CN118754799A - A kind of synthesis method of 2,6-difluorostyrene - Google Patents

Abstract

The invention relates to the technical field of chemical organic synthesis, in particular to a synthesis method of 2, 6-difluorostyrene. The invention takes cheap and easily available 2, 6-difluorotoluene as a starting material, firstly obtains secondary amine through Mannich reaction, and then obtains 2, 6-difluorostyrene through quaternization and deamination under alkaline conditions. The synthesis method of 2, 6-difluorostyrene provided by the invention has the advantages that the raw materials involved in the whole experimental process are cheap and easy to obtain, the reaction steps are few, the reaction conditions are mild, the product purity is high, and the method is suitable for industrial production.

Description

A kind of synthesis method of 2,6-difluorostyrene

Technical Field

The invention relates to the technical field of chemical organic synthesis, and in particular to a method for synthesizing 2,6-difluorostyrene.

Background Art

The information disclosed in this background technology section is only intended to enhance the understanding of the overall background of the invention, and should not necessarily be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art.

Fluoxathiapiprolin, commonly known as oxathiapiprolin in English and trade name Zorcec, has a chemical name of 1-(4-[4-[(5RS)-5-(2,6-difluorophenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl]-1-piperidinyl)-2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]ethanone, CAS No. 1003318-67-9. It is the first piperidinyl thiazole isoxazoline fungicide developed by DuPont. Studies have shown that fluoxathiapiprolin has very favorable toxicological and environmental properties, and its dosage is also small, making it safer for users, agricultural producers and the environment. The application amount of this agent is only 1/5 to 1/100 of that of commonly used fungicides, and it is highly effective against Phytophthora infestans, which causes late blight of potatoes and tomatoes. Fluthiazolinone is highly active and effective against all developmental stages of Phytophthora infestans. It can be transported over long distances in the host plant and can effectively control late blight even in extremely adverse conditions. The development of this product is mainly aimed at diseases that harm potatoes and other crops, and the control targets are oomycete pathogens that affect the yield and economic benefits of grapes, melons, tomatoes and other vegetable crops. Studies have found that fluthiazolinone is better than or equivalent to azoxystrobin in preventing sunflower downy mildew (Plasmopara halstedii); foliar spraying can effectively control basil downy mildew (Peronospora belbahrii) in South Florida; it can also effectively control tobacco black shank (Phytophthora nicotianae).

2,6-Difluorostyrene, CAS No. 207226-37-7, is a key intermediate for the synthesis of thiazolinone. The currently reported method for synthesizing this compound is mainly to use m-difluorobenzene to extract hydrogen in butyl lithium and diisopropylamine below -65°C, and then react with ethyl formate to prepare the intermediate 2,6-difluorobenzaldehyde; then use the Wittig reaction with methyl triphenylphosphonium bromide under butyl lithium conditions to generate the target product 2,6-difluorostyrene. However, the synthesis method has harsh conditions and high reagent risks, and is not feasible for large-scale production.

Summary of the invention

In order to overcome the above problems, the present invention provides a method for synthesizing 2,6-difluorostyrene.

In order to achieve the above technical objectives, the present invention adopts the following technical solutions:

The present invention provides a method for synthesizing 2,6-difluorostyrene, comprising:

Using 2,6-difluorotoluene as a raw material, the intermediate 1 is obtained by the Mannich reaction under the conditions of formaldehyde and dimethylamine hydrochloride, and then reacted with an alkyl halide or a sulfate to obtain a quaternary ammonium salt intermediate 2, and the amine is directly removed under alkaline conditions without separation to obtain the target product 2,6-difluorostyrene;

The synthetic route is:

In one or more embodiments, the specific method of using 2,6-difluorotoluene as a raw material and using the Mannich reaction under the conditions of formaldehyde and dimethylamine hydrochloride to obtain the intermediate 1 includes:

2,6-Difluorotoluene and dimethylamine hydrochloride are stirred and heated to 85-100°C, and formaldehyde aqueous solution is added dropwise. After the addition is completed, the mixture is reacted at reflux temperature. After the reaction is completed, the mixture is cooled to room temperature, and the pH value is adjusted to 9-10. The mixture is extracted with dichloromethane, the organic phase is collected, and the solvent is removed to obtain a crude product of intermediate 1.

Preferably, the mass ratio of 2,6-difluorotoluene, dimethylamine hydrochloric acid and formaldehyde is: (9.5-10.5): (6.0-7.0): (3.0-4.0), preferably 10:6.4:3.5.

Preferably, the temperature of the reflux reaction is 95-100° C., and the time of the reflux reaction is 4-6 h, preferably 5 h.

Preferably, the mass fraction of formaldehyde in the formaldehyde aqueous solution is 30% to 40%, preferably 35%.

In one or more embodiments, the alkyl halide includes alkyl chloride, alkyl bromide and alkyl iodide, preferably ethyl bromide and methyl iodide.

In one or more embodiments, the sulfate ester is preferably dimethyl sulfate and diethyl sulfate.

In one or more embodiments, the intermediate 1 reacts with an alkyl halide or a sulfate to obtain a quaternary ammonium salt intermediate 2, and the amine is directly removed under alkaline conditions without separation to obtain the target product 2,6-difluorostyrene. The specific method includes:

The intermediate 1 is dispersed in deionized water, and sodium hydroxide solution is added to the system under stirring at room temperature, followed by stirring at room temperature for 20 to 40 minutes. Under the condition of controlling the reaction temperature at 30 to 40°C, alkyl halide or sulfate is added dropwise, and the internal temperature is controlled not to be higher than 40°C during the addition process. After the addition is completed, the reaction is continued at 30 to 40°C for 2 to 4 hours. After the reaction is completed, the temperature is lowered to room temperature, extracted with dichloromethane, the organic phase is collected, and the solvent is removed to obtain a crude 2,6-difluorostyrene.

Preferably, the mass ratio of intermediate 1 to deionized water is 1:2.5-3.5.

Preferably, the molar ratio of intermediate 1 to alkyl halide or sulfate is 1:1 to 1.2.

Preferably, the mass ratio of intermediate 1 to sodium hydroxide is 10:4.9-5.0.

Preferably, the mass fraction of sodium hydroxide is 25% to 35%, preferably 30%.

The beneficial effects of the present invention are:

(1) The method for synthesizing 2,6-difluorostyrene provided by the present invention uses cheap and readily available 2,6-difluorotoluene as a starting material, firstly obtains a secondary amine through a Mannich reaction, then performs quaternization, and then deaminates under alkaline conditions to obtain 2,6-difluorostyrene.

(2) The method for synthesizing 2,6-difluorostyrene provided by the present invention has a high product yield of more than 90%, and a product purity of up to 98%, while also accelerating the reaction rate.

(3) The method for synthesizing 2,6-difluorostyrene provided by the present invention has cheap and easily available raw materials involved in the entire experimental process, fewer reaction steps, mild reaction conditions, and high product purity, which is suitable for industrial production.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

FIG1 is a hydrogen NMR spectrum of 2,6-difluorostyrene prepared in Example 2 of the present invention.

DETAILED DESCRIPTION

It should be noted that the following detailed descriptions are exemplary and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used in the present invention have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit exemplary embodiments according to the present invention. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprising" and/or "including" are used in this specification, it indicates the presence of features, steps, operations, devices, components and/or combinations thereof.

In order to enable those skilled in the art to more clearly understand the technical solution of the present application, the technical solution of the present application will be described in detail below in conjunction with specific embodiments.

The synthetic route involved in the present invention is:

Example 1

Synthesis of intermediate 1:

Add 10kg of 2,6-difluorotoluene and 6.4kg of dimethylamine hydrochloride to a 100L reactor, stir and heat to 90°C; add 10kg of 35% formaldehyde aqueous solution, and the addition is completed in about 30 minutes. Heat to reflux temperature (95-100°C), reflux reaction for 5 hours, after the reaction is completed, cool to room temperature, add 20% sodium hydroxide solution to adjust the pH value to 10, then add dichloromethane to extract, collect the organic phase, concentrate, and obtain the crude product. The crude product is distilled to obtain 12.3kg of pure product, with a purity of 97% and a yield of 84%.

Example 2

Synthesis of 2,6-difluorostyrene:

Add 30 kg of water and 10 kg of intermediate II into a 100 L reactor, add 16.5 kg of 30% sodium hydroxide solution to the system under stirring at room temperature, and stir at room temperature for 30 min after the addition;

Control the internal temperature at about 35°C, add 6.5 kg of ethyl bromide dropwise, and add it in about 1 hour. During the addition, control the internal temperature not higher than 40°C. After the addition, continue to keep the reaction at 35-40°C for 3 hours;

The system was cooled to room temperature, dichloromethane was added and the extraction was completed, the organic phase was concentrated to obtain a crude product, and the crude product was distilled to obtain 6.1 kg of pure 2,6-difluorostyrene, with a purity of 98% and a yield of 81%. ¹ H NMR (CDCl ₃ -d ₆ ): δ＝5.55～5.59(d,1H),6.02～6.07(d,1H),6.69～6.73(m,1H),6.84～6.89(m,2H),7.10～7.17(,1H).

Example 3

Synthesis of 2,6-difluorostyrene:

Add 30 kg of water and 10 kg of intermediate II into a 100 L reactor, add 16.5 kg of 30% sodium hydroxide solution to the system under stirring at room temperature, and stir at room temperature for 30 min after the addition;

Control the internal temperature at about 35°C, add 7.5 kg of dimethyl sulfate dropwise, and add it in about 1 hour. Control the internal temperature not higher than 40°C during the addition process. After the addition is completed, continue to keep the reaction at 35-40°C for 3 hours;

The system was cooled to room temperature, dichloromethane was added and the extraction was completed, the organic phase was concentrated to obtain a crude product, and the crude product was distilled to obtain 6.5 kg of pure 2,6-difluorostyrene, with a purity of 98% and a yield of 86%. ¹ H NMR (CDCl ₃ -d ₆ ): δ＝5.55～5.59(d,1H),6.02～6.07(d,1H),6.69～6.73(m,1H),6.84～6.89(m,2H),7.10～7.17(,1H).

Example 4

Synthesis of 2,6-difluorostyrene:

Add 30 kg of water and 10 kg of intermediate II into a 100 L reactor, add 16.5 kg of 30% sodium hydroxide solution to the system under stirring at room temperature, and stir at room temperature for 30 min after the addition;

Control the internal temperature at about 35°C, add 9.16 kg of diethyl sulfate dropwise, and add it in about 1 hour. Control the internal temperature not higher than 40°C during the addition process. After the addition is completed, continue to keep the reaction at 35-40°C for 3 hours;

The system was cooled to room temperature, dichloromethane was added and the extraction was completed, the organic phase was concentrated to obtain a crude product, and the crude product was distilled to obtain 6.5 kg of pure 2,6-difluorostyrene, with a purity of 98% and a yield of 86%. ¹ H NMR (CDCl ₃ -d ₆ ): δ＝5.55～5.59(d,1H),6.02～6.07(d,1H),6.69～6.73(m,1H),6.84～6.89(m,2H),7.10～7.17(,1H).

Example 5

Synthesis of 2,6-difluorostyrene:

Add 30 kg of water and 10 kg of intermediate II into a 100 L reactor, add 16.5 kg of 30% sodium hydroxide solution to the system under stirring at room temperature, and stir at room temperature for 30 min after the addition;

Control the internal temperature at about 30°C, add 8.5 kg of iodomethane dropwise, and add it in about 1 hour. During the addition process, control the internal temperature not higher than 40°C. After the addition is completed, continue to keep the reaction at 30-40°C for 3 hours;

The system was cooled to room temperature, dichloromethane was added and the extraction was completed, the organic phase was concentrated to obtain a crude product, and the crude product was distilled to obtain 6.9 kg of pure 2,6-difluorostyrene, with a purity of 98% and a yield of 91%. ¹ H NMR (CDCl ₃ -d ₆ ): δ＝5.55～5.59(d,1H),6.02～6.07(d,1H),6.69～6.73(m,1H),6.84～6.89(m,2H),7.10～7.17(,1H).

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims (10)

1. A method for synthesizing 2,6-difluorostyrene, comprising: Using 2,6-difluorotoluene as a raw material, the intermediate 1 is obtained by the Mannich reaction under the conditions of formaldehyde and dimethylamine hydrochloride, and then reacted with an alkyl halide or a sulfate to obtain a quaternary ammonium salt intermediate 2, and the amine is directly removed under alkaline conditions without separation to obtain the target product 2,6-difluorostyrene; The synthetic route is: 2. The synthesis method according to claim 1, characterized in that the specific method of using 2,6-difluorotoluene as a raw material and utilizing the Mannich reaction under the conditions of formaldehyde and dimethylamine hydrochloride to obtain the intermediate 1 comprises: 2,6-Difluorotoluene and dimethylamine hydrochloride are stirred and heated to 85-100°C, and formaldehyde aqueous solution is added dropwise. After the addition is completed, the mixture is reacted at reflux temperature. After the reaction is completed, the mixture is cooled to room temperature, and the pH value is adjusted to 9-10. The mixture is extracted with dichloromethane, the organic phase is collected, and the solvent is removed to obtain a crude product of intermediate 1. 3. The synthesis method according to claim 2, characterized in that the mass ratio of 2,6-difluorotoluene, dimethylamine hydrochloric acid and formaldehyde is: (9.5-10.5): (6.0-7.0): (3.0-4.0), preferably 10:6.4:3.5. 4. The synthesis method according to claim 2, characterized in that the temperature of the reflux reaction is 95-100°C, and the time of the reflux reaction is 4-6 hours, preferably 5 hours. 5. The synthesis method according to claim 2, characterized in that the mass fraction of formaldehyde in the formaldehyde aqueous solution is 30% to 40%, preferably 35%. 6. The synthesis method according to claim 1, characterized in that the alkyl halide comprises alkyl chloride, alkyl bromide and alkyl iodide, preferably ethyl bromide and methyl iodide. 7. The synthetic method as claimed in claim 1, characterized in that the sulfate is preferably dimethyl sulfate and diethyl sulfate. 8. The synthesis method according to claim 1, characterized in that the intermediate 1 reacts with an alkyl halide or a sulfate to obtain a quaternary ammonium salt intermediate 2, and the amine is directly removed under alkaline conditions without separation to obtain the target product 2,6-difluorostyrene. The specific method includes: The intermediate 1 is dispersed in deionized water, and sodium hydroxide solution is added to the system under stirring at room temperature, followed by stirring at room temperature for 20 to 40 minutes. Under the condition of controlling the reaction temperature at 30 to 40°C, alkyl halide or sulfate is added dropwise, and the internal temperature is controlled not to be higher than 40°C during the addition process. After the addition is completed, the reaction is continued at 30 to 40°C for 2 to 4 hours. After the reaction is completed, the temperature is lowered to room temperature, extracted with dichloromethane, the organic phase is collected, and the solvent is removed to obtain a crude 2,6-difluorostyrene. 9. The synthesis method according to claim 8, characterized in that the mass ratio of intermediate 1 to deionized water is 1:2.5-3.5; Or, the molar ratio of intermediate 1 to alkyl halide or sulfate is 1:1 to 1.2. 10. The synthesis method according to claim 8, characterized in that the mass ratio of intermediate 1 to sodium hydroxide is 10:4.9-5.0; Alternatively, the mass fraction of sodium hydroxide is 25% to 35%, preferably 30%.