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

Preparation method of 3-hydroxy-4-methylbenzoic acid Download PDF

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CN115894211A
CN115894211A CN202211407157.7A CN202211407157A CN115894211A CN 115894211 A CN115894211 A CN 115894211A CN 202211407157 A CN202211407157 A CN 202211407157A CN 115894211 A CN115894211 A CN 115894211A
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alkylbenzoic
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鲁喜成
陈庆先
朱晶
刘鹏飞
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Shanghai Enong Biotechnology Co ltd
Shandong Longliheng Pharmaceutical Co ltd
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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):
Figure DDA0003937295360000011
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

一种3-羟基-4-甲基苯甲酸的制备方法A kind of preparation method of 3-hydroxy-4-methylbenzoic acid

技术领域technical field

本发明属于有机化合物合成领域,具体涉及一种3-羟基-4-烷基苯甲酸的制备方法。The invention belongs to the field of organic compound synthesis, and in particular relates to a preparation method of 3-hydroxy-4-alkylbenzoic acid.

背景技术Background technique

羟基-4-甲基苯甲酸是一种重要的有机合成中间体,广泛用于医药、农、有机切块等,特别在新的制药领域应用广泛。Hydroxy-4-methylbenzoic acid is an important intermediate in organic synthesis, widely used in medicine, agriculture, organic cutting, etc., especially in new pharmaceutical fields.

以往的制备方法中,若苯环上带有卤素原子,例如溴苯,如果与氢氧化钠等碱性物质反应,不仅需要高温高压的条件,还需要Cu等金属作为催化剂才可以发生取代反应;羟基-4-甲基苯甲酸现有的合成方法例如引用文献1使用了3-甲氧基-4-甲基苯甲酸甲酯先脱甲醚然后通过水解制得3-羟基-4-甲基苯甲酸,但是该制备方法原料成本相对较高,此方法的反应路径如下: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:

Figure BDA0003937295340000011
Figure BDA0003937295340000011

引用文献2采用对甲基苯甲酸先磺化再水解的方式得到3-羟基4-甲基苯甲酸,该制备方法反应原料的成本较高,磺化反应步骤需要150度的高温,并且产生大量废水,此方法的反应路径如下: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:

Figure BDA0003937295340000012
Figure BDA0003937295340000012

引用文献:Citation:

引用文献1:WO2015161011Citation 1: WO2015161011

引用文献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)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)

发明内容Contents of the invention

发明要解决的问题The problem to be solved by the invention

针对如上所述的现有技术中存在的问题,亟需开发一种反应步骤少,不需使用催化剂,操作简便,总体耗时短,原料成本低,产品的纯度以及收率高,产生的三废少的3-羟基-4-烷基苯甲酸的制备方法。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.

用于解决问题的方案solutions to problems

具体地,本发明提供了如下的技术方案:Specifically, the present invention provides the following technical solutions:

[1]一种3-羟基-4-烷基苯甲酸的制备方法,其特征在于,所述3-羟基-4-烷基苯甲酸具有以下通式(I):[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):

Figure BDA0003937295340000021
Figure BDA0003937295340000021

其中,R为C1~C20的烷基;Wherein, R is a C1-C20 alkyl group;

并且,所述制备方法包括将3-卤代-4-烷基苯甲酸与碱、极性溶剂混合反应的步骤。Moreover, the preparation method includes the step of mixing and reacting 3-halogeno-4-alkylbenzoic acid with alkali and polar solvent.

[2]根据[1]所述的制备方法,其中,所述制备方法还包括:[2] The preparation method according to [1], wherein the preparation method further comprises:

将反应体系升温进行反应的步骤、调节反应体系pH值的步骤、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,

以及对反应体系进行后处理以得到3-羟基-4-烷基苯甲酸的步骤。And the step of post-processing the reaction system to obtain 3-hydroxyl-4-alkylbenzoic acid.

[3]根据[1]或[2]所述的制备方法,其中,[3] The production method according to [1] or [2], wherein,

所述R选自甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基中的任一种。The R is selected from any one of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

[4]根据[1]~[3]任一技术方案所述的制备方法,其中,[4] The preparation method according to any one of [1] to [3], wherein,

所述碱选自碱金属的氢氧化物、碱金属盐、碱土金属的氢氧化物、碱金属盐、氨水中的任意一种;The alkali is selected from any one of alkali metal hydroxides, alkali metal salts, alkaline earth metal hydroxides, alkali metal salts, and ammonia;

所述极性溶剂选自水、四氢呋喃、二氧六环中的任意一种。The polar solvent is selected from any one of water, tetrahydrofuran and dioxane.

[5]根据[1]~[4]中任一技术方案所述的制备方法,其中,[5] The preparation method according to any one of [1] to [4], wherein,

所述3-卤代-4-烷基苯甲酸与所述碱的摩尔比为1:(2.0~3.0)。The molar ratio of the 3-halo-4-alkylbenzoic acid to the base is 1:(2.0-3.0).

[6]根据[1]~[5]中任一技术方案所述的制备方法,其中,[6] The preparation method according to any one of [1] to [5], wherein,

所述极性溶剂的用量为3-卤代-4-甲基苯甲酸质量的1~20倍。The amount of the polar solvent used is 1 to 20 times the mass of the 3-halo-4-methylbenzoic acid.

[7]根据[1]~[6]中任一技术方案所述的制备方法,其中,[7] The preparation method according to any one of [1] to [6], wherein,

所述将反应体系升温指的是将温度升至50~180℃;Said raising the temperature of the reaction system refers to raising the temperature to 50-180°C;

所述进行反应的时间为1~10h。The time for the reaction is 1-10 hours.

[8]根据[1]~[7]中任一技术方案所述的制备方法,其中,[8] The preparation method according to any one of [1] to [7], wherein,

所述调节反应体系pH值的步骤是将pH值调节至4~6.5。The step of adjusting the pH value of the reaction system is to adjust the pH value to 4-6.5.

[9]根据[1]~[8]中任一技术方案所述的制备方法,其特征在于,[9] The preparation method according to any one of [1] to [8], characterized in that,

所述后处理包括过滤、洗涤和干燥。The post-processing includes filtering, washing and drying.

[10]根据[1]~[9]任一技术方案所述的制备方法,其中,[10] The preparation method according to any one of [1] to [9], wherein,

所述3-卤代-4-烷基苯甲酸通过将对烷基苯甲酸、硝酸和卤代试剂混合加热后再进行后处理,即得;The 3-halogenated-4-alkylbenzoic acid is obtained by mixing and heating p-alkylbenzoic acid, nitric acid and a halogenating agent before post-processing;

其中,所述卤代试剂选自氯化氢、氯化钠、氯化钾、溴化氢、溴化钠、溴化钾、氢碘酸、碘化钠、碘化钾或其水溶液中的一种或多种;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 ;

进一步地,所述硝酸的浓度为30%~85%;Further, the concentration of the nitric acid is 30%-85%;

更进一步地,所述对烷基苯甲酸与所述卤代试剂的摩尔比为1:(1.0~3.0)。Furthermore, the molar ratio of the p-alkylbenzoic acid to the halogenating agent is 1:(1.0-3.0).

发明的效果The effect of the invention

与现有技术相比,本发明具有以下的有益效果:Compared with the prior art, the present invention has the following beneficial effects:

1、本发明的制备方法对设备要求相对较低,不需要使用催化剂,反应步骤少,操作简便,总体耗时短,产生的三废很少;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、本发明的制备方法使用的原料成本低,并且在不使用催化剂的情况下,将反应时间显著缩短,并且能够以高收率、高纯度获得目标产物。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、在本发明的一些优选实施方式中,本发明所采用的原料3-卤代-4-烷基苯甲酸可以通过将对烷基苯甲酸、硝酸和卤代试剂混合得到,该方法不使用昂贵的卤素单质,原料成本低,没有添加催化剂等复杂的操作步骤,且使用后的稀硝酸可以进行回收再利用,产生的三废极少。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.

需要说明的是,上述的记载并不是公开了本发明的全部实施方式和本发明的全部优点。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.

附图说明Description of drawings

图1:制备例1得到的3-氯-4-甲基苯甲酸的核磁谱图Fig. 1: the nuclear magnetic spectrum of the 3-chloro-4-methylbenzoic acid that preparation example 1 obtains

图2:制备例2得到的3-溴-4-甲基苯甲酸的核磁谱图Fig. 2: the nuclear magnetic spectrum of the 3-bromo-4-methylbenzoic acid that preparation example 2 obtains

图3:实施例2得到的3-羟基-4-甲基苯甲酸的核磁谱图Fig. 3: The nuclear magnetic spectrum of the 3-hydroxyl-4-methylbenzoic acid that embodiment 2 obtains

图4:实施例2得到的3-羟基-4-甲基苯甲酸的液相色谱图Fig. 4: the liquid chromatogram of the 3-hydroxyl-4-methylbenzoic acid that embodiment 2 obtains

具体实施方式Detailed ways

以下对本发明的实施方式进行说明,但本发明不限定于此。本发明不限于以下说明的各构成,在发明请求保护的范围内可以进行各种变更,而适当组合不同实施方式、实施例中各自公开的技术手段而得到的实施方式、实施例也包含在本发明的技术范围中。另外,本说明书中记载的文献全部作为参考文献在本说明书中进行援引。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.

除非另有定义,本发明所用的技术和科学术语具有与本发明所属技术领域中的普通技术人员所通常理解的相同含义。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.

本说明书中,使用“数值A~数值B”表示的数值范围是指包含端点数值A、B的范围。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.

本说明书中,使用“以上”或“以下”表示的数值范围是指包含本数的数值范围。In this specification, the numerical range represented by "above" or "below" means a numerical range including the number.

本说明书中,“室温”指不施加温度控制操作,一般指20℃~30℃。In this specification, "room temperature" refers to an operation without temperature control, and generally refers to 20°C to 30°C.

本说明书中,使用“可以”表示的含义包括了进行某种处理以及不进行某种处理两方面的含义。In this specification, the meaning expressed by "may" includes the meaning of performing certain processing and not performing certain processing.

本说明书中,使用“任选地”或“任选的”表示某些物质、组分、执行步骤、施加条件等因素使用或者不使用。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.

本说明书中,所使用的单位名称均为国际标准单位名称,并且如果没有特别声明,所使用的“%”均表示重量或质量百分含量。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.

本发明的说明书和权利要求书中的术语“包括”以及它们任何变形,意图在于覆盖不排他的包含。例如包含一系列步骤或单元的过程、方法或系统、产品或设备没有限定于已列出的步骤或单元,而是可选地还包括没有列出的步骤或单元,或可选地还包括对于这些过程、方法、产品或设备固有的其它步骤或单元。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.

本说明书中,所提及的“优选的实施方案”、“实施方案”等是指所描述的与该实施方案有关的特定要素(例如,特征、结构、性质和/或特性)包括在此处所述的至少一种实施方案中,并且可存在于其它实施方案中或者可不存在于其它实施方案中。另外,应理解,所述要素可以任何合适的方式组合在各种实施方案中。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.

本说明书中,极性溶剂是指溶剂分子为极性分子的溶剂。In this specification, a polar solvent refers to a solvent whose solvent molecule is a polar molecule.

本说明书中,3-卤代-4-烷基苯甲酸与碱的摩尔比是以溶液中的碱的摩尔数为基准进行计算的。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.

本发明提供了一种3-羟基-4-烷基苯甲酸的制备方法,所述方法包括将3-卤代-4-烷基苯甲酸与碱、极性溶剂混合反应的步骤。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.

以下将针对以上每一步骤进行逐一说明。The following will describe each of the above steps one by one.

本发明所述的3-羟基-4-烷基苯甲酸具有以下通式(I):3-hydroxyl-4-alkylbenzoic acid of the present invention has following general formula (I):

Figure BDA0003937295340000051
Figure BDA0003937295340000061
Figure BDA0003937295340000051
Figure BDA0003937295340000061

其中,R为C1~C20的烷基,在本发明的一些具体实施方式中,可以选自甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基中的任一种,在本发明一些优选的实施方案中,R为甲基。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.

<混合的步骤><mixing steps>

混合的步骤指的是将3-卤代-4-烷基苯甲酸与氨溶液进行混合。The mixing step refers to mixing the 3-halo-4-alkylbenzoic acid with the ammonia solution.

3-卤代-4-烷基苯甲酸3-Halo-4-alkylbenzoic acid

在以往的3-卤代-4-烷基苯甲酸的制备方法中,一般采用将烷基取代的苯甲酸和水加入至反应容器中,并加入卤素单质(氯气和溴素等)进行加热反应,但在实际的使用过程中,氯气气体较难控制通入量,容易导致反应底物反应不完全或者被过多的氯取代,溴素的价格也相对昂贵,并且,该反应在加入卤素单质之前,还需添加一定量的季铵盐类相转移催化剂,反应所需原料成本较高,对于大规模的工业生产来说,并不能说是合适的。此外,有的合成反应中还会采用过氧化氢等作为氧化剂,但可能会增加爆炸的风险,在工业生产中降低安全系数。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.

而在本发明的一些优选的实施方案中,所述3-卤代-4-烷基苯甲酸可以通过将对烷基苯甲酸、硝酸和卤代试剂混合加热反应之后再进行后处理得到。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.

其中,反应所涉及的方程式为:Wherein, the equation involved in the reaction is:

Figure BDA0003937295340000062
Figure BDA0003937295340000062

其中,R为C1~C20的烷基,在本发明的一些具体实施方式中,可以选自甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基中的任一种,在本发明一些优选的实施方案中,R为甲基。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为卤素,可以为氯、溴或碘,在本发明一些优选的实施方案中,X为氯、溴,更优选的,可以为溴。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.

本申请所述的卤代试剂(HX或者MX)可以选自氯化氢、氯化钠、氯化钾、溴化氢、溴化钠、溴化钾、氢碘酸、碘化钠、碘化钾或其水溶液中的一种或多种。其中,所述卤代试剂的水溶液可以为盐酸(氯化氢的水溶液)、氢溴酸(溴化氢的水溶液)等,所述卤代试剂的水溶液的浓度可以为25%~60%,优选地可以为30%~50%,例如,盐酸的浓度优选的为31%,氢溴酸的浓度优选的为48%。若水溶液的浓度过高,则会造成资源的浪费,还有可能产生其他的副产物影响目标产物的收率及纯度;若水溶液的浓度过低则有可能难以发生取代反应而导致目标产物产率过低。基于卤素的反应活性,在本发明一些具体的实施方案中,所述卤代试剂或其水溶液优选为盐酸、氢溴酸、溴化钠。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.

在混合步骤中,所述硝酸的浓度可以为30%~85%,优选为35%~65%,进一步优选为37%~60%,更优选为40%~50%。如果硝酸的浓度过低,则产生的氧化作用不强,使得卤素难以与苯环发生取代,影响产品最终的收率;若硝酸的浓度过高,操作危险性增加,在加热反应的过程中硝酸可能会因挥发而冒烟,使得反应难以进行,成为得到高纯度高产率的目标产物的障碍。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.

对于硝酸的用量,没有特别限定,在一些具体的实施方案中,1mol对烷基苯甲酸可以对应加入700~1400mL的浓度为35%~45%的硝酸,从节省原料又保证收率的角度考虑,优选地为1mol对烷基苯甲酸对应加入800~1200mL的浓度为35%~45%的硝酸,更优选的可以为1mol对烷基苯甲酸对应加入850~1000mL的浓度为35%~45%的硝酸。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.

在一些具体的实施方案中,加入的对烷基苯甲酸与卤代试剂的摩尔比为1:(1.0~3.0),优选地为1:(1.05~2.7),更优选的为1:(1.2~2.3)。加入适当的量的卤代试剂,可以使其最大限度的在3位上进行取代,得到高收率的目标产物的同时,也不至于造成反应底物的浪费。如果卤代试剂加入的量较少,反应所需时间有可能显著变长,多则3~4天,并且转化率与收率也会变低;若加入较多的卤代试剂,不仅不符合经济节约的原则,还有可能影响反应产物的纯度和收率。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.

另外,对于三种反应物加入的先后顺序没有特别限定,在一些具体的实施方案中,可以将对烷基苯甲酸加入至硝酸中,然后再加入卤代试剂;也可以在硝酸中加入对烷基苯甲酸再加入卤代试剂。先将对烷基苯甲酸与硝酸混合,最后再加入卤代试剂能够使反应更容易进行,最大限度的减少副产物的产生。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.

在一些具体的实施方式中,加热反应是指将反应体系加热升温至50~110℃,进一步地为60~100℃。温度对苯环上的卤代反应存在一定的影响,如果加热的温度过高,则可能会导致硝酸挥发损耗大,并且增加安全风险,如果加热的温度过低,则可能会使得反应进行不完全,反应产率下降,并且卤素原子容易2位进行取代,导致反应产生其他异构体。对于加热的维持时间没有特别限定,通常可以使反应体系升温至出现回流即可,然后保持该温度使反应体系进行反应。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.

对于加热升温的方式,没有特别限定,可以为空气浴、水浴等间接加热方式。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.

反应时间在一些具体的实施方式中,为2.5~8h,优选地可以为3~6h,更优选地为4h。In some specific embodiments, the reaction time is 2.5-8 hours, preferably 3-6 hours, more preferably 4 hours.

在另外一些具体的实施方式中,在后处理的步骤之前还可以包括冷却的步骤,优选的,将反应体系冷却至室温。In other specific embodiments, a cooling step may be included before the post-treatment step, preferably, the reaction system is cooled to room temperature.

在一些具体的实施方式中,将反应体系冷却至室温后对反应体系进行后处理,其中后处理的步骤包括过滤、洗涤和干燥。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.

其中过滤可以通过固液分离进行,其中分离的方法没有特别限制,可以使用抽滤。过滤之后可以将未反应(或剩余)的硝酸收集起来,通过补入较高浓度(比如50%以上)的硝酸调节浓度,以重新作为3-卤代-4-烷基苯甲酸的制备方法中的反应底物进行反应,从而实现了循环利用,提高了反应原料的利用率,节约了成本,还很大程度上减少了废液的产生。对于补入的硝酸的浓度,优选地为60%~85%的硝酸,进一步为60%~70%的硝酸,对于补入的硝酸的体积,优选的为将未反应的硝酸收集之后,测定其体积,计算其与原始硝酸体积的差值,补入较高浓度的硝酸将体积补至原始硝酸体积,将其重新作为3-卤代-4-烷基苯甲酸的反应原料进行反应。反应过程中可通过有机化学中常规的分析手段,例如薄层色谱分析法(点板)或高效液相色谱法(HPLC)来判断对烷基苯甲酸是否反应完全,如尚未反应完全,可继续补入少量较高浓度的硝酸,促使反应进行完全。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.

过滤之后为洗涤的步骤,洗涤可以将得到的固体用清水洗涤。然后干燥以得到3-卤代-4-烷基苯甲酸,其中干燥的方法优选地可以使用加热真空干燥,干燥之后称重。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.

上述得到3-卤代-4-烷基苯甲酸的反应,采用烷基在对位(4位)取代的苯甲酸作为起始反应物,加入具有氧化作用的硝酸再加入卤代试剂提供卤族元素,生成卤正离子进攻苯环,从而得到目标产物。由于烷基定位基团在邻对位,羧酸定位基团是间位,2位是被钝化的位置,不会上取代,因此基本反应的卤素不会在除3位以外的位置上进行卤代反应,因此不会生成多种的位置异构体,得到的产物纯度及产率均较高。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

本发明的碱选自碱金属的氢氧化物、碱金属盐、碱土金属的氢氧化物、碱金属盐、氨水中的任意一种,或者也可以选择上述碱的水溶液,可以列举的为氢氧化钠、氢氧化钾、氢氧化钙等,在本发明的一些具体的实施方式中,所述碱优选的为氢氧化钾或其水溶液。其中,以溶液的质量计,所述碱的水溶液的质量分数为60%~95%,优选地为70~93%,更优选的为80%~91%。如果碱的水溶液质量分数过低,则会使得羟基难以与苯环发生取代,影响产品最终的收率;若碱的质量分数过高,则会造成反应原料的浪费。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.

对于碱的用量,本申请没有特别限定,在本申请一些具体的实施方案中,1mol的3-氯-4-甲基苯甲酸可以对应加入的5~11g的质量分数为80%~95%的氢氧化钾;从节省原料又保证收率的角度考虑,优选地为1mol的3-氯-4-甲基苯甲酸可以对应加入6~10g的质量分数为82%~93%的氢氧化钾;更优选的可以为1mol的3-氯-4-甲基苯甲酸对应加入7~9.5g的质量分数为80%~91%的氢氧化钾。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.

在本申请一些具体的实施方案中,加入的3-卤代-4-烷基苯甲酸与碱的摩尔比为1:(2.0~3.0),优选地为1:(2.1~2.8),更优选的为1:(2.3~2.7)。加入本申请所限定的适当量的碱,可以使其最大限度的在3位上将卤素原子取代为羟基,得到高收率的目标产物的同时,也不至于造成反应底物的浪费。如果碱加入的量较少,反应所需时间有可能显著变长,并且转化率与收率也会变低;若加入较多的碱,不仅不符合经济节约的原则,还有可能影响反应产物的纯度和收率。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.

溶剂solvent

本申请的制备方法对于溶剂的选择没有特别限制,通常可以选用沸点高、混合后不破坏碱性的极性溶剂,可以列举的有水、四氢呋喃、二氧六环等,在本发明的一些具体的实施方案中,所述溶剂为水。本申请对于溶剂的用量没有特别限制,在本发明一些具体的实施方案中,所述溶剂的用量可以为3-卤代-4-甲基苯甲酸质量的1~20倍,优选地为5~15倍,更优选地为6~10倍;用量过多会使碱的浓度过低从而导致反应无法进行,还会造成浪费;用量过少则无法将碱全部溶解,也会造成反应无法进行。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.

混合mix

本申请对于混合反应的条件没有特别限定,在本发明一些具体的实施方案中,优选在高压下进行反应。其中,所述的高压指的是压力为1MPa~10MPa,进一步地可以为2~5MPa。所使用的反应容器没有特别限定,优选使用本领域常用的高压釜/高压罐等。对反应容器的容量也没有特别限定。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.

<将反应体系升温进行反应的步骤><Procedure for raising the temperature of the reaction system to carry out the reaction>

升温heat up

在本发明一些具体的实施方式中,在高压下进行反应时,将反应体系升温至50~180℃,进一步地为60~160℃;在本发明一些具体的实施方式中,3-卤代-4-烷基苯甲酸中的卤素为氯元素时,由于氯元素较不活泼,因此优选在高压下进行,反应温度优选为100~180℃。在常压下进行反应时,反应体系升温至90~110℃,进一步地为95~105℃;在本发明一些具体的实施方式中,3-卤代-4-烷基苯甲酸中的卤素为溴元素时,由于溴元素较活泼,可以在常压下进行反应,此时温度优选为100~105℃。温度对苯环上羟基的取代反应存在一定的影响,如果加热的温度过高,则可能会增加安全风险,如果加热的温度过低,则可能会使得反应进行不完全,反应产率下降,若温度过高,则有可能造成反应时压力过大,危险性大,还有可能造成能源的浪费。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.

对于升温的方式,本申请没有特别限定,在本发明一些具体的实施例中,可以是电加热、导热油电加热、也可以是采用饱和蒸汽或者高压过热蒸汽将反应体系进行升温处理的蒸汽升温方式,其可以为敞开式,也可以为密闭式;在本发明的一些具体的实施方式中,采用导热油电加热的方式进行升温处理。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.

反应reaction

本申请的反应时间与反应条件有关,如果反应条件为高温高压,则反应耗时显著缩短,在本发明一些具体的实施方式中,为1~3h;若反应不采用高压的方式,仅提高温度,在本发明一些具体的实施方式中,为6~10h。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.

反应的方程式如下:The equation for the reaction is as follows:

Figure BDA0003937295340000111
Figure BDA0003937295340000111

X选自氟、氯、溴、碘X is selected from fluorine, chlorine, bromine, iodine

其中,R为C1~C20的烷基,在本发明的一些具体实施方式中,可以选自甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基中的任一种,在本发明一些优选的实施方案中,R为甲基。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为卤素,可以为氟、氯、溴或碘,在本发明一些优选的实施方案中,X为氯、溴。X is halogen, which can be fluorine, chlorine, bromine or iodine. In some preferred embodiments of the present invention, X is chlorine or bromine.

在本申请的另外一些具体的实施方式中,在后处理的步骤之前还可以包括冷却的步骤,优选的,将反应体系冷却至室温。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.

<调节反应体系pH值><Adjust the pH value of the reaction system>

在本发明一些具体的实施方式中,将反应体系冷却至室温后,进行调节反应体系pH值的步骤。其中,调节反应体系pH值的步骤包括在反应体系中加入盐酸、苹果酸、柠檬酸、酒石酸、乳酸中的一种或多种,其中,优选地可以加入氯化氢质量分数为30%~35%的盐酸,更优选的为常规市售浓度为31%的盐酸;将反应体系的pH值调节至4~6.5,优选地为调节至4.5~6。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.

<后处理步骤><Post-processing steps>

在本发明一些具体的实施方式中,将反应体系冷却至室温后对反应体系进行后处理,其中后处理的步骤包括过滤、洗涤和干燥。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.

其中过滤可以通过固液分离进行,其中分离的方法没有特别限制,可以使用抽滤。The filtration can be carried out by solid-liquid separation, and the separation method is not particularly limited, and suction filtration can be used.

过滤之后为洗涤的步骤,洗涤可以将得到的固体用清水洗涤。然后干燥以得到目标产物3-羟基-4-烷基苯甲酸,其中干燥的方法优选地可以使用加热真空干燥,干燥之后称重,通过目的产物(实际)生成量/目的产物的理论生成量×100%计算收率。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.

在本申请的一些优选实施方式中,在对烷基苯甲酸中加入具有氧化作用的硝酸再加入卤代试剂提供卤族元素,生成卤正离子进攻苯环,由于烷基定位基团在邻对位,羧酸定位基团是间位,2位是被钝化的位置,不会上取代,因此基本反应的卤素不会在除3位以外的位置上进行卤代反应,从而得到3-卤代-4-烷基苯甲酸。之后将3-卤代-4-烷基苯甲酸与碱、以及极性溶剂混合、升温、调节反应体系pH值至酸性,再进行后处理,由于羧基的吸电效应,使得苯环上的卤素原子被活化,降低了卤素活化能,因此该反应不使用催化剂就能反应,并且可以得到产率高收率也高的目标产物3-羟基-4-烷基苯甲酸。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.

由下面的实施例进一步说明本发明,但不构成限制。The invention is further illustrated, but not limited, by the following examples.

实施例Example

制备例1Preparation Example 1

将对甲基苯甲酸(5克)加入到40%的硝酸(30毫升)中,加入盐酸(31%浓度,5.2克),升温至100℃,反应3小时,监测反应完毕,冷却,固体抽滤,用清水洗涤,烘干得到产品3-氯-4-甲基苯甲酸(5.9克),纯度:97.9%收率:94%。产品的核磁图参见图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.

制备例2Preparation example 2

将对甲基苯甲酸(5克)加入到40%的硝酸(30毫升)中,加入氢溴酸(48%浓度,7.5克),升温至100℃,反应2.5小时,监测反应完毕,冷却,固体抽滤,用清水洗涤,烘干得到产品3-溴-4-甲基苯甲酸(7.4克),纯度:98.2%收率:94%。产品的核磁图参见图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.

制备例3Preparation example 3

在制备例1的过滤回收硝酸(26毫升)中,加入4毫升65%的硝酸,然后加入对甲基苯甲酸(5克)、盐酸(31%浓度,5克),升温至100℃,反应3小时,监测反应完毕,冷却,固体抽滤,用清水洗涤,烘干得到产品3-氯-4-甲基苯甲酸(5.92克),纯度:97.7%收率:94%。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%.

实施例1Example 1

在200毫升高压罐中加入3-氯-4-甲基苯甲酸(10克)、氢氧化钾(质量分数为90%,9.1克)、水(80克),封闭高压罐,升温到160度,反应8小时,监测反应完毕,冷却,反应液用浓盐酸,冰浴调节pH值到5,固体抽滤,用清水洗涤,烘干得到产品3-羟基-4-甲基苯甲酸(8.35克)。纯度:98.7%,收率:93%。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%.

实施例2Example 2

在200毫升高压罐中加入3-溴-4-甲基苯甲酸(10克)、氢氧化钾(质量分数为90%,6.4克)、水(80克),封闭高压罐,升温到100度,反应3小时,监测反应完毕,冷却,反应液用浓盐酸,冰浴调节pH值到5,固体抽滤,用清水洗涤,烘干得到产品3-羟基-4-甲基苯甲酸(6.86克)。纯度:99%,收率:97%,对所得产品进行核磁和液相色谱表征,结果见图3和图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 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.

实施例3Example 3

在250毫升单口瓶中加入3-溴-4-甲基苯甲酸(10克)、氢氧化钾(质量分数为90%,6.4克)、水(80克),接上回流管,升温到100度,反应3小时,监测反应完毕,冷却,反应液用浓盐酸,冰浴调节pH值到5,固体抽滤,用清水洗涤,烘干得到产品3-羟基-4-甲基苯甲酸(6.83克)。纯度:98.7%,收率:97%。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%.

实施例4Example 4

在200毫升高压罐中加入3-溴-4-甲基苯甲酸(10克)、氢氧化钾(质量分数为90%,6.4克)、水(80克),封闭高压罐,升温到160度,反应1小时,监测反应完毕,冷却,反应液用浓盐酸,冰浴调节pH值到5,固体抽滤,用清水洗涤,烘干得到产品3-羟基-4-甲基苯甲酸(6.81克)。纯度:99%,收率:98%。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%.

由以上实施例可以看出,本申请的3-羟基-4-烷基苯甲酸的制备方法,操作简单,产物收率达到93%以上,纯度达到98.7%以上。较现有技术中的制备方法,本申请的反应条件对设备要求低,反应步骤简单,原料成本低,产生的三废极少,且产品的收率以及纯度很高。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.

以上实施例仅用于阐明本发明的若干实施方案,其描述较为具体和详细,但并不能因此而理解为对本发明的范围产生任何限制。应当明确的是,对于本领域技术人员来说,在不脱离本发明构思的前提下,还可以做出若干变形和改进,这些都属于本发明的保护范围之内。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.

产业上的可利用性Industrial availability

本发明的制备方法可以广泛用于工业上3-羟基-4-烷基苯甲酸的制备。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):
Figure FDA0003937295330000011
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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