Synthesis method of 2, 6-dihydroxybenzoic acid

Abstract

The invention discloses a novel preparation method of 2, 6-dihydroxybenzoic acid, the synthetic route is shown as follows: # imgabs0 takes resorcinol as a raw material, and a key intermediate product compound II can be obtained with higher yield. Due to the existence of tertiary butyl, the generation of a byproduct 2, 4-dihydroxybenzoic acid in the Kolbe-Schmitt reaction can be effectively prevented. And removing the tert-butyl group to obtain the 2, 6-dihydroxybenzoic acid. According to the method, corrosion of molten reactants to equipment in a solvent-free method is avoided, the production safety is improved, the reaction time is shortened, and the energy consumption is reduced. And the reaction does not need complex post-treatment, the final product 2, 6-dihydroxybenzoic acid can be obtained with extremely high yield and purity, the utilization efficiency of equipment is improved, and the production period is shortened.

Description

[Technical field]

[0001] The invention belongs to the technical field of fine chemicals, and in particular relates to a method for synthesizing 2,6-dihydroxybenzoic acid, a key pharmaceutical and pesticide intermediate. [Background technology]

[0002] 2,6-Dihydroxybenzoic acid, also known as γ-razoic acid, is an important fine chemical intermediate. Because it has the properties of both phenol and carboxylic acid, it has good processing properties. Therefore, it is widely used in the fields of medicine, pesticides, dyes, etc., such as for the preparation of insecticide bispyribac-sodium, herbicide KIH-2023, antibiotic methicillin sodium, etc.

[0003] Traditional methods for synthesizing 2,6-dihydroxybenzoic acid mostly use the Kolbe-Schmitt reaction to introduce carboxyl groups into resorcinol under high pressure. That is, resorcinol is used as a raw material, and resorcinol is first converted into a metal salt through an alkaline system, and then carbon dioxide gas is introduced to synthesize 2,6-dihydroxybenzoic acid through a carboxylation reaction under high temperature and high pressure.

[0004] Patent IN2013MU00332 A reports a method for synthesizing 2,6-dihydroxybenzoic acid by solvent method. Toluene, water, N,N-dimethylformamide, butanone, etc. are used as reaction solvents, potassium carbonate, potassium bicarbonate or sodium carbonate is used to form salt with resorcinol, and the reaction is carried out under carbon dioxide pressure. The single-pass yield of the product is within 35.8%. Usually, the carboxylation reaction occurs at the ortho position of the hydroxyl group. In addition to the main product 2,6-dihydroxybenzoic acid, there is also the generation of the by-product 2,4-dihydroxybenzoic acid. And the properties of the target product and the by-product are very similar, so it is difficult to purify and separate them through existing post-processing means, resulting in a low yield.

[0005] Patent CN1394843A reports a high-pressure solvent-free method for synthesizing 2,6-dihydroxybenzoic acid. A mixture of alkali metal salt and resorcinol is directly added to an autoclave, and a certain pressure of carbon dioxide is introduced in a molten state for 3 hours. The mixture is recrystallized using ethanol and water, and the product purity reaches 99%, with a single-pass yield of about 27%. This method is a gas-solid two-phase reaction. Due to the low mass transfer efficiency of the reaction, the reaction system will be heated unevenly, and the reaction process is difficult to control, resulting in a low yield and a complicated post-processing process.

[0006] In summary, the prior art methods for preparing 2,6-dihydroxybenzoic acid still have problems such as many reaction by-products, low yield, and complicated post-processing. Therefore, a reaction route with fewer reaction by-products, high yield, and simple post-processing is urgently needed. [Summary of the invention]

[0007] In order to overcome the above-mentioned shortcomings of the prior art, the present invention provides an efficient and simple method for synthesizing 2,6-dihydroxybenzoic acid, which can obtain the target product with extremely high yield and purity.

[0008] A method for preparing 2,6-dihydroxybenzoic acid is achieved by the following technical scheme:

[0009] The specific synthetic route is as follows:

[0010]

[0011] Specific steps:

[0012] 1) Resorcinol and tert-butyl alcohol shown in formula I are used as reactants, a catalyst is added, the temperature is raised to react, and after completion, the reaction is filtered and dried to obtain a compound shown in formula II;

[0013] 2) The compound of formula II prepared in step 1) is placed in a high-pressure reactor, solid base and solvent are added, carbon dioxide gas is introduced, and the reaction is carried out under pressure and temperature. After the reaction is completed, the solvent is removed by distillation under reduced pressure, acid is added to adjust the pH to acidic, and a solid compound of formula II is obtained by suction filtration;

[0014] 3) Add a solvent and a catalyst to the compound of formula II prepared in step 2), heat the mixture to react, distill off the solvent, add ice water, extract with dichloromethane, and distill to obtain 2,6-dihydroxybenzoic acid of formula IV.

[0015] The molar ratio of resorcinol and tert-butyl alcohol represented by formula I in step 1) is 1:2-5, and the reaction temperature is 30-83°C.

[0016] The reaction time is 8 to 12 hours.

[0017] The catalyst in step 1) is a mixture of one or more of boron trifluoride, ferrous chloride and cupric chloride.

[0018] The molar ratio of the compound represented by formula II to the solid base in step 2) is 1:2-8, the pressure of the carbon dioxide gas is 0.5-3.0 MPa, the reaction temperature is 80-180° C., and the reaction time is 2-12 h.

[0019] The solid base in step 2) is sodium hydroxide, potassium hydroxide or a mixture of the two, and the solvent is a mixture of tetrahydrofuran, toluene and acetonitrile or more.

[0020] The reaction temperature in step 3) is 20-100°C and the reaction time is 8-14h.

[0021] The catalyst in step 3) is a mixture of one or more of boron trifluoride, ferrous chloride and cupric chloride, and the solvent is o-dichlorobenzene.

[0022] The advantages or beneficial effects of the above technical solution include at least:

[0023] The present invention provides an efficient and simple method for preparing 2,6-dihydroxybenzoic acid, which uses resorcinol as a raw material and can obtain a key intermediate compound II with a high yield. The presence of a tert-butyl group can effectively prevent the formation of a by-product 2,4-dihydroxybenzoic acid in the Kolbe-Schmitt reaction. After removing the tert-butyl group, the final product IV is obtained. The method avoids the corrosion of the molten reactants to the equipment in the solvent-free method, improves production safety, shortens the reaction time, and reduces energy consumption. In addition, the reaction does not require complicated post-treatment, and the final product 2,6-dihydroxybenzoic acid can be obtained with extremely high yield and purity by suction filtration, thereby improving the utilization efficiency of the equipment and shortening the production cycle.

Brief Description of the Drawings

[0024] Figure 1 This is the hydrogen nuclear magnetic resonance spectrum of the 2,6-dihydroxybenzoic acid product. [Specific implementation method]

[0025] The present invention will be further described below in conjunction with specific embodiments, but the present invention is not limited to the following embodiments.

[0026] Example 1

[0027] Step 1): Preparation of Compound II

[0028] 11.0g (0.10mol) of resorcinol, 15.56g (0.21mol) of tert-butyl alcohol and 0.1g of boron trifluoride were placed in a reaction bottle. After the addition was completed, the temperature was slowly raised to 80°C and stirred for 10 hours. After the reaction was completed, the reaction system was cooled to room temperature. Filtered and dried the filter cake to obtain 22.06g of white solid compound II with a purity of 99.1% and a yield of 98.52%.

[0029] Step 2): Preparation of Compound III

[0030] 22.2g (0.10mol) of compound II and 4.0g of sodium hydroxide were placed in a high-pressure reactor, 50.0g of tetrahydrofuran was added, 1.0MPa of carbon dioxide gas was charged, the temperature was raised to 100°C and stirred, and the temperature was kept for 2h. After the reaction was completed, the solvent in the system was distilled off under reduced pressure, the pH was adjusted to acidic by adding acid, and 23.4g of white solid compound III was obtained by suction filtration, with a purity of 99.5% and a yield of 87.53%.

[0031] Step 3): Preparation of Compound IV

[0032] 13.3g (0.05mol) of compound III and 0.5g of boron trifluoride were placed in a round-bottom flask, and 30.0g of o-dichlorobenzene was added. The temperature was raised to 100°C and the reaction was carried out for 8h. After the reaction was completed, the solvent was distilled off, ice water was added, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with water, the solvent was evaporated under reduced pressure, and dried to obtain 7.6g of white solid compound IV with a purity of 99.4% and a yield of 98.1%.

[0033] Example 2

[0034] Step 1): Preparation of Compound II

[0035] 11.0g (0.10mol) of resorcinol, 18.50g (0.25mol) of tert-butyl alcohol and 0.1g of ferrous chloride were placed in a reaction bottle. After the addition was completed, the temperature was slowly raised to 30°C and stirred for 10 hours. After the reaction was completed, the reaction system was cooled to room temperature. Filtered and dried the filter cake to obtain 21.9g of white solid compound II with a purity of 99.6% and a yield of 98.2%.

[0036] Step 2): Preparation of Compound III

[0037] 22.2g (0.10mol) of compound II and 5.0g of sodium hydroxide were placed in a high-pressure reactor, 50.0g of tetrahydrofuran was added, 1.5MPa of carbon dioxide gas was charged, the temperature was raised to 110°C with stirring, and the reaction was kept warm for 3h. After the reaction was completed, the solvent in the system was distilled off under reduced pressure, the pH was adjusted to acidic by adding acid, and 22.6g of white solid compound III was obtained by suction filtration, with a purity of 98.9% and a yield of 84.0%.

[0038] Step 3): Preparation of Compound IV

[0039] 13.3g (0.05mol) of compound III and 0.5g of ferrous chloride were placed in a round-bottom flask, and 30.0g of o-dichlorobenzene was added. The temperature was raised to 100°C and the reaction was carried out for 8h. After the reaction was completed, the solvent was distilled off, ice water was added, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with water, the solvent was evaporated under reduced pressure, and dried to obtain 7.6g of white solid compound IV with a purity of 99.6% and a yield of 98.3%.

[0040] Example 3

[0041] Step 1): Preparation of Compound II

[0042] 11.0g (0.10mol) of resorcinol, 37..04g (0.5mol) of tert-butyl alcohol and 0.1g of cupric chloride were placed in a reaction bottle. After the addition was completed, the temperature was slowly raised to 50°C and stirred for 10 hours. After the reaction was completed, the reaction system was cooled to room temperature. Filtered and dried the filter cake to obtain 21.7g of white solid compound II with a purity of 99.0% and a yield of 96.8%.

[0043] Step 2): Preparation of Compound III

[0044] 22.2g (0.10mol) of compound II and 4.1g of sodium hydroxide were placed in a high-pressure reactor, 50.0g of tetrahydrofuran was added, 2.0MPa of carbon dioxide gas was charged, the temperature was raised to 90°C with stirring, and the reaction was kept warm for 2h. After the reaction was completed, the solvent in the system was distilled off under reduced pressure, acid was added to adjust the pH to acidic, and 21.9g of white solid compound III was obtained by suction filtration, with a purity of 99.7% and a yield of 81.0%.

[0045] Step 3): Preparation of Compound IV

[0046] 13.3g (0.05mol) of compound III and 0.5g of copper chloride were placed in a round-bottom flask, and 30.0g of o-dichlorobenzene was added. The temperature was raised to 100°C and the reaction was carried out for 8h. After the reaction was completed, the solvent was distilled off, ice water was added, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with water, the solvent was evaporated under reduced pressure, and dried to obtain 7.4g of white solid compound IV with a purity of 98.7% and a yield of 94.9%.

[0047] Example 4

[0048] Step 1): Preparation of Compound II

[0049] 11.0g (0.10mol) of resorcinol, 15.56g (0.21mol) of tert-butyl alcohol and 0.1g of boron trifluoride were placed in a reaction bottle. After the addition was completed, the temperature was slowly raised to 83°C and stirred for 10 hours. After the reaction was completed, the reaction system was cooled to room temperature. Filtered and dried the filter cake to obtain 22.0g of white solid compound II with a purity of 99.8% and a yield of 98.9%.

[0050] Step 2): Preparation of Compound III

[0051] 22.2g (0.10mol) of compound II and 6.0g of sodium hydroxide were placed in the inner tank of a high-pressure reactor, 50.0g of toluene was added, 2.5MPa of carbon dioxide gas was charged, the temperature was raised to 150°C with stirring, and the reaction was kept warm for 10h. After the reaction was completed, the solvent in the system was distilled off under reduced pressure, acid was added to adjust the pH to acidic, and 22.5g of white solid compound III was obtained by suction filtration, with a purity of 99.5% and a yield of 84.2%.

[0052] Step 3): Preparation of Compound IV

[0053] 13.3g (0.05mol) of compound III and 0.5g of boron trifluoride were placed in a round-bottom flask, and 30.0g of o-dichlorobenzene was added. The temperature was raised to 90°C and the reaction was carried out for 8h. After the reaction was completed, the solvent was distilled off, ice water was added, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with water, the solvent was evaporated under reduced pressure, and dried to obtain 7.6g of white solid compound IV with a purity of 99.2% and a yield of 97.9%.

[0054] Example 5

[0055] Step 1): Preparation of Compound II

[0056] 11.0g (0.10mol) of resorcinol, 29.64g (0.4mol) of tert-butyl alcohol and 0.1g of ferrous chloride were placed in a reaction bottle. After the addition was completed, the temperature was slowly raised to 45°C and stirred for 10 hours. After the reaction was completed, the reaction system was cooled to room temperature. Filtered and dried the filter cake to obtain 22.0g of white solid compound II with a purity of 99.8% and a yield of 98.9%.

[0057] Step 2): Preparation of Compound III

[0058] 22.2g (0.10mol) of compound II and 8.0g of sodium hydroxide were placed in a high-pressure reactor, 50.0g of toluene was added, 1.0MPa of carbon dioxide gas was introduced, the temperature was raised to 180°C with stirring, and the reaction was kept warm for 12h. After the reaction was completed, the solvent in the system was distilled off under reduced pressure, the pH was adjusted to acidic by adding acid, and 22.7g of white solid compound III was obtained by suction filtration, with a purity of 99.8% and a yield of 85.2%.

[0059] Step 3): Preparation of Compound IV

[0060] 13.3g (0.05mol) of compound III and 0.5g of ferrous chloride were placed in a round-bottom flask, and 30.0g of o-dichlorobenzene was added. The temperature was raised to 100°C and the reaction was carried out for 8h. After the reaction was completed, the solvent was distilled off, ice water was added, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with water, the solvent was evaporated under reduced pressure, and dried to obtain 7.6g of white solid compound IV with a purity of 98.8% and a yield of 97.5%.

[0061] Example 6

[0062] Step 1): Preparation of Compound II

[0063] 11.0g (0.10mol) of resorcinol, 25.9g (0.35mol) of tert-butyl alcohol and 0.1g of cupric chloride were placed in a reaction bottle. After the addition was completed, the temperature was slowly raised to 80°C and stirred for 10 hours. After the reaction was completed, the reaction system was cooled to room temperature. Filtered and dried the filter cake to obtain 22.1g of white solid compound II with a purity of 99.6% and a yield of 99.2%.

[0064] Step 2): Preparation of Compound III

[0065] 22.2g (0.10mol) of compound II and 4.0g of sodium hydroxide were placed in a high-pressure reactor, 50.0g of toluene was added, 3.0MPa of carbon dioxide gas was introduced, the temperature was raised to 120°C with stirring, and the reaction was kept warm for 8h. After the reaction was completed, the solvent in the system was distilled off under reduced pressure, the pH was adjusted to acidic by adding acid, and 22.8g of white solid compound III was obtained by suction filtration, with a purity of 98.2% and a yield of 84.2%.

[0066] Step 3): Preparation of Compound IV

[0067] 13.3g (0.05mol) of compound III and 0.5g of copper chloride were placed in a round-bottom flask, and 30.0g of o-dichlorobenzene was added. The temperature was raised to 30°C and the reaction was carried out for 8h. After the reaction was completed, the solvent was distilled off, ice water was added, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with water, the solvent was evaporated under reduced pressure, and dried to obtain 7.5g of white solid compound IV with a purity of 99.8% and a yield of 97.2%.

[0068] Example 7

[0069] Step 1): Preparation of Compound II

[0070] 11.0g (0.10mol) of resorcinol, 15.56g (0.21mol) of tert-butyl alcohol and 0.1g of boron trifluoride were placed in a reaction bottle. After the addition was completed, the temperature was slowly raised to 70°C and stirred for 10 hours. After the reaction was completed, the reaction system was cooled to room temperature. Filtered and dried the filter cake to obtain 21.2g of white solid compound II with a purity of 99.6% and a yield of 95.1%.

[0071] Step 2): Preparation of Compound III

[0072] 22.2g (0.10mol) of compound II and 5.0g of sodium hydroxide were placed in a high-pressure reactor, 50.0g of acetonitrile was added, 2.3MPa of carbon dioxide gas was charged, the temperature was raised to 150°C with stirring, and the reaction was kept warm for 6h. After the reaction was completed, the solvent in the system was distilled off under reduced pressure, the pH was adjusted to acidic by adding acid, and 20.3g of white solid compound III was obtained by suction filtration, with a purity of 98.8% and a yield of 75.4%.

[0073] Step 3): Preparation of Compound IV

[0074] 13.3g (0.05mol) of compound III and 0.5g of boron trifluoride were placed in a round-bottom flask, and 30.0g of o-dichlorobenzene was added. The temperature was raised to 30°C and the reaction was carried out for 8h. After the reaction was completed, the solvent was distilled off, ice water was added, and the mixture was extracted with dichloromethane. The organic phases were combined, washed with water, the solvent was evaporated under reduced pressure, and dried to obtain 7.4g of white solid compound IV with a purity of 99.0% and a yield of 95.1%.

[0075] The above description is only a preferred embodiment of the present invention, which is merely illustrative and not restrictive of the present invention. It is understood by those skilled in the art that many changes, modifications, and even equivalent changes may be made thereto within the scope defined by the patent claims of the present invention, but all of them will fall within the protection scope of the present invention.

Claims

1. A method for preparing 2,6-dihydroxybenzoic acid, characterized in that: The specific synthetic route is as follows: Specific steps: 1) Resorcinol and tert-butyl alcohol shown in formula I are used as reactants, a catalyst is added, the temperature is raised to react, and after completion, the reaction is filtered and dried to obtain a compound shown in formula II; 2) The compound of formula II prepared in step 1) is placed in a high-pressure reactor, solid base and solvent are added, carbon dioxide gas is introduced, and the reaction is carried out under pressure and temperature. After the reaction is completed, the solvent is removed by distillation under reduced pressure, acid is added to adjust the pH to acidic, and a solid compound of formula II is obtained by suction filtration; 3) Add a solvent and a catalyst to the compound of formula II prepared in step 2), heat the mixture to react, distill off the solvent, add ice water, extract with dichloromethane, and distill to obtain 2,6-dihydroxybenzoic acid of formula IV.

2. The method for preparing 2,6-dihydroxybenzoic acid according to claim 1, characterized in that: The molar ratio of resorcinol and tert-butyl alcohol represented by formula I in step 1) is 1:2-5, the reaction temperature is 30-83°C, and the reaction time is 8-12 hours.

3. The method for preparing 2,6-dihydroxybenzoic acid according to claim 1, characterized in that: The catalyst in step 1) is a mixture of one or more of boron trifluoride, ferrous chloride and cupric chloride.

4. The method for preparing 2,6-dihydroxybenzoic acid according to claim 1, characterized in that: The molar ratio of the compound represented by formula II to the solid base in step 2) is 1:2-8, the pressure of the carbon dioxide gas is 0.5-3.0 MPa, the reaction temperature is 80-180° C., and the reaction time is 2-12 h.

5. The method for preparing 2,6-dihydroxybenzoic acid according to claim 1, characterized in that: The solid base in step 2) is sodium hydroxide, potassium hydroxide or a mixture of the two, and the solvent is a mixture of tetrahydrofuran, toluene and acetonitrile or more.

6. The method for preparing 2,6-dihydroxybenzoic acid according to claim 1, characterized in that: The reaction temperature in step 3) is 20-100°C and the reaction time is 8-14h.

7. The method for preparing 2,6-dihydroxybenzoic acid according to claim 1, characterized in that: The catalyst in step 3) is a mixture of one or more of boron trifluoride, ferrous chloride and cupric chloride, and the solvent is o-dichlorobenzene.

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