Preparation method of 2, 6-dihydroxytoluene

Abstract

The invention discloses a preparation method of 2, 6-dihydroxytoluene, and belongs to the technical field of organic synthesis. The preparation method comprises the following steps: reacting 3, 5-dichloro-4-methyl benzoic acid serving as a raw material with acetate under the action of a catalyst to generate a 3, 5-diacetoxy-4-methyl benzoic acid intermediate; the method comprises the following steps: carrying out decarboxylation reaction on 3, 5-diacetoxy-4-methyl benzoic acid and a copper tetraphenylporphyrin catalyst under the action of alkali, and hydrolyzing to generate 2, 6-dihydroxytoluene. The route is overall reasonable and is carried out in two steps, and a simple and effective new route is provided for preparation of the 2, 6-dihydroxytoluene.

Description

Technical Field

[0001] The invention relates to a method for preparing 2,6-dihydroxytoluene, and belongs to the technical field of organic synthesis. Background Art

[0002] 2,6-Dihydroxytoluene is an important organic synthesis intermediate with many important physical and chemical properties, so it has very important applications in the chemical industry. Its application areas are divided into synthetic resins, dyeing, medicine, pesticides, pigments, dyes, hair dyes, agricultural chemicals, photosensitive materials and explosives, etc. Moreover, due to its good disinfection and sterilization functions, it has also been widely used in shampoo, skin care products and other products in recent years.

[0003] Pharmaceutical pesticide field: 2,6-dihydroxytoluene is widely used in medicine. It can be cyclized with phthalic anhydride to obtain 1,3-dihydroxy-2-methylanthraquinone, which can be further synthesized into drugs for the treatment of nasopharyngeal carcinoma through acetylation, methylation and other reactions. In addition, it can also be used as an intermediate for salicylic acid dipyrimidine herbicides, which has important applications in the pesticide field.

[0004] Materials Science: 2,6-dihydroxytoluene can also be used as a raw material to synthesize a series of porphyrin and porphine compounds, which are widely used in polymer materials, molecular targeted drugs and chemical catalysis. In addition, 2,6-dihydroxytoluene can also be used to synthesize new colored pigments with two different functions of electron-donating groups. This colorant can be used on high-energy polymers.

[0005] In summary, 2,6-dihydroxytoluene plays an important role in many fields due to its unique chemical properties and reactivity.

[0006] There are many methods for synthesizing 2,6-dihydroxytoluene, among which [Chemical Science, 2015, 6, 4674-4680; Journal of Organic Chemistry, 1988, 53, 3752-3757; US19945276198; CN117567249] reported that 2-methyl-1,3-cyclohexanedione was used as raw material and obtained by reduction reaction with a yield of 39-94%. The chemical reaction equation is as follows:

[0007]

[0008] Patents [CN113698276; CN113214051; CN104341275; CN111620761] report the use of 2,6-dichloro / bromotoluene or 3-chloro-2-methylphenol hydrolysis reaction to obtain 2,6-dihydroxytoluene. The chemical reaction equation is as follows:

[0009]

[0010] Patent [CN113831223 / CN113582820] reports the synthesis of 2,6-dihydroxytoluene by methylation reaction of resorcinol and methanol under catalysis; the chemical reaction equation is as follows:

[0011]

[0012] In view of the shortcomings of the above methods, the present invention adopts a preparation method with simple process, mild reaction conditions, low equipment requirements and high total yield, which is suitable for factory production to meet the growing market demand. Summary of the invention

[0013] In order to overcome the above technical defects, the present invention provides a method for preparing 2,6-dihydroxytoluene. 3,5-dichloro-4-methylbenzoic acid is used as a raw material and acetate is reacted with a catalyst to generate a 3,5-diacetoxy-4-methylbenzoic acid intermediate; the 3,5-diacetoxy-4-methylbenzoic acid intermediate is decarboxylated and hydrolyzed under the action of a tetraphenylporphyrin copper catalyst and a base to generate 2,6-dihydroxytoluene. The route of the present invention is overall reasonable and is carried out in two steps, providing a concise and effective new path for the preparation of 2,6-dihydroxytoluene.

[0014] The method for preparing 2,6-dihydroxytoluene of the present invention comprises the following steps:

[0015] A. Mix 3,5-dichloro-4-methylbenzoic acid, acetate and a catalyst in acetic anhydride, and react to generate 3,5-diacetoxy-4-methylbenzoic acid under elevated temperature conditions;

[0016] B. Mix copper tetraphenylporphyrin and an organic base in an organic solvent, add 3,5-diacetoxy-4-methylbenzoic acid solution under elevated temperature conditions for decarboxylation reaction, and then hydrolyze to obtain the product 2,6-dihydroxytoluene.

[0017] The reaction equation is shown as follows:

[0018]

[0019] Furthermore, in the above step A, the acetate is sodium acetate, cesium acetate, potassium acetate or lithium acetate.

[0020] Furthermore, in the above step A, the catalyst is potassium hexacyanoferrate or sodium hexafluoroferrate.

[0021] Furthermore, in the above technical solution, in step A, the molar ratio of 3,5-dichloro-4-methylbenzoic acid, acetate and catalyst is 1:2.2-2.8:0.05-0.1.

[0022] Furthermore, in the above technical solution, in step B, the organic base is selected from 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,5-diazabicyclo[4.3.0]non-5-ene (DBN); preferably DBU.

[0023] Furthermore, in the above technical solution, in step B, the organic solvent is selected from NMP and DMSO; preferably DMSO.

[0024] Furthermore, in the above technical solution, in step B, the molar ratio of the 3,5-diacetoxy-4-methylbenzoic acid, the copper catalyst and the base is 1:0.05-0.1:0.05-0.1.

[0025] Furthermore, in the above technical solution, in step B, the hydrolysis is carried out by heating an acid aqueous solution (hydrochloric acid aqueous solution) or by using an alkali aqueous solution (sodium hydroxide aqueous solution or potassium hydroxide aqueous solution) at room temperature.

[0026] Beneficial effects of the invention:

[0027] A. The present invention uses 3,5-dichloro-4-methylbenzoic acid as a raw material. 3,5-dichloro-4-methylbenzoic acid is an important chemical and pharmaceutical intermediate, which is widely used in the fields of fungicides, pesticides, pharmaceutical intermediates, etc. At present, there is a large amount of overproduction. A new use of it is developed, and the problem of overcapacity is solved.

[0028] B. The present invention uses acetate to react with 3,5-dichloro-4-methylbenzoic acid to generate 3,5-diacetoxy-4-methylbenzoic acid, and the route is creative and provides a route reference for synthesizing such compounds.

[0029] C. In the second step of the present invention, the catalyst and base are added first, and then 3,5-diacetoxy-4-methylbenzoic acid is added dropwise at high temperature, thereby reducing the amount of catalyst and base used. Specific embodiments

[0030] The present invention will be further described below by specific examples. These embodiments should be understood to be only used to illustrate the present invention and not to limit the scope of protection of the present invention. After reading the content of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention.

[0031] Example 1

[0032] Under nitrogen protection, 20.5 g (0.1 mol) of 3,5-dichloro-4-methylbenzoic acid, 21.3 g (0.26 mol) of sodium acetate and 2.3 g (0.007 mol) of potassium hexacyanoferrate were mixed in 80 mL of acetic anhydride, heated to reflux and reacted for 4 hours, cooled to room temperature, filtered, and then added to 200 mL of water, filtered, and the crude product was recrystallized with ethanol and water to obtain 20.7 g of 3,5-diacetoxy-4-methylbenzoic acid with a yield of 82%. LC-MS [M+H] + =253.3

[0033] Under nitrogen protection, 5.4 g (0.008 mol) of tetraphenylporphyrin copper and 1.2 g (0.008 mol) of DBU were mixed in 60 mL of DMSO, and the temperature was raised to 110-115 ° C. 25.2 g (0.1 mol) of 3,5-diacetoxy-4-methylbenzoic acid and 30 mL of DMSO solution were added dropwise. After the addition was completed, the reaction was continued for 3 hours, cooled to room temperature, filtered, and concentrated. 40 mL of hydrochloric acid (6N) was then added to the obtained product, and refluxed for 5 hours, and then 150 mL of toluene was added to reflux with water, and then the toluene was concentrated. The crude product was distilled under reduced pressure to obtain 10.6 g of 2,6-dihydroxytoluene with a yield of 85% and a chemical purity of 99.2%. 1 HNMR(400MHz, CDCl3):9.38(s,2H),7.37-6.85(m,2H),6.46-6.17(m,1H),2.15(s,3H).

[0034] Example 2

[0035] Under nitrogen protection, 20.5 g (0.1 mol) of 3,5-dichloro-4-methylbenzoic acid, 42.2 g (0.22 mol) of cesium acetate and 2.4 g (0.01 mol) of sodium hexafluoroferrate were mixed in 120 mL of acetic anhydride, heated to reflux and reacted for 6 hours, cooled to room temperature, filtered, and then added to 300 mL of water, filtered, and the crude product was recrystallized from ethanol and water to obtain 19.7 g of 3,5-diacetoxy-4-methylbenzoic acid with a yield of 78%.

[0036] Under nitrogen protection, 5.4 g (0.008 mol) of tetraphenylporphyrin copper and 1.2 g (0.01 mol) of DBN were mixed in 60 mL of NMP, the temperature was raised to 110-115 ° C, 25.2 g (0.1 mol) of 3,5-diacetoxy-4-methylbenzoic acid and 30 mL of NMP solution were added dropwise, and the reaction was continued for 5 hours. The temperature was cooled to room temperature, filtered, and concentrated. 40 mL of hydrochloric acid (6N) was then added to the obtained product, and the reaction was refluxed for 5 hours, and then 150 mL of toluene was added to reflux with water, and then the toluene was concentrated. The crude product was distilled under reduced pressure to obtain 9.5 g of 2,6-dihydroxytoluene with a yield of 77% and a chemical purity of 99.1%.

[0037] Example 3

[0038] Under nitrogen protection, 20.5 g (0.1 mol) of 3,5-dichloro-4-methylbenzoic acid, 27.4 g (0.28 mol) of potassium acetate and 3.2 g (0.01 mol) of potassium hexacyanoferrate were mixed in 80 mL of acetic anhydride, heated to reflux for reaction for 4 hours, cooled to room temperature, filtered, then added to 200 mL of water, filtered, and the crude product was recrystallized from ethanol and water to obtain 19.9 g of 3,5-diacetoxy-4-methylbenzoic acid with a yield of 79%.

[0039] Under nitrogen protection, 6.8 g (0.01 mol) of tetraphenylporphyrin copper and 1.5 g (0.01 mol) of DBU were mixed in 60 mL of DMSO, the temperature was raised to 110-115 ° C, 25.2 g (0.1 mol) of 3,5-diacetoxy-4-methylbenzoic acid and 30 mL of DMSO solution were added dropwise, and the reaction was continued for 3 hours. The temperature was lowered to room temperature, filtered, and concentrated. The obtained product was then added with 120 mL of sodium hydroxide aqueous solution (20%), reacted at room temperature for 3 hours, 2N hydrochloric acid was added to adjust the pH to 1-2, and then 100 mL of dichloromethane was added for extraction twice, and then the dichloromethane was concentrated. The crude product was distilled under reduced pressure to obtain 10.3 g of the product 2,6-dihydroxytoluene, with a yield of 83% and a chemical purity of 99.1%.

[0040] Example 4

[0041] Under nitrogen protection, 20.5 g (0.1 mol) of 3,5-dichloro-4-methylbenzoic acid, 14.5 g (0.22 mol) of lithium acetate and 1.7 g (0.005 mol) of potassium hexacyanoferrate were mixed in 80 mL of acetic anhydride, heated to reflux for reaction for 4 hours, cooled to room temperature, filtered, then added to 200 mL of water, filtered, and the crude product was recrystallized from ethanol and water to obtain 19.1 g of 3,5-diacetoxy-4-methylbenzoic acid with a yield of 76%.

[0042] Under nitrogen protection, 6.8 g (0.01 mol) of tetraphenylporphyrin copper and 0.6 g (0.005 mol) of DBN were mixed in 60 mL of DMSO, the temperature was raised to 110-115 ° C, 25.2 g (0.1 mol) of 3,5-diacetoxy-4-methylbenzoic acid and 30 mL of DMSO solution were added dropwise, and the reaction was continued for 7 hours. The temperature was cooled to room temperature, filtered, and concentrated. The obtained product was then added with 130 mL of potassium hydroxide aqueous solution (20%), reacted at room temperature for 2 hours, 2N hydrochloric acid was added to adjust the pH to 1-2, and then 120 mL of dichloromethane was added for extraction twice, and then the dichloromethane was concentrated. The crude product was distilled under reduced pressure to obtain 9.1 g of the product 2,6-dihydroxytoluene with a yield of 73% and a chemical purity of 99.0%.

[0043] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing 2,6-dihydroxytoluene, characterized in that: The steps include: A. Mix 3,5-dichloro-4-methylbenzoic acid, acetate and a catalyst in acetic anhydride, and react to generate 3,5-diacetoxy-4-methylbenzoic acid under elevated temperature conditions; B. Mix copper tetraphenylporphyrin and an organic base in an organic solvent, add 3,5-diacetoxy-4-methylbenzoic acid solution under elevated temperature conditions for decarboxylation reaction, and then hydrolyze to obtain the product 2,6-dihydroxytoluene.

2. The method for preparing 2,6-dihydroxytoluene according to claim 1, characterized in that: In step A, the acetate is sodium acetate, cesium acetate, potassium acetate or lithium acetate.

3. The method for preparing 2,6-dihydroxytoluene according to claim 1, characterized in that: In step A, the catalyst is potassium hexacyanoferrate or sodium hexafluoroferrate.

4. The method for preparing 2,6-dihydroxytoluene according to claim 1, characterized in that: In step A, the molar ratio of 3,5-dichloro-4-methylbenzoic acid, acetate and catalyst is 1:2.2-2.8:0.05-0.

1.

5. The method for preparing 2,6-dihydroxytoluene according to claim 1, characterized in that: In step B, the organic base is selected from 1,8-diazabicyclo[5.4.0]undec-7-ene or 1,5-diazabicyclo[4.3.0]non-5-ene.

6. The method for preparing 2,6-dihydroxytoluene according to claim 5, characterized in that: In step B, the organic base is 1,8-diazabicyclo[5.4.0]undec-7-ene.

7. The method for preparing 2,6-dihydroxytoluene according to claim 1, characterized in that: In step B, the organic solvent is selected from NMP or DMSO.

8. The method for preparing 2,6-dihydroxytoluene according to claim 7, characterized in that: In step B, the organic solvent is DMSO.

9. The method for preparing 2,6-dihydroxytoluene according to claim 1, characterized in that: In step B, the molar ratio of 3,5-diacetoxy-4-methylbenzoic acid, copper catalyst and base is 1:0.05-0.1:0.05-0.

1.

10. The method for preparing 2,6-dihydroxytoluene according to claim 1, characterized in that: In step B, the hydrolysis is carried out by heating an acid aqueous solution or by using an alkali aqueous solution at room temperature.

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