CN111269106A - Synthesis method of 4-phenoxybenzoic acid - Google Patents
Synthesis method of 4-phenoxybenzoic acid Download PDFInfo
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Abstract
The invention relates to a synthesis process of 4-phenoxybenzoic acid, belonging to the technical field of chemical synthesis. The method comprises the following steps: a. adding dichloroethane, phenyl ether and ferric trichloride into a reaction kettle, and controlling the temperature to be 5-30 ℃; b. adding acetyl chloride, controlling the temperature to react, transferring the reaction liquid into a large amount of ice water, stirring, standing for layering, and collecting an organic phase; c. concentrating the collected organic phase, adding a proper amount of water and tetrabutylammonium bromide, heating to 50-80 ℃, dropwise adding a sufficient amount of sodium hypochlorite solution, and continuously reacting for 2-5 hours; d. and after the reaction is finished, standing for layering, thermally extracting for 2-3 times at 50-80 ℃ by using dichloroethane, adjusting the pH of a water phase to 0-2 by using dilute hydrochloric acid, and centrifugally drying to obtain the finished product of 4-phenoxybenzoic acid. The invention obviously simplifies the production process, improves the production efficiency, reduces the production cost and improves the yield and the purity of the product.
Description
Technical Field
The invention relates to a synthesis process of 4-phenoxybenzoic acid, belonging to the technical field of chemical synthesis.
Background
4-phenoxy benzoic acid not only can be used as an intermediate of medicines and pesticides, but also can be widely applied to ester liquid crystals and high-temperature resistant materials. Therefore, the market demand and development prospect are very large.
The existing synthesis process for synthesizing 4-phenoxybenzoic acid mainly has three routes, the first is to utilize phenyl ether and acetic anhydride to make reaction, and 4-position of phenyl ether is connected with one-COCH3Radical, then-COCH3The methyl group in the group is substituted by hydroxyl, as in the invention patent application with the application number CN 201911106061.5; the second route is to use a reaction between phenyl ether and acetyl chloride, to attach a-COCH-to the 4-position of the phenyl ether3Radical, then-COCH3The methyl in the group is substituted by hydroxyl, such as Chinese patent with application number CN 201610266786.0; the third one is to produce 4-phenoxybenzoic acid by using sodium phenolate and p-chlorobenzoic acid as raw materials, for example, the invention patent application with the application number of CN 201911106061.5.
In the three routes, the first and the second are similar in nature, and all adopt acetylation reagents, so that acetyl chloride is relatively more active, the reaction rate is higher, the quality of the product is more reliable, and the process requirement is higher. The p-chlorobenzoic acid or p-chlorotoluene used as the raw material in the third process has certain biological toxicity and can exist in the environment for a long time, and m-chlorobenzoic acid is possibly mixed in the p-chlorobenzoic acid raw material, so that the product is impure and difficult to separate.
Disclosure of Invention
The invention aims to solve the problems and provides a synthesis method of 4-phenoxybenzoic acid. The method adopts the second route, optimizes the original process, simplifies the production process and greatly improves the production efficiency on the basis of ensuring the product quality and yield.
The technical scheme for solving the problems is as follows:
a synthetic method of 4-phenoxybenzoic acid comprises the following steps:
a. adding dichloroethane, phenyl ether and ferric trichloride into a reaction kettle, and stirring at the temperature of 5-30 ℃;
b. dropwise adding acetyl chloride within 3h, controlling the temperature to react for 1-3 h after the acetyl chloride is completely added, transferring the reaction liquid into a large amount of ice water, stirring, standing for layering, and collecting an organic phase;
c. concentrating the collected organic phase, adding a proper amount of water and tetrabutylammonium bromide, heating to 50-80 ℃, dropwise adding 5-15 wt% of sufficient sodium hypochlorite solution within 5 hours, and then continuing to react for 2-5 hours;
d. and after the reaction is finished, standing for layering, thermally extracting for 2-3 times at 50-80 ℃ by using dichloroethane, adjusting the pH of a water phase to 0-2 by using dilute hydrochloric acid, and centrifugally drying to obtain the finished product of 4-phenoxybenzoic acid.
In the prior art, the first step adopts volatile chloroform with low boiling point as an acylation reaction solvent, so that the solvent loss is large in the production process, and the harm to the environment and human bodies is also large. The catalyst is aluminum trichloride, has strong catalytic activity, and needs to be carried out at low temperature, such as 5 ℃, in order to reduce the generation of ortho-meta isomer, so that the time and energy are wasted; after the reaction is finished, the chloroform can be recovered; the process requires adding n-hexane for crystallization, centrifugation, refining, drying and other operations to obtain an intermediate. The second step of reaction, using methanol as solvent, obtaining sodium salt after oxidation reaction, obtaining crude product after acidification, and difficult separation and purification due to the physical and chemical properties of impurities and products being very similar; therefore, the finished product can be obtained only by carrying out two or more times of recrystallization by using petroleum ether as a refining solvent, the purity of the finished product is still only 99 percent, and the actual yield is about 65 percent.
In the technical scheme, dichloroethane with high boiling point and difficult volatilization is used as an acylation reaction solvent, ferric trichloride with weaker activity is used as a catalyst to carry out reaction at normal temperature, water is used as an oxidation reaction solvent instead of methanol harmful to human bodies and the environment, a small amount of tetrabutylammonium bromide is added as a phase transfer catalyst, and one-pot operation can be directly carried out without refining the intermediate product prepared in the step b into powder and then reacting with sodium hypochlorite; after the reaction is finished, impurities in a reaction system can be extracted by dichloroethane through direct thermal stratification, and the dichloroethane as a solvent can be recycled, so that a complex post-treatment process is omitted, and the discharge of three wastes is greatly reduced.
In the above technical means, the addition amount of tetrabutylammonium bromide is preferably 5 to 20wt% based on the mass of acetyl chloride.
Preferably, the organic phase is collected by concentration in step c, and at the same time, dichloroethane is recovered and recycled to step a.
Preferably, the mass ratio of dichloroethane, phenyl ether, ferric trichloride and acetyl chloride is dichloroethane: phenyl ether: ferric chloride: acetyl chloride = 10: (3-5): (3-5): (1-3).
Preferably, in the step b, the temperature is controlled to be 5-30 ℃.
Preferably, in the step b, the mass of the ice water is 8-12 times of that of the acetyl chloride.
Preferably, in the step b, the addition amount of water is 3-6 times of the mass of acetyl chloride.
Preferably, in the step c, the mass fraction of the sodium hypochlorite is 8-12 wt%, and the mass is 16-25 times of that of the acetyl chloride.
Preferably, in the step d, the pH is adjusted to 0.8-1.2.
Preferably, in the step d, the mass fraction of the dilute hydrochloric acid used for adjusting the pH is 12-20 wt%.
In conclusion, the invention has the following beneficial effects:
1. the method adopts dichloroethane with high boiling point and difficult volatilization as an acylation reaction solvent, and has better environmental safety compared with volatile chloroform;
2. compared with the traditional aluminum trichloride catalyst, the ferric trichloride catalyst has weaker catalytic activity, but is more favorable for controlling reaction conditions, and the reaction conditions can be widened to room temperature without being carried out at low temperature; therefore, the reaction rate can be improved, and the generation of the ortho-position meta-isomer can be effectively controlled;
3. the invention is at the handle-COCH3In the link that methyl in the group is replaced by hydroxyl, water is adopted to replace the original methanol as a solvent, so that the harm to human bodies and the environment is obviously reduced; adding small amount ofTetrabutylammonium bromide is used as a phase transfer catalyst, and can be operated by adopting a one-pot method without carrying out operations such as crystallization, centrifugation, refining, drying and the like after acylation reaction as disclosed in the prior art to obtain an intermediate, then oxidizing to obtain a sodium salt, acidifying to obtain a crude product, and finally recrystallizing twice by using petroleum ether; the one-pot method can be operated in an organic phase obtained by acylation reaction, namely water and tetrabutylammonium bromide are added into the organic phase, the temperature is raised to 50-80 ℃, 5-15 wt% of sufficient sodium hypochlorite solution is dripped, standing and layering are carried out after complete reaction, then thermal extraction is carried out, and finally the pH value is adjusted; therefore, the production process is obviously simplified, the production efficiency is improved, the production cost is reduced, the yield and the purity of the product are improved, great promotion effect is generated on the technical improvement of enterprises, and a solid foundation is laid for the market positioning of the product.
Detailed Description
This detailed description is to be construed as illustrative only and is not limiting, since modifications will occur to those skilled in the art upon reading the preceding specification, and it is intended to be protected by the following claims.
Example 1
A synthetic method of 4-phenoxybenzoic acid comprises the following steps:
a. 300kg of dichloroethane, 120kg of phenylate and 100kg of iron trichloride are added into a 2000L enamel reaction kettle, the temperature is controlled to be about 20 ℃, and the materials are slowly stirred at the rotating speed of about 45 rpm;
b. dropwise adding 60kg of acetyl chloride within 3h, controlling the temperature to be about 20 ℃ after the acetyl chloride is completely added, and reacting for 2 h; slowly adding the reaction solution into 600kg of ice water, stirring for 1h, standing for layering, and collecting an organic phase;
c. concentrating the collected organic phase by a vacuum concentrator, adding 300kg of water and 6kg of tetrabutylammonium bromide after the organic phase is concentrated and dried, heating to 60 ℃, dropwise adding 1200kg of 9% sodium hypochlorite solution, finishing the addition within 5h, continuing to react for 3h, standing and layering for two times at 60 ℃, thermally extracting by using 250kg of dichloroethane, adjusting the pH value of the aqueous phase to be pH =1 by using 15% dilute hydrochloric acid, centrifuging, and drying to obtain 132.6kg of finished product.
Example 2
A synthetic method of 4-phenoxybenzoic acid comprises the following steps:
a. 300kg of dichloroethane, 90kg of phenylate and 60kg of iron trichloride are added into a 2000L enamel reaction kettle, the temperature is controlled to be about 25 ℃, and the materials are slowly stirred at the rotating speed of about 45 rpm;
b. dropwise adding 30kg of acetyl chloride within 3h, controlling the temperature to be about 25 ℃ after the acetyl chloride is completely added, and reacting for 2 h; slowly adding the reaction solution into 300kg of ice water, stirring for 1h, standing for layering, and collecting an organic phase;
c. concentrating the collected organic phase by a vacuum concentrator, adding 150kg of water and 3kg of tetrabutylammonium bromide after the organic phase is concentrated and dried, heating to 60 ℃, dropwise adding 600kg of 9% sodium hypochlorite solution, finishing the addition within 3h, continuing to react for 2h, standing and layering for two times at 60 ℃, thermally extracting by 150kg of dichloroethane, adjusting the pH value of the aqueous phase to be pH =1 by 15% of dilute hydrochloric acid, centrifuging, and drying to obtain 96.5kg of finished product.
Example 3
A synthetic method of 4-phenoxybenzoic acid comprises the following steps:
a. 300kg of dichloroethane, 150kg of phenylate and 120kg of iron trichloride are added into a 2000L enamel reaction kettle, the temperature is controlled to be about 25 ℃, and the materials are slowly stirred at the rotating speed of about 45 rpm;
b. 80kg of acetyl chloride is added dropwise within 3h, and after the acetyl chloride is added, the temperature is controlled to be about 25 ℃ for reaction for 2 h; slowly adding the reaction solution into 450kg of ice water, stirring for 1h, standing for layering, and collecting an organic phase;
c. concentrating the collected organic phase by a vacuum concentrator, adding 200kg of water and 9kg of tetrabutylammonium bromide after the organic phase is concentrated and dried, heating to 60 ℃, dropwise adding 900kg of 9% sodium hypochlorite solution, finishing the addition within 3h, continuing to react for 3h, thermally extracting twice by 300kg of dichloroethane at the temperature of 60 ℃ after standing and layering, adjusting the pH value of the aqueous phase to be pH =1 by 15% of dilute hydrochloric acid, centrifuging, and drying to obtain 158.8kg of a finished product.
Comparative example 1
A synthetic method of 4-phenoxybenzoic acid comprises the following steps:
a. putting 320kg of dichloromethane, 120kg of phenylate and 100kg of aluminum trichloride into an enamel reaction kettle, and slowly stirring at the rotation speed of about 45rpm under the condition of controlling the temperature to be 30 ℃;
b. dropwise adding 50kg of acetyl chloride into the reaction kettle for 3h, controlling the temperature to react for 2h after the acetyl chloride is dropwise added, slowly adding the reaction liquid into 600kg of ice water after the reaction is finished, stirring for 1h, standing for layering, and collecting an organic phase;
c. concentrating the collected organic phase by a vacuum concentrator, adding 300kg of normal hexane after concentrating and drying, cooling to 10 ℃, stirring for 2h, centrifuging and drying to obtain an intermediate;
d. adding 120kg of intermediate and 240kg of methanol into a reaction kettle, heating to 60 ℃, dropwise adding 900kg of 1200kg of sodium hypochlorite solution with the concentration of 9%, reacting for 3 hours, cooling the reaction solution after the reaction is finished
Cooling to 50 ℃, adjusting the pH value of the reaction solution to 1, centrifuging and drying to obtain a crude product;
e. taking 100kg of crude product, adding 200kg of ethanol, mixing, heating to 75 ℃, preserving heat for 1h, cooling, crystallizing, centrifuging and drying to obtain 79.54kg of product.
Example 4
High performance liquid chromatography assay was performed as in example one
Chromatographic column conditions: octadecylsilane chemically bonded silica is used as a filler, the particle size is 5 micrometers, the temperature of a column chamber is room temperature, the theoretical plate number is 5000, and the volume fraction of 0.8% of ethyl acetate aqueous solution: methanol volume ratio of 50: 50 is mobile phase, flow rate is 1ml/min, and injection volume is 5 microliter.
Preparing a standard sample: 0.0613g of standard 4-phenoxybenzoic acid is accurately weighed and placed in a 100ml volumetric flask, 20ml of mobile phase is added, ultrasonic oscillation is carried out to dissolve the mixture, the mixture is cooled to room temperature and then diluted to scale by the mobile phase, and a standard sample is obtained for later use.
Sample preparation: accurately weighing 0.0625g of the 4-phenoxybenzoic acid in the first embodiment, placing the weighed material in a 100ml volumetric flask, adding 20ml of mobile phase, ultrasonically oscillating to dissolve the material, cooling the material to room temperature, and diluting the material to a scale with the mobile phase to obtain a sample for later use.
Testing and data processing: after the self-checking of the starting machine is passed, under the specified operation condition, after the instrument baseline is stable, injecting a standard sample, calculating each relative response value, when the relative response value of two adjacent needles is changed by less than 1.0%, sequentially injecting samples according to the sequence of the standard sample, a test sample and the standard sample, detecting at the wavelength of 245nm, and obtaining the following data:
calculating by substituting into a formula:
X1=（A2*m1*P1）/（A1*m1）=(33172367*0.0613*99.95)/（32525695*0.0625）
the resulting value was calculated, X1= 99.98.
Example 5
High performance liquid chromatography assay as comparative example one
Chromatographic column conditions: octadecylsilane chemically bonded silica is used as a filler, the particle size is 5 micrometers, the temperature of a column chamber is room temperature, the theoretical plate number is 5000, and the volume fraction of 0.8% of ethyl acetate aqueous solution: methanol volume ratio of 50: 50 is mobile phase, flow rate is 1ml/min, and injection volume is 5 microliter.
Preparing a standard sample: accurately weighing 0.0678g of standard 4-phenoxybenzoic acid, placing in a 100ml volumetric flask, adding 20ml of mobile phase, ultrasonically oscillating for dissolution, cooling to room temperature, and diluting to scale with the mobile phase to obtain a standard sample for later use.
Sample preparation: 0.0603g of 4-phenoxybenzoic acid of comparative example 1 is weighed accurately, placed in a 100ml volumetric flask, added with 20ml of mobile phase, dissolved by ultrasonic oscillation, cooled to room temperature, and diluted to the scale with the mobile phase to obtain a sample for later use.
Testing and data processing: after the self-checking of the starting machine is passed, under the specified operation condition, after the instrument baseline is stable, injecting a standard sample, calculating each relative response value, when the relative response value of two adjacent needles is changed by less than 1.0%, sequentially injecting samples according to the sequence of the standard sample, a test sample and the standard sample, detecting at the wavelength of 245nm, and obtaining the following data:
calculating by substituting into a formula:
X1=（A2*m1*P1）/（A1*m1）=(33056499*0.0603*99.95)/（32467879*0.0625）
the resulting value was calculated, X1= 98.18.
Claims (10)
1. A synthetic method of 4-phenoxybenzoic acid comprises the following steps:
a. adding dichloroethane, phenyl ether and ferric trichloride into a reaction kettle, controlling the temperature to be 5-30 ℃, and stirring;
b. dropwise adding acetyl chloride within 3h, controlling the temperature to react for 1-3 h after the acetyl chloride is completely added, transferring the reaction liquid into a large amount of ice water, stirring, standing for layering, and collecting an organic phase;
c. concentrating the collected organic phase, adding a proper amount of water and tetrabutylammonium bromide, heating to 50-80 ℃, dropwise adding 5-15 wt% of sufficient sodium hypochlorite solution within 5 hours, and then continuing to react for 2-5 hours;
d. and after the reaction is finished, standing for layering, thermally extracting for 2-3 times at 50-80 ℃ by using dichloroethane, adjusting the pH of a water phase to 0-2 by using dilute hydrochloric acid, and centrifugally drying to obtain the finished product of 4-phenoxybenzoic acid.
2. The method for synthesizing 4-phenoxybenzoic acid according to claim 1, which is characterized in that: the addition amount of tetrabutylammonium bromide is 5-20 wt% of the mass of acetyl chloride.
3. The method for synthesizing 4-phenoxybenzoic acid according to claim 1, which is characterized in that: and c, recovering dichloroethane while concentrating and collecting the organic phase in the step c, and recycling the dichloroethane to the step a.
4. The method for synthesizing 4-phenoxybenzoic acid according to claim 1, which is characterized in that: the mass ratio of dichloroethane, phenyl ether, ferric trichloride and acetyl chloride is as follows: phenyl ether: ferric chloride: acetyl chloride = 10: (3-5): (3-5): (1-3).
5. The method for synthesizing 4-phenoxybenzoic acid according to claim 1, which is characterized in that: in the step b, the temperature is controlled to be 5-30 ℃.
6. The method for synthesizing 4-phenoxybenzoic acid according to claim 1, which is characterized in that: in the step b, the mass of the ice water is 8-12 times of that of the acetyl chloride.
7. The method for synthesizing 4-phenoxybenzoic acid according to claim 1, which is characterized in that: in the step b, the addition amount of water is 3-6 times of the mass of acetyl chloride.
8. The method for synthesizing 4-phenoxybenzoic acid according to claim 1, which is characterized in that: in the step c, the mass fraction of the sodium hypochlorite is 8-12 wt%, and the mass of the sodium hypochlorite is 16-25 times of that of the acetyl chloride.
9. The method for synthesizing 4-phenoxybenzoic acid according to claim 1, which is characterized in that: in the step d, the pH value is adjusted to 0.8-1.2.
10. The method for synthesizing 4-phenoxybenzoic acid according to claim 1, which is characterized in that: in the step d, the mass fraction of the dilute hydrochloric acid used for adjusting the pH is 12-20 wt%.
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2020
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| EP0046194A1 (en) * | 1980-08-20 | 1982-02-24 | BASF Aktiengesellschaft | Process for the preparation of o,o-disubstituted benzoic acids and their salts |
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