A method for synthesizing 2,6-dimethoxyphenol

Abstract

The application discloses a method for synthesizing 2,6-dimethoxyphenol and relates to the technical field of organic compound synthesis, and comprises the following steps: S1, a methylation reaction: 2,6-dihydroxybenzoic acid is used as a starting raw material, concentrated sulfuric acid is used as a catalyst, and methyl alcohol is used as a methylation reagent to obtain 2,6-dimethoxybenzoic acid methyl ester; S2, a Grignard reaction: ethyl magnesium chloride is used as a Grignard reagent to obtain 1-(2,6-dimethoxyphenyl)-1-propanone; S3, a Baeyer-Villiger oxidation reaction: 2,6-dimethoxyphenyl propionic acid ester is obtained; and S4, a hydrolysis reaction: 2,6-dimethoxyphenol is obtained under alkaline conditions. The method is very simple in each reaction step, the reaction condition is simple, post-treatment is convenient, industrial production is easy, and the reaction conversion rate is high.

Description

Technical Field

[0001] This invention relates to the field of organic compound synthesis technology, and in particular to a method for synthesizing 2,6-dimethoxyphenol. Background Technology

[0002] 2,6-Dimethoxyphenol, also known as syringol, has a woody and medicinal aroma. It is naturally found in tobacco leaves and is readily soluble in ether, ethanol, and alkaline solutions, and slightly soluble in water. It is an important food flavoring agent used in blending licorice, nut, coffee, vanilla, rum, meat flavorings, and tobacco flavorings. 2,6-Dimethoxyphenol is also an important intermediate in organic synthesis, serving as a crucial precursor for the study of Claisen rearrangements, the synthesis of acetylsyleugenone and other natural products.

[0003] 2,6-Dimethoxyphenol is naturally found in tobacco leaves, but the content of 2,6-dimethoxyphenol in natural plants is not only low, but also difficult to separate, making it difficult to meet market demand. At present, it is mainly prepared by chemical synthesis.

[0004] In 1997, the journal *Chemical Bulletin* reported that Lanzhou University used dimethyl sulfate to methylate pyrogallol (pyrogallol), followed by selective etherification using a (zinc chloride / propionic acid) system to obtain the product in high yield. This method uses readily available raw materials and is simple to operate; however, the first step generates a significant amount of wastewater, and the second step has low selectivity and a low yield.

[0005]

[0006] CN106631714A discloses a method for synthesizing 2,6-dimethoxyphenol, using a microreactor as the reaction equipment and tetrabutylammonium bromide as the catalyst, selectively etherifying pyrogallol with dimethyl carbonate to generate 2,6-dimethoxyphenol. This method has high yield and simple post-processing, but requires a microreactor, making large-scale production difficult.

[0007]

[0008] CN115093312A discloses a method for preparing 5-bromo-1,2,3-trimethoxybenzene and its intermediates, using resorcinol as a raw material, first undergoing nitration, methylation, reduction, and finally diazotization and hydrolysis to obtain the product. This route is simple, but involves hazardous processes such as nitration and diazotization.

[0009]

[0010] In 1993, *Organic Reactions* reported a method using a special catalyst, bis(2-nitrobenzene)diselene, to remove aldehyde groups and convert them into phenols under hydrogen peroxide conditions. However, this method requires expensive raw materials and the catalyst is not readily available.

[0011]

[0012] In 2023, *Chinese Chemical Letters* reported a route that uses syringaldehyde as a raw material and a special catalyst to remove the aldehyde group to obtain the product. However, the catalyst for this route is special and not easy to obtain.

[0013]

[0014] As can be seen from the above literature, there are currently many methods for synthesizing 2,6-dimethoxyphenol, with diverse reactions. Different routes have different drawbacks, such as generating a lot of waste, complex processes, harsh reaction conditions, low yields, and expensive raw materials. Summary of the Invention

[0015] To address the shortcomings of existing technologies, this invention provides a method for synthesizing 2,6-dimethoxyphenol, which features a simple process, simple reaction conditions, convenient post-processing, ease of industrial production, and high reaction conversion rate.

[0016] In order to achieve the objective of this invention, the following solution is proposed:

[0017] A method for synthesizing 2,6-dimethoxyphenol includes the following steps:

[0018]

[0019] S1. Methylation reaction: Using 2,6-dihydroxybenzoic acid as the starting material, concentrated sulfuric acid as the catalyst, and methanol as the methylating agent, methyl 2,6-dimethoxybenzoate is obtained.

[0020] The amount of concentrated sulfuric acid used is 0.5%-1% of the amount of raw materials used, the reaction temperature is 50℃-65℃, and the reaction solvent is methanol.

[0021] S2. Grignard reaction: Ethyl magnesium chloride is used as a Grignard reagent to give 1-(2,6-dimethoxyphenyl)-1-propanone.

[0022] The amount of ethyl magnesium chloride used was 1.0 eq-1.2 eq of methyl 2,6-dimethoxybenzoate, the reaction temperature was 0℃-20℃, and the reaction solvent was tetrahydrofuran.

[0023] S3, Baeyer-Villiger oxidation reaction: yields 2,6-dimethoxyphenylpropionate.

[0024] The oxidant is selected from one or more of potassium persulfate, ammonium persulfate, sodium persulfate, and sodium perborate; the amount of oxidant used is 2.0 eq-4.0 eq of 1-(2,6-dimethoxyphenyl)-1-propanone equivalent; the reaction temperature is 0℃-80℃; and the reaction solvent is selected from one or more of dichloromethane and chloroform.

[0025] S4. Hydrolysis reaction: under alkaline conditions, the reaction yields 2,6-dimethoxyphenol.

[0026] The base is selected from one or more of sodium hydroxide and potassium hydroxide; the reaction temperature is 0℃-80℃; and the reaction solvent is water.

[0027] The beneficial effects of this invention are as follows: This invention uses 2,6-dihydroxybenzoic acid as a starting material to synthesize 2,6-dimethoxyphenol through methylation reaction, Grignard reaction, BV oxidation reaction and hydrolysis reaction. Each reaction step is very simple, the reaction conditions are simple, the post-processing is convenient, it is easy to industrialize and produce, and the reaction conversion rate is high. Detailed Implementation

[0028] Example 1

[0029] Step 1: Preparation of methyl 2,6-dimethoxybenzoate: 150g of 2,6-dihydroxybenzoic acid, 500g of methanol, and 1g of concentrated sulfuric acid were added to a reaction vessel and stirred until homogeneous. The reaction temperature was raised to reflux temperature of 65℃ and reacted for 20h. GC monitoring showed that the residual raw material was less than 5%. The mixture was then cooled, and a small amount of sodium bicarbonate solid was added for neutralization. The methanol solvent was removed by vacuum concentration. The crude product was then distilled to obtain 183g of methyl 2,6-dimethoxybenzoate, with a yield of 95%.

[0030] Example 2

[0031] The second step was to prepare 1-(2,6-dimethoxyphenyl)-1-propanone: 160 g of methyl 2,6-dimethoxybenzoate and 200 g of tetrahydrofuran were added to the reaction vessel, and the temperature was lowered to 10 °C. Then, 408 mL of a 2.0 mol / L tetrahydrofuran solution of ethyl magnesium chloride was slowly added dropwise. After the addition was complete, the mixture was kept warm and stirred for 4 h. GC monitoring showed that there was no remaining raw material. The reaction solution was quenched in a 3.0 mol / L dilute hydrochloric acid solution, and the mixture was separated into layers. The organic phase was concentrated under reduced pressure to remove the tetrahydrofuran solvent. The crude product was then distilled to obtain 118 g of 1-(2,6-dimethoxyphenyl)-1-propanone, with a yield of 74%.

[0032] Example 3

[0033] The third step is to prepare 2,6-dimethoxyphenyl propionate: 100g of 1-(2,6-dimethoxyphenyl)-1-propanone, 200g of dichloromethane, 400g of water, and 235g of ammonium persulfate are added to the reactor and stirred evenly. The reaction temperature is raised to 40℃ and the reaction is carried out for 24 hours. GC monitoring shows that the residual raw material is less than 5%. The temperature is lowered, the layers are separated, and the organic phase is separated. The aqueous phase is extracted once again with 100g of dichloromethane. The organic phases are combined, and the dichloromethane solvent is removed by vacuum concentration. The crude product is then distilled to obtain 89g of 2,6-dimethoxyphenyl propionate, with a yield of 82%.

[0034] Example 4

[0035] The third step is to prepare 2,6-dimethoxyphenyl propionate: 100g of 1-(2,6-dimethoxyphenyl)-1-propanone, 200g of chloroform, 400g of water, and 246g of sodium persulfate are added to the reactor and stirred evenly. The reaction temperature is raised to 60℃ and the reaction is carried out for 24 hours. GC monitoring shows that the residual raw material is less than 5%. The temperature is lowered, the layers are separated, and the organic phase is separated. The aqueous phase is extracted once again with 100g of chloroform. The organic phases are combined, and the chloroform solvent is removed by vacuum concentration. The crude product is then distilled to obtain 83g of 2,6-dimethoxyphenyl propionate, with a yield of 76%.

[0036] Example 5

[0037] The fourth step was to prepare 2,6-dimethoxyphenol: 120g of 2,6-dimethoxyphenyl propionate and 500g of 5% sodium hydroxide solution were added to the reactor, stirred evenly, and reacted at 40℃ for 10h. GC monitoring showed no raw material remaining. The mixture was cooled, and 3.0mol / L dilute hydrochloric acid solution was added to adjust the pH to 2-3. Then, 500g of dichloromethane was added for extraction. The organic phase was concentrated under reduced pressure to remove the dichloromethane solvent. The crude product was then distilled to obtain 85g of 2,6-dimethoxyphenol, with a yield of 97%.

[0038] Note: In Example 5, sodium hydroxide was replaced with potassium hydroxide. Sodium hydroxide and potassium hydroxide are essentially the same in the reaction, with a yield of 97%, but the amount used varies due to their different relative molecular masses.

[0039] Comparative Example 1

[0040] The second step involves preparing 1-(2,6-dimethoxyphenyl)-1-propanone (using 2-methyltetrahydrofuran as the solvent), replacing the tetrahydrofuran in Example 2 with 2-methyltetrahydrofuran, as detailed below:

[0041] 160 g of methyl 2,6-dimethoxybenzoate and 200 g of 2-methyltetrahydrofuran were added to the reaction vessel and cooled to 10 °C. Then, 408 mL of a 2.0 mol / L solution of ethyl magnesium chloride in 2-methyltetrahydrofuran was slowly added dropwise. After the addition was complete, the mixture was kept warm and stirred for 4 h. GC monitoring showed that no raw material remained. The reaction solution was quenched in a 3.0 mol / L dilute hydrochloric acid solution, and the mixture was separated into layers. The organic phase was concentrated under reduced pressure to remove the tetrahydrofuran solvent. The crude product was then distilled to obtain 76 g of 1-(2,6-dimethoxyphenyl)-1-propanone, with a yield of 48%.

[0042] Note: Tetrahydrofuran is used in this invention. Replacing it with 2-methyltetrahydrofuran will increase side reactions. Using solvents such as dichloromethane, methanol, acetonitrile, ethyl acetate, and cyclohexane will almost always result in side reactions.

[0043] Comparative Example 2

[0044] The third step involves preparing 2,6-dimethoxyphenyl propionate. In Example 4, sodium persulfate was replaced with potassium persulfate. Specifically, 100g of 1-(2,6-dimethoxyphenyl)-1-propanone, 200g of chloroform, 400g of water, and 280g of potassium persulfate were added to the reactor and stirred until homogeneous. The reaction was heated to 60°C and carried out for 24 hours. GC monitoring showed that the residual raw material was less than 5%. The mixture was then cooled, and the layers were separated. The organic phase was separated, and the aqueous phase was extracted again with 100g of chloroform. The organic phases were combined, and the chloroform solvent was removed by vacuum concentration. The crude product was then distilled to obtain 83g of 2,6-dimethoxyphenyl propionate, with a yield of 73%.

[0045] The third step involves preparing 2,6-dimethoxyphenyl propionate. Sodium persulfate in Example 4 was replaced with sodium perborate, as follows: 100g of 1-(2,6-dimethoxyphenyl)-1-propanone, 200g of chloroform, 400g of water, and 87g of sodium perborate were added to the reactor and stirred until homogeneous. The reaction was carried out at 60°C for 24 hours. GC monitoring showed that the residual raw material was less than 5%. The mixture was then cooled, and the layers were separated. The organic phase was separated, and the aqueous phase was extracted again with 100g of chloroform. The organic phases were combined, and the chloroform solvent was removed by vacuum concentration. The crude product was then distilled to obtain 76g of 2,6-dimethoxyphenyl propionate, with a yield of 69%.

[0046] Note: In addition to the four oxidants used in this invention (potassium persulfate, ammonium persulfate, sodium persulfate, and sodium perborate), replacing them with hydrogen peroxide, m-chloroperoxybenzoic acid, or peracetic acid will produce products, but the yield is low and the reaction operation is dangerous.

[0047] Comparative Example 3

[0048] The third step involves preparing 2,6-dimethoxyphenyl propionate by replacing dichloromethane with chloroform in Example 3. Specifically, 100g of 1-(2,6-dimethoxyphenyl)-1-propanone, 200g of chloroform, 400g of water, and 235g of ammonium persulfate were added to the reactor and stirred until homogeneous. The reaction was carried out at 40°C for 24 hours. GC monitoring showed that the residual raw material was less than 5%. The mixture was then cooled, and the layers were separated. The organic phase was separated, and the aqueous phase was extracted once more with 100g of dichloromethane. The organic phases were combined, and the dichloromethane solvent was removed by vacuum concentration. The crude product was then distilled to obtain 88g of 2,6-dimethoxyphenyl propionate, with a yield of 81%.

[0049] Note: Dichloromethane and chloroform are essentially indistinguishable in the reaction; their main purpose is to dissolve the raw materials and for extraction in post-processing. Replacing them with acetonitrile or tetrahydrofuran results in poor reaction performance; replacing them with methanol or N,N-dimethylformamide allows for normal reaction, but separation is difficult in post-processing, leading to the loss of most of the product.

[0050] The above embodiments are only used to illustrate the technical concept and features of the present invention, and are not intended to be unique or to limit the present invention. Those skilled in the art should understand that various changes or equivalent substitutions made to the present invention without departing from its scope are all within the protection scope of the present invention.

Claims

1. A method for synthesizing 2,6-dimethoxyphenol, characterized in that, Includes the following steps: S1. Methylation reaction: Using 2,6-dihydroxybenzoic acid as the starting material, concentrated sulfuric acid as the catalyst, and methanol as the methylating agent, methyl 2,6-dimethoxybenzoate is obtained. S2, Grignard reaction: Ethyl magnesium chloride is used as a Grignard reagent to give 1-(2,6-dimethoxyphenyl)-1-propanone; S3, Baeyer-Villiger oxidation reaction: yields 2,6-dimethoxyphenylpropionate; S4. Hydrolysis reaction: under alkaline conditions, the reaction yields 2,6-dimethoxyphenol.

2. The method for synthesizing 2,6-dimethoxyphenol according to claim 1, characterized in that, In step S1, the amount of concentrated sulfuric acid used is 0.5%-1% of the amount of raw material used, the reaction temperature is 50℃-65℃, and the reaction solvent is methanol.

3. The method for synthesizing 2,6-dimethoxyphenol according to claim 1, characterized in that, In step S2, the amount of ethyl magnesium chloride used is 1.0 eq-1.2 eq of methyl 2,6-dimethoxybenzoate equivalent, and the reaction temperature is 0℃-20℃.

4. The method for synthesizing 2,6-dimethoxyphenol according to claim 1, characterized in that, In step S2, the reaction solvent is tetrahydrofuran.

5. The method for synthesizing 2,6-dimethoxyphenol according to claim 1, characterized in that, In step S3, the oxidant is selected from one or more of potassium persulfate, ammonium persulfate, sodium persulfate, and sodium perborate.

6. The method for synthesizing 2,6-dimethoxyphenol according to claim 1, characterized in that, In step S3, the amount of oxidant used is 2.0 eq-4.0 eq of 1-(2,6-dimethoxyphenyl)-1-propanone equivalent, and the reaction temperature is 0℃-80℃.

7. The method for synthesizing 2,6-dimethoxyphenol according to claim 1, characterized in that, In step S3, the reaction solvent is one or more of dichloromethane and chloroform.

8. The method for synthesizing 2,6-dimethoxyphenol according to claim 1, characterized in that, In step S4, the alkali is selected from one or more of sodium hydroxide and potassium hydroxide.

9. The method for synthesizing 2,6-dimethoxyphenol according to claim 1, characterized in that, In step S4, the reaction temperature is 0℃-80℃, and the reaction solvent is water.

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