Synthesis method of 2, 6-difluorostyrene

Abstract

The invention belongs to the technical field of pesticides, and particularly relates to a synthesis method of 2, 6-difluorostyrene. According to the method, 2, 6-difluorobromobenzene is adopted as a Grignard reagent, so that the reaction is mild; the raw materials are easy to obtain, the production cost is low, the conversion rate is high, the two-step total yield can reach 85% or above, and the raw materials are completely converted; the product is easy to separate, water washing, liquid separation and distillation are performed after the reaction is completed, excessive acetaldehyde directly enters a water phase, and the product is left in an organic phase.

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. Oxathiapiprolin is an inhibitor of oxysterol binding protein (OSBP), and is highly effective against Phytophthora mutans that causes potato late blight and tomato late blight. 2,6-Difluorostyrene is an important intermediate of the fungicide oxathiapiprolin. Existing literature reports that when synthesizing 2,6-difluorostyrene, 2,6-difluorobenzaldehyde is used as a raw material, and 2,6-difluorostyrene is generated by a Wittig reaction. The raw material triphenylphosphine used in this method has a large molecular weight and low atomic utilization, which is not suitable for industrial production. After the reaction is completed, the byproduct triphenylphosphine oxide is difficult to remove, resulting in low product content, difficult purification, and a large amount of three wastes. Summary of the invention

[0003] Aiming at the problems of high raw material cost, low product content and large amount of three wastes in the prior art using triphenylphosphine, the present invention provides a method for synthesizing 2,6-difluorostyrene, which uses 2,6-difluorobromobenzene as Grignard reagent, has mild reaction, easy-to-obtain raw materials, low production cost, high conversion rate, two-step total yield can reach more than 85%, and raw materials are completely converted; the product is easy to separate, and after the reaction is completed, it is washed with water, separated and distilled, and the excess acetaldehyde directly enters the water phase, and the product remains in the organic phase.

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

[0005] A method for synthesizing 2,6-difluorostyrene, the reaction scheme of which is as follows:

[0006]

[0007] The specific synthesis method comprises the following steps:

[0008] (1) 2,6-difluorobromobenzene is dissolved in a solvent, and then slowly added into a reaction bottle containing metal magnesium and a solvent to react to generate a Grignard reagent; acetaldehyde is slowly added into the generated Grignard reagent to react at -5 to 10°C to synthesize 2,6-difluoro-α-methylbenzyl alcohol.

[0009] (2) 2,6-Difluoro-α-methylbenzyl alcohol is dehydrated in the presence of a catalyst to synthesize 2,6-difluorostyrene.

[0010] Preferably, in step (1), the molar ratio of 2,6-difluorobromobenzene to metallic magnesium is 1:1 to 1.5.

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

[0012] Preferably, the solvent in step (1) is one or more of diethyl ether, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, and toluene. More preferably, the solvent is selected from diethyl ether, toluene, and 2-methyltetrahydrofuran.

[0013] Preferably, the temperature of the grout reaction in step (1) is -20°C to 80°C; more preferably, the temperature of the grout reaction is -5°C to 65°C.

[0014] Preferably, the volume mass ratio of the total amount of the solvent used in step (1) to 2,6-difluorobromobenzene is 6 to 10:1 (unit: ml / g).

[0015] Preferably, the catalyst described in step (2) is selected from sulfuric acid, potassium hydrogen sulfate, phosphoric acid, p-toluenesulfonic acid, etc.

[0016] Preferably, in step (2), the molar ratio of 2,6-difluoro-α-methylbenzyl alcohol to the catalyst is 1:0.02-0.15.

[0017] Preferably, the dehydration temperature in step (2) is 70-120°C.

[0018] More preferably, the treatment method after the reaction in step (1) is as follows: adding the reaction solution to ice water, stirring, adding 10% dilute hydrochloric acid to adjust the pH to 7, adding solvent extraction, separating the organic phase, washing with water twice; removing the solvent to obtain 2,6-difluoro-α-methylbenzyl alcohol. Preferably, the solvent is removed by rotary evaporation.

[0019] The beneficial effects of the present invention are:

[0020] (1) The raw materials in the synthesis method of the present invention are easily available and inexpensive, and are suitable for industrial production.

[0021] (2) The synthesis method of the present invention has simple reaction, is easy to purify, and has high product content.

[0022] (3) The by-products in the synthesis method of the present invention are inorganic salts and water, and the atom economy is good.

[0023] (4) The product obtained in the synthesis method of the present invention is easy to separate and the operation is simple. After the intermediate of the Grignard reaction is post-treated with hydrochloric acid acidification and solvent extraction, the product remains in the organic phase, and the by-product inorganic salt directly enters the aqueous phase. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 HNMR detection spectrum of the product prepared in Example 1 of the present invention.

[0025] Figure 2 HNMR detection spectrum of the product prepared in Example 7 of the present invention. DETAILED DESCRIPTION

[0026] 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.

[0027] Example 1

[0028] Under stirring, add 100 ml of ether and 3.7 g of magnesium chips to a 500 ml four-necked reaction bottle protected by nitrogen, and heat to reflux. Dissolve 19.3 g of 2,6-difluorobromobenzene in 50 ml of ether, stir evenly, and slowly drop the solution into the four-necked bottle containing magnesium chips. Keep the reaction system in a reflux state during the dropwise addition. After the dropwise addition is completed, continue to reflux for 3 hours to generate Grignard reagent. Liquid phase detection shows that 2,6-difluorobromobenzene is completely converted and the temperature is lowered to 0-5°C.

[0029] Add 100 ml of ether to a 250 ml reaction bottle, cool to 0-5°C, add 6.6 g of acetaldehyde and stir evenly. 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. The Grignard reagent reaction is complete by liquid phase detection.

[0030] 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 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 distilled to obtain 15.1 g of the product 2,6-difluoro-α-methylbenzyl alcohol, with a yield of 94.2%. The product was tested by HPLC, and the purity was 98.7%.

[0031] The product was tested by HNMR, and the test data were as follows:

[0032] 1H NMR (400MHz, CDCl3): δ7.16-7.24(m,1H),6.83-6.90(m,2H),5.22-5.27(m,1H),2.40(s,1H),1.61-1.63(d,3H).

[0033] Example 2

[0034] Under stirring, add 100 ml of ether and 2.9 g of magnesium chips to a 500 ml four-necked reaction bottle protected by nitrogen, and heat to reflux. Dissolve 19.3 g of 2,6-difluorobromobenzene in 50 ml of ether, stir evenly, and slowly drop the solution into the four-necked bottle containing magnesium chips. Keep the reaction system in a reflux state during the dropwise addition. Continue to reflux for 3 hours after the dropwise addition is completed. Liquid phase detection shows that 2,6-difluorobromobenzene is completely converted, and the temperature is lowered to 0-5°C.

[0035] Add 100 ml of ether to a 250 ml reaction bottle, cool to 0-5°C, add 5.3 g of acetaldehyde and stir evenly. 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. The Grignard reagent reaction is complete by liquid phase detection.

[0036] 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 ether (50ml×2), and the organic phases were combined. The organic phase was washed twice with water, dried over anhydrous sodium sulfate, and distilled to obtain 15.0g of the product 2,6-difluoro-α-methylbenzyl alcohol, with a yield of 94.0%. The product was tested by HPLC, and the purity was 99.1%.

[0037] Example 3

[0038] Under stirring, add 100 ml of ether and 2.5 g of magnesium chips to a 500 ml four-necked reaction bottle protected by nitrogen, and heat to reflux. Dissolve 19.3 g of 2,6-difluorobromobenzene in 50 ml of ether, stir evenly, and slowly drop the solution into the four-necked bottle containing magnesium chips. Keep the reaction system in a reflux state during the dropwise addition. Continue to reflux for 3 hours after the dropwise addition is completed. Liquid phase detection shows that 2,6-difluorobromobenzene remains at 2.7%, and the temperature is lowered to 0-5°C.

[0039] Add 100 ml of ether to a 250 ml reaction bottle, cool to 0-5 ° C, add 4.5 g of acetaldehyde and stir evenly. Slowly drop the solution into the above Grignard reagent, keep the temperature at 0-5 ° C, keep warm for 2 hours after the addition is completed, pour the reaction solution into ice water to quench, add 10% hydrochloric acid to adjust the pH to 7, separate the organic layer, continue to extract the aqueous phase with ether (50 ml × 2) twice, and combine the organic phases. Wash the organic phase twice, dry it with anhydrous sodium sulfate, and distill to obtain 15.3 g of 2,6-difluoro-α-methylbenzyl alcohol, with a yield of 91.2%. The product was tested by HPLC, and the purity was 94.3%.

[0040] Example 4

[0041] Add 100 ml of toluene and 200 ml of 2-methyltetrahydrofuran into a 500 ml single-necked bottle, and stir to mix evenly.

[0042] Under stirring, add 100 ml of the above-mentioned mixed solution of toluene and 2-methyltetrahydrofuran and 2.9 g of magnesium chips to a 500 ml four-necked reaction bottle protected by nitrogen, and heat to 60°C. Dissolve 19.3 g of 2,6-difluorobromobenzene in 50 ml of the mixed solution of toluene and 2-methyltetrahydrofuran, stir evenly, and slowly drop the solution into the four-necked bottle containing magnesium chips. Keep the reaction system at 60-65°C during the dropwise addition, and keep warm for 7 hours after the dropwise addition is completed. Liquid phase detection shows that 2,6-difluorobromobenzene is completely converted, and the temperature is lowered to 15-20°C.

[0043] Add 100 ml of a mixture of toluene and 2-methyltetrahydrofuran to a 250 ml reaction bottle, cool to 15-20 ° C, add 5.3 g of acetaldehyde and stir evenly. Slowly drop the solution into the above Grignard reagent, keep the temperature at 15-20 ° C, and continue to keep warm for 3 hours after the dropwise addition is completed. The liquid phase detects that the Grignard reagent has reacted completely. Pour the reaction solution into ice water to quench, add 10% hydrochloric acid to adjust the pH to 7, separate the organic layer, continue to extract the aqueous phase with toluene (100 ml × 2) twice, and combine the organic phases. Wash the organic phase twice, dry it with anhydrous sodium sulfate, and distill to obtain 15.2 g of the product 2,6-difluoro-α-methylbenzyl alcohol, with a yield of 94.7%. The product was tested by HPLC, and the purity was: 98.5%.

[0044] Example 5

[0045] Add 100 ml of toluene and 200 ml of 2-methyltetrahydrofuran into a 500 ml single-necked bottle, and stir to mix evenly.

[0046] Under stirring, add 100 ml of the above-mentioned mixed solution of toluene and 2-methyltetrahydrofuran and 2.9 g of magnesium chips to a 500 ml four-necked reaction bottle protected by nitrogen, and heat to 60°C. Dissolve 19.3 g of 2,6-difluorobromobenzene in 50 ml of the mixed solution of toluene and 2-methyltetrahydrofuran, stir evenly, and slowly drop the solution into the four-necked bottle containing magnesium chips. Keep the reaction system at 60-65°C during the dropwise addition, and keep warm for 7 hours after the dropwise addition is completed. Liquid phase detection shows that 2,6-difluorobromobenzene is completely converted and the temperature is lowered to 5-10°C.

[0047] Add 100 ml of a mixture of toluene and 2-methyltetrahydrofuran to a 250 ml reaction bottle, cool to 5-10 ° C, add 5.3 g of acetaldehyde and stir evenly. Slowly drop the solution into the above Grignard reagent, keep the temperature at 5-10 ° C, and continue to keep warm for 3 hours after the dropwise addition is completed. The liquid phase detection shows that the Grignard reagent has reacted completely. Pour the reaction solution into ice water to quench, add 10% hydrochloric acid to adjust the pH to 7, separate the organic layer, continue to extract the aqueous phase with toluene (100 ml × 2) twice, and combine the organic phases. Wash the organic phase twice, dry it with anhydrous sodium sulfate, and distill to obtain 15.1 g of the product 2,6-difluoro-α-methylbenzyl alcohol, with a yield of 94.2%. The product was tested by HPLC, and the purity was: 98.7%.

[0048] Example 6

[0049] Add 100 ml of toluene and 200 ml of 2-methyltetrahydrofuran into a 500 ml single-necked bottle, and stir to mix evenly.

[0050] Under stirring, add 100 ml of the above-mentioned mixed solution of toluene and 2-methyltetrahydrofuran and 2.9 g of magnesium chips to a 500 ml four-necked reaction bottle protected by nitrogen, and heat to 60°C. Dissolve 19.3 g of 2,6-difluorobromobenzene in 50 ml of the mixed solution of toluene and 2-methyltetrahydrofuran, stir evenly, and slowly drop the solution into the four-necked bottle containing magnesium chips. Keep the reaction system at 60-65°C during the dropwise addition, and keep warm for 7 hours after the dropwise addition is completed. Liquid phase detection shows that 2,6-difluorobromobenzene is completely converted and the temperature is lowered to 0-5°C.

[0051] Add 100 ml of a mixture of toluene and 2-methyltetrahydrofuran to a 250 ml reaction bottle, cool to 0-5 ° C, add 5.3 g of acetaldehyde and stir evenly. Slowly drop the solution into the above Grignard reagent, keep the temperature at 0-5 ° C, and continue to keep warm for 3 hours after the dropwise addition is completed. The liquid phase detection shows that the Grignard reagent has reacted completely. Pour the reaction solution into ice water to quench, add 10% hydrochloric acid to adjust the pH to 7, separate the organic layer, continue to extract the aqueous phase with toluene (100 ml × 2) twice, and combine the organic phases. Wash the organic phase twice with water, dry it with anhydrous sodium sulfate, and distill to obtain 15.1 g of the product 2,6-difluoro-α-methylbenzyl alcohol, with a yield of 94.3%. The product was tested by HPLC, and the purity was: 98.8%.

[0052] Example 7

[0053] Under stirring, add 300ml toluene, 15.94g 2,6-difluoro-α-methylbenzyl alcohol (purity 99.1%), and 1.7g p-toluenesulfonic acid to a 500ml four-necked reaction bottle equipped with a water separator, heat and reflux for 4h (the oil bath is set to 140℃ until the system refluxes and separates water), until no water is separated from the water separator, the reaction is complete, and the raw material conversion is complete according to HPLC. Cool to room temperature, pour the reaction solution into water for washing, wash the separated organic phase with saturated sodium bicarbonate, continue to wash the organic phase with water three times, and dry. Distill toluene under normal pressure, and the product 2,6-difluorostyrene is distilled under negative pressure (oil bath temperature 90℃, distillation head temperature 59-60℃, vacuum degree 51 mmHg) to obtain 13.1g, yield: 92.7%. The product is tested by HPLC, and the purity is 99.2%.

[0054] The product was tested by HNMR, and the test data were as follows:

[0055] 1H NMR (400MHz, CDCl3): δ7.06-7.17(m,1H), 6.82-6.89(m,2H), 6.69-6.76(m,1H), 6.02-6.06(dd,1H), 5.56-5.59(dd,1H).

[0056] Example 8

[0057] Under stirring, add 300ml toluene, 15.94g 2,6-difluoro-α-methylbenzyl alcohol (purity 99.1%), and 0.86g p-toluenesulfonic acid to a 500ml four-necked reaction bottle equipped with a water separator, heat and reflux to separate water for 6h, until no water is separated from the water separator, the reaction is complete, and HPLC detects that the raw material is completely converted. Cool to room temperature, pour the reaction solution into water for washing, wash the separated organic phase with saturated sodium bicarbonate, continue to wash the organic phase with water three times, and dry. Distill toluene at normal pressure, and the product 2,6-difluorostyrene is obtained by negative pressure distillation to obtain 13.0g, with a yield of 92.1%. The product is tested by HPLC, and the purity is 99.3%.

[0058] Example 9

[0059] Under stirring, add 300ml toluene, 15.94g 2,6-difluoro-α-methylbenzyl alcohol (purity of 99.1%), and 0.5g 98% concentrated sulfuric acid to a 500ml four-necked reaction bottle equipped with a water separator, heat and reflux to separate water for 5h, until no water is separated from the water separator, the reaction is complete, and HPLC detects that the raw material is completely converted. Cool to room temperature, pour the reaction solution into water for washing, wash the separated organic phase with saturated sodium bicarbonate, continue to wash the organic phase with water three times, and dry. Distill toluene at normal pressure, and the product 2,6-difluorostyrene is obtained by negative pressure distillation to obtain 11.7g, with a yield of 82.2%. The product is tested by HPLC, and the purity is 98.5%.

[0060] Example 10

[0061] Under stirring, add 300 ml of toluene, 15.94 g of 2,6-difluoro-α-methylbenzyl alcohol (purity of 99.1%), and 0.6 g of 85% phosphoric acid to a 500 ml four-necked reaction bottle equipped with a water separator, heat and reflux to separate water for 12 hours, and HPLC detection shows that the remaining raw material is 2.7%. Cool to room temperature, pour the reaction solution into water for washing, wash the separated organic phase with saturated sodium bicarbonate, continue to wash the organic phase with water three times, and dry. Distill toluene at normal pressure, and the product 2,6-difluorostyrene is obtained by negative pressure distillation to obtain 12.1 g, with a yield of 80.8%. The product is tested by HPLC, and the purity is 93.6%.

[0062] 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 94%, and the content can reach more than 98%. It can be seen from the test data of Examples 4 to 7 that when 2-methyltetrahydrofuran and toluene are used as solvent, the initiation temperature obviously increases compared with ether, and the yield can reach more than 94%, and the content can reach more than 98%. It can be seen from Examples 8 to 11 that when p-methylbenzenesulfonic acid is used as dehydration catalyst, the yield can reach more than 92%, and the content can reach more than 99%.

[0063] 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: The reaction route is as follows:

2. The method for synthesizing 2,6-difluorostyrene according to claim 1, characterized in that: The specific synthesis method comprises the following steps: (1) dissolving 2,6-difluorobromobenzene in a solvent, and then slowly adding the solvent into a reaction bottle containing magnesium metal and the solvent to generate a Grignard reagent; slowly adding acetaldehyde into the generated Grignard reagent to react at -5 to 10° C. to synthesize 2,6-difluoro-α-methylbenzyl alcohol; (2) 2,6-Difluoro-α-methylbenzyl alcohol is dehydrated in the presence of a catalyst to synthesize 2,6-difluorostyrene.

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

5.

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

5.

5. 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, tetrahydrofuran, 2-methyltetrahydrofuran, and toluene; the reaction temperature in step (1) is -20°C to 80°C.

6. The method for synthesizing 2,6-difluorostyrene according to claim 5, characterized in that: The solvent described in step (1) is selected from ether, toluene, and 2-methyltetrahydrofuran; the reaction temperature in step (1) is -5°C to 65°C.

7. The method for synthesizing 2,6-difluorostyrene according to claim 1, characterized in that: The volume mass ratio of the total amount of the solvent described in step (1) to 2,6-difluorobromobenzene is 6 to 10:

1.

8. The method for synthesizing 2,6-difluorostyrene according to claim 1, characterized in that: The catalyst described in step (2) is selected from sulfuric acid, potassium hydrogen sulfate, phosphoric acid, and p-toluenesulfonic acid.

9. The method for synthesizing 2,6-difluorostyrene according to claim 1, characterized in that: In step (2), the molar ratio of 2,6-difluoro-α-methylbenzyl alcohol to the catalyst is 1:0.02-0.

15.

10. The method for synthesizing 2,6-difluorostyrene according to claim 1, characterized in that: The dehydration temperature in step (2) is 70-120°C.

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