阅读说明：本技术 一种2,6-二甲基苯氧基乙酸的生产工艺 (Production process of 2, 6-dimethylphenoxy acetic acid ) 是由 张�荣 吴德全 于 2020-12-17 设计创作，主要内容包括：本发明公开一种2,6-二甲基苯氧基乙酸的生产工艺,属于有机化工技术领域。本发明通过控制取代反应和酯水解反应两步过程制得2,6-二甲基苯氧基乙酰氯的上游物2,6-二甲基苯氧基乙酸,所制得的2,6-二甲基苯氧基乙酸纯度高,没有产生较大杂质,利于后续用于制备洛匹那韦。(The invention discloses a production process of 2, 6-dimethylphenoxy acetic acid, belonging to the technical field of organic chemical industry. The 2, 6-dimethylphenoxy acetic acid as the upstream product of the 2, 6-dimethylphenoxy acetyl chloride is prepared by controlling the two-step process of the substitution reaction and the ester hydrolysis reaction, and the prepared 2, 6-dimethylphenoxy acetic acid has high purity, does not generate larger impurities and is beneficial to being subsequently used for preparing lopinavir.)

1. A production process of 2, 6-dimethylphenoxy acetic acid is characterized by comprising the following steps:

carrying out substitution reaction on 1, 2, 6-dimethylphenol and ethyl chloroacetate to generate 2, 6-dimethyl phenoxyacetic acid ethyl ester;

and 2, hydrolyzing the 2, 2, 6-dimethyl phenoxy ethyl acetate under an alkaline condition to obtain the 2, 6-dimethyl phenoxy acetic acid.

2. The production process according to claim 1, wherein: the specific process of the step 1 is as follows: dissolving 2, 6-dimethylphenol in acetone, adding potassium carbonate particles, stirring and mixing, dropwise adding ethyl chloroacetate into a system, adding sodium iodide after dropwise adding, heating and refluxing for reaction, filtering the reaction solution after the reaction is finished, and washing a filter cake with acetone to obtain a mother solution containing 2, 6-dimethylphenoxy ethyl acetate.

3. The production process according to claim 2, wherein: the particle size of the potassium carbonate particles is less than 88 microns.

4. The production process according to claim 2, wherein: the mol ratio of the 2, 6-dimethylphenol to the potassium carbonate to the ethyl chloroacetate is 1: 1.5: 1.5.

5. the production process according to claim 2, wherein: the time of the reflux reaction is 8-10 h.

6. The production process according to claim 1, wherein: the specific process of the step 2 is as follows: dropwise adding a sodium hydroxide aqueous solution into a mother solution containing 2, 6-dimethyl phenoxyacetic acid ethyl ester, reacting for 20-40 min at 20-30 ℃, concentrating under reduced pressure to obtain a solvent acetone, adjusting the pH of the system to 2-3 with concentrated hydrochloric acid at 20-30 ℃, keeping the temperature at 20-30 ℃ after adjusting, stirring for 1h, performing suction filtration, washing a filter cake with water, and performing vacuum drying to obtain the 2, 6-dimethyl phenoxyacetic acid.

7. The production process according to claim 6, wherein: the concentration of the aqueous sodium hydroxide solution was 10 wt.%.

8. The production process according to claim 6, wherein: the dropping time of dropping concentrated hydrochloric acid is not less than 1 h.

Technical Field

The invention belongs to the technical field of organic chemical industry, and particularly relates to a production process of 2, 6-dimethylphenoxy acetic acid.

Background

Lopinavir (LPV), an anti-HIV protease inhibitor, exerts its anti-HIV effect mainly by blocking Gag-Pol polyprotein cleavage, generating immature, non-infectious virions, often combined clinically with low doses of ritonavir to improve its pharmacokinetic properties. The lopinavir and low-dose ritonavir compound tablet is approved by the United states food and drug administration to market in 2000, has reliable curative effect, less side effect and small food influence, is used as a first-line or second-line treatment medicament for resisting human immunodeficiency virus at present, and plays an important role in antiviral treatment of HIV patients who fail to initially treat the medicament.

Lopinavir contains 4 chiral carbons with S-configuration, and intermediates involved in the synthesis process all have diastereoisomers (about 10% in total), so that the number of impurities is increased, and further, the difficulty of quality control in industrial production is increased. In the lopinavir synthesis process, 2, 6-dimethylphenoxy acetic acid is one of key reactants, and if the purity of the 2, 6-dimethylphenoxy acetic acid is not high, more impurities are brought into the subsequent synthesis process, so that the yield and the purity of the lopinavir are greatly influenced.

Disclosure of Invention

The invention aims to provide a production process of 2, 6-dimethylphenoxy acetic acid, and the prepared 2, 6-dimethylphenoxy acetic acid has high purity and does not generate larger impurities, thereby being beneficial to the subsequent preparation of lopinavir.

In order to achieve the above purpose, the solution of the invention is:

a production process of 2, 6-dimethylphenoxy acetic acid comprises the following steps:

carrying out substitution reaction on 1, 2, 6-dimethylphenol and ethyl chloroacetate to generate 2, 6-dimethyl phenoxyacetic acid ethyl ester;

and 2, hydrolyzing the 2, 2, 6-dimethyl phenoxy ethyl acetate under an alkaline condition to obtain the 2, 6-dimethyl phenoxy acetic acid.

Further, the specific process of step 1 is as follows: dissolving 2, 6-dimethylphenol in acetone, adding potassium carbonate particles, stirring and mixing, dropwise adding ethyl chloroacetate into a system, adding sodium iodide after dropwise adding, heating and refluxing for reaction, filtering the reaction solution after the reaction is finished, and washing a filter cake with acetone to obtain a mother solution containing 2, 6-dimethylphenoxy ethyl acetate.

Further, the particle size of the potassium carbonate particles is less than 88 microns.

Further, the molar ratio of the 2, 6-dimethylphenol to the potassium carbonate to the ethyl chloroacetate is 1: 1.5: 1.5.

further, the time of the reflux reaction is 8-10 h.

Further, the specific process of step 2 is as follows: dropwise adding a sodium hydroxide aqueous solution into a mother solution containing 2, 6-dimethyl phenoxyacetic acid ethyl ester, reacting for 20-40 min at 20-30 ℃, concentrating under reduced pressure to obtain a solvent acetone, adjusting the pH of the system to 2-3 with concentrated hydrochloric acid at 20-30 ℃, keeping the temperature at 20-30 ℃ after adjusting, stirring for 1h, performing suction filtration, washing a filter cake with water, and performing vacuum drying to obtain the 2, 6-dimethyl phenoxyacetic acid.

Further, the concentration of the aqueous sodium hydroxide solution was 10 wt.%.

Further, the dropping time of dropping concentrated hydrochloric acid is not less than 1 h.

After the scheme is adopted, in order to control the purity of the reactant 2, 6-dimethylphenoxy acetyl chloride in the lopinavir synthesis process, the invention prepares the 2, 6-dimethylphenoxy acetic acid which is an upstream product of the 2, 6-dimethylphenoxy acetyl chloride by controlling two steps of processes of substitution reaction and ester hydrolysis reaction, and the prepared 2, 6-dimethylphenoxy acetic acid has high purity and does not generate larger impurities, thereby being beneficial to the subsequent preparation of lopinavir.

Detailed Description

The present invention is described in further detail below with reference to specific examples, but the present invention should not be construed as being limited thereto. Modifications or substitutions to methods, procedures, or conditions of the invention may be made without departing from the spirit and scope of the invention. The experimental methods and reagents of the formulations not specified in the examples are in accordance with the conventional conditions in the art.

Example 1

The invention provides a production process of 2, 6-dimethylphenoxy acetic acid, which comprises the following reaction processes:

the reaction process comprises two steps: the first step of substitution reaction generates an intermediate, and the second step of reaction is hydrolysis reaction of an ester group. The reaction process has no large impurity produced and can control the purity of 2, 6-dimethyl phenoxy acetic acid.

The feeding ratio is as follows:

wherein, the granularity data of the potassium carbonate are as follows:

d(0.1)	d(0.5)	d(0.9)
			1.55μm	9.9μm	87.9μm

the specific process comprises the following steps:

(one) substitution reaction

1. Adding 50g of 2, 6-dimethylphenol and 400mL of acetone into a 1L multi-mouth reaction bottle to be mechanically stirred, and stirring at room temperature to dissolve;

2. adding 85g of potassium carbonate (the particle size d (0.9) <88 microns), and stirring at room temperature for 10-30 min;

3. dropwise adding 75.3g of ethyl chloroacetate into the system, finishing the adding for 5-30 min (the amplification process can prolong the adding time), adding 1g of sodium iodide, and stirring for 5-15 min after the adding is finished;

4. heating until the system reflows (the temperature in a small test is about 55-57 ℃), reacting for 8-10 h, and displaying that the raw material disappears and the iodine shows that the raw material is very light and nearly disappears by TLC (petroleum ether: methyl tert-ether: 10:1)254nm ultraviolet (the point plate controls the phenol to be less than about 1%);

5. and cooling to below 25 ℃, carrying out suction filtration, and leaching the filter cake with 25mL of acetone for three times to obtain mother liquor containing the intermediate ester.

(II) hydrolysis reaction

1. Adding 328g of 10% NaOH aqueous solution into the mother liquor containing the intermediate ester dropwise, controlling the internal temperature to be less than 25 ℃ (half of the system is obviously exothermic before dropwise adding, the later dropwise adding speed can be accelerated), reacting for 20-40 min at 20-30 ℃ after dropwise adding, and displaying that the intermediate ester disappears by TLC (petroleum ether: methyl tert-ether: 10:1) ultraviolet at 254 nm;

concentrating acetone in the reaction solution under reduced pressure in water bath at 2.30 ℃ until no fraction is obtained (the system is concentrated to the volume of about 400mL), and obtaining hydrolysate;

3. cooling the hydrolysate to 20-30 ℃, dropwise adding 65.3g of concentrated hydrochloric acid to adjust the pH of the system to 2-3 (the specific dosage is based on the pH of the system), wherein the dropwise adding time is not less than 1h, stirring for 1h at 20-30 ℃, performing suction filtration, and leaching a filter cake with 25mL of water for three times to obtain a wet product;

discharging the material when the water content is less than 0.10% at 4.50 ℃ in vacuum to obtain the 2, 6-dimethylphenoxy acetic acid, wherein the HPLC purity is more than or equal to 99.5%.

In order to control the purity of a reactant 2, 6-dimethylphenoxy acetyl chloride in the lopinavir synthesis process, the invention prepares the 2, 6-dimethylphenoxy acetic acid which is an upstream product of the 2, 6-dimethylphenoxy acetyl chloride by controlling two steps of processes of substitution reaction and ester hydrolysis reaction. Specifically, the method comprises the following steps: firstly, 2, 6-dimethylphenol and ethyl chloroacetate are subjected to substitution reaction in the presence of potassium carbonate to generate 2, 6-dimethylphenoxy ethyl acetate, and in the step, the granularity of the potassium carbonate is controlled to be below 88 microns, so that the aims of complete reaction and high product purity can be fulfilled; and hydrolyzing the 2, 6-dimethyl phenoxy ethyl acetate under an alkaline condition to obtain 2, 6-dimethyl phenoxy acetic acid, and adjusting the pH value by adopting concentrated hydrochloric acid after the 2, 6-dimethyl phenoxy ethyl acetate is completely hydrolyzed into the 2, 6-dimethyl phenoxy acetic acid in a sodium hydroxide solution to ensure that the separated 2, 6-dimethyl phenoxy acetic acid has larger particles, thereby effectively improving the yield of the product.

The above embodiments are only for illustrating the technical idea of the present invention, and the protection scope of the present invention is not limited thereby, and any modifications made on the basis of the technical scheme according to the technical idea of the present invention fall within the protection scope of the present invention.