CN103804176A - Synthesis method for 2, 5-dimethyl phenylacetic acid - Google Patents

Abstract

The invention discloses a synthesis method for 2, 5-dimethyl phenylacetic acid. Paraxylene is taken as the raw material to generate 2, 5-dimethyl benzyl bromide through bromine methylation, then the 2, 5-dimethyl benzyl bromide and CO generate carbonylation to generate 2, 5-dimethyl phenylacetic acid. The synthesis method uses cheap raw material, is simple and convenient to operate, is applicable to industrial production in a large scale, and has high application value. The synthesis method adopts CO and a catalyst for carbonylation, so that the reaction processes are shortened, three wastes are greatly reduced, and the energy consumption is also lowered as the processes are shortened.

Description

A kind of synthetic method of 2,5-dimethylphenylacetic acid

technical field

The invention relates to the field of compound preparation, in particular to a method for synthesizing 2,5-dimethylphenylacetic acid.

Background technique

Spirotetramat is so far the only modern insecticide with bidirectional systemic conduction in xylem and phloem. The compound can move up and down throughout the plant, reaching the foliage and bark, thereby controlling pests such as those hidden on the inner leaves of lettuce and cabbage and on the bark of fruit trees. This unique systemic property protects new stems, leaves and roots from the growth of pest eggs and larvae. Two-way systemic conductivity means that pests have no safe place to hide, and the control effect is more thorough. Another feature is its long-lasting effect, which can provide effective control for up to 8 weeks. 2,5-Dimethylphenylacetic acid is a key intermediate for the synthesis of spirotetramat, and it is also an important fine chemical intermediate, widely used in the fields of pesticides and medicines.

At present, with reference to domestic and foreign literature, the synthesis of 2,5-dimethylphenylacetic acid mainly includes the following methods: (1) p-xylene is prepared by chloromethylation, cyanation, and hydrolysis. The three-step total yield of this method is Only 38% of the theoretical value, chloromethylation may produce highly toxic chloromethyl ether, and the cyanide reagent is highly toxic; (2) 2,5-dimethylacetophenone with morphine, sulfur, by Willgerodt-Kindler The reaction is obtained by hydrolysis and acidification. This method generates a large amount of sulfur-containing waste, and may also produce volatile sulfides with a very foul smell.

Contents of the invention

The purpose of this invention is to provide a kind of synthetic method of 2,5-dimethylphenylacetic acid, and this synthetic method is economical, environment-friendly, efficient, solves the highly toxic reaction raw material in existing 2,5-dimethylphenylacetic acid synthesis, produces Toxic intermediate products, low yield of synthetic products and other problems.

In order to solve the above problems, the present invention adopts the following technical solutions:

A kind of synthetic method of 2,5-dimethylphenylacetic acid, comprises the steps:

Step 1, adding p-xylene and paraformaldehyde into glacial acetic acid in a molar ratio of 1 to 1.5:1, and mixing evenly to obtain a mixed solution, wherein the paraformaldehyde is converted into formaldehyde for calculation;

Step 2. Under vigorous stirring, add the aqueous hydrogen bromide solution to the mixed solution described in step 1 at a rate of 0.2-0.5ml/min, then raise the temperature to 60-85°C, and reflux for 4-8 hours; wherein, hydrogen bromide The molar ratio of hydrogen bromide contained in the aqueous solution to the p-xylene described in step 1 is 1:1～1.5;

Step 3, after the reflux reaction is completed, the reaction solution is cooled to room temperature, then poured into distilled water, left to separate the liquid, separate the organic phase, dry, and filter to obtain the filtrate;

Step 4, the filtrate described in step 3 is distilled under reduced pressure at a vacuum degree of 0.08 to 0.09 MPa and a temperature of 50 to 60° C. to remove glacial acetic acid and unreacted reactants to obtain 2,5-dimethylbenzyl bromide;

Step 5. Dissolve the 2,5-dimethylbenzyl bromide and sodium hydroxide in the molar ratio of 1:1 to 1.5 in the organic solvent aqueous solution in the step 4, add it to the closed reaction kettle, and then add potassium iodide, catalyst and Phase transfer catalyst; N ₂ is introduced to replace the air in the reactor, the temperature is raised to 40-100°C, and CO is introduced to replace the N ₂ in the reactor, and then reacted for 6-20 hours; wherein, the potassium iodide and 2,5-di The molar ratio of methyl benzyl bromide is 1:20～50;

Step 6. After the reaction is finished, cool the reaction solution to room temperature, pass N ₂ to replace the gas in the reaction kettle, then let the reaction solution stand for stratification, take out the water phase, adjust the pH to 1-4, and obtain white flaky crystals , filtered and dried to obtain the 2,5-dimethylphenylacetic acid.

The vigorous stirring speed described in step 2 is 500-1500 rpm.

The organic solvent described in Step 5 is formic acid, ethanol or n-butanol; the catalyst is cyclooctadienyl rhodium dimer [RhCl(COD)] ₂ , dicobalt octacarbonyl Co ₂ (CO) ₈ or bis Triphenylphosphonium palladium dichloride Pd(PPh ₃ ) ₂ Cl ₂ ; the phase transfer catalyst is polyethylene glycol, tetrabutylammonium bromide or dodecyltrimethylammonium chloride.

Beneficial effects of the present invention:

1. In the process of preparing 2,5-dimethylbenzyl bromide, glacial acetic acid is used as a solvent, and hydrogen bromide can be well dissolved in it to avoid volatilization;

2. The carbon monoxide plus catalyst direct carbonylation route is adopted, which shortens the process route, reduces the production cost, and reduces the generation of three wastes;

3. Potassium iodide is added in the carbonylation process, because iodide ion is a good leaving group, which is also equivalent to the role of catalyst in the reaction, which improves the yield of the product;

4. The raw materials of the present invention are cheap, the process is simple, the operation is convenient, the large-scale industrial production is easy, and the application value is high.

Detailed ways

Below in conjunction with embodiment the present invention is further explained. The following examples are only used to illustrate the present invention, but are not intended to limit the scope of the present invention.

The present invention uses p-xylene as a raw material to generate 2,5-dimethylbenzyl bromide through a bromomethylation reaction, and the preparation process is as follows:

And then generate 2,5-dimethylphenylacetic acid through carbonylation reaction with CO, the preparation process is as follows:

Concrete preparation comprises the following steps:

Step 1, adding p-xylene and paraformaldehyde into glacial acetic acid in a molar ratio of 1 to 1.5:1, and mixing evenly to obtain a mixed solution, wherein the paraformaldehyde is converted into formaldehyde for calculation;

Step 2. Under vigorous stirring at 500-1500 rpm, add hydrogen bromide aqueous solution to the mixed solution described in step 1 at a rate of 0.2-0.5 ml/min, then raise the temperature to 60-85° C., and reflux for 4-8 hours; wherein , the molar ratio of hydrogen bromide contained in the hydrogen bromide aqueous solution to the p-xylene described in step 1 is 1:1～1.5;

Step 3, after the reflux reaction is completed, the reaction solution is cooled to room temperature, then poured into distilled water, left to separate the liquid, separate the organic phase, dry, and filter to obtain the filtrate;

Step 4, the filtrate described in step 3 is distilled under reduced pressure at a vacuum degree of 0.08 to 0.09 MPa and a temperature of 50 to 60° C. to remove glacial acetic acid and unreacted reactants to obtain 2,5-dimethylbenzyl bromide;

Step 5. Dissolve the 2,5-dimethylbenzyl bromide and sodium hydroxide in the molar ratio of 1:1 to 1.5 in the organic solvent aqueous solution in the step 4, add it to the closed reaction kettle, and then add potassium iodide, catalyst and Phase transfer catalyst; N ₂ is introduced to replace the air in the reactor, the temperature is raised to 40-100°C, and CO is introduced to replace the N ₂ in the reactor, and then reacted for 6-20 hours; wherein, the organic solvent is formic acid, ethanol or n-butanol; the catalyst is chloride cyclooctadienyl rhodium dimer, dicobalt octacarbonyl or bistriphenylphosphine palladium dichloride; the phase transfer catalyst is polyethylene glycol, tetrabutyl bromide ammonium chloride or dodecyltrimethylammonium chloride; the molar ratio of potassium iodide to 2,5-dimethylbenzyl bromide is 1:20～50;

Step 6. After the reaction is finished, cool the reaction solution to room temperature, pass N ₂ to replace the gas in the reaction kettle, then let the reaction solution stand for stratification, take out the water phase, adjust the pH to 1-4, and obtain white flaky crystals , filtered and dried to obtain the 2,5-dimethylphenylacetic acid.

The following examples [RhCl(COD)] ₂ were provided by Aladdin Reagent Co., Ltd., Co ₂ (CO) ₈ was provided by Bailingwei Technology Co., Ltd., and Pd(PPh ₃ ) ₂ Cl ₂ was provided by Aladdin Reagent Co., Ltd.

Example 1

(1) Take 16g of p-xylene and 4.5g of paraformaldehyde in a 250ml four-neck bottle, add 75ml of glacial acetic acid and stir well. At room temperature, while vigorously stirring at 1000rpm, another 12ml of 47% (wt) hydrogen bromide aqueous solution was added dropwise to the mixture, and the dropwise addition was completed in about 1 hour. Then, the temperature was raised to 60°C, and the reaction was refluxed for 4 hours. After cooling to room temperature, the solution was poured into 300ml of distilled water, allowed to stand for liquid separation, and the organic phase was separated, dried with anhydrous sodium sulfate, and filtered. The filtrate was distilled under reduced pressure (vacuum degree: 0.09 MPa, temperature: 50°C), and after glacial acetic acid and unreacted reactants were evaporated, 12.34 g of 2,5-dimethylbenzyl bromide was obtained with a yield of 62%.

(2) Add 10.0g 2,5-dimethylbenzyl bromide, 2g sodium hydroxide (2,5-dimethylbenzyl bromide:sodium hydroxide molar ratio 1:1), 61g formic acid, 9g water to 150ml for reaction Into the kettle, add 0.17g potassium iodide (2,5-dimethylbenzyl bromide: potassium iodide molar ratio 50:1), 2.5g [RhCl(COD)] ₂ , and 1.75g polyethylene glycol. Use N ₂ to replace the air in the reactor, raise the temperature to 40°C and feed CO gas until the pressure does not drop, and react for 6 hours. After the reaction was completed, it was lowered to room temperature, and then the gas in the reactor was replaced with N ₂ , and the reaction solution was transferred to a 150ml separatory funnel, and allowed to stand for stratification. The aqueous phase was taken out, and the organic phase with the catalyst remaining was used for the next reaction. The aqueous phase was acidified with concentrated hydrochloric acid to pH = 1 to obtain white flaky crystals, which were filtered and dried to obtain 3.86 g of finished 2,5-dimethylphenylacetic acid with a yield of 47%.

Example 2

(1) Take 16g of p-xylene and 4.5g of paraformaldehyde in a 250ml four-neck bottle, add 75ml of glacial acetic acid and stir well. At room temperature, while vigorously stirring at 1500rpm, another 17ml of 47% (wt) hydrogen bromide aqueous solution was added dropwise to the mixture, and the dropwise addition was completed in about 1 hour. The temperature was raised to 70°C, and the reaction was refluxed for 6 hours. After cooling to room temperature, the solution was poured into 300ml of distilled water, allowed to stand for liquid separation, and the organic phase was separated, dried with anhydrous sodium sulfate, and filtered. The filtrate was distilled under reduced pressure (vacuum degree: 0.08MPa, temperature: 60°C), and after glacial acetic acid and unreacted reactants were distilled off, 21.66 g of 2,5-dimethylbenzyl bromide was obtained with a yield of 74%.

(2) Add 10.0g 2,5-dimethylbenzyl bromide, 2.4g sodium hydroxide (2,5-dimethylbenzyl bromide:sodium hydroxide molar ratio 1:1.2), 40g ethanol, and 9g water Add 0.28g of potassium iodide (2,5-dimethylbenzyl bromide: potassium iodide molar ratio 30:1), 1.7g of Co ₂ (CO) ₈ , and 0.8g of tetrabutylammonium bromide into a 150ml reaction kettle. Use N ₂ to replace the air in the reactor, raise the temperature to 40°C and feed CO gas until the pressure does not drop, and react for 6 hours. After the reaction was completed, it was lowered to room temperature, and then the gas in the reactor was replaced with N ₂ , and the reaction solution was transferred to a 150ml separatory funnel, and allowed to stand for stratification. The aqueous phase was taken out, and the organic phase with the catalyst remaining was used for the next reaction. The aqueous phase was acidified with concentrated hydrochloric acid to pH = 2 to obtain white flaky crystals, which were filtered and dried to obtain 3.45 g of finished 2,5-dimethylphenylacetic acid with a yield of 42%.

Example 3

(1) Take 16g of p-xylene and 4.5g of paraformaldehyde in a 250ml four-neck bottle, add 75ml of glacial acetic acid and stir well. At room temperature, while stirring vigorously at 500rpm, another 14ml of 47% (wt) hydrogen bromide aqueous solution was added dropwise to the mixture, and the dropwise addition was completed in about 1 hour. Then, the temperature was raised to 80°C, and the reaction was refluxed for 8 hours. After cooling to room temperature, the solution was poured into 300ml of distilled water, allowed to stand for liquid separation, and the organic phase was separated, dried with anhydrous sodium sulfate, and filtered. The filtrate was distilled under reduced pressure (vacuum degree: 0.09 MPa, temperature: 60°C), and after glacial acetic acid and unreacted reactants were evaporated, 16.13 g of 2,5-dimethylbenzyl bromide was obtained with a yield of 68%.

(2) Add 10.0g 2,5-dimethylbenzyl bromide, 3g sodium hydroxide (2,5-dimethylbenzyl bromide:sodium hydroxide molar ratio 1:1.5), 40g n-butanol, 9g water In a 150ml reactor, add 0.42g potassium iodide (2,5-dimethylbenzyl bromide: potassium iodide molar ratio 20:1), 3.5g Pd(PPh ₃ ) ₂ Cl ₂ , 0.66g dodecyl trimethyl chloride Ammonium. Use N ₂ to replace the air in the reactor, raise the temperature to 60°C and feed CO gas until the pressure does not drop, and react for 12 hours. After the reaction was completed, it was lowered to room temperature, and then the gas in the reactor was replaced with N ₂ , and the reaction solution was transferred to a 150ml separatory funnel, and allowed to stand for stratification. The aqueous phase was taken out, and the organic phase with the catalyst remaining was used for the next reaction. The aqueous phase was acidified with concentrated hydrochloric acid to pH = 4 to obtain white flaky crystals, which were filtered and dried to obtain 3.12 g of finished 2,5-dimethylphenylacetic acid with a yield of 38%.

Example 4

(1) The operation is the same as Example 3

(2) Add 10.0g 2,5-dimethylbenzyl bromide, 3g sodium hydroxide (2,5-dimethylbenzyl bromide:sodium hydroxide molar ratio 1:1.5), 61g formic acid, 9g water to 150ml for reaction Add 0.17g of potassium iodide (2,5-dimethylbenzyl bromide: potassium iodide molar ratio 50:1), 2.5g of [RhCl(COD)] ₂ , and 0.66g of dodecyltrimethylammonium chloride into the kettle. Use N ₂ to replace the air in the reactor, raise the temperature to 60°C and feed CO gas until the pressure does not drop, and react for 12 hours. After the reaction was completed, it was lowered to room temperature, and then the gas in the reactor was replaced with N ₂ , and the reaction solution was transferred to a 150ml separatory funnel, and allowed to stand for stratification. The aqueous phase was taken out, and the organic phase with the catalyst remaining was used for the next reaction. The aqueous phase was acidified with concentrated hydrochloric acid to pH = 1 to obtain white flaky crystals, which were filtered and dried to obtain 4.6 g of finished 2,5-dimethylphenylacetic acid with a yield of 56%.

Example 5

(1) The operation is the same as Example 3

(2) Add 10.0g of 2,5-dimethylbenzyl bromide, 3g of sodium hydroxide (2,5-dimethylbenzyl bromide:sodium hydroxide molar ratio 1:1.5), 40g of ethanol, and 9g of water into 150ml for reaction Into the kettle, add 0.42g potassium iodide (2,5-dimethylbenzyl bromide: potassium iodide molar ratio 20:1), 2.5g [RhCl(COD)] ₂ , and 0.8g tetrabutylammonium bromide. Use N ₂ to replace the air in the reactor, raise the temperature to 60°C and feed CO gas until the pressure does not drop, and react for 12 hours. After the reaction was completed, it was lowered to room temperature, and then the gas in the reactor was replaced with N ₂ , and the reaction solution was transferred to a 150ml separatory funnel, and allowed to stand for stratification. The aqueous phase was taken out, and the organic phase with the catalyst remaining was used for the next reaction. The aqueous phase was acidified with concentrated hydrochloric acid to pH = 1 to obtain white flaky crystals, which were filtered and dried to obtain 5.25 g of finished 2,5-dimethylphenylacetic acid with a yield of 64%.

Example 6

(1) The operation is the same as Example 3

(2) Add 10.0g 2,5-dimethylbenzyl bromide, 3g sodium hydroxide (2,5-dimethylbenzyl bromide:sodium hydroxide molar ratio 1:1.5), 61g formic acid, 9g water to 150ml for reaction Into the kettle, add 0.42g potassium iodide (2,5-dimethylbenzyl bromide: potassium iodide molar ratio 20:1), 2.5g [RhCl(COD)] ₂ , and 0.8g tetrabutylammonium bromide. Use N ₂ to replace the air in the reactor, raise the temperature to 60°C and feed CO gas until the pressure does not drop, and react for 18 hours. After the reaction was completed, it was lowered to room temperature, and then the gas in the reactor was replaced with N ₂ , and the reaction solution was transferred to a 150ml separatory funnel, and allowed to stand for stratification. The aqueous phase was taken out, and the organic phase with the catalyst remaining was used for the next reaction. The aqueous phase was acidified with concentrated hydrochloric acid to pH = 1 to obtain white flaky crystals, which were filtered and dried to obtain 6.9 g of finished 2,5-dimethylphenylacetic acid with a yield of 84%.

Example 7

(1) The operation is the same as Example 3

(2) Add 10.0g 2,5-dimethylbenzyl bromide, 3g sodium hydroxide (2,5-dimethylbenzyl bromide:sodium hydroxide molar ratio 1:1.5), 40g n-butanol, 9g water Add 0.42g of potassium iodide (2,5-dimethylbenzyl bromide: potassium iodide molar ratio 20:1), 1.7g of Co ₂ (CO) ₈ , and 1.75g of polyethylene glycol into a 150ml reaction kettle. Use N ₂ to replace the air in the reactor, raise the temperature to 80°C and feed CO gas until the pressure does not drop, and react for 18 hours. After the reaction was completed, it was lowered to room temperature, and then the gas in the reactor was replaced with N ₂ , and the reaction solution was transferred to a 150ml separatory funnel, and allowed to stand for stratification. The aqueous phase was taken out, and the organic phase with the catalyst remaining was used for the next reaction. The aqueous phase was acidified with concentrated hydrochloric acid to pH = 1 to obtain white flaky crystals, which were filtered and dried to obtain 5.83 g of finished 2,5-dimethylphenylacetic acid with a yield of 71%.

Example 8

(1) The operation is the same as Example 3

(2) Add 10.0g 2,5-dimethylbenzyl bromide, 3g sodium hydroxide (2,5-dimethylbenzyl bromide:sodium hydroxide molar ratio 1:1.5), 40g n-butanol, 9g water Add 0.42g of potassium iodide (2,5-dimethylbenzyl bromide: potassium iodide molar ratio 20:1), 3.5g of Pd(PPh ₃ ) ₂ Cl ₂ , and 0.8g of tetrabutylammonium bromide into a 150ml reaction kettle. Use N ₂ to replace the air in the reactor, raise the temperature to 80°C and feed CO gas until the pressure does not drop, and react for 18 hours. After the reaction was completed, it was lowered to room temperature, and then the gas in the reactor was replaced with N ₂ , and the reaction solution was transferred to a 150ml separatory funnel, and allowed to stand for stratification. The aqueous phase was taken out, and the organic phase with the catalyst remaining was used for the next reaction. The aqueous phase was acidified with concentrated hydrochloric acid to pH = 1 to obtain white flaky crystals, which were filtered and dried to obtain 5.0 g of finished 2,5-dimethylphenylacetic acid with a yield of 61%.

Claims (5)

1. a synthetic method of 2,5-dimethylphenylacetic acid, is characterized in that, comprises the steps: Step 1, adding p-xylene and paraformaldehyde into glacial acetic acid in a molar ratio of 1 to 1.5:1, and mixing evenly to obtain a mixed solution, wherein the paraformaldehyde is converted into formaldehyde for calculation; Step 2. Under vigorous stirring, add the aqueous hydrogen bromide solution to the mixed solution described in step 1 at a rate of 0.2-0.5ml/min, then raise the temperature to 60-85°C, and reflux for 4-8 hours; wherein, hydrogen bromide The molar ratio of hydrogen bromide contained in the aqueous solution to the p-xylene described in step 1 is 1:1～1.5; Step 3, after the reflux reaction is completed, the reaction solution is cooled to room temperature, then poured into distilled water, left to separate the liquid, separate the organic phase, dry, and filter to obtain the filtrate; Step 4, the filtrate described in step 3 is distilled under reduced pressure at a vacuum degree of 0.08 to 0.09 MPa and a temperature of 50 to 60° C. to remove glacial acetic acid and unreacted reactants to obtain 2,5-dimethylbenzyl bromide; Step 5. Dissolve the 2,5-dimethylbenzyl bromide and sodium hydroxide in the molar ratio of 1:1 to 1.5 in the organic solvent aqueous solution in the step 4, add it to the closed reaction kettle, and then add potassium iodide, catalyst and Phase transfer catalyst; N ₂ is introduced to replace the air in the reactor, the temperature is raised to 40-100°C, and CO is introduced to replace the N ₂ in the reactor, and then reacted for 6-20 hours; wherein, the potassium iodide and 2,5-di The molar ratio of methyl benzyl bromide is 1:20～50; Step 6. After the reaction is finished, cool the reaction solution to room temperature, pass N ₂ to replace the gas in the reaction kettle, then let the reaction solution stand for stratification, take out the water phase, adjust the pH to 1-4, and obtain white flaky crystals , filtered and dried to obtain the 2,5-dimethylphenylacetic acid. 2. The synthetic method of a kind of 2,5-dimethylphenylacetic acid according to claim 1, characterized in that, the vigorous stirring speed described in step 2 is 500～1500rpm. 3. a kind of 2 according to claim 1, the synthetic method of 5-dimethylphenylacetic acid is characterized in that, the organic solvent described in step 5 is formic acid, ethanol or n-butanol. 4. a kind of 2 according to claim 1, the synthetic method of 5-dimethylphenylacetic acid is characterized in that, the catalyzer described in step 5 is chloride cyclooctadienyl rhodium dimer, dicobalt octacarbonyl Or bistriphenylphosphine palladium dichloride. 5. a kind of 2 according to claim 1, the synthetic method of 5-dimethylphenylacetic acid is characterized in that, the phase-transfer catalyst described in step 5 is polyethylene glycol, tetrabutylammonium bromide or dodecyl Alkyltrimethylammonium Chloride.