figure 4 .

[0124] Example 3

[0125] Add 3-bromo-4-methylbenzoic acid (10 g) and ammonia water (25% ammonia content, 20 g) to a 100 ml single-mouth bottle, connect a reflux tube, heat to 100 degrees and reflux, react for 3 hours, monitor the reaction and it is not complete, add ammonia water (25% content, 20 g), react for 8 hours, monitor the reaction and it is complete, cool, vacuum the reaction solution to remove most of the ammonia, adjust the pH value to 6 with concentrated hydrochloric acid in an ice bath, filter the solid, wash with clean water, and dry to obtain the product 3-amino-4-methylbenzoic acid (5.92 g). Purity: 98.1%, yield: 84.3%

[0126] Example 4

[0127] Add 3-bromo-4-methylbenzoic acid (10 g) and ammonia water (ammonia content 25%, 50 g) to a 100 ml autoclave, seal the autoclave, heat to 160 degrees, react for 1 hour, monitor the completion of the reaction, cool, blow nitrogen into the reaction solution to drive away most of the ammonia, adjust the pH to 6 with concentrated hydrochloric acid in an ice bath, filter the solid, wash with clean water, and dry to obtain the product 3-amino-4-methylbenzoic acid (6.9 g). Purity: 99%, yield: 98%.

[0128] As can be seen from the above examples, the preparation method of 3-amino-4-alkylbenzoic acid of the present application is simple to operate, the product yield reaches more than 93.4%, and the purity reaches more than 97.9%. Compared with the preparation method in the prior art, the reaction conditions of the present application have low equipment requirements, simple reaction steps, no precious metals or other toxic substances are used as special catalysts, low raw material costs, no safety hazards of temperature explosion, very little three wastes are generated, and the yield and purity of the product are very high.

[0129] The above embodiments are only used to illustrate several embodiments of the present invention, and the description thereof is relatively specific and detailed, but it should not be understood that any limitation is imposed on 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 fall within the scope of protection of the present invention.

[0130] Industrial Applicability

[0131] The preparation method of the invention can be widely used in the preparation of 3-amino-4-alkylbenzoic acid in industry.

Claims

1. A method for preparing 3-amino-4-alkylbenzoic acid, characterized in that: The 3-amino-4-alkylbenzoic acid has the following general formula (I): Wherein, R is a C1-C20 alkyl group; Furthermore, the preparation method comprises the step of mixing 3-halogenated-4-alkylbenzoic acid with an ammonia solution for reaction, and the preparation method further comprises the step of heating the reaction system for reaction, The heating of the reaction system refers to heating the temperature to 60-160°C. The mass percentage of ammonia in the ammonia solution is 22% to 30%.

2. The preparation method according to claim 1, characterized in that: The preparation method further comprises: Steps for adjusting the pH value of the reaction system, And the step of post-treating the reaction system to obtain 3-amino-4-alkylbenzoic acid.

3. The preparation method according to claim 1 or 2, characterized in that: 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 claim 1 or 2, characterized in that: The ammonia solution is selected from any one of aqueous ammonia, methanol, ethanol or tetrahydrofuran solutions of ammonia.

5. The preparation method according to claim 1 or 2, characterized in that: The molar ratio of the 3-halogenated-4-alkylbenzoic acid to the ammonia solution is 1:(2.0-20.0).

6. The preparation method according to claim 1 or 2, characterized in that: The reaction time is 1 to 12 hours.

7. The preparation method according to claim 2, characterized in that: The step of adjusting the pH value of the reaction system is to adjust the pH value to 4-6.

5.

8. The preparation method according to claim 2, characterized in that: The post-treatment includes filtration, washing and drying.

9. The preparation method according to claim 1 or 2, characterized in that: The 3-halogenated-4-alkylbenzoic acid is obtained by mixing p-alkylbenzoic acid, nitric acid and a halogenating agent, heating the mixture and then performing post-treatment.

10. The preparation method according to claim 9, characterized in that: 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 their aqueous solutions.

11. The preparation method according to claim 9, characterized in that: The concentration of the nitric acid is 30% to 85%.

12. The preparation method according to claim 9, characterized in that: The molar ratio of the p-alkylbenzoic acid to the halogenating agent is 1:(1.0-3.0).

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