Process for the preparation of 4-halo-5-substituted phthalic acids and products and uses thereof

Abstract

The application discloses a preparation method of 4-halogen-5-substituted phthalic acid and 4-halogen-5-substituted phthalic acid obtained by the method and application of the 4-halogen-5-substituted phthalic acid. The preparation method comprises the following steps: (1) mixing 4-substituted phthalic acid and / or anhydride thereof, a strong alkali aqueous solution, a quaternary ammonium salt and a halogen element to perform a reaction; (2) adding a reducing agent solution after the reaction is completed; and (3) performing post-treatment to obtain the 4-halogen-5-substituted phthalic acid. The method avoids the method of using concentrated sulfuric acid as an auxiliary reagent for bromination in the prior art, and the reaction condition is mild.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic aromatic anhydrides, and particularly relates to the synthesis of organic aromatic acids, and specifically relates to a preparation method of 4-halogenated-5-substituted phthalic acid and the product and application thereof. BACKGROUND

[0002] Polyimide (PI) materials synthesized from 3,3',4,4'-biphenyl tetracarboxylic dianhydride (BPDA) and related diamines have very excellent material properties. PI materials based on the modification of BPDA structure are expected to achieve better and more excellent properties and further expand the related applications of PI materials. For example, simple methyl-substituted BPDA, i.e., 6,6'-dimethyl-3,3',4,4'-biphenyl tetracarboxylic dianhydride (DMPBDA), can reduce the expansion rate of PI and improve the light transmittance and processability of PI (EP1013650A, 2000; CN104513395A, 2015), and has important application value in precision electronic packaging materials. DMPBDA is prepared by dehalogenation coupling reaction of 4-bromo-5-methyl phthalic acid, and therefore the development of an economical and effective synthesis method of 4-halogenated-5-substituted phthalic acid compounds is of great significance for the mass production of DMPBDA.

[0003] Currently, there is only one reported method for preparing 4-halogenated-5-substituted phthalic acid compounds, and only the preparation of 4-bromo-5-methyl phthalic acid is reported (EP1013650A, 2000). This method uses 4-methyl phthalic anhydride as a raw material, and potassium bromate as a brominating reagent in the presence of concentrated sulfuric acid to prepare 4-bromo-5-methyl phthalic acid. This strong oxidizing system of concentrated acid has potential danger. A method for preparing related 4-halogenated phthalic acid by direct halogenation is reported in the existing literature. For example, CN1526710A reports a method for directly preparing 4-chlorophthalic acid from phthalic acid in an aqueous phase. If this method is used to prepare 4-halogenated-5-substituted phthalic acid, 4-substituted phthalic acid must be used as a raw material. Due to the steric effect of the substituent group, the difficulty of this type of substitution reaction is increased, which limits the direct halogenation reaction in the preparation of 4-halogenated-5-substituted phthalic acid. SUMMARY

[0004] In order to overcome the problems in the prior art, the present application provides a preparation method of 4-halogenated-5-substituted phthalic acid, and the product and application thereof. The preparation method uses halogen halogenation to prepare the 4-halogenated-5-substituted phthalic acid in the presence of a quaternary ammonium salt. The method avoids the method of using concentrated sulfuric acid as an auxiliary reagent for bromination in EP1013650A. The method has a short route, a high yield, greatly improved preparation conditions, and a good industrialization prospect.

[0005] One of the objects of the present application is to provide a preparation method of 4-halogenated-5-substituted phthalic acid, comprising:

[0006] (1) mixing 4-substituted phthalic acid and / or its anhydride, an aqueous strong base, a quaternary ammonium salt, and halogen elements to react;

[0007] (2) adding a reducing agent solution after the reaction is completed;

[0008] In step (1), the quaternary ammonium salt can form a complex with the halogen element, promoting the smooth occurrence of halogenation, that is, the halogenation reaction speed is improved by using a quaternary ammonium salt. The purpose of adding a reducing agent solution in step (2) is to neutralize the unreacted halogen element;

[0009] (3) post-treatment to obtain the 4-halogenated-5-substituted phthalic acid.

[0010] In a preferred embodiment, in step (1), the 4-substituted phthalic acid and / or its anhydride is at least one selected from compounds represented by formula (I) and formula (II):

[0011]

[0012] In formula (I), R and R in formula (II) are each independently selected from a hydrocarbon group, a hydrocarbon oxy group, a substituted hydrocarbon group, or a substituted hydrocarbon oxy group, and R in formula (I) is the same as or different from R in formula (II).

[0013] In a preferred embodiment, in formula (I), R and R in formula (II) are each independently selected from an alkyl group, an alkoxy group, a substituted alkyl group (preferably a halogen-substituted alkyl group), or a substituted alkoxy group (preferably a halogen-substituted alkoxy group), and R in formula (I) is the same as or different from R in formula (II).

[0014] In a further preferred embodiment, in formula (I), R and R in formula (II) are each independently selected from a C1-C10 alkyl group, a C1-C10 alkoxy group, a C1-C10 substituted alkyl group, or a C1-C10 substituted alkoxy group, and R in formula (I) is the same as or different from R in formula (II).

[0015] In a further preferred embodiment, R in formula (I) and R in formula (II) are each independently selected from C1-C4 alkyl, C1-C4 alkoxy, C1-C4 substituted alkyl or C1-C4 substituted alkoxy, R in formula (I) and R in formula (II) being the same or different.

[0016] For example, R is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, trifluoromethyl or trifluoromethoxy.

[0017] In a preferred embodiment, in step (1), the strong base is selected from at least one of sodium hydroxide, potassium hydroxide and cesium hydroxide.

[0018] In a preferred embodiment, in step (1), the weight ratio of the strong base to 4-substituted phthalic acid and / or anhydride thereof in the aqueous strong base solution is 1:(1-4), preferably 1:(1.8-3.2).

[0019] When the weight ratio of the strong base to 4-substituted phthalic acid and / or anhydride thereof is greater than 1:1, a side reaction occurs, i.e. the generated 4-halo-5-substituted phthalic acid is further hydrolyzed into 4-hydroxy-5-substituted phthalic acid.

[0020] For example, in step (1), the weight ratio of the strong base to 4-substituted phthalic acid and / or anhydride thereof in the aqueous strong base solution is 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5 or 1:4.

[0021] In a preferred embodiment, in step (1), the weight ratio of the aqueous strong base solution to 4-substituted phthalic acid and / or anhydride thereof is (2-30):1, preferably (5-20):1.

[0022] For example, in step (1), the weight ratio of the aqueous strong base solution to 4-substituted phthalic acid and / or anhydride thereof is 2:1, 3:1, 4:1, 5:1, 6:1, 8:1, 10:1, 12:1, 14:1, 16:1, 18:1, 20:1, 25:1 or 30:1.

[0023] In a preferred embodiment, in step (1), the quaternary ammonium salt has a structure as shown in formula (R 1 R 2 R 3 R 4 )NX’ wherein R 1 , R 2 , R 3 , R 4 are each independently selected from one of C1-C20 alkyl, and X’ is selected from one of halide anion and acid anion.

[0024] In a further preferred embodiment, in step (1), the quaternary ammonium salt has a structure as shown in (R 1 R 2 R 3 R 4 )NX’ wherein R 1 , R 2 , R 3 , R 4 are each independently selected from one of C1-C10 alkyl groups, and X’ is selected from one of halide anions, and preferably is consistent with the elemental species of the halogen element added subsequently.

[0025] For example, (R 1 R 2 R 3 R 4 )N- can be selected from tetraethylammonium, tetrapropylammonium or tetrabutylammonium, and the anion X’ is selected from chloride, bromide or iodide, and is consistent with the halogen element added subsequently.

[0026] In a preferred embodiment, in step (1), the weight ratio of the quaternary ammonium salt to 4-substituted phthalic acid and / or anhydride thereof is (0.05-1):1, preferably (0.1-0.5):1.

[0027] The quaternary ammonium salt has a role of promoting the halogenation reaction to occur. When the weight ratio of the quaternary ammonium salt to 4-substituted phthalic acid and / or anhydride thereof is higher than 0.5:1, it will increase the difficulty of subsequent separation and purification, resulting in a reduced yield.

[0028] For example, in step (1), the weight ratio of the quaternary ammonium salt to 4-substituted phthalic acid and / or anhydride thereof is 0.05:1, 0.08:1, 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, 0.6:1, 0.8:1 or 1:1.

[0029] In a preferred embodiment, in step (1), the halogen element is selected from at least one of chlorine, bromine, iodine.

[0030] In a preferred embodiment, in step (1), the weight ratio of the halogen element to 4-substituted phthalic acid and / or anhydride thereof is (0.2-2):1, preferably (0.4-1.6):1.

[0031] For example, the weight ratio of the halogen element to 4-substituted phthalic acid and / or anhydride thereof is 0.2:1, 0.3:1, 0.4:1, 0.6:1, 0.8:1, 1.0:1, 1.2:1, 1.4:1, 1.6:1, 1.8:1 or 2:1.

[0032] In a preferred embodiment, in step (1), the 4-substituted phthalic acid and / or anhydride thereof, aqueous strong base, and quaternary ammonium salt are mixed (preferably until the 4-substituted phthalic acid and / or anhydride thereof is completely dissolved), and then the elemental halogen is added to react.

[0033] In a preferred embodiment, in step (1), the temperature of the reaction is 0-100°C, and the reaction time is 3-36 hours.

[0034] In a further preferred embodiment, in step (1), the temperature of the reaction is 25-80°C, and the reaction time is 6-24 hours.

[0035] For example, in step (1), the temperature of the reaction is 25°C, 30°C, 40°C, 50°C, 60°C, 70°C, or 80°C, and the time is 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 22 hours, or 24 hours.

[0036] In a preferred embodiment, in step (2), after the reaction is completed, the reaction system is first cooled to room temperature, and then the reducing agent solution is added.

[0037] In a further preferred embodiment, in step (2), the reducing agent solution is selected from at least one of sodium sulfite solution, sodium bisulfite solution, sodium thiosulfate solution, sodium hydrosulfite solution, hydrazine hydrate, and hydroxylamine solution, preferably, the weight concentration of the aqueous reducing agent solution is 10-25 wt%, and more preferably, the weight usage ratio of the aqueous reducing agent solution to the 4-substituted phthalic acid and / or anhydride thereof is (0.05-0.6):1, preferably (0.1-0.4):1.

[0038] For example, the weight usage ratio of the aqueous reducing agent solution to the 4-substituted phthalic acid and / or anhydride thereof is 0.05:1, 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1, or 0.6:1.

[0039] In a preferred embodiment, in step (3), the post-treatment includes: (3.1) adjusting the pH value of the reaction system to 0-4, (3.2) extracting the aqueous phase with an organic solvent, (3.3) drying the organic phase obtained after extraction, and optionally concentrating to obtain the crude 4-halogenated-5-substituted phthalic acid, and (3.4) obtaining the pure 4-halogenated-5-substituted phthalic acid through optional recrystallization.

[0040] In a further preferred embodiment, in step (3.1), a strong acid is used to adjust the pH of the reaction system, preferably the strong acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid; more preferably, the pH is adjusted to between 1 and 2.

[0041] In a further preferred embodiment, in step (3.2), the organic solvent is selected from one or more of ethyl acetate, diethyl ether, methyl tert-butyl ether, tetrahydrofuran. Preferably, in step (3.2), the extraction is performed multiple times, preferably 2 to 4 times.

[0042] In a further preferred embodiment, in step (3.3), the drying is performed using a drying agent, preferably the drying agent is selected from one or more of anhydrous sodium sulfate, anhydrous magnesium sulfate, 3A molecular sieve, 4A molecular sieve, silica gel drying agent.

[0043] In a further preferred embodiment, when step (3.4) is performed, recrystallization is performed using a solvent selected from at least one of ethyl acetate, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, acetone, methyl isobutyl ketone and n-hexane; preferably, the ratio of the use of the crude 4-halogenated-5-substituted phthalic acid to the solvent is 1: (4.0-10.0), preferably 1: (4.0-6.0).

[0044] For example, the ratio of the use of the crude 4-halogenated-5-substituted phthalic acid to the solvent is 4.0:1, 5.0:1, 6.0:1, 7.0:1, 8.0:1, 9.0:1 or 10.0:1.

[0045] The second object of the present application is to provide a 4-halogenated-5-substituted phthalic acid prepared by the method according to the first object of the present application.

[0046] The 4-halogenated-5-substituted phthalic acid according to the present application has a structure as shown in formula (III):

[0047]

[0048] In formula (III), R has the same definition as described above, and X is selected from halogen, preferably from chlorine element, bromine element or iodine element.

[0049] In a preferred embodiment, the purity of the 4-halogenated-5-substituted phthalic acid is greater than 95%, preferably greater than 98%.

[0050] The third object of the present application is to provide the use of the 4-halogen-5-substituted phthalic acid prepared by the method of the first object of the present application or the 4-halogen-5-substituted phthalic acid of the second object of the present application in the preparation of 6,6'-dialkyl-3,3',4,4'-biphenyltetracarboxylic acid and its dianhydride.

[0051] The endpoints of the ranges of the present application as well as any numerical values included in the present application are not limited to the precise values recited. The ranges and numerical values should be interpreted as approximations. Any numerical value, however, can include any reasonable amount that is either the same as or approximately the same as that amount. Any numerical value, range or value that is approximately the same as a value disclosed herein should be considered to be disclosed herein. Any numerical value, range or value that is the same as a value disclosed herein should be considered to be disclosed herein.

[0052] Compared with the prior art, the present application has the following beneficial effects:

[0053] The present application prepares 4-halogen-5-substituted phthalic acid under alkaline conditions, avoiding the method of using concentrated sulfuric acid as an auxiliary reagent for bromination in the prior art (e.g. EP1013650A), and the reaction conditions are mild. BRIEF DESCRIPTION OF DRAWINGS

[0054] Figure 1 A nuclear magnetic resonance hydrogen spectrum of the 4-halogen-5-substituted phthalic acid prepared in Example 1 of the present application is shown;

[0055] Figure 2 A mass spectrum of the 4-halogen-5-substituted phthalic acid prepared in Example 1 of the present application is shown;

[0056] Figure 3 An HPLC chart of the 4-halogen-5-substituted phthalic acid prepared in Example 1 of the present application is shown. DETAILED DESCRIPTION

[0057] The present application will be described in detail below with reference to specific examples. It is necessary to point out that the following examples are only used to further illustrate the present application and cannot be understood as limiting the protection scope of the present application. Some non-essential improvements and adjustments to the present application made by those skilled in the art based on the content of the present application still fall within the protection scope of the present application.

[0058] In addition, it should be noted that each specific technical feature described in the following detailed description can be combined in any appropriate manner without contradiction. In order to avoid unnecessary repetition, the present application will not further describe various possible combinations.

[0059] Moreover, the various embodiments of the present application can be combined in any manner, as long as the idea of the present application is not deviated, and the technical scheme formed by the combination belongs to the original disclosure of the present specification and falls within the protection scope of the present application.

[0060] The raw materials used in the examples and comparative examples are, if not particularly limited, publicly known, for example, commercially available or prepared according to the publicly known preparation method.

[0061] Example 1

[0062] In a reaction vessel, 2400 g of distilled water containing 108 g of sodium hydroxide and 19.4 g of tetraethylammonium bromide were stirred uniformly, and then 194 g of 4-methylphthalic anhydride was added and dissolved. Subsequently, 218 g of bromine was introduced at room temperature, and stirred at 40°C for 3 hours. After cooling to room temperature, 36 g of 25 wt% sodium bisulfite aqueous solution was added to neutralize the unreacted bromine. Subsequently, the pH was adjusted to 1 with concentrated hydrochloric acid, and the water phase was extracted with ethyl acetate three times. The organic phase was dried with anhydrous sodium sulfate, and concentrated to obtain a white powder of crude product, 4-bromomethyl-5-methylphthalic acid, 224 g. The crude product was recrystallized in 2240 g of tetrahydrofuran to obtain pure 4-bromomethyl-5-methylphthalic acid, 211 g, at a total yield of 68%. The purity of 4-bromomethyl-5-methylphthalic acid was 99.2% as measured by HPLC.

[0063] Example 2

[0064] In a reaction vessel, 2400 g of distilled water containing 97 g of sodium hydroxide and 75 g of tetrabutylammonium bromide were stirred uniformly, and then 312 g of 4-isopropylphthalic acid was added and dissolved. Subsequently, 270 g of bromine was introduced at room temperature, and stirred at 25°C for 6 hours. After cooling to room temperature, 48 g of 20 wt% sodium sulfite aqueous solution was added to neutralize the unreacted bromine. Subsequently, the pH was adjusted to 2 with concentrated hydrochloric acid, and the water phase was extracted with ethyl acetate three times. The organic phase was dried with anhydrous magnesium sulfate, and concentrated to obtain a white powder of crude product, 4-bromomethyl-5-isopropylphthalic acid, 315 g. The crude product was recrystallized in 1260 g of acetone to obtain pure 4-bromomethyl-5-isopropylphthalic acid, 280 g, at a total yield of 65%. The purity of 4-bromomethyl-5-isopropylphthalic acid was 98.9% as measured by HPLC.

[0065] Example 3

[0066] In a reaction tank, 1260 g of distilled water and 63 g of tetrabutylammonium chloride were added to dissolve 126 g of sodium hydroxide, stirred until uniform, then 252 g of 4-methylphthalic acid was added and dissolved completely, then 104 g of chlorine was introduced at room temperature, stirred at 80°C for 12 hours, cooled to room temperature, 98 g of 10 wt% sodium thiosulfate aqueous solution was added to neutralize the unreacted chlorine, then neutralized to pH=3 with phosphoric acid, the water phase was extracted with methyl tert-butyl ether for 3 times, the organic phase was dried with 3A molecular sieve, concentrated to obtain the crude product 4-chloro-5-methylphthalic acid 232 g in white powder, the obtained crude product was recrystallized in 1752 g of methyl isobutyl ketone to obtain the pure product 4-chloro-5-methylphthalic acid 212 g, the yield was 71%, the purity of 4-chloro-5-methylphthalic acid was 98.1% determined by HPLC.

[0067] [Example 4]

[0068] In a reaction tank, 5184 g of distilled water and 129.5 g of tetrabutylammonium iodide were added to dissolve 144 g of sodium hydroxide, stirred until uniform, then 259.2 g of 4-methylphthalic anhydride was added and dissolved completely, then 414.7 g of elemental iodine was introduced at room temperature, stirred at 35°C for 24 hours, cooled to room temperature, 58 g of 15 wt% sodium sulfite aqueous solution was added to neutralize the unreacted elemental iodine, then neutralized to pH=4 with concentrated hydrochloric acid, the water phase was extracted with ethyl acetate for 3 times, the organic phase was dried with silica gel, concentrated to obtain the crude product 4-iodo-5-methylphthalic acid 390 g in white powder, the obtained crude product was recrystallized in 3960 g of n-hexane to obtain the pure product 4-iodo-5-methylphthalic acid 357 g, the yield was 73%, the purity of 4-iodo-5-methylphthalic acid was 98.5% determined by HPLC.

[0069] [Example 5]

[0070] In a reaction tank, 2400 g of distilled water and 41 g of tetrapropylammonium bromide were added to dissolve 108 g of sodium hydroxide, stirred until uniform, then 211.2 g of 4-ethylphthalic anhydride was added and dissolved completely, then 201.6 g of liquid bromine was introduced at room temperature, stirred at 50°C for 3 hours, cooled to room temperature, 58 g of 15 wt% sodium sulfite aqueous solution was added to neutralize the unreacted bromine, then neutralized to pH=0 with concentrated hydrochloric acid, the water phase was extracted with diethyl ether for 3 times, the organic phase was dried with anhydrous sodium sulfate, concentrated to obtain the crude product 4-bromo-5-ethylphthalic acid 238 g in white powder, the obtained crude product was recrystallized in 1960 g of tetrahydrofuran to obtain 4-bromo-5-ethylphthalic acid 206.5 g, the yield was 63%, the purity of 4-bromo-5-ethylphthalic acid was 98.2% determined by HPLC.

[0071] [Example 6]

[0072] In a reaction vessel, 2000 g of distilled water containing 98 g of sodium hydroxide and 37 g of tetrapropylammonium bromide were added, stirred until uniform, then 216 g of 4-trifluoromethylphthalic anhydride was added and dissolved, then 198 g of liquid bromine was introduced at room temperature, stirred at 90°C for 12 hours, after cooling to room temperature, 58 g of 15 wt% aqueous sodium sulfite solution was added to neutralize the unreacted bromine, then neutralized to pH = 0 with concentrated hydrochloric acid, the aqueous phase was extracted with ether three times, the organic phase was dried with anhydrous sodium sulfate, concentrated to obtain white powder of crude product 4-bromo-5-trifluoromethylphthalic acid 208 g, the obtained crude product was recrystallized in 1500 g of acetone, to obtain 4-bromo-5-trifluoromethylphthalic acid 185.9 g, the yield was 63%, the purity of 4-bromo-5-trifluoromethylphthalic acid was 98.3% measured by HPLC.

[0073] [Example 7]

[0074] In a reaction vessel, 3000 g of distilled water containing 97.5 g of sodium hydroxide and 37.5 g of tetraethylammonium chloride were added, stirred until uniform, then 306 g of 4-butylphthalic anhydride was added and dissolved, then 129 g of chlorine was introduced at room temperature, stirred at 30°C for 36 hours, after cooling to room temperature, 30.6 g of 20 wt% hydrazine hydrate solution was added to neutralize the unreacted chlorine, then neutralized to pH = 2 with phosphoric acid, the aqueous phase was extracted with ether three times, the organic phase was dried with anhydrous sodium sulfate, concentrated to obtain white powder of crude product 4-chloro-5-butylphthalic acid 266 g, the obtained crude product was recrystallized in 1550 g of acetone; to obtain 4-chloro-5-butylphthalic acid 231 g, the yield was 60%, the purity of 4-chloro-5-butylphthalic acid was 99.0% measured by HPLC.

[0075] [Example 8]

[0076] In a reaction vessel, 1000 g of distilled water containing 45 g of sodium hydroxide and 8.1 g of tetraethylammonium chloride were added, stirred until uniform, then 81 g of 4-methylphthalic anhydride was added and dissolved, then 41 g of chlorine was introduced at room temperature, stirred at 80°C for 6 hours, after cooling to room temperature, 15 g of 25 wt% sodium bisulfite solution was added to neutralize the unreacted chlorine, then neutralized to pH = 1 with hydrochloric acid, the aqueous phase was extracted with ethyl acetate three times, the organic phase was dried with anhydrous sodium sulfate, concentrated to obtain white powder of crude product 4-chloro-5-methylphthalic acid 172 g, the obtained crude product was recrystallized in 1560 g of ethyl acetate / n-hexane = 1:1, to obtain 4-chloro-5-methylphthalic acid 160.5 g, the yield was 75%, the purity of 4-chloro-5-methylphthalic acid was 98.1% measured by HPLC.

[0077] [Comparative Example 1]

[0078] According to the method declared in the prior art (patent CN1526710A, 2003), 49 g of 4-methylphthalic acid monosodium salt and 170 g of water were added into a three-necked flask, heated to 90°C to dissolve, then cooled to 70°C, chlorine was bubbled into the bottom of the reaction solution at a speed of 0.127 g / min, and the reaction temperature was controlled at 70°C, the reaction was carried out for 1 h, NaHCO3 solution was added to neutralize the by-product hydrogen chloride during the reaction, so that the pH value of the reaction system was basically unchanged, then the chlorine speed was changed to 0.082 g / min, the reaction was carried out at 50°C for 3 h, 30 g of concentrated hydrochloric acid was added to acidify for 2 h, then cooled to room temperature, and extracted with diethyl ether to spin dry to obtain 45 g of crude product, the purity of 4-chloro-5-methylphthalic acid was 36% by HPLC determination, and there was a large amount of unreacted 4-methylphthalic acid in the crude product.

[0079]

Experimental Example

[0080] 1. Nuclear magnetic resonance characterization

[0081] The 4-bromo-5-methylphthalic acid prepared in Example 1 was characterized by nuclear magnetic resonance hydrogen spectrum, and the results are shown in Table 1. Figure 1 In the nuclear magnetic resonance hydrogen spectrum, the single peak at δ = 8.16 ppm belongs to the hydrogen atom at position 3 between the bromine atom and the carbonyl group on the benzene ring, which is affected by the electron-withdrawing carbonyl group and the electronegativity of the bromine atom to shift to the low field; the single peak at δ = 7.86 ppm belongs to the hydrogen atom at position 6 between the methyl group and the carbonyl group on the benzene ring, which is affected by the electron-donating methyl group and the electron-withdrawing carbonyl group to shift to the low field; δ = 7.26 ppm is the solvent peak of deuterated chloroform; the single peak at δ = 2.61 ppm is the methyl hydrogen atom peak, indicating that the prepared product is indeed 4-bromo-5-methylphthalic acid. Moreover, the obtained nuclear magnetic spectrum is pure, and no other obvious signal peaks are found, indicating that the content of other impurities in the sample is less than 5%.

[0082] The 4-bromo-5-methylphthalic acid prepared in Example 1 was characterized by nuclear magnetic resonance hydrogen spectrum, and the results are shown in Table 1.

[0083] 2. Mass spectrometry characterization

[0084] The 4-bromo-5-methylphthalic acid prepared in Example 1 was characterized by mass spectrometry, and the results are shown in Table 2. Figure 2 [M+2H2O+H] + (C9H 12 BrO6) m / z theoretical value is 294.9812, and the measured value is 294.9573; [M-2H+Na] + (C9H 11The theoretical value of BrNaO6 is 316.9631, and the measured value is 316.9397, and there are obvious bromine isotope peaks in the two groups of peaks, indicating that the prepared is 4-bromo-5-methyl phthalic acid.

[0085] The 4-halo-5-substituted phthalic acids prepared in Examples 2-8 are also subjected to mass spectrometry detection, and it is verified that the obtained is indeed 4-halo-5-substituted phthalic acid.

[0086] 3. HPLC characterization

[0087] The 4-bromo-5-methyl phthalic acid in Example 1 is subjected to HPLC characterization, and the results are shown in Table 1. Figure 3 The signal peak with a retention time of 6.923 min is the main product peak, and the purity after normalization integration is 99.2%.

[0088] The 4-halo-5-substituted phthalic acids prepared in Examples 2-8 are also subjected to purity analysis, and the purity of the obtained products is all above 98%.

[0089] The above detailed description of the present application is combined with specific embodiments and exemplary examples, but these descriptions cannot be understood as limiting the present application. Those skilled in the art understand that various equivalent substitutions, modifications or improvements can be made to the technical solutions and embodiments of the present application without departing from the spirit and scope of the present application, and these all fall within the scope of the present application. The scope of protection of the present application is subject to the appended claims.

Claims

1. A process for the preparation of 4-halo-5-substituted phthalic acids comprising: (1) mixing 4-substituted phthalic acid and / or its anhydride, aqueous solution of strong base, quaternary ammonium salt, halogen element to react, (2) adding reducing agent solution after the reaction is completed, (3) post-treatment to obtain the 4-halogenated-5-substituted phthalic acid; the structural formula of the quaternary ammonium salt is as shown in (R 1 R 2 R 3 R 4 )NX' wherein, (R 1 R 2 R 3 R 4 )N- is selected from tetraethylammonium, tetrapropylammonium or tetrabutylammonium, X' is selected from one of halogen negative ions and is consistent with the element type of the halogen element, the weight ratio of the quaternary ammonium salt to 4-substituted phthalic acid and / or its anhydride is (0.1~1):1; the strong base is selected from at least one of sodium hydroxide, potassium hydroxide, cesium hydroxide, the weight dosage ratio of strong base to 4-substituted phthalic acid and / or its anhydride in the aqueous solution of strong base is 1:(1.8~4); In step (1), the 4-substituted phthalic acid and / or its anhydride is selected from at least one of the compounds shown in formula (I) and formula (II): wherein R in formula (I) and R in formula (II) are each independently selected from C1-C4 alkyl or trifluoromethyl, and R in formula (I) is the same as or different from R in formula (II).

2. The preparation method according to claim 1, wherein, In step (1), the weight ratio of the strong base to the 4-substituted phthalic acid and / or its anhydride in the strong base aqueous solution is 1:(1.8-3.2); and / or, In step (1), the weight ratio of the strong base aqueous solution to the 4-substituted phthalic acid and / or its anhydride is (2-30):

1.

3. The production method according to claim 1, characterized by, In step (1), the weight ratio of the strong base aqueous solution to the 4-substituted phthalic acid and / or its anhydride is (5-20):

1.

4. The preparation method according to claim 1, wherein, In step (1), the weight ratio of the quaternary ammonium salt to the 4-substituted phthalic acid and / or its anhydride is (0.1-0.5):1; and / or, In step (1), the halogen element is selected from at least one of chlorine, bromine, and iodine. The weight ratio of the halogen element to the 4-substituted phthalic acid and / or its anhydride is (0.2-2):

1.

5. The production method according to claim 1, characterized by, The weight ratio of the halogen element to the 4-substituted phthalic acid and / or its anhydride is (0.4-1.6):

1.

6. The production method according to claim 1, characterized by, In step (1), the 4-substituted phthalic acid and / or its anhydride, the strong base aqueous solution, and the quaternary ammonium salt are mixed first, and then the halogen element is added for reaction.

7. The preparation method according to claim 1, characterized in that, 8. The preparation method according to claim 1, wherein, In step (1), the reaction temperature is 0-100°C; and / or, In step (1), the reaction time is 3-36 hours.

9. The preparation method according to claim 1, wherein, In step (1), the reaction temperature is 25-80°C; and / or, In step (1), the reaction time is 6-24 hours. In step (2), the reaction system is first cooled to room temperature after the reaction is completed, and then the reducing agent solution is added.

10. The method of claim 1, wherein, The reducing agent solution is selected from at least one of sodium sulfite solution, sodium bisulfite solution, sodium thiosulfate solution, sodium hydrosulfite solution, hydrazine hydrate, and hydroxylamine solution.

11. The method of claim 1, wherein, The weight ratio of the reducing agent aqueous solution to the 4-substituted phthalic acid and / or its anhydride is (0.05-0.6):

1.

12. The production method according to claim 1, characterized by, The weight ratio of the reducing agent aqueous solution to the 4-substituted phthalic acid and / or its anhydride is (0.1-0.4):

1.

13. The method of claim 1, wherein, In step (3), the post-treatment includes: (3.1) adjusting the pH value of the reaction system to 0-4, (3.2) extracting the aqueous phase with an organic solvent, (3.3) drying the organic phase obtained after extraction, and optionally concentrating to obtain a 4-halo-5-substituted phthalic acid crude product, and (3.4) optionally recrystallizing to obtain a 4-halo-5-substituted phthalic acid pure product.

14. The method of any one of claims 1 to 13, wherein the method is performed in a single step.

15. The preparation method according to claim 14, wherein, ​ In step (3.1), a strong acidic substance is used to adjust the pH value of the reaction system; and / or, In step (3.2), the organic solvent is selected from one or more of ethyl acetate, diethyl ether, methyl tert-butyl ether, and tetrahydrofuran; and / or, In step (3.2), the extraction is performed multiple times; and / or, In step (3.3), the drying is performed using a drying agent; and / or, When step (3.4) is performed, recrystallization is performed using a solvent selected from at least one of ethyl acetate, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, acetone, methyl isobutyl ketone, and n-hexane.

16. The preparation method of claim 15, wherein, the strong acidic substance is selected from one or more of hydrochloric acid, sulfuric acid, and phosphoric acid; and / or, the ratio of the use amount of the crude 4-halogenated-5-substituted phthalic acid to the solvent is (4.0-10.0):

1.

17. The preparation method of claim 15, wherein, the pH is adjusted to between 1 and 2; and / or, the ratio of the use amount of the crude 4-halogenated-5-substituted phthalic acid to the solvent is (4.0-6.0):1.

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