阅读说明：本技术 一种苯醚甲环唑中间体的合成方法及其应用 (Synthetic method and application of difenoconazole intermediate ) 是由 冯魏 陈华 贾利华 陈石秀 徐武亮 邢燕 于 2021-08-13 设计创作，主要内容包括：本发明提供一种苯醚甲环唑中间体的合成方法及其用途,本发明合成方法为1)2,4～(,)-二氯二苯醚、乙酰氯进行酰化反应制得中间体Ⅰ；2)中间体Ⅰ、甲醇淬灭制得中间体Ⅱ；3)中间体Ⅱ与丙二醇制得苯醚甲环唑中间体。本发明的合成方法反应速度快,反应彻底,本发明合成的苯醚甲环唑中间体用于制备苯醚甲环唑。(The invention provides a synthetic method and application of a difenoconazole intermediate, wherein the synthetic method is 1)2,4 ， Carrying out acylation reaction on dichlorodiphenyl ether and acetyl chloride to obtain an intermediate I; 2) quenching the intermediate I and methanol to obtain an intermediate II; 3) and preparing the difenoconazole intermediate from the intermediate II and propylene glycol. The synthesis method has the advantages of high reaction speed and thorough reaction, and the difenoconazole intermediate synthesized by the invention is used for preparing the difenoconazole.)

1. A method for synthesizing a difenoconazole intermediate is characterized in that the synthetic route is as follows:

1)2, 4' -dichlorodiphenyl ether and acetyl chloride are subjected to acylation reaction to prepare an intermediate I

2) Intermediate I and methanol quenching to prepare intermediate II

3) And (4) cyclizing the intermediate II and propylene glycol to obtain a difenoconazole intermediate.

2. The synthesis method according to claim 1, characterized by the following steps:

1) heating 2, 4' -dichlorodiphenyl ether in the presence of anhydrous aluminum trichloride and dichloroethane, dropwise adding acetyl chloride, and keeping the temperature to be less than or equal to 0.5% after dropwise adding, thereby preparing an intermediate I;

2) heating the intermediate I, dropwise adding methanol to quench and react, keeping the temperature until the intermediate I in the reaction liquid is less than or equal to 1%, dropwise adding the reaction liquid into sufficient alkali liquor, separating a water phase from dichloroethane after dropwise adding, and removing dichloroethane to obtain an intermediate II;

3) adding a solvent, 1, 2-propylene glycol and p-toluenesulfonic acid into the intermediate II, heating and refluxing, carrying methanol to a water separator until methanol is not separated out until the intermediate II is less than or equal to 0.5%, and cooling and removing cyclohexane to obtain the difenoconazole intermediate.

3. The method of synthesis according to claim 2, characterized in that:

in the step 1), the feeding molar ratio of the 2, 4-dichlorodiphenyl ether to the acetyl chloride to the anhydrous aluminum trichloride is 1:1.1-1.2: 1.3-1.5.

4. The method of synthesis according to claim 2, characterized in that: and 2) performing aqueous phase separation in the step 2), extracting with dichloroethane, and combining dichloroethane layers.

5. The method of synthesis according to claim 2, characterized in that: in the step 3), the molar ratio of the intermediate II to the propylene glycol is 1:1.05-1.1, and the reflux time is 6 h.

The method of synthesis according to claim 2, characterized in that: the refluxing time in the step 3) is 5 h.

6. The method of synthesis according to claim 2, characterized in that: the solvent in the step 3) is cyclohexane or methylcyclohexane.

7. The method of synthesis according to claim 2, characterized in that: the molar ratio of the catalyst p-toluenesulfonic acid to the intermediate II in the step 3) is 0.005-0.01: 1.

8. The method of synthesis according to claim 2, characterized in that: the prepared difenoconazole intermediate is used for preparing difenoconazole.

Technical Field

The invention relates to a synthetic method and application of a difenoconazole intermediate.

Background art:

the difenoconazole is an excellent variety of high-efficiency, broad-spectrum and low-toxicity vegetable and fruit bactericides, 2- (2-chloro-4- (4-chlorophenoxy) phenyl) -2, 4-dimethyl-1, 3-dioxolane is prepared from 2, 4' -dichlorodiphenyl ether serving as a raw material through acylation and ketal when the difenoconazole intermediate 2- (2-chloro-4- (4-chlorophenoxy) phenyl) -2, 4-dimethyl-1, 3-dioxolane is industrially produced at present, the reaction time of the ketal step is longer, and the step needs 30-40 hours in common industrial production, so that the equipment utilization rate is low, and the energy consumption is large.

The process route is as follows:

the invention content is as follows:

the invention aims to provide a novel method for synthesizing a difenoconazole intermediate, namely a method for synthesizing 2- (2-chloro-4- (4-chlorophenoxy) phenyl) -2, 4-dimethyl-1, 3-dioxolane, which takes 2, 4' -dichlorodiphenyl ether as a raw material to prepare the 2- (2-chloro-4- (4-chlorophenoxy) phenyl) -2, 4-dimethyl-1, 3-dioxolane through acylation, ketal and alcohol exchange.

The technical scheme adopted by the invention for realizing the purpose is as follows:

1)2, 4' -dichlorodiphenyl ether and acetyl chloride are subjected to acylation reaction to prepare an intermediate I

2) Intermediate I and methanol quenching to prepare intermediate II

3) And preparing the difenoconazole intermediate from the intermediate II and propylene glycol.

Further, the method for synthesizing the difenoconazole intermediate specifically comprises the following steps:

1) heating 2,4 '-dichlorodiphenyl ether in the presence of anhydrous aluminum trichloride and dichloroethane, dropwise adding acetyl chloride for reaction, and keeping the temperature until the 2, 4' -dichlorodiphenyl ether is less than or equal to 0.5% after dropwise adding to obtain an intermediate I;

2) heating the intermediate I, dropwise adding methanol to quench and react, keeping the temperature until the intermediate I is less than or equal to 1% after dropwise adding, dropwise adding the reaction solution into sufficient alkali liquor, separating a water phase from dichloroethane after dropwise adding, and removing dichloroethane to obtain an intermediate II;

3) adding a solvent, 1, 2-propylene glycol and p-toluenesulfonic acid into the intermediate II, heating and refluxing, carrying methanol to a water separator until methanol is not separated out until the intermediate II is less than or equal to 0.5%, and cooling and desolventizing to obtain a difenoconazole intermediate finished product.

Further, in the above-mentioned case,

in the step 1), the feeding molar ratio of the 2, 4' -dichlorodiphenyl ether to the acetyl chloride to the anhydrous aluminum trichloride is 1:1.1-1.2:1.3-1.5, the dichloroethane is relatively excessive, and the dichloroethane is removed from a reaction system after the reaction is finished.

The temperature rise in the step 1) is 30-40 ℃, and the temperature rise in the step 2) is 50-60 ℃.

And 2) performing water phase separation in the step 2), extracting for 2 times by using dichloroethane, and combining dichloroethane layers.

In the step 2), the adding amount of the methanol is excessive relative to that of the anhydrous aluminum trichloride, and the methanol is removed from the reaction system after the reaction is finished.

The alkali in the step 2) is common alkali, such as sodium hydroxide, potassium hydroxide and the like, and the concentration is 50%.

The water generated in the step 2) is absorbed by anhydrous aluminum trichloride to realize rapid dehydration.

In the step 3), the molar ratio of the intermediate II to the propylene glycol is 1:1.05-1.1, the reflux time is less than or equal to 6 hours, preferably less than or equal to 5 hours, the methanol is brought by reflux, and the water brought by reflux in the conventional technology is usually long, usually 30 hours or more, because the boiling point of water is higher than that of the methanol and the hydrogen bonding effect among water molecules is obvious.

The solvent in the step 3) is cyclohexane or methylcyclohexane.

The molar ratio of the catalyst p-toluenesulfonic acid to the intermediate II in the step 3) is 0.005-0.01:1

The reaction in the step 3) is carried out until the intermediate II is less than or equal to 0.5 percent, the reaction is thorough, and the corresponding reaction intermediate II in the prior art is less than or equal to 2 percent.

The difenoconazole intermediate synthesized by the invention is used for preparing difenoconazole, and the preparation method comprises the steps of bromination, condensation and purification to obtain a difenoconazole technical material.

The method takes 2, 4' -dichlorodiphenyl ether as a raw material to carry out acylation reaction, after the reaction is finished, enough methanol is used for quenching the complexation of aluminum trichloride and a product, the temperature is raised to 50-60 ℃, a methanol ketal intermediate is generated, the methanol ketal intermediate and propylene glycol carry methanol in solvents such as cyclohexane, methylcyclohexane and the like in a refluxing manner, the difenoconazole intermediate with qualified content and yield can be obtained only in 5-6 hours, and the excessive methanol is recycled and reused, so that the cost is saved.

Compared with the prior art, the invention has the following beneficial effects:

1) the invention adopts a new method to synthesize the difenoconazole intermediate;

2) the method takes 2, 4' -dichlorodiphenyl ether as a raw material to carry out acylation reaction, the reaction is controlled to be finished, sufficient methanol quenches the complexation of aluminum trichloride and a product to generate an intermediate II, the reaction speed is high, and the reaction is thorough;

3) the intermediate II and propylene glycol carry methanol in solvents such as cyclohexane, methylcyclohexane and the like in a refluxing manner to generate a difenoconazole intermediate, the reaction speed is high, the production time is saved, and the equipment utilization rate is high;

4) the invention needs conventional equipment and facilities and has strong practicability.

The specific implementation mode is as follows:

the present invention is described in further detail below with reference to specific examples:

example 1:

1) 239g of 2, 4' -dichlorodiphenyl ether, 173.5g of anhydrous aluminum trichloride and 500g of dichloroethane are put into a reaction kettle, the temperature is increased to 30-40 ℃, 86.5g of acetyl chloride is dripped, and the temperature is kept to be less than or equal to 0.5 percent after 2-3h dripping is finished, so as to prepare an intermediate I;

2) heating the intermediate I to 50-60 ℃, dropwise adding 200g of methanol, keeping the temperature until the intermediate I is less than or equal to 1% after dropwise adding, dropwise adding the reaction solution into 500g of 50% alkali liquor, stirring for 0.5-1h after dropwise adding, separating dichloroethane, extracting a water layer for 2 times by using 100g of dichloroethane, combining dichloroethane layers, and removing dichloroethane to obtain an intermediate II;

3) adding 300g of cyclohexane, 79.8g of 1, 2-propylene glycol and 0.86g of p-toluenesulfonic acid into the intermediate II, heating and refluxing, carrying methanol to a water separator until methanol is not separated (about 4-5h), refluxing for 0.5-1h, wherein II is less than or equal to 0.5%, cooling and removing cyclohexane to obtain 332.1g of a difenoconazole intermediate finished product with the purity of 97.2% and the yield of 95.2%.

Example 2:

1) 239g of 2, 4' -dichlorodiphenyl ether, 200.5g of anhydrous aluminum trichloride and 500g of dichloroethane are put into a reaction kettle, the temperature is increased to 30-40 ℃, 94.2g of acetyl chloride is dripped, and the temperature is kept to be less than or equal to 0.5 percent after dripping for 2-3h to prepare an intermediate I;

2) heating the intermediate I to 50-60 ℃, dropwise adding 200g of methanol, keeping the temperature until the intermediate I is less than or equal to 1% after dropwise adding, dropwise adding the reaction solution into 500g of 50% alkali liquor, stirring for 0.5-1h after dropwise adding, separating dichloroethane, extracting a water layer for 2 times by using 100g of dichloroethane, combining dichloroethane layers, and removing dichloroethane to obtain an intermediate II;

3) adding 300g of cyclohexane, 83.6g of 1, 2-propylene glycol and 1.72g of p-toluenesulfonic acid into the intermediate II, heating and refluxing, carrying methanol to a water separator, separating methanol (about 4-5h), refluxing for 0.5-1h, wherein II is less than or equal to 0.5%, cooling and removing cyclohexane to obtain 333.5g of a difenoconazole intermediate finished product with purity of 97.1% and yield of 95.5%.

Example 3:

1) 239g of 2, 4' -dichlorodiphenyl ether, 195g of anhydrous aluminum trichloride and 500g of dichloroethane are put into a reaction kettle, the temperature is raised to 30-40 ℃, 88.5g of acetyl chloride is dripped, and the temperature is kept to be less than or equal to 0.5 percent after dripping for 2-3h to prepare an intermediate I;

2) heating the intermediate I to 50-60 ℃, dropwise adding 200g of methanol, keeping the temperature until the intermediate I is less than or equal to 1% after dropwise adding, dropwise adding the reaction solution into 500g of 50% alkali liquor, stirring for 0.5-1h after dropwise adding, separating dichloroethane, extracting a water layer for 2 times by using 100g of dichloroethane, combining dichloroethane layers, and removing dichloroethane to obtain an intermediate II;

3) adding 300g of cyclohexane, 82.5g of 1, 2-propylene glycol and 1.5g of p-toluenesulfonic acid into the intermediate II, heating and refluxing, carrying methanol to a water separator until methanol is not separated (about 4-5h), refluxing for 0.5-1h, wherein II is less than or equal to 0.5%, cooling and removing cyclohexane to obtain 332.9g of a difenoconazole intermediate finished product with purity of 97.4% and yield of 95.6%.

Example 4:

1) 239g of 2, 4' -dichlorodiphenyl ether, 198g of anhydrous aluminum trichloride and 500g of dichloroethane are put into a reaction kettle, the temperature is raised to 30-40 ℃, 90.0g of acetyl chloride is dripped, and the temperature is kept to be less than or equal to 0.5 percent after dripping for 2-3h to obtain an intermediate I;

2) heating the intermediate I to 50-60 ℃, dropwise adding 200g of methanol, keeping the temperature until the intermediate I is less than or equal to 1% after dropwise adding, dropwise adding the reaction solution into 500g of 50% alkali liquor, stirring for 0.5-1h after dropwise adding, separating dichloroethane, extracting a water layer for 2 times by using 100g of dichloroethane, combining dichloroethane layers, and removing dichloroethane to obtain an intermediate II;

3) adding 300g of cyclohexane, 81.0g of 1, 2-propylene glycol and 1.2g of p-toluenesulfonic acid into the intermediate II, heating and refluxing, carrying methanol to a water separator, separating methanol (about 4-5h), refluxing for 0.5-1h, wherein II is less than or equal to 0.5%, cooling and removing cyclohexane to obtain 333.0g of a difenoconazole intermediate finished product with purity of 97.3% and yield of 95.5%.