A method for preparing an aromatic compound

Abstract

The application provides a preparation method of an m-diphenol compound. The m-diphenol compound shown in formula (2) is prepared by using a compound shown in formula (1) as a raw material and performing a reaction in the presence of a catalytic system and a peroxide; wherein formula (1) is as shown in the description; formula (2) is as shown in the description; the catalytic system comprises a first catalyst, a second catalyst and a cocatalyst; the first catalyst comprises a metal salt and an amide acid ligand, the metal salt is a palladium salt and / or a copper salt, the second catalyst is selected from one or more of a molybdenum complex, a molybdenum oxide, a vanadium complex, a tungsten oxide, a chromium oxide and a titanium alkoxide, and the cocatalyst is an inorganic base. The preparation method has a short reaction flow, can efficiently realize the double hydroxylation reaction of aromatic compounds by using a one-step method, and is simple to operate.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, and particularly relates to a preparation method of an m-diphenol compound. BACKGROUND

[0002] Diphenol compounds are important organic chemicals, which have wide applications in the fields of medicine, dye, resin, paint and the like. For example, o-diphenol can be used for synthesizing berberine, isopropyl adrenaline and the like drugs; m-diphenol can be used for preparing azo dyes, phenolic resin and other fine chemicals; p-diphenol can be used for synthesizing anthraquinone dyes and azo dyes, and can also be used for preparing a stabilizer and an antioxidant of paint varnish and the like.

[0003] At present, the industrial synthesis methods of m-diphenol compounds mainly include a benzene sulphonation alkali fusion method, an m-diisopropylbenzene oxidation method and a phenol hydroxylation method. These traditional processes can meet the needs of industrial production to some extent, but generally have problems of low reaction efficiency, great environmental pollution and difficult product separation, and the specific performances are as follows:

[0004] The benzene sulphonation alkali fusion method: this method takes benzene as a raw material, and obtains m-diphenol through three steps of sulphonation, alkali fusion and acidification. This process route is simple, has low investment cost and mature technology, but the product yield is only 50% to 60%, and a large amount of waste containing inorganic salts is generated in the reaction process, which causes great burden to the environment and does not meet the development requirements of green chemistry.

[0005] The m-diisopropylbenzene oxidation method: this method also takes benzene as a raw material, and obtains the target product through three steps of alkylation, oxidation and decomposition. The yield thereof can reach about 80%, the environmental pollution is relatively small, and it is suitable for large-scale continuous production. However, the process route is long, the single-pass conversion rate is low, and two moles of acetone are by-produced for generating one mole of m-diphenol, which increases the cost of subsequent separation and treatment, and limits the economic benefits.

[0006] The phenol hydroxylation method: as a process with relatively great development potential, this method takes phenol and hydrogen peroxide as raw materials, and generates a diphenol compound through a hydroxylation reaction under the action of a catalyst. Compared with the above two methods, this process route is short and simple. However, due to the limitation of the action mechanism of the catalyst, the reaction usually simultaneously generates three kinds of diphenol isomers of ortho, meta and para positions, which leads to complex product composition, great difficulty in separation and purification and high cost. In addition, since the product is more prone to oxidation than the raw material phenol, in order to inhibit over-reaction, the single-pass conversion rate of phenol is usually limited to below 10%, which causes great circulation amount of reaction materials and high energy consumption, and restricts the industrialization promotion thereof.

[0007] In summary, the existing synthesis techniques of resorcinol compounds generally have one or more problems such as low product yield, large waste discharge, high energy consumption, and poor economic benefits. Therefore, it is urgent to develop a new method that meets the requirements of green chemistry to replace the traditional synthesis methods. SUMMARY

[0008] The purpose of the present application is to provide a new preparation method of resorcinol compounds, which has a short reaction flow and can realize continuous two-step hydroxylation reaction in one-pot reaction.

[0009] To achieve the above purpose, the technical solution adopted by the present application is as follows:

[0010] The present application provides a preparation method of resorcinol compounds, which uses a compound represented by formula (1) as a raw material, and performs a reaction in the presence of a catalytic system and a peroxide to obtain a resorcinol compound represented by formula (2);

[0011] The formula (1) is: ; wherein DG is selected from carboxyl, carboxylate, sulfonyl, amido, carbonyl or imido, R 1 , R 2 , R 3 are independently selected from hydrogen, C1-C10 linear or branched alkyl, C5-C10 cycloalkyl, aryl, alkoxy, halogen, hydroxyl, cyano, nitro, amino or acyl, and R 4 is selected from hydrogen or hydroxyl;

[0012] The formula (2) is: ; wherein DG, R 1 , R 2 , R 3 in formula (2) are each independently corresponding to DG, R 1 , R 2 , R 3 in formula (1);

[0013] The catalytic system comprises a first catalyst, a second catalyst and a cocatalyst; wherein the first catalyst comprises a metal salt and an amido acid ligand, the metal salt is a palladium salt and / or a copper salt; the second catalyst is selected from one or more of a molybdenum complex, a molybdenum oxide, a vanadium complex, a tungsten oxide, a chromium oxide and a titanium alkoxide; and the cocatalyst is an inorganic base.

[0014] The catalytic system composed of the first catalyst, the second catalyst and the cocatalyst can realize the continuous two-step hydroxylation reaction of aromatic compounds. The reaction process follows the catalytic mechanism as shown in formula (3): Figure 1

[0015] ​First, the directing group (DG, exemplified by benzoic acid) on formula (1) coordinates with the first catalyst (metal salt, exemplified by palladium acetate) to form Pd-C complex. Meanwhile, the peroxide (exemplified by tert-butyl hydroperoxide) forms an adduct with the second catalyst (exemplified by molybdenum acetylacetonate), which can release organic peroxy radical (t-BuOO•) with higher oxidation activity. Subsequently, t-BuOO• reacts with Pd-C complex to form intermediate C of tetravalent Pd, accompanied by the generation of tert-butoxy radical (t-BuO•). Intermediate C undergoes rearrangement to form carbon-oxygen bond, and then ligand exchange with acetic acid in the system to finally obtain the product; while the generated t-BuO• can continue to react with the second catalyst to convert into tert-butyl alcohol (t-BuOH).

[0016] In some embodiments, the palladium salt is selected from one or more of palladium acetate, palladium trifluoroacetate, and palladium chloride.

[0017] In some embodiments, the copper salt is selected from one or more of copper acetate, copper trifluoroacetate, and copper chloride.

[0018] In some embodiments, the amido acid ligand has the structural formula , wherein R is selected from phenyl, C1-C5 linear or branched alkyl. As preferred, the amido acid ligand is selected from one or more of N-acetyl-L-leucine, N-acetyl-D / L-phenylglycine, acetyl-L-isoleucine, and N-acetyl-L-valine.

[0019] In some embodiments, the molar ratio of the metal salt to the amido acid ligand is 1:(1.5-3), preferably 1:(1.5-2.5), such as 1:1.5, 1:1.8, 1:2, 1:2.3, 1:2.5.

[0020] In some embodiments, the molar ratio of the metal salt to the compound of formula (1) is (0.05-0.5):1, preferably (0.1-0.3):1, such as 0.1:1, 0.15:1, 0.2:1, 0.25:1, 0.3:1.

[0021] In some embodiments, the molybdenum complex is molybdenum acetylacetonate and / or molybdenum hexacarbonyl. The generation of organic peroxy radical with higher oxidation activity is required for the dihydroxylation reaction, and molybdenum can promote the generation of such active species.

[0022] In some embodiments, the molybdenum oxide is molybdenum trioxide.

[0023] In some embodiments, the vanadium complex is vanadium acetylacetonate.

[0024] In some embodiments, the oxide of tungsten is tungsten oxide.

[0025] In some embodiments, the oxide of chromium is chromium oxide.

[0026] In some embodiments, the titanium alkoxide is tetraisopropyl titanate.

[0027] In some embodiments, the molar ratio of the second catalyst to the compound of formula (1) is (0.01-0.1): 1, preferably (0.02-0.05): 1, such as 0.02: 1, 0.025: 1, 0.03: 1, 0.04: 1, 0.05: 1.

[0028] In some embodiments, the inorganic base is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, potassium acetate, sodium bicarbonate, disodium hydrogen phosphate, cesium carbonate.

[0029] In some embodiments, the molar ratio of the inorganic base to the compound of formula (1) is (0.5-2): 1, preferably (0.8-1.2): 1.

[0030] In some embodiments, the peroxide is an organic peroxide and / or an inorganic peroxide. Further, the organic peroxide is selected from one or more of tert-butyl hydroperoxide, cyclohexane hydroperoxide, ethylbenzene hydroperoxide, cumene hydroperoxide. The inorganic peroxide is hydrogen peroxide.

[0031] In some embodiments, the molar ratio of the peroxide to the compound of formula (1) is (1-5): 1, preferably (2-4): 1, such as 2: 1, 2.5: 1, 3: 1, 3.5: 1, 4: 1.

[0032] In some embodiments, the reaction is carried out in the presence of a solvent, which is one or more of an alcohol solvent (such as tert-butanol), an amide solvent (such as N, N-dimethylacetamide), a nitrile solvent (such as acetonitrile). As a preference, the solvent is an alcohol solvent or an amide solvent. Further, the mass ratio of the solvent to the compound of formula (1) is (1-50): 1, preferably (15-40): 1, such as 15: 1, 20: 1, 25: 1, 30: 1, 35: 1, 40: 1.

[0033] In some embodiments, the reaction temperature is 20-100℃, preferably 60-100℃, and more preferably 70-90℃. The reaction time is 0.2-24h, preferably 3-6h, and more preferably 3.5-5h. If the reaction condition is too weak, the reaction cannot achieve a good result. If the reaction condition is too strong, the side reaction will be promoted, and the requirement for equipment will be increased, and the production cost will be increased. Therefore, the above reaction condition is preferred.

[0034] In some embodiments, the DG is selected from carboxyl, carboxylate, -SO2NHC2H5, and -CONHC2H5. Preferably, the DG is selected from carboxyl or carboxylate, and the carboxylate includes, but is not limited to, sodium carboxylate.

[0035] In some embodiments, the R 1 , R 2 , R 3 are independently selected from hydrogen, C1-C5 linear or branched alkyl, C5-C7 cycloalkyl, aryl, C1-C3 alkoxy, halogen, or nitro. Preferably, the R 1 , R 3 are hydrogen, and the R 2 is selected from hydrogen, C1-C5 linear or branched alkyl, C5-C7 cycloalkyl, aryl, or halogen.

[0036] In some embodiments, the preparation method further comprises decarboxylation of the meta-diphenol compound under the catalysis of silver carbonate or high-temperature heating to prepare a resorcinol. Further, the mass ratio of the meta-diphenol compound to the silver carbonate is 1: (0.05-0.5), and preferably 1: (0.1-0.3). The reaction temperature of the meta-diphenol compound with silver carbonate is 100-140℃, and preferably 110-130℃. The reaction of the meta-diphenol compound with silver carbonate is carried out in the presence of an organic solvent, and the organic solvent includes, but is not limited to, dimethyl sulfoxide.

[0037] In some embodiments, the preparation method further comprises a step of separating the prepared meta-diphenol compound from the reaction system, and specifically comprises the following steps: evaporating the solvent in the reaction system to dryness, then adding deionized water for recrystallization, filtering, and drying to obtain the meta-diphenol compound.

[0038] By using the above technical solution, the present application has the following advantages compared with the prior art:

[0039] The preparation method of the present application has a short reaction flow, and can efficiently realize the double-hydroxylation reaction of the aromatic compound by using a one-step method, and the operation is simple. BRIEF DESCRIPTION OF DRAWINGS

[0040] Figure 1Schematic diagram of the mechanism of the two-step hydroxylation reaction process for aromatic compounds. DETAILED DESCRIPTION

[0041] The application will be further described in conjunction with the following examples. However, the application is not limited to the following examples. The implementation conditions used in the examples can be further adjusted according to different requirements of specific use, and the implementation conditions not specified are the conventional conditions in the industry. The technical features involved in each embodiment of the application can be combined with each other as long as there is no conflict. Unless otherwise specified, all raw materials used in the following examples and comparative examples are obtained from commercial or prepared by conventional methods in the art.

[0042] Example 1: This example provides a method for preparing 2,6-dihydroxybenzoic acid, which comprises:

[0043] In a 15 mL reaction tube, add palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g), stir until uniform, then add 65 wt% tert-butyl hydroperoxide (207.9 mg, 1.5 mmol) and benzoic acid (61 mg, 0.5 mmol), heat the reaction solution to 80°C, and react for 4 hours under rapid stirring. After the reaction is completed, cool to room temperature 25°C, acidify with 5 wt% sulfuric acid (0.5 g), and use high performance liquid chromatography to quantitatively analyze the reaction solution (results shown in Table 1).

[0044] Product separation: transfer the reaction solution to a round-bottom flask, use a rotary evaporator to evaporate the solvent, then recrystallize the product with deionized water, filter and dry to obtain 62 mg of 2,6-dihydroxybenzoic acid with a recovery rate of 83%, and use nuclear magnetic resonance hydrogen spectrum to analyze the purity, which is 98%.

[0045] Product decarboxylation: add 62 mg of 2,6-dihydroxybenzoic acid obtained from the above reaction to a 10 mL reaction tube, continue to add 2.5 g of DMSO (dimethyl sulfoxide) and 11 mg of silver carbonate, heat the reaction solution to 120°C, and react for 16 hours under rapid stirring. After the reaction is completed, cool to room temperature 25°C, and use high performance liquid chromatography to analyze the reaction solution, the conversion rate of 2,6-dihydroxybenzoic acid is 99%, and the decarboxylation yield of resorcinol is 83%.

[0046] Example 2: This example provides a method for preparing 2,6-dihydroxybenzoic acid, which comprises:

[0047] In a 15 mL reaction tube, palladium acetate (5.6 mg, 0.025 mmol), N-acetyl-L-isoleucine (8.7 mg, 0.05 mmol), molybdenum acetylacetonate oxide (1.6 mg, 0.005 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were stirred uniformly, then 65 wt% tert-butyl hydroperoxide (207.9 mg, 1.5 mmol) and benzoic acid (61 mg, 0.5 mmol) were added, the reaction liquid was heated to 80°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, acidified by adding 5 wt% sulfuric acid (0.5 g), and the reaction liquid was quantitatively analyzed by high performance liquid chromatography (the results are shown in Table 1).

[0048] Example 3: This example provides a method for preparing 2,6-dihydroxybenzoic acid, which comprises:

[0049] In a 15 mL reaction tube, palladium trifluoroacetate (16.6 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were stirred uniformly, then 65 wt% tert-butyl hydroperoxide (207.9 mg, 1.5 mmol) and benzoic acid (61 mg, 0.5 mmol) were added, the reaction liquid was heated to 80°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, acidified by adding 5 wt% sulfuric acid (0.5 g), and the reaction liquid was quantitatively analyzed by high performance liquid chromatography (the results are shown in Table 1).

[0050] Example 4: This example provides a method for preparing 2,6-dihydroxybenzoic acid, which comprises:

[0051] In a 15 mL reaction tube, palladium trifluoroacetate (16.6 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were stirred uniformly, then 65 wt% tert-butyl hydroperoxide (207.9 mg, 1.5 mmol) and benzoic acid (61 mg, 0.5 mmol) were added, the reaction liquid was heated to 80°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, acidified by adding 5 wt% sulfuric acid (0.5 g), and the reaction liquid was quantitatively analyzed by high performance liquid chromatography (the results are shown in Table 1).

[0052] Example 5: This example provides a method for preparing 2,6-dihydroxybenzoic acid, which comprises:

[0053] In a 15 mL reaction tube, add palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-leucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g), stir well, then add 65 wt% tert-butyl hydroperoxide (207.9 mg, 1.5 mmol) and benzoic acid (61 mg, 0.5 mmol), heat the reaction solution to 80°C, react for 4 hours under rapid stirring, after the reaction is completed, cool to room temperature 25°C, acidify by adding 5 wt% sulfuric acid (0.5 g), and quantitatively analyze the reaction solution using high performance liquid chromatography (results shown in Table 1).

[0054] Example 6: This example provides a method for preparing 2,6-dihydroxybenzoic acid, which comprises:

[0055] In a 15 mL reaction tube, add palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-D / L-phenylglycine (19.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g), stir well, then add 65 wt% tert-butyl hydroperoxide (207.9 mg, 1.5 mmol) and benzoic acid (61 mg, 0.5 mmol), heat the reaction solution to 80°C, react for 4 hours under rapid stirring, after the reaction is completed, cool to room temperature 25°C, acidify by adding 5 wt% sulfuric acid (0.5 g), and quantitatively analyze the reaction solution using high performance liquid chromatography (results shown in Table 1).

[0056] Example 7: This example provides a method for preparing 2,6-dihydroxybenzoic acid, which comprises:

[0057] In a 15 mL reaction tube, copper trifluoroacetate (14.5 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were added and stirred uniformly, then 65 wt% tert-butyl hydroperoxide (207.9 mg, 1.5 mmol) and benzoic acid (61 mg, 0.5 mmol) were added, the reaction liquid was heated to 80°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, acidified by adding 5 wt% sulfuric acid (0.5 g), and the reaction liquid was quantitatively analyzed by high performance liquid chromatography (the results are shown in Table 1).

[0058] Example 8: This example provides a method for preparing 2,6-dihydroxybenzoic acid, which comprises:

[0059] In a 15 mL reaction tube, copper trifluoroacetate (14.5 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were added and stirred uniformly, then 65 wt% tert-butyl hydroperoxide (207.9 mg, 1.5 mmol) and benzoic acid (61 mg, 0.5 mmol) were added, the reaction liquid was heated to 80°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, acidified by adding 5 wt% sulfuric acid (0.5 g), and the reaction liquid was quantitatively analyzed by high performance liquid chromatography (the results are shown in Table 1).

[0060] Example 9: This example provides a method for preparing 2,6-dihydroxybenzoic acid, which comprises:

[0061] In a 15 mL reaction tube, copper trifluoroacetate (14.5 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were added and stirred uniformly, then 65 wt% tert-butyl hydroperoxide (207.9 mg, 1.5 mmol) and benzoic acid (61 mg, 0.5 mmol) were added, the reaction liquid was heated to 80°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, acidified by adding 5 wt% sulfuric acid (0.5 g), and the reaction liquid was quantitatively analyzed by high performance liquid chromatography (the results are shown in Table 1).

[0062] Example 10: This example provides a method for preparing 2,6-dihydroxybenzoic acid, comprising:

[0063] In a 15 mL reaction tube, add palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), chromium oxide (1.7 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N, N-dimethylacetamide (2 g), stir well, then add 65 wt% tert-butyl hydroperoxide (207.9 mg, 1.5 mmol) and benzoic acid (61 mg, 0.5 mmol), heat the reaction solution to 80°C, react for 4 hours under rapid stirring, after the reaction is completed, cool to room temperature 25°C, acidify by adding 5 wt% sulfuric acid (0.5 g), and quantitatively analyze the reaction solution using high performance liquid chromatography (results shown in Table 1).

[0064] Example 11: This example provides a method for preparing 2,6-dihydroxybenzoic acid, comprising:

[0065] In a 15 mL reaction tube, add palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), chromium oxide (1.7 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N, N-dimethylacetamide (2 g), stir well, then add 65 wt% tert-butyl hydroperoxide (207.9 mg, 1.5 mmol) and benzoic acid (61 mg, 0.5 mmol), heat the reaction solution to 80°C, react for 4 hours under rapid stirring, after the reaction is completed, cool to room temperature 25°C, acidify by adding 5 wt% sulfuric acid (0.5 g), and quantitatively analyze the reaction solution using high performance liquid chromatography (results shown in Table 1).

[0066] Example 12: This example provides a method for preparing 2,6-dihydroxybenzoic acid, comprising:

[0067] In a 15 mL reaction tube, palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), tungsten oxide (2.3 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were added and stirred uniformly, then 65 wt% tert-butyl hydroperoxide (207.9 mg, 1.5 mmol) and benzoic acid (61 mg, 0.5 mmol) were added, the reaction liquid was heated to 80°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, acidified by adding 5 wt% sulfuric acid (0.5 g), and the reaction liquid was quantitatively analyzed by high performance liquid chromatography (the results are shown in Table 1).

[0068] Example 13: This example provides a method for preparing 2,6-dihydroxybenzoic acid, which comprises:

[0069] In a 15 mL reaction tube, palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), tungsten oxide (2.3 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were added and stirred uniformly, then 65 wt% tert-butyl hydroperoxide (207.9 mg, 1.5 mmol) and benzoic acid (61 mg, 0.5 mmol) were added, the reaction liquid was heated to 80°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, acidified by adding 5 wt% sulfuric acid (0.5 g), and the reaction liquid was quantitatively analyzed by high performance liquid chromatography (the results are shown in Table 1).

[0070] Example 14: This example provides a method for preparing 2,6-dihydroxybenzoic acid, which comprises:

[0071] In a 15 mL reaction tube, palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), tungsten oxide (2.3 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were added and stirred uniformly, then 65 wt% tert-butyl hydroperoxide (207.9 mg, 1.5 mmol) and benzoic acid (61 mg, 0.5 mmol) were added, the reaction liquid was heated to 80°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, acidified by adding 5 wt% sulfuric acid (0.5 g), and the reaction liquid was quantitatively analyzed by high performance liquid chromatography (the results are shown in Table 1).

[0072] Comparative Example 1: This comparative example provides a method for preparing 2,6-dihydroxybenzoic acid, which comprises:

[0073] In a 15 mL reaction tube, add palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N, N-dimethylacetamide (2 g), stir until uniform, then add 65 wt% tert-butyl hydroperoxide (207.9 mg, 1.5 mmol) and benzoic acid (61 mg, 0.5 mmol), heat the reaction solution to 80°C, react for 4 hours under rapid stirring, after the reaction is completed, cool to room temperature 25°C, acidify by adding 5 wt% sulfuric acid (0.5 g), and quantitatively analyze the reaction solution using high performance liquid chromatography (results shown in Table 1).

[0074]

[0075] Referring to Table 1, the catalytic system (first catalyst, second catalyst and cocatalyst) of the present application can efficiently achieve the dihydroxylation reaction of aromatic compounds by a one-step method. This process is simple to operate and can significantly shorten the synthetic route.

[0076] As for the first catalyst, the combination of palladium salt and amide acid ligand can effectively promote the generation of the target product. Among them, palladium acetate is the best, especially when combined with N-acetyl-L-isoleucine, followed by palladium acetate / N-acetyl-L-leucine, palladium acetate / N-acetyl-D / L-phenylglycine, etc.

[0077] As for the first catalyst, molybdenum complexes show the best effect.

[0078] Example 15: This example provides a method for preparing 2,6-dihydroxybenzoic acid, which comprises:

[0079] In a 15 mL reaction tube, palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), cesium hydroxide (75 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were stirred uniformly, then 65 wt% tert-butyl hydroperoxide (207.9 mg, 1.5 mmol) and benzoic acid (61 mg, 0.5 mmol) were added, the reaction liquid was heated to 80°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, acidified by adding 5 wt% sulfuric acid (0.5 g), and the reaction liquid was quantitatively analyzed by high performance liquid chromatography (the results are shown in Table 2).

[0080] Example 16: This example provides a method for preparing 2,6-dihydroxybenzoic acid, which comprises:

[0081] In a 15 mL reaction tube, palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), sodium hydroxide (20 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were stirred uniformly, then 65 wt% tert-butyl hydroperoxide (207.9 mg, 1.5 mmol) and benzoic acid (61 mg, 0.5 mmol) were added, the reaction liquid was heated to 80°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, acidified by adding 5 wt% sulfuric acid (0.5 g), and the reaction liquid was quantitatively analyzed by high performance liquid chromatography (the results are shown in Table 2).

[0082] Example 17: This example provides a method for preparing 2,6-dihydroxybenzoic acid, which comprises:

[0083] In a 15 mL reaction tube, palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and tert-butyl alcohol (2 g) were stirred uniformly, then 65 wt% tert-butyl hydroperoxide (207.9 mg, 1.5 mmol) and benzoic acid (61 mg, 0.5 mmol) were added, the reaction liquid was heated to 80°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, acidified by adding 5 wt% sulfuric acid (0.5 g), and the reaction liquid was quantitatively analyzed by high performance liquid chromatography (the results are shown in Table 2).

[0084] Example 18: This example provides a method for preparing 2,6-dihydroxybenzoic acid, comprising:

[0085] In a 15 mL reaction tube, palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and acetonitrile (2 g) were added and stirred uniformly, then 65 wt% tert-butyl hydroperoxide (207.9 mg, 1.5 mmol) and benzoic acid (61 mg, 0.5 mmol) were added, the reaction liquid was heated to 80°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, acidified by adding 5 wt% sulfuric acid (0.5 g), and the reaction liquid was quantitatively analyzed using high performance liquid chromatography (the results are shown in Table 2).

[0086] Example 19: This example provides a method for preparing 2,6-dihydroxybenzoic acid, comprising:

[0087] In a 15 mL reaction tube, palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were added and stirred uniformly, then 65 wt% tert-butyl hydroperoxide (207.9 mg, 1.5 mmol) and benzoic acid (61 mg, 0.5 mmol) were added, the reaction liquid was heated to 60°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, acidified by adding 5 wt% sulfuric acid (0.5 g), and the reaction liquid was quantitatively analyzed using high performance liquid chromatography (the results are shown in Table 2).

[0088] Example 20: This example provides a method for preparing 2,6-dihydroxybenzoic acid, comprising:

[0089] In a 15 mL reaction tube, palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were added and stirred uniformly, then 65 wt% tert-butyl hydroperoxide (207.9 mg, 1.5 mmol) and benzoic acid (61 mg, 0.5 mmol) were added, the reaction liquid was heated to 100°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, acidified by adding 5 wt% sulfuric acid (0.5 g), and the reaction liquid was quantitatively analyzed by high performance liquid chromatography (the results are shown in Table 2).

[0090] Example 21: This example provides a method for preparing 2,6-dihydroxybenzoic acid, which comprises:

[0091] In a 15 mL reaction tube, palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were added and stirred uniformly, then 65 wt% tert-butyl hydroperoxide (207.9 mg, 1.5 mmol) and benzoic acid (61 mg, 0.5 mmol) were added, the reaction liquid was heated to 100°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, acidified by adding 5 wt% sulfuric acid (0.5 g), and the reaction liquid was quantitatively analyzed by high performance liquid chromatography (the results are shown in Table 2).

[0092] Example 22: This example provides a method for preparing 2,6-dihydroxybenzoic acid, which comprises:

[0093] In a 15 mL reaction tube, palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were added and stirred uniformly, then 65 wt% tert-butyl hydroperoxide (207.9 mg, 1.5 mmol) and benzoic acid (61 mg, 0.5 mmol) were added, the reaction liquid was heated to 100°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, acidified by adding 5 wt% sulfuric acid (0.5 g), and the reaction liquid was quantitatively analyzed by high performance liquid chromatography (the results are shown in Table 2).

[0094] Example 23: This example provides a method for preparing 2,6-dihydroxybenzoic acid, comprising:

[0095] In a 15 mL reaction tube, palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol), and N,N-dimethylacetamide (2 g) were added and stirred uniformly, then 80 wt% cumene hydroperoxide (285 mg, 1.5 mmol) and benzoic acid (61 mg, 0.5 mmol) were added, the reaction liquid was heated to 80°C, and reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, acidified by adding 5 wt% sulfuric acid (0.5 g), and the reaction liquid was quantitatively analyzed using high performance liquid chromatography (the results are shown in Table 2).

[0096] Example 24: This example provides a method for preparing 2,6-dihydroxybenzoic acid, comprising:

[0097] In a 15 mL reaction tube, palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol), and N,N-dimethylacetamide (2 g) were added and stirred uniformly, then 30 wt% hydrogen peroxide (170 mg, 1.5 mmol) and benzoic acid (61 mg, 0.5 mmol) were added, the reaction liquid was heated to 80°C, and reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, acidified by adding 5 wt% sulfuric acid (0.5 g), and the reaction liquid was quantitatively analyzed using high performance liquid chromatography (the results are shown in Table 2).

[0098] Example 25: This example provides a method for preparing 2,6-dihydroxybenzoic acid, comprising:

[0099] A 15 mL reaction tube was added with palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N, N-dimethylacetamide (2 g), stirred uniformly, then added with 65 wt% tert-butyl hydroperoxide (207.9 mg, 1.5 mmol) and benzoic acid (61 mg, 0.5 mmol), heated to 80°C, reacted for 3 hours under rapid stirring, cooled to room temperature 25°C after the reaction, acidified with 5 wt% sulfuric acid (0.5 g), and quantitatively analyzed by high performance liquid chromatography (results shown in Table 2).

[0100]

[0101] As for the co-catalyst, potassium hydroxide is the best, followed by sodium hydroxide.

[0102] As for the solvent, N, N-dimethylacetamide is the best, followed by tert-butanol.

[0103] As for the oxidant, organic peroxide is better than hydrogen peroxide. Among organic peroxides, tert-butyl hydroperoxide is better.

[0104] Both too high and too low reaction temperature will affect the product yield. As a preferred, the reaction temperature is 70-90°C, and more preferably 70-90°C. The reaction time also affects the product yield. As a preferred, the reaction time is ≥3h, and more preferably 4-5h.

[0105] Example 26:

[0106] A 15 mL reaction tube was added with palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N, N-dimethylacetamide (2 g), stirred uniformly, then added with 65 wt% tert-butyl hydroperoxide (207.9 mg, 1.5 mmol) and benzoic acid (61 mg, 0.5 mmol), heated to 80°C, reacted for 3 hours under rapid stirring, cooled to room temperature 25°C after the reaction, acidified with 5 wt% sulfuric acid (0.5 g), and quantitatively analyzed by high performance liquid chromatography (results shown in Table 2).

[0107] Example 27:

[0108] In a 15 mL reaction tube, palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were added and stirred uniformly, then 65 wt% tert-butyl hydroperoxide (277.2 mg, 2 mmol) and p-ethylbenzoic acid (75 mg, 0.5 mmol) were added, the reaction liquid was heated to 80°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, and the reaction liquid was quantitatively analyzed using nuclear magnetic resonance hydrogen spectrum (the results are shown in Table 3).

[0109] Example 28:

[0110] In a 15 mL reaction tube, palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were added and stirred uniformly, then 65 wt% tert-butyl hydroperoxide (277.2 mg, 2 mmol) and p-propylbenzoic acid (82 mg, 0.5 mmol) were added, the reaction liquid was heated to 80°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, and the reaction liquid was quantitatively analyzed using nuclear magnetic resonance hydrogen spectrum (the results are shown in Table 3).

[0111] Example 29:

[0112] In a 15 mL reaction tube, palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were added and stirred uniformly, then 65 wt% tert-butyl hydroperoxide (277.2 mg, 2 mmol) and p-tert-butylbenzoic acid (89 mg, 0.5 mmol) were added, the reaction liquid was heated to 80°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, and the reaction liquid was quantitatively analyzed using nuclear magnetic resonance hydrogen spectrum (the results are shown in Table 3).

[0113] Example 30:

[0114] In a 15 mL reaction tube, palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were added and stirred uniformly, then 65 wt% tert-butyl hydroperoxide (277.2 mg, 2 mmol) and p-methoxybenzoic acid (76 mg, 0.5 mmol) were added, the reaction liquid was heated to 80°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, and the reaction liquid was quantitatively analyzed using nuclear magnetic resonance hydrogen spectrum (the results are shown in Table 3).

[0115] Example 31:

[0116] In a 15 mL reaction tube, palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were added and stirred uniformly, then 65 wt% tert-butyl hydroperoxide (277.2 mg, 2 mmol) and p-cyclohexylbenzoic acid (102 mg, 0.5 mmol) were added, the reaction liquid was heated to 80°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, and the reaction liquid was quantitatively analyzed using nuclear magnetic resonance hydrogen spectrum (the results are shown in Table 3).

[0117] Example 32:

[0118] In a 15 mL reaction tube, palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were added and stirred uniformly, then 65 wt% tert-butyl hydroperoxide (277.2 mg, 2 mmol) and p-phenylbenzoic acid (99 mg, 0.5 mmol) were added, the reaction liquid was heated to 80°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, and the reaction liquid was quantitatively analyzed using nuclear magnetic resonance hydrogen spectrum (the results are shown in Table 3).

[0119] Example 33:

[0120] Into a 15 mL reaction tube, palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were added and stirred well, then 65 wt% tert-butyl hydroperoxide (277.2 mg, 2 mmol) and 3,5-dimethylbenzoic acid (76 mg, 0.5 mmol) were added, the reaction was heated to 80°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, and the reaction liquid was quantitatively analyzed using nuclear magnetic resonance hydrogen spectrum (the results are shown in Table 3).

[0121] Example 34:

[0122] Into a 15 mL reaction tube, palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were added and stirred well, then 65 wt% tert-butyl hydroperoxide (277.2 mg, 2 mmol) and 3,5-dimethylbenzoic acid (76 mg, 0.5 mmol) were added, the reaction was heated to 80°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, and the reaction liquid was quantitatively analyzed using nuclear magnetic resonance hydrogen spectrum (the results are shown in Table 3).

[0123] Example 35:

[0124] Into a 15 mL reaction tube, palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were added and stirred well, then 65 wt% tert-butyl hydroperoxide (277.2 mg, 2 mmol) and 3,5-dimethylbenzoic acid (76 mg, 0.5 mmol) were added, the reaction was heated to 80°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, and the reaction liquid was quantitatively analyzed using nuclear magnetic resonance hydrogen spectrum (the results are shown in Table 3).

[0125] Example 36:

[0126] In a 15 mL reaction tube, palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were added and stirred uniformly, then 65 wt% tert-butyl hydroperoxide (277.2 mg, 2 mmol) and p-nitrobenzoic acid (83 mg, 0.5 mmol) were added, the reaction liquid was heated to 80°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, and the reaction liquid was quantitatively analyzed using nuclear magnetic resonance hydrogen spectrum (the results are shown in Table 3).

[0127] Example 37:

[0128] In a 15 mL reaction tube, palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were added and stirred uniformly, then 65 wt% tert-butyl hydroperoxide (277.2 mg, 2 mmol) and N-ethylbenzenesulfonamide (92.5 mg, 0.5 mmol) were added, the reaction liquid was heated to 80°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, and the reaction liquid was quantitatively analyzed using nuclear magnetic resonance hydrogen spectrum (the results are shown in Table 3).

[0129] Example 38:

[0130] In a 15 mL reaction tube, palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were added and stirred uniformly, then 65 wt% tert-butyl hydroperoxide (277.2 mg, 2 mmol) and N-ethylbenzenesulfonamide (92.5 mg, 0.5 mmol) were added, the reaction liquid was heated to 80°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, and the reaction liquid was quantitatively analyzed using nuclear magnetic resonance hydrogen spectrum (the results are shown in Table 3).

[0131] Example 39:

[0132] In a 15 mL reaction tube, palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were stirred uniformly, then 65 wt% tert-butyl hydroperoxide (138.6 mg, 1 mmol) and salicylic acid (69 mg, 0.5 mmol) were added, the reaction liquid was heated to 80°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, acidified by adding 5 wt% sulfuric acid (0.5 g), and the reaction liquid was quantitatively analyzed by high performance liquid chromatography (the results are shown in Table 3).

[0133] Example 40:

[0134] In a 15 mL reaction tube, palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were stirred uniformly, then 65 wt% tert-butyl hydroperoxide (138.6 mg, 1 mmol) and sodium salicylate (80 mg, 0.5 mmol) were added, the reaction liquid was heated to 80°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, acidified by adding 5 wt% sulfuric acid (0.5 g), and the reaction liquid was quantitatively analyzed by high performance liquid chromatography (the results are shown in Table 3).

[0135] Example 41:

[0136] In a 15 mL reaction tube, palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), molybdenum acetylacetonate oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N,N-dimethylacetamide (2 g) were stirred uniformly, then 65 wt% tert-butyl hydroperoxide (138.6 mg, 1 mmol) and 4-methyl salicylic acid (76 mg, 0.5 mmol) were added, the reaction liquid was heated to 80°C, reacted for 4 hours under rapid stirring, after the reaction was completed, it was cooled to room temperature 25°C, acidified by adding 5 wt% sulfuric acid (0.5 g), and the reaction liquid was quantitatively analyzed by high performance liquid chromatography (the results are shown in Table 3).

[0137] Example 42:

[0138] In a 15 mL reaction tube, add palladium acetate (11.2 mg, 0.05 mmol), N-acetyl-L-isoleucine (17.3 mg, 0.1 mmol), acetylacetone molybdenum oxide (3.2 mg, 0.01 mmol), potassium hydroxide (28 mg, 0.5 mmol) and N, N-dimethylacetamide (2 g), stir until uniform, then add 65 wt% tert-butyl hydroperoxide (138.6 mg, 1 mmol) and 4-chlorosalicylic acid (86 mg, 0.5 mmol), heat the reaction liquid to 80°C, react for 4 hours under rapid stirring, after the reaction is completed, cool to room temperature 25°C, acidify with 5 wt% sulfuric acid (0.5 g), and quantitatively analyze the reaction liquid using high performance liquid chromatography (results shown in Table 3).

[0139]

[0140]

[0141] The preparation method of the present application is widely applicable, and can obtain an interval diphenol compound using a compound of formula (1) as a raw material. In the formula, R 1 to R 4 groups are different, which will have a certain impact on the yield of the product. As a preferred, when R 1 , R 3 is hydrogen, and R 2 is selected from hydrogen, a straight-chain or branched-chain alkyl group of C1-C5, a cycloalkyl group of C5-C7, an aryl group or a halogen, the yield of the product is higher.

[0142] The above has described the present application in detail, the purpose is to let the person who is familiar with this field technology can understand the content of the present application and implement, and cannot limit the protection scope of the present application by this, all equivalent changes or modifications according to the spirit of the present application should be covered in the protection scope of the present application.

Claims

1. A method for preparing a resorcinol compound, characterized in that: Using the compound shown in formula (1) as a raw material, the reaction was carried out in the presence of a catalytic system, peroxide and solvent to prepare the resorcinol compound shown in formula (2); The formula (1) is: ; wherein DG is selected from carboxyl, carboxylate, sulfonyl, amido, carbonyl, or imido, R 1 , R 2 , R 3 are independently selected from hydrogen, C1-C5 straight or branched chain alkyl, C5-C7 cycloalkyl, aryl, C1-C3 alkoxy, or halogen, R 4 is selected from hydrogen or hydroxyl; The formula (2) is: ; wherein DG, R 1 , R 2 , R 3 each independently corresponds to DG, R 1 , R 2 , R 3 in the formula (1); The catalytic system includes a first catalyst, a second catalyst, and a co-catalyst; The first catalyst comprises a metal salt and an amide acid ligand, the metal salt is a palladium salt and / or a copper salt, the palladium salt is selected from one or more of palladium acetate, palladium trifluoroacetate and palladium chloride; the copper salt is selected from one or more of copper acetate, copper trifluoroacetate and copper chloride; the structural formula of the amide acid ligand is wherein R is selected from a phenyl group, a straight-chain or branched alkyl group with 1-5 carbon atoms; The second catalyst is selected from one or more of molybdenum complexes, molybdenum oxides, and titanium alkoxides, wherein the molybdenum complex is molybdenum acetylacetonate and / or molybdenum hexacarbonyl, the molybdenum oxide is molybdenum trioxide, and the titanium alkoxide is tetraisopropyl titanate. The co-catalyst is an inorganic base; The solvent is one or more of alcohol solvents and amide solvents.

2. The method for preparing resorcinol compounds according to claim 1, characterized in that: The ammonium acid ligand is selected from one or more of N-acetyl-L-leucine, N-acetyl-D / L-phenylglycine, acetyl-L-isoleucine, and N-acetyl-L-valine.

3. The method of producing an interval diol compound according to claim 1 or 2, characterized by: The molar ratio of the metal salt to the amyl acid ligand is 1:(1.5~3); and / or, The molar ratio of the metal salt to the compound shown in formula (1) is (0.05~0.5):

1.

4. The method of claim 1, wherein the method is represented by the following scheme: ###0000033### The molar ratio of the second catalyst to the compound shown in formula (1) is (0.01~0.1):

1.

5. The method of claim 1, wherein the method is represented by the following scheme: ###0002### Scheme 1 The inorganic base is selected from one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, potassium acetate, sodium bicarbonate, disodium hydrogen phosphate, and cesium carbonate; and / or, The molar ratio of the inorganic base to the compound shown in formula (1) is (0.5~2):

1.

6. The method for preparing resorcinol compounds according to claim 1, characterized in that: The peroxide is an organic peroxide and / or an inorganic peroxide, wherein the organic peroxide is selected from one or more of tert-butyl hydroperoxide, cyclohexane hydroperoxide, ethylbenzene hydroperoxide, and cumene hydroperoxide, and the inorganic peroxide is hydrogen peroxide; and / or... The molar ratio of the peroxide to the compound shown in formula (1) is (1~5):

1.

7. The method for preparing resorcinol compounds according to claim 1, characterized in that: The alcohol solvent is tert-butanol; and / or, The amide solvent is N,N-dimethylacetamide.

8. The method of claim 1 or 7, wherein the method is characterized by: The mass ratio of the solvent to the compound shown in formula (1) is (1~50):

1.

9. The method for preparing resorcinol compounds according to claim 1, characterized in that: The reaction temperature is 20℃~100℃, and the time is 0.2h~24h.

10. The method for preparing resorcinol compounds according to claim 1, characterized in that: The DG is selected from carboxyl groups, carboxyl salts, -SO2NHC2H5, and -CONHC2H5.

11. The method for preparing resorcinol compounds according to claim 1, characterized in that: The preparation method further includes causing the resorcinol compound to undergo a decarboxylation reaction under silver carbonate catalysis or high-temperature heating to produce resorcinol.

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