Synthetic method of p-methoxybenzoic acid

Abstract

The invention provides a synthetic method of p-methoxybenzoic acid, which comprises the following steps: adding parachlorobenzoic acid, a methylation reagent, a solvent and a phase transfer catalyst into a reaction kettle, starting stirring, and heating to react for 2-4 hours to finish. Cooling, acidizing, filtering, rinsing, and carrying out reduced pressure distillation on the obtained filtrate to obtain a crude product p-methoxybenzoic acid. And finally, refining, freezing, crystallizing and drying to obtain a high-purity p-methoxybenzoic acid product. According to the invention, the synthesis of p-methoxybenzoic acid is realized by adopting a one-step method, and the synthesis of p-methoxybenzoic acid is simply and quickly completed through a single reaction kettle. The raw materials are common materials, the cost is low, most of the used solvent can be recovered after distillation, and meanwhile, byproducts with large pollution do not exist in the reaction process, so that the method has the effect of being green and environment-friendly. Meanwhile, the p-methoxybenzoic acid product produced by the method also has the advantages of high yield and high purity.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, and in particular to a method for synthesizing p-methoxybenzoic acid. Background Technology

[0002] p-Anisic acid is an organic compound, also known as 4-methoxybenzoic acid or anisic acid. It is an intermediate in pharmaceuticals and fragrances. As a pharmaceutical intermediate, it can be used to synthesize piracetam, tyrosinase inhibitors, and ethylamine sulfadiazine. As a fragrance intermediate, it can be used to prepare anisaldehyde, anisyl alcohol, and their esters, which are used to flavor toothpaste, tooth powder, alcoholic beverages, candies, soft drinks, and tobacco. It can also be used in daily-use fragrances. Currently, its main synthetic methods include: a one-step method using p-hydroxybenzoic acid and dimethyl sulfate; a two-step method using methylphenol (p-hydroxybenzaldehyde, p-hydroxybenzyl alcohol) methylation and oxidation; and a two-step method using p-hydroxybenzonitrile methylation and hydrolysis or p-chlorobenzonitrile methylation and alkaline hydrolysis.

[0003] Regarding the one-step method of p-hydroxybenzoic acid and dimethyl sulfate: p-hydroxybenzoic acid is used as a raw material, and it undergoes a methylation reaction with dimethyl sulfate in an alkaline solution. The resulting sodium p-methoxybenzoate is then acidified to produce p-methoxybenzoic acid. In the prior art, Chinese invention patent application number CN201510337536.7 discloses a method for preparing trimethoxybenzoic acid. Although the technical solution disclosed in this patent has the advantages of being environmentally friendly and having high yield and purity, the raw material cost is high, the amount of liquid alkali used is large leading to cumbersome subsequent processing, and the methylation reagent dimethyl sulfate used is a toxic and carcinogenic substance, polluting the environment and failing to meet the requirements of green chemical development.

[0004] Regarding the two-step methylation oxidation method for methylphenol (p-hydroxybenzaldehyde, p-hydroxybenzyl alcohol): Using methylphenol (p-hydroxybenzaldehyde, p-hydroxybenzyl alcohol) as raw material, the phenolic hydroxyl group is methylated with a methylating agent to generate a methoxy group, and the para-group is then oxidized to a carboxylic acid, namely p-methoxybenzoic acid. The disadvantages of this method are that the raw materials are expensive and their sources are scarce and unstable; the methylation process inevitably involves the use of highly toxic or high-risk methylating agents; the catalyst used in the oxidation reaction has low reusability; and the two-step synthesis reaction yield is low, making it unsuitable for industrial production.

[0005] Regarding the two-step method of methylation hydrolysis of p-hydroxybenzonitrile or methylation alkaline hydrolysis of p-chlorobenzonitrile: p-hydroxybenzonitrile or p-chlorobenzonitrile is used as a raw material, reacted with methylating agents such as sodium methoxide in a solvent, and after solvent removal, hydrolysis or alkaline hydrolysis is carried out to generate p-methoxybenzoic acid. In the prior art, Chinese invention patent application number CN201410440332.1 discloses a method for preparing methoxybenzoic acid, but the raw materials used are relatively expensive, and the reaction needs to be carried out under certain pressure, posing certain safety risks.

[0006] Overall, all of the above production methods have certain drawbacks, and a simpler synthesis method suitable for industrial production is needed. Summary of the Invention

[0007] In view of the shortcomings of the prior art, the present invention provides a method for synthesizing p-methoxybenzoic acid, which solves the problems of high raw material cost, low yield, or environmental pollution in the prior art.

[0008] According to an embodiment of the present invention, a method for synthesizing p-methoxybenzoic acid includes the following steps: S1. Add p-chlorobenzoic acid and methylating agent as raw materials to the reaction vessel, add solvent and phase transfer catalyst, start stirring to carry out the reaction, and when the system temperature no longer rises, start heating and maintain the temperature inside the reaction vessel at 80-120℃. S2. After reacting for 2 to 4 hours, take a sample for gas chromatography analysis. When the starting material p-methoxybenzoic acid is no longer detectable, stop the reaction and start cooling. S3. After the reaction solution cools to room temperature, add an appropriate amount of 32% hydrochloric acid to adjust the pH. After the reaction solution becomes neutral, filter and rinse 2-3 times. S4. The filtrate is subjected to vacuum distillation, with the distillation temperature controlled at 60-120℃ and the vacuum degree at -0.03--0.09MPa. Vacuum distillation yields crude p-methoxybenzoic acid with a content greater than 96.0%. S5. Add 20% (w / w) alcohol aqueous solution to the distillate, heat to dissolve the distillate, and after complete dissolution, add 2‰ (w / w) of activated carbon for decolorization. After filtration, transfer to a freeze crystallizer. S6. The filtered solution is cooled from room temperature to -1 to 5°C for freeze crystallization, and then centrifuged, rinsed and vacuum dried to obtain the p-methoxybenzoic acid product.

[0009] Preferably, in step S1, the methylating agent includes one of sodium methoxide, sodium ethoxide, and sodium tert-butyl.

[0010] Preferably, the molar ratio of p-chlorobenzoic acid to the methylating agent is 1:2 to 1:2.4.

[0011] Preferably, in step S1, the solvent includes one or a mixture of two of N,N-dimethylformamide and N-methylpyrrolidone.

[0012] Preferably, the mass of the solvent is 2 to 4 times the mass of p-chlorobenzoic acid.

[0013] Preferably, in step S1, the phase transfer catalyst includes one of tetraethylammonium bromide, polyethylene glycol 400, and tetrabutylammonium bromide.

[0014] Preferably, the phase transfer catalyst is 0.5 to 1.0‰ of the total mass of the raw materials.

[0015] Compared with the prior art, the present invention has the following beneficial effects: This invention essentially employs a one-step method to synthesize p-methoxybenzoic acid, which can be easily and rapidly synthesized in a single reaction vessel. The raw materials used in this invention are all common and inexpensive. The solvent used can be largely recovered after distillation, and there are no highly polluting byproducts during the reaction, thus making it environmentally friendly. Furthermore, the p-methoxybenzoic acid produced by this invention also boasts high yield and high purity. Attached Figure Description

[0016] Figure 1 This is the gas chromatographic analysis spectrum of p-methoxybenzoic acid in Example 1 of the present invention. Detailed Implementation

[0017] The technical solutions of the present invention will be further described below with reference to the accompanying drawings and embodiments.

[0018] Example 1: This embodiment describes a method for synthesizing p-methoxybenzoic acid, comprising the following steps: S1. Add p-chlorobenzoic acid and methylating agent as raw materials to the reactor at a molar ratio of 1:2, along with solvent and phase transfer catalyst. The solvent mass is twice the mass of p-chlorobenzoic acid, and the phase transfer catalyst is 0.5‰ of the total raw material mass. Start stirring to initiate the reaction, and simultaneously open the tail gas valve. Observe the temperature rise and the material condition inside the reactor. When the system temperature stops rising, start heating to continue the reaction, controlling the reactor temperature to be maintained between 80 and 120°C.

[0019] S2. After 2 hours of reaction, a sample is taken for gas chromatography analysis. When the starting material p-methoxybenzoic acid is no longer detectable, the reaction is stopped and the temperature is lowered.

[0020] S3. After the reaction solution cools to room temperature, add an appropriate amount of 32% hydrochloric acid to adjust the pH. Once the reaction solution is neutral, filter and rinse twice.

[0021] S4. The filtrate is subjected to vacuum distillation, with the distillation temperature controlled at 60℃ and the vacuum degree at -0.03MPa. Vacuum distillation yields crude p-methoxybenzoic acid with a purity of 96.9%.

[0022] S5. Add 20% (w / w) of alcohol aqueous solution to the distillate, heat to dissolve the distillate, and after complete dissolution, add 2‰ (w / w) of activated carbon for decolorization treatment. After filtration, transfer to a freeze crystallizer.

[0023] S6. The filtered solution is cooled from room temperature to -1°C for freeze crystallization, and then centrifuged, rinsed and vacuum dried to obtain the p-methoxybenzoic acid product.

[0024] Preferably, in this embodiment, the methylating agent is sodium methoxide. The solvent is N,N-dimethylformamide. The phase transfer catalyst is tetraethylammonium bromide.

[0025] The p-methoxybenzoic acid prepared in this embodiment has a purity of 99.3% and a yield of 97.6%.

[0026] Example 2: This embodiment describes a method for synthesizing p-methoxybenzoic acid, comprising the following steps: S1. Add p-chlorobenzoic acid and methylating agent as raw materials to the reactor at a molar ratio of 1:2.2, along with solvent and phase transfer catalyst. The solvent mass is 3 times the mass of p-chlorobenzoic acid, and the phase transfer catalyst is 0.7‰ of the total raw material mass. Start stirring to initiate the reaction, and simultaneously open the tail gas valve. Observe the temperature rise and the material condition inside the reactor. When the system temperature stops rising, start heating to continue the reaction, controlling the reactor temperature to maintain at 90℃.

[0027] S2. After 3 hours of reaction, a sample is taken for gas chromatography analysis. When the starting material p-methoxybenzoic acid is no longer detectable, the reaction is stopped and the temperature is lowered.

[0028] S3. After the reaction solution cools to room temperature, add an appropriate amount of 32% hydrochloric acid to adjust the pH. After the reaction solution becomes neutral, filter and rinse three times.

[0029] S4. The filtrate is subjected to vacuum distillation, with the distillation temperature controlled at 80℃ and the vacuum degree at -0.05MPa. Vacuum distillation yields crude p-methoxybenzoic acid with a content greater than 97.1%.

[0030] S5. Add 20% (w / w) of alcohol aqueous solution to the distillate, heat to dissolve the distillate, and after complete dissolution, add 2‰ (w / w) of activated carbon for decolorization treatment. After filtration, transfer to a freeze crystallizer.

[0031] S6. The filtered solution is cooled from room temperature to 1°C for freeze crystallization, and then centrifuged, rinsed and vacuum dried to obtain the p-methoxybenzoic acid product.

[0032] Preferably, in this embodiment, the methylating agent is sodium ethoxide. The solvent is N-methylpyrrolidone. The phase transfer catalyst is polyethylene glycol 400.

[0033] The p-methoxybenzoic acid prepared in this embodiment has a purity of 99.2% and a yield of 96.7%.

[0034] Example 3: This embodiment describes a method for synthesizing p-methoxybenzoic acid, comprising the following steps: S1. Add p-chlorobenzoic acid and methylating agent as raw materials to the reactor at a molar ratio of 1:2.3, along with solvent and phase transfer catalyst. The solvent mass is 3 times the mass of p-chlorobenzoic acid, and the phase transfer catalyst is 0.9‰ of the total raw material mass. Start stirring to initiate the reaction, and simultaneously open the tail gas valve. Observe the temperature rise and the material condition inside the reactor. When the system temperature stops rising, start heating to continue the reaction, controlling the reactor temperature to remain at 100℃.

[0035] S2. After 3 hours of reaction, a sample is taken for gas chromatography analysis. When the starting material p-methoxybenzoic acid is no longer detectable, the reaction is stopped and the temperature is lowered.

[0036] S3. After the reaction solution cools to room temperature, add an appropriate amount of 32% hydrochloric acid to adjust the pH. After the reaction solution becomes neutral, filter and rinse three times.

[0037] S4. The filtrate is subjected to vacuum distillation, with the distillation temperature controlled at 100℃ and the vacuum degree at -0.07MPa. Vacuum distillation yields crude p-methoxybenzoic acid with a content greater than 97.3%.

[0038] S5. Add 20% (w / w) of alcohol aqueous solution to the distillate, heat to dissolve the distillate, and after complete dissolution, add 2‰ (w / w) of activated carbon for decolorization treatment. After filtration, transfer to a freeze crystallizer.

[0039] S6. The filtered solution is cooled from room temperature to 3°C for freeze crystallization, and then centrifuged, rinsed and vacuum dried to obtain the p-methoxybenzoic acid product.

[0040] Preferably, in this embodiment, the methylating agent is sodium tert-butyl. The solvent is a mixture of N,N-dimethylformamide and N-methylpyrrolidone in equal proportions. The phase transfer catalyst is tetrabutylammonium bromide.

[0041] The p-methoxybenzoic acid prepared in this embodiment has a purity of 99.4% and a yield of 95.6%.

[0042] Example 4: This embodiment describes a method for synthesizing p-methoxybenzoic acid, comprising the following steps: S1. Add p-chlorobenzoic acid and methylating agent as raw materials to the reactor at a molar ratio of 1:2.4, along with solvent and phase transfer catalyst. The mass of solvent is 4 times the mass of p-chlorobenzoic acid, and the mass of phase transfer catalyst is 1.0‰ of the total mass of raw materials. Start stirring to initiate the reaction, and simultaneously open the tail gas valve. Observe the temperature rise and the material condition inside the reactor. When the system temperature stops rising, start heating to continue the reaction, controlling the temperature inside the reactor to maintain at 120℃.

[0043] S2. After 4 hours of reaction, a sample is taken for gas chromatography analysis. When the starting material p-methoxybenzoic acid is no longer detectable, the reaction is stopped and the temperature is lowered.

[0044] S3. After the reaction solution cools to room temperature, add an appropriate amount of 32% hydrochloric acid to adjust the pH. After the reaction solution becomes neutral, filter and rinse three times.

[0045] S4. The filtrate is subjected to vacuum distillation, with the distillation temperature controlled at 60-120℃ and the vacuum degree at -0.09MPa. Vacuum distillation yields crude p-methoxybenzoic acid with a content greater than 96.7%.

[0046] S5. Add 20% (w / w) of alcohol aqueous solution to the distillate, heat to dissolve the distillate, and after complete dissolution, add 2‰ (w / w) of activated carbon for decolorization treatment. After filtration, transfer to a freeze crystallizer.

[0047] S6. The filtered solution is cooled from room temperature to 5°C for freeze crystallization, and then centrifuged, rinsed and vacuum dried to obtain the p-methoxybenzoic acid product.

[0048] Preferably, in this embodiment, the methylating agent is sodium methoxide. The solvent is N-methylpyrrolidone. The phase transfer catalyst is polyethylene glycol 400.

[0049] The p-methoxybenzoic acid prepared in this embodiment has a purity of 99.1% and a yield of 95.5%.

[0050] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications or substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A method for synthesizing p-methoxybenzoic acid, characterized in that, Includes the following steps: S1. Add p-chlorobenzoic acid and methylating agent as raw materials to the reaction vessel, add solvent and phase transfer catalyst, start stirring to carry out the reaction, and when the system temperature no longer rises, start heating and maintain the temperature inside the reaction vessel at 80-120℃. S2. After reacting for 2 to 4 hours, take a sample for gas chromatography analysis. When the starting material p-methoxybenzoic acid is no longer detectable, stop the reaction and start cooling. S3. After the reaction solution cools to room temperature, add an appropriate amount of 32% hydrochloric acid to adjust the pH. After the reaction solution becomes neutral, filter and rinse 2-3 times. S4. The filtrate is subjected to vacuum distillation, with the distillation temperature controlled at 60-120℃ and the vacuum degree at -0.03--0.09MPa. Vacuum distillation yields crude p-methoxybenzoic acid with a content greater than 96.0%. S5. Add 20% (w / w) alcohol aqueous solution to the distillate, heat to dissolve the distillate, and after complete dissolution, add 2‰ (w / w) of activated carbon for decolorization. After filtration, transfer to a freeze crystallizer. S6. The filtered solution is cooled from room temperature to -1 to 5°C for freeze crystallization, and then centrifuged, rinsed and vacuum dried to obtain the p-methoxybenzoic acid product.

2. The method for synthesizing p-methoxybenzoic acid as described in claim 1, characterized in that: In step S1, the methylating agent includes one of sodium methoxide, sodium ethoxide, and sodium tert-butyl.

3. The method for synthesizing p-methoxybenzoic acid as described in claim 2, characterized in that: The molar ratio of p-chlorobenzoic acid to the methylating agent is 1:2 to 1:2.

4.

4. The method for synthesizing p-methoxybenzoic acid as described in claim 1, characterized in that: In step S1, the solvent includes one or a mixture of two of N,N-dimethylformamide and N-methylpyrrolidone.

5. The method for synthesizing p-methoxybenzoic acid as described in claim 4, characterized in that: The mass of the solvent is 2 to 4 times the mass of p-chlorobenzoic acid.

6. The method for synthesizing p-methoxybenzoic acid as described in claim 1, characterized in that: In step S1, the phase transfer catalyst includes one of tetraethylammonium bromide, polyethylene glycol 400, and tetrabutylammonium bromide.

7. The method for synthesizing p-methoxybenzoic acid as described in claim 6, characterized in that: The phase transfer catalyst is 0.5 to 1.0‰ of the total mass of the raw materials.

Images