Synthesis method of 2, 6-difluorostyrene

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By forming Grignard reagent under nitrogen protection and reacting with 2,6-difluorobenzaldehyde, and synthesizing 2,6-difluorobenzaldehyde with acidic resin dehydration, the problem of large amount of triphenylphosphorus in the prior art is solved. It has achieved low-cost and high-content 2,6-difluorostyrene synthesis, which is suitable for industrial production.

CN119306568APending Publication Date: 2025-01-14JINGBO AGROCHEM TECH CO LTD

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Patent Information

Application Number: CN202411585795.7
Authority / Receiving Office: CN · China
Patent Type: Applications(China)
Current Assignee / Owner
Filing Date: 2024-11-07
Publication Date: 2025-01-14

AI Technical Summary

Technical Problem

The existing 2,6-difluorostyrene synthesis method uses triphenylphosphorus in large amounts and expensive prices. It is difficult to remove by-products after the reaction is completed, resulting in low product content and large amount of three wastes, which is difficult to suit industrial production.

Method used

Grignard reagent is used to generate under nitrogen protection and react with 2,6-difluorobenzaldehyde. 2,6-difluorobenzaldehyde is synthesized by dehydration of acid resin, and the acid resin is recycled and regenerated, simplifying the purification process and reducing the by-products. Inorganic salt and water.

Benefits of technology

It reduces production costs, increases product content, simplifies operating procedures, reduces the production of inorganic salts and water of by-products, is suitable for industrial production, and by-products are easy to separate and recover.

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Abstract

The invention belongs to the technical field of pesticides, and particularly relates to a synthesis method of 2, 6-difluorostyrene. The method comprises the following steps: introducing methane chloride gas into a reaction bottle containing magnesium metal and a solvent, and reacting to generate the Grignard reagent. And slowly adding 2, 6-difluorobenzaldehyde into the generated Grignard reagent, and reacting to synthesize the 2, 6-difluoro-alpha-methylbenzyl alcohol. And dehydrating the generated 2, 6-difluoro-alpha-methyl benzyl alcohol through an acidic catalyst to generate the 2, 6-difluorostyrene. The method has the advantages that (1) methane chloride is used as a Grignard reagent, and the reaction is simple; and (2) methane chloride is adopted as a Grignard reagent, so that the product is easy to purify, and the content of the intermediate 2, 6-difluoro-alpha-methylbenzyl alcohol is high. And (3) the yield is high by adopting methane chloride as the Grignard reagent, and the main material 2, 6-difluorobenzaldehyde is completely reacted. And (4) the production cost is low by using methane chloride as the Grignard reagent, and the method is suitable for industrial application. And (5) the dehydration catalyst can be recycled and reused by adopting cation exchange resin.

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Description

Technical Field

[0001] The invention belongs to the technical field of pesticides, and specifically relates to a method for synthesizing 2,6-difluorostyrene. Background Art

[0002] Oxathiapiprolin (trade name: Zorvec, Zengweiyinglu) is a new piperidine fungicide developed by DuPont. The drug is low in toxicity and has excellent preventive effects on downy mildew and late blight. 2,6-Difluorostyrene is the raw material for the synthesis of the pesticide oxathiapiprolin. Existing literature reports that when synthesizing 2,6-difluorostyrene, 2,6-difluorobenzaldehyde is used as the raw material, and 2,6-difluorostyrene is generated through the Wittig reaction. The raw material triphenylphosphine used in this method is large in amount and expensive, and is not suitable for industrial production. After the reaction is completed, the by-product triphenylphosphine oxide is difficult to remove, resulting in many problems such as low product content, difficulty in purification, and large amount of three wastes. Summary of the invention

[0003] Aiming at the problems of large amount of triphenylphosphine, low product content and large amount of three wastes in the prior art, the present invention provides a method for synthesizing 2,6-difluorostyrene to solve the above problems.

[0004] The technical solution of the present invention is:

[0005] A method for synthesizing 2,6-difluorostyrene, using the following route:

[0006]

[0007] The specific reaction steps include:

[0008] (1) Under nitrogen protection, chloromethane is slowly introduced into a reaction bottle containing magnesium metal and a solvent to react to generate a Grignard reagent; 2,6-difluorobenzaldehyde is slowly added to the generated Grignard reagent to react at 0-5°C to synthesize 2,6-difluoro-α-methylbenzyl alcohol.

[0009] (2) 2,6-Difluoro-α-methylbenzyl alcohol was dehydrated in the presence of an acidic resin to synthesize 2,6-difluorostyrene.

[0010] Preferably, the solvent in step (1) is one or more of diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, and toluene.

[0011] Preferably, in step (1), the molar ratio of 2,6-difluorobenzaldehyde to metallic magnesium is 1:1 to 1.5.

[0012] Preferably, in step (1), the molar ratio of 2,6-difluorobenzaldehyde to methyl chloride is 1:1 to 1.6.

[0013] Preferably, the reaction temperature of the Grignard reagent in step (1) is 0°C to 80°C.

[0014] Preferably, the treatment method after the reaction in step (1) is completed is: adding the reaction solution into ice water, stirring, adding 10% dilute hydrochloric acid to adjust the pH to 7, adding solvent for extraction, separating the organic phase, and washing with water for more than 2 times; removing the solvent to obtain 2,6-difluoro-α-methylbenzyl alcohol.

[0015] Preferably, the acidic resin in step (2) is cation exchange resin IR120 (H type).

[0016] Preferably, the post-dehydration treatment method in step (2) is: after the reaction is completed, the acidic resin is filtered out, desolventized, and the product 2,6-difluorostyrene is obtained after reduced pressure distillation.

[0017] The beneficial effects of the present invention are:

[0018] (1) The present invention has low production cost and is suitable for industrial production.

[0019] (2) The present invention has a simple reaction, is easy to purify, and has a high product content.

[0020] (3) The present invention has good atom economy, and the by-products are inorganic salts and water.

[0021] (4) The product of the present invention is easy to separate and simple to operate. After the Grignard reaction is treated with hydrochloric acid and solvent extraction, the product remains in the organic phase, and the by-product inorganic salt directly enters the aqueous phase.

[0022] (5) The acidic resin used in the dehydration process of the present invention can be recycled and regenerated, thereby effectively reducing the generation of acid-containing wastewater. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 This is the HNMR detection spectrum of the product prepared in Example 1 of the present invention.

[0024] Figure 2 This is the HNMR detection spectrum of the product prepared in Example 6 of the present invention. DETAILED DESCRIPTION

[0025] In order to enable those skilled in the art to better understand the technical solutions in the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work should fall within the scope of protection of the present invention.

[0026] Example 1

[0027] Preparation of Grignard reagent: Add 150 ml of ether and 3.7 g of magnesium chips to a 500 ml four-necked reaction bottle protected by nitrogen with stirring, and heat to reflux. Slowly pass 8.1 g of monochloromethane into the above ether-magnesium chips system, and keep the system in reflux during the ventilation process. After the magnesium chips completely disappear, cool down to 0-5°C.

[0028] Preparation of 2,6-difluoro-α-methylbenzyl alcohol: Add 100 ml of ether to a 250 ml reaction bottle, cool to 0-5°C, add 14.2 g of 2,6-difluorobenzaldehyde and stir to dissolve. Slowly drop the solution into the above Grignard reagent, keep the temperature at 0-5°C, and keep warm for 2 hours after the addition is completed. Liquid phase detection shows that the reaction of 2,6-difluorobenzaldehyde is complete.

[0029] The reaction solution was poured into ice water for quenching, 10% hydrochloric acid was added to adjust the pH to 7, the organic layer was separated, the aqueous phase was extracted twice with ether (50 ml x 2), and the organic phases were combined. The organic phase was washed twice with water, dried over anhydrous sodium sulfate, and desolventized to obtain 15.2 g of the product 2,6-difluoro-α-methylbenzyl alcohol, with a yield of 95.4%. The product was tested by HPLC, and the purity was 99.3%.

[0030] The product was tested by HNMR, and the test data were as follows:

[0031] 1H NMR (400MHz, DMSO-d6): δ7.29-7.37(m,1H),6.99-7.06(m,2H),5.35-5.36(d,1H),5.08-5.14(m,1H),1.46-1.48(d,3H).

[0032] Example 2

[0033] Under stirring, add 150 ml of tetrahydrofuran and 3.2 g of magnesium chips to a 500 ml four-necked reaction bottle protected by nitrogen, and heat to reflux. Slowly pass 7.1 g of monochloromethane into the above tetrahydrofuran-magnesium chips system, keep the system in reflux during the ventilation process, and cool to 0-5°C after the magnesium chips completely disappear.

[0034] Add 100 ml of tetrahydrofuran to a 250 ml reaction bottle, cool to 0-5°C, add 14.2 g of 2,6-difluorobenzaldehyde and stir to dissolve. Slowly drop the solution into the above Grignard reagent, keep the temperature at 0-5°C, and keep warm for 2 hours after the dropwise addition is completed. Liquid phase detection shows that the reaction of 2,6-difluorobenzaldehyde is complete.

[0035] The reaction solution was poured into ice water for quenching, 10% hydrochloric acid was added to adjust the pH to 7, 50 ml of toluene was added for extraction, the organic layer was separated, the aqueous phase was extracted twice with toluene (30 ml x 2), and the organic phases were combined. The organic phase was washed with water twice, dried over anhydrous sodium sulfate, and desolventized to obtain 15.2 g of the product 2,6-difluoro-α-methylbenzyl alcohol, with a yield of 95.6%. The product was tested by HPLC, and the purity was 99.5%.

[0036] Example 3

[0037] Under stirring, add 150 ml of methyl tert-butyl ether and 2.7 g of magnesium chips to a 500 ml four-necked reaction bottle protected by nitrogen, and heat to reflux. Slowly pass 6.1 g of methyl chloride into the above methyl tert-butyl ether magnesium chips system, keep the system in reflux state during the ventilation process, and cool to 0-5°C after the magnesium chips completely disappear.

[0038] Add 100 ml of methyl tert-butyl ether to a 250 ml reaction bottle, cool to 0-5°C, add 14.2 g of 2,6-difluorobenzaldehyde and stir to dissolve. Slowly drop the solution into the above Grignard reagent, keep the temperature at 0-5°C, and keep warm for 2 hours after the dropwise addition is completed. Liquid phase detection shows that the reaction of 2,6-difluorobenzaldehyde is complete.

[0039] The reaction solution was poured into ice water for quenching, 10% hydrochloric acid was added to adjust the pH to 7, the organic layer was separated, the aqueous phase was extracted twice with methyl tert-butyl ether (50 ml x 2), and the organic phases were combined. The organic phase was washed twice with water, dried over anhydrous sodium sulfate, and desolventized to obtain 15.1 g of the product 2,6-difluoro-α-methylbenzyl alcohol, with a yield of 95.2%. The product was tested by HPLC, and the purity was 99.7%.

[0040] Example 4

[0041] Under stirring, add 150 ml of ethylene glycol dimethyl ether and 2.7 g of magnesium chips in a 500 ml four-necked reaction bottle protected by nitrogen, and heat to reflux. Slowly pass 6.1 g of monochloromethane into the above ethylene glycol dimethyl ether magnesium chips system, keep the system in reflux state during the ventilation process, and cool to 0-5°C after the magnesium chips completely disappear.

[0042] Add 100 ml of ethylene glycol dimethyl ether to a 250 ml reaction bottle, cool to 0-5°C, add 14.2 g of 2,6-difluorobenzaldehyde and stir to dissolve. Slowly drop the solution into the above Grignard reagent, keep the temperature at 0-5°C, and keep warm for 2 hours after the dropwise addition is completed. Liquid phase detection shows that the reaction of 2,6-difluorobenzaldehyde is complete.

[0043] The reaction solution was poured into ice water for quenching, 10% hydrochloric acid was added to adjust the pH to 7, the organic layer was separated, the aqueous phase was extracted twice with ethylene glycol dimethyl ether (50 ml x 2), and the organic phases were combined. The organic phase was washed twice with water, dried over anhydrous sodium sulfate, and desolventized to obtain 15.1 g of the product 2,6-difluoro-α-methylbenzyl alcohol, with a yield of 96.1%. The product was tested by HPLC, and the purity was 99.0%.

[0044] Example 5

[0045] Under stirring, add 150 ml of 2-methyltetrahydrofuran and toluene (1:4) and 2.7 g of magnesium chips in a 500 ml four-necked reaction bottle protected by nitrogen, and heat to reflux. Slowly pass 6.1 g of monochloromethane into the above mixed solvent magnesium chips system, keep the system in reflux during the ventilation process, and cool to 0-5 ° C after the magnesium chips completely disappear.

[0046] Add 100 ml of toluene to a 250 ml reaction bottle, cool to 0-5°C, add 14.2 g of 2,6-difluorobenzaldehyde and stir to dissolve. Slowly drop the solution into the above Grignard reagent, keep the temperature at 0-5°C, and keep warm for 2 hours after the dropwise addition is completed. Liquid phase detection shows that the reaction of 2,6-difluorobenzaldehyde is complete.

[0047] The reaction solution was poured into ice water to quench, 10% hydrochloric acid was added to adjust the pH to 7, the organic layer was separated, the aqueous phase was extracted twice with toluene (50 ml x 2), and the organic phases were combined. The organic phase was washed twice with water, dried over anhydrous sodium sulfate, and desolventized to obtain 15.1 g of the product 2,6-difluoro-α-methylbenzyl alcohol, with a yield of 97.0%. The product was tested by HPLC, and the purity was 99.5%.

[0048] Example 6

[0049] Under stirring, add 300ml of toluene, 15.88g of 2,6-difluoro-α-methylbenzyl alcohol (purity 99.5%), and 15.8g of cation exchange resin IR120 (H type) in sequence to a 500ml four-necked reaction bottle equipped with a water separator, heat and reflux to separate water, and after reacting for 1h, no water is generated. HPLC detection shows that the raw material conversion is complete. Cool to room temperature, filter and recover the resin. Wash the filtrate three times with water, evaporate toluene at normal pressure, and obtain 13.3g of the product 2,6-difluorostyrene by negative pressure distillation, with a yield of 94.1%. HPLC detection of the product shows a purity of 99.1%.

[0050] The product was tested by HNMR, and the test data were as follows:

[0051] 1H NMR (400MHz, DMSO-d6): δ7.34-7.42(m,1H),7.06-7.16(m,2H),6.67-6.75(m,1H),5.96-6.01(d,1H),5.65-5.68(d,1H).

[0052] Example 7

[0053] Under stirring, 300 ml of toluene, 15.88 g of 2,6-difluoro-α-methylbenzyl alcohol (purity 99.5%), and cation exchange resin IR120 (H type) (recovered in Example 6, the residual solvent after filtration is not dried, sealed and stored directly for application) are added to a 500 ml four-necked reaction bottle equipped with a water separator, heated to reflux and water is separated, and after reacting for 1 hour, no water is generated, and the raw material conversion is complete when detected by HPLC. Cool to room temperature, filter and recover the resin. The filtrate is washed with water three times, and toluene is evaporated at normal pressure. The product 2,6-difluorostyrene is obtained by negative pressure distillation to obtain 13.5 g, with a yield of 95.4%. The product is tested by HPLC, and the purity is 99.0%.

[0054] Example 8

[0055] Under stirring, 300 ml of toluene, 15.88 g of 2,6-difluoro-α-methylbenzyl alcohol (purity 99.5%), and cation exchange resin IR120 (H type) (recovered in Example 7, the residual solvent after filtration is not dried, sealed and stored directly for application) are added to a 500 ml four-necked reaction bottle equipped with a water separator, heated to reflux and water is separated, and no water is generated after reaction for 1 hour. HPLC detection shows that the raw material conversion is complete. Cool to room temperature, filter and recover the resin. The filtrate is washed with water three times, and toluene is evaporated at normal pressure. The product 2,6-difluorostyrene is obtained by negative pressure distillation to obtain 13.3 g, with a yield of 94.2%. The product is tested by HPLC, and the purity is 99.2%.

[0056] It can be seen from the test data of Examples 1 to 3 that when ether is used as solvent, the yield can reach more than 95% and the content can reach more than 99%. It can be seen from the test data of Examples 4 to 6 that when cation exchange resin IR120 (H type) is used as dehydration catalyst, the yield can reach more than 94% and the content can reach more than 99%, and the yield remains basically unchanged when applied three times.

[0057] Although the present invention has been described in detail by referring to the accompanying drawings and in combination with the preferred embodiments, the present invention is not limited thereto. Without departing from the spirit and essence of the present invention, a person of ordinary skill in the art may make various equivalent modifications or substitutions to the embodiments of the present invention, and these modifications or substitutions shall be within the scope of the present invention. Any person of ordinary skill in the art who is familiar with the present invention may easily think of changes or substitutions within the technical scope disclosed by the present invention, and all of these shall be within the scope of protection of the present invention. Therefore, the scope of protection of the present invention shall be subject to the scope of protection described in the claims.

Claims

1. A method for synthesizing 2,6-difluorostyrene, characterized in that: Take the following route:

2. The method for synthesizing 2,6-difluorostyrene according to claim 1, characterized in that: The specific reaction steps include: (1) Under nitrogen protection, chloromethane is slowly introduced into a reaction bottle containing magnesium metal and a solvent to react to generate a Grignard reagent; 2,6-difluorobenzaldehyde is slowly added to the generated Grignard reagent to react at 0-5°C to synthesize 2,6-difluoro-α-methylbenzyl alcohol. (2) 2,6-Difluoro-α-methylbenzyl alcohol was dehydrated in the presence of an acidic resin to synthesize 2,6-difluorostyrene.

3. The method for synthesizing 2,6-difluorostyrene according to claim 1, characterized in that: The solvent described in step (1) is one or more of diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, and toluene.

4. The method for synthesizing 2,6-difluorostyrene according to claim 1, characterized in that: In step (1), the molar ratio of 2,6-difluorobenzaldehyde to metallic magnesium is 1:1 to 1.

5.

5. The method for synthesizing 2,6-difluorostyrene according to claim 1, characterized in that: In step (1), the molar ratio of 2,6-difluorobenzaldehyde to methyl chloride is 1:1 to 1.

6.

6. The method for synthesizing 2,6-difluorostyrene according to claim 1, characterized in that: The reaction temperature of the Grignard reagent in step (1) is 0°C to 80°C.

7. The method for synthesizing 2,6-difluorostyrene according to claim 1, characterized in that: After the reaction in step (1) is completed, the treatment method is as follows: adding the reaction solution into ice water, adding dilute hydrochloric acid to adjust the pH to 7, adding solvent for extraction, separating the organic phase, and washing with water; removing the solvent to obtain 2,6-difluoro-α-methylbenzyl alcohol.

8. The method for synthesizing 2,6-difluorostyrene according to claim 1, characterized in that: The acidic resin described in step (2) is cation exchange resin IR120 (H type).

9. The method for synthesizing 2,6-difluorostyrene according to claim 1, characterized in that: The post-dehydration treatment method of step (2) is as follows: after the reaction is completed, the acidic resin is filtered out, the solvent is removed, and the product 2,6-difluorostyrene is obtained after reduced pressure distillation.