CN112851539B - Preparation method of 2, 6-difluorobenzamide - Google Patents
Preparation method of 2, 6-difluorobenzamide Download PDFInfo
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- CN112851539B CN112851539B CN202110042184.8A CN202110042184A CN112851539B CN 112851539 B CN112851539 B CN 112851539B CN 202110042184 A CN202110042184 A CN 202110042184A CN 112851539 B CN112851539 B CN 112851539B
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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- C01B7/00—Halogens; Halogen acids
- C01B7/01—Chlorine; Hydrogen chloride
- C01B7/07—Purification ; Separation
- C01B7/0706—Purification ; Separation of hydrogen chloride
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- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B7/00—Halogens; Halogen acids
- C01B7/19—Fluorine; Hydrogen fluoride
- C01B7/191—Hydrogen fluoride
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups
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Abstract
The invention provides a preparation method of 2, 6-difluorobenzamide, which takes hydrogen fluoride as a reaction raw material, improves the atom utilization rate of the reaction, can produce acid by-product, effectively reduces the production cost of the product, and improves the market competitiveness of the product; and the whole process does not generate mixed waste salt, and the process flow is simpler.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of 2, 6-difluorobenzamide.
Background
Benzoyl urea pesticide belongs to chitin synthesis inhibitor, and aims to kill insects by inhibiting the biosynthesis of chitin in insect bodies to thin insect epidermis and lose shielding effect. The pesticide has the characteristics of high insecticidal activity, wide insecticidal varieties, capability of decomposing pesticide residues by microorganisms, strong selectivity, difficulty in generating drug resistance, safety to people and livestock and the like, is a novel fluorine-containing pesticide variety which is environment-friendly, and opens up a new way for chemical pest control. In recent years, benzoyl urea insecticides have been developed rapidly due to their unique insecticidal mechanism and excellent properties, and there have been developed agricultural chemicals such as diflubenzuron, hexaflumuron, teflubenzuron, flufenoxuron, chlorbenzuron, fluazuron, and the like.
2, 6-difluorobenzamide is used as a key intermediate for synthesizing benzoyl urea chemical pesticides, and has great demand on markets at home and abroad. The synthesis of the 2, 6-difluorobenzamide mainly takes 2, 6-dichlorobenzonitrile as a raw material and is prepared by fluorination and hydrolysis.
The methods for synthesizing 2, 6-difluorobenzonitrile (DFBN for short) reported at home and abroad at present mainly comprise the following methods: the method comprises the steps of taking 2, 6-dichlorobenzonitrile as a raw material, taking alkali metal fluoride as a fluorinating agent, and synthesizing DFBN at a high temperature; the 2,3, 6-trichlorobenzonitrile is used as a raw material, and the DFBN is synthesized through fluorination and hydrogenation reduction. The first method is the common method, but the method has the disadvantages of waste salt generation, poor treatment and complex operation process.
DE3322936 uses DCBN and potassium fluoride as raw materials, and reacts at 350 ℃ for 3 hours in nitrogen atmosphere, the pressure is kept at 1.43MPa, the yield is 83%, and the content is 99%. The method is simple to operate, but has high reaction temperature and complicated reaction equipment, and is not suitable for industrial use.
CN104788341A takes DCBN and potassium fluoride as raw materials, sulfolane as a solvent, N-alkyl pyridine quaternary ammonium salt and the like as catalysts, and reacts for 15 to 20 hours at a temperature of between 150 and 250 ℃, and the yield is 98 percent. However, the catalyst used in the method is difficult to obtain, and mixed waste salts (potassium fluoride and potassium chloride) generated after the reaction need to be treated.
CN1218935C uses DFBN as raw material, sodium hydroxide, sodium carbonate solid or 1. The method has the disadvantages of complicated operation due to the solid catalyst.
Therefore, it is urgently needed to provide a preparation method of 2, 6-difluorobenzamide, which has the advantages of convenient operation, high atom utilization rate and recyclable by-products.
Disclosure of Invention
In order to solve the technical problems, the invention provides a preparation method of 2, 6-difluorobenzamide, which takes hydrogen fluoride as a reaction raw material, does not generate waste salt, simplifies the production steps, can recycle the hydrogen fluoride which is a tail gas of the reaction as a byproduct, has high atom utilization rate, realizes resource utilization, has high reaction efficiency and low cost, and improves the market competitiveness of the 2, 6-difluorobenzamide.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a preparation method of 2, 6-difluorobenzamide, which comprises the following steps:
(1) Reacting 2, 6-dichlorobenzonitrile with hydrogen fluoride in an organic solvent to obtain 2, 6-difluorobenzonitrile;
(2) And hydrolyzing the 2, 6-difluorobenzonitrile to obtain the 2, 6-difluorobenzamide.
The preparation method of the 2, 6-difluorobenzamide provided by the invention uses the hydrogen fluoride as a raw material to replace the original metal fluoride fluorinating reagent, does not generate mixed waste salt in the reaction, can recycle the hydrogen fluoride in the tail gas as a byproduct acid, improves the atom utilization rate, and has simple process and convenient operation.
Preferably, the organic solvent in step (1) comprises any one of N-methylpyrrolidone, N-N dimethylformamide, N-N dimethylacetamide or sulfolane or a combination of at least two thereof, wherein typical non-limiting combinations are a combination of N-methylpyrrolidone and N-N dimethylformamide, a combination of N-methylpyrrolidone and N-N dimethylacetamide, a combination of N-N dimethylformamide and N-N dimethylacetamide, and a combination of N-N dimethylacetamide and sulfolane.
Preferably, the reaction temperature is 150 to 250 ℃, for example, can be 150 ℃, 162 ℃, 173 ℃, 184 ℃, 195 ℃, 206 ℃, 217 ℃, 228 ℃, 239 ℃ or 250 ℃, but not limited to the cited values, in the range of other not listed values are equally applicable, preferably 170 to 220 ℃.
Preferably, the reaction time is 4 to 12 hours, for example, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, etc., but not limited to the recited values, and other values not recited in the range are also applicable.
Preferably, the molar ratio of the hydrogen fluoride to 2, 6-dichlorobenzonitrile is from 2.0 to 4.0, and may be, for example, 2.0, 2.1, 2.2, 2.3, 2.5, 2.8, 3.0, 3.2, 3.5, 3.8, or 4.0, but is not limited to the values recited, and other values not recited in this range are also applicable, preferably from 2.5 to 3.0.
The invention preferably selects the molar ratio of the hydrogen fluoride to the 2, 6-dichlorobenzonitrile to be 2.5-3.0, and is more favorable for improving the yield and the purity of the 2, 6-difluorobenzonitrile.
Preferably, step (1) comprises: mixing 2, 6-dichlorobenzonitrile with an organic solvent, heating to the reaction temperature, preserving the temperature, dropwise adding a hydrogen fluoride liquid, and continuously preserving the temperature after dropwise adding.
The hydrogen fluoride is difficult to store and the gas phase reaction utilization rate is relatively low during reaction, so that the 2, 6-difluorobenzonitrile is prepared by generally adopting solid fluorinating reagents such as potassium fluoride and the like, but the invention adopts a mode of slowly dripping the liquid phase, thereby not only overcoming the problem that the hydrogen fluoride phase is difficult to store, but also being more beneficial to controlling the reaction rate and inhibiting the generation of side reaction by slowly dripping the hydrogen fluoride in the form of the liquid phase, obviously improving the yield of the 2, 6-difluorobenzonitrile, and effectively avoiding the problems of long reaction time and separation treatment of mixed salts after the reaction caused by adopting the metal fluoride as the fluorinating agent.
The duration of the dropwise addition is preferably from 3 to 8h, and may be, for example, 3h, 3.6h, 4.2h, 4.7h, 5.3h, 5.8h, 6.4h, 6.9h, 7.5h or 8h, without being limited to the values listed, and other values not listed in this range are likewise suitable.
Preferably, the duration of the continuous incubation is 1 to 4 hours, for example, 1 hour, 1.4 hours, 1.7 hours, 2 hours, 2.4 hours, 2.7 hours, 3 hours, 3.4 hours, 3.7 hours or 4 hours, etc., but not limited to the recited values, and other values not recited in the range are also applicable.
Preferably, the temperature of the hydrogen fluoride liquid is 2 to 10 ℃, for example, 2 ℃,3 ℃,4 ℃,5 ℃,6 ℃, 7 ℃, 8 ℃,9 ℃ or 10 ℃ and the like, but is not limited to the recited values, and other values not recited in the range are also applicable.
The hydrogen fluoride is stored in an environment of 2-10 ℃ in a liquid phase form, so that the aims of controlling relatively low temperature and preventing vaporization are fulfilled.
Preferably, after the reaction in step (1), a fraction of 2, 6-difluorobenzonitrile is collected under negative pressure.
Preferably, the negative pressure is 0.5 to 1.5kPa, for example, 0.5kPa, 0.6kPa, 0.8kPa, 0.9kPa, 1.0kPa, 1.1kPa, 1.2kPa, 1.5kPa, or the like, but is not limited to the values listed, and other values not listed in the range are also applicable.
Preferably, the fraction at 70 to 90 ℃ is collected, and may be, for example, 70 ℃, 72 ℃, 75 ℃, 78 ℃, 80 ℃, 82 ℃, 85 ℃, 88 ℃ or 90 ℃, etc., but is not limited to the recited values, and other values not recited in the range are also applicable.
Preferably, the undistilled product is recycled to the reaction of the next batch of step (1) for reuse.
Because the solution is mainly an organic solvent and does not contain solid salt to be separated, the solution can be directly recycled to the reaction of the next batch of step (1) for reuse.
Preferably, the off-gas of the reaction in step (1) is cooled to capture hydrogen fluoride.
The tail gas contains hydrogen fluoride and hydrogen chloride, and the hydrogen fluoride is easier to condense, so that the hydrogen fluoride and the hydrogen chloride are directly separated in a cooling mode, the hydrogen fluoride can be recycled to the next batch, and the hydrogen chloride can be used as a secondary acid, so that the utilization rate of resources is improved.
Preferably, the captured hydrogen fluoride is recycled to the reaction of step (1).
Preferably, the gas that is not condensed in the cooling is absorbed in the liquid phase to obtain a by-product.
Preferably, the liquid phase comprises water.
Preferably, the by-product comprises an acid.
Preferably, the acid is hydrochloric acid.
Preferably, the hydrolysis in the step (2) comprises a hydrolysis reaction of 2, 6-difluorobenzonitrile and hydrogen peroxide under the catalysis of an alkali source to prepare a reaction product containing 2, 6-difluorobenzamide.
Preferably, the alkali source is a solution containing sodium hydroxide.
The invention preferably adopts the solution containing sodium hydroxide as the catalyst, and compared with a solid phase catalyst, the reaction is more uniform and reliable.
Preferably, the sodium hydroxide-containing solution has a concentration of 10 to 30 wt.%, and can be, for example, 10 wt.%, 13 wt.%, 15 wt.%, 17 wt.%, 19 wt.%, 22 wt.%, 24 wt.%, 26 wt.%, 28 wt.%, or 30 wt.%, and the like, without limitation to the recited values, and other values not recited within this range are equally applicable.
Preferably, the molar ratio of the base in the source of alkalinity to 2, 6-difluorobenzonitrile is from 0.3 to 4, and may be, for example, 0.3, 0.8, 1.2, 1.6, 2, 2.4, 2.8, 3.2, 3.6 or 4, and the like, but is not limited to the recited values, and other values not recited in this range are equally applicable, preferably from 0.6 to 2.0.
The invention preferably controls the mol ratio of the alkali in the alkali source to the 2, 6-difluorobenzonitrile to be 0.6-2.0, and is more favorable for improving the yield and the purity of the product.
The molar ratio of the hydrogen peroxide to the 2, 6-difluorobenzonitrile is preferably 1 to 5, and may be, for example, 1, 1.5, 2.0, 2.4, 2.8, 3.0, 3.3, 3.7, 4.0, 4.2, 4.6, or 5, but is not limited to the values recited, and other values not recited in this range are also applicable, preferably 2 to 4.
The invention preferably controls the molar ratio of the hydrogen peroxide to the 2, 6-difluorobenzonitrile to be 2-4, and is more favorable for improving the yield and the purity of the product.
Preferably, the concentration of the hydrogen peroxide is 20 to 35wt%, and may be, for example, 20wt%, 22wt%, 24wt%, 25wt%, 27wt%, 29wt%, 30wt%, 32wt%, 34wt%, 35wt%, or the like, but is not limited to the recited values, and other values not recited in the range are also applicable.
The temperature of the hydrolysis reaction is preferably 30 to 60 ℃ and may be, for example, 30 ℃, 34 ℃, 35 ℃, 37 ℃,40 ℃, 44 ℃, 45 ℃, 47 ℃, 50 ℃, 54 ℃, 55 ℃, 57 ℃ or 60 ℃ or the like, but is not limited to the recited values, and other values not recited in the range are also applicable, preferably 45 to 55 ℃. The hydrolysis temperature is controlled to be 45-55 ℃, and the hydrolysis effect can be further improved.
Preferably, the hydrolysis reaction time is 2 to 10 hours, for example, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, etc., but not limited to the recited values, and other values not recited within this range are also applicable.
Preferably, step (2) comprises: mixing an alkali source and 2, 6-difluorobenzonitrile, heating to the temperature of hydrolysis reaction, preserving heat, dropwise adding hydrogen peroxide, and continuously preserving heat after dropwise adding is finished to prepare a reaction product containing 2, 6-difluorobenzamide.
The duration of the dropwise addition is preferably from 1 to 6h, and may be, for example, 1h, 1.6h, 2.2h, 2.7h, 3.3h, 3.8h, 4.4h, 4.9h, 5.5h or 6h, without being limited to the values listed, and other values not listed in this range are likewise suitable.
Preferably, the duration of the continuous incubation is 1 to 4 hours, for example, 1 hour, 1.4 hours, 1.7 hours, 2 hours, 2.4 hours, 2.7 hours, 3 hours, 3.4 hours, 3.7 hours or 4 hours, etc., but not limited to the recited values, and other values not recited in the range are also applicable.
Preferably, the reaction product in the step (2) is sequentially subjected to temperature reduction, pH adjustment and solid-liquid separation to obtain the 2, 6-difluorobenzamide.
Preferably, the temperature is reduced to 20 to 30 ℃, for example, 20 ℃, 22 ℃, 23 ℃, 24 ℃, 25 ℃, 26 ℃, 27 ℃, 28 ℃, 29 ℃ or 30 ℃, but not limited to the recited values, and other values not recited in the range are also applicable.
Preferably, the pH adjustment comprises: adding acid, keeping the temperature and stirring to adjust the pH value.
Preferably, the acid comprises hydrochloric acid.
Preferably, the hydrochloric acid has a concentration of 7 to 15wt%, and may be, for example, 7wt%, 8wt%, 9wt%, 10wt%, 11wt%, 12wt%, 13wt%, 14wt%, 15wt%, or 15wt%, etc., but is not limited to the recited values, and other values not recited in this range are also applicable.
Preferably, the stirring time at the temperature is 1 to 2 hours, for example, 1 hour, 1.2 hours, 1.3 hours, 1.4 hours, 1.5 hours, 1.6 hours, 1.7 hours, 1.8 hours, 1.9 hours or 2 hours, etc., but not limited to the recited values, and other values not recited in the range are also applicable.
Preferably, the pH is adjusted to a pH of 6.0 to 8.0, for example, 6.0, 6.1, 6.2, 6.4, 6.5, 6.7, 7.0, 7.2, 7.4, 7.5, 7.7 or 8.0, etc., but not limited to the values recited, and other values not recited within this range are equally applicable, preferably 6.8 to 7.2.
The reaction product is wastewater containing sodium chloride, and the adjustment to the neutral range is beneficial to the later-stage wastewater treatment, so that the wastewater is prevented from being acidic to corrode equipment materials, and the recovered sodium chloride is prevented from containing sodium hydroxide impurities.
Preferably, the solid-liquid separation comprises temperature reduction and suction filtration.
Preferably, after the solid-liquid separation, washing and drying are also included.
As a preferred technical scheme of the invention, the preparation method comprises the following steps:
(1) Mixing 2, 6-dichlorobenzonitrile and an organic solvent, heating to 150-250 ℃, storing hydrogen fluoride to an environment of 2-10 ℃, slowly preserving heat for 3-8 h, dropwise adding a hydrogen fluoride liquid, keeping the molar ratio of the hydrogen fluoride to the 2, 6-dichlorobenzonitrile at 2.0-4.0, and continuously preserving heat for 1-4 h after dropwise adding is finished, and reacting; in the reaction process, cooling the tail gas of the reaction, capturing hydrogen fluoride, mechanically applying the captured hydrogen fluoride to the reaction in the step (1), and absorbing uncondensed gas in the cooling process by water to obtain a secondary acid;
after the reaction is finished, collecting the fraction of 2, 6-difluorobenzonitrile at 70-90 ℃ under the negative pressure condition of 0.5-1.5 kPa;
(2) Mixing 10-30 wt% of solution containing sodium hydroxide and 2, 6-difluorobenzonitrile, heating to 30-60 ℃, keeping the temperature, dropwise adding 20-35 wt% of hydrogen peroxide for 1-6 h, keeping the molar ratio of the hydrogen peroxide to the 2, 6-difluorobenzonitrile to 1-5, continuously keeping the temperature for 1-4 h after dropwise adding, preparing a reaction product containing the 2, 6-difluorobenzamide, cooling the reaction product to 20-30 ℃, adding 7-15 wt% of hydrochloric acid, keeping the temperature, stirring for 1-2 h, adjusting the pH value to 6.8-7.2, and sequentially carrying out solid-liquid separation, washing and drying to obtain the 2, 6-difluorobenzamide.
The washing method of the present invention is not limited, and any method and washing solution that can be used for washing, which are well known to those skilled in the art, may be used, for example, immersion, rinsing, etc., and the washing solution may be a solution such as water, etc., and is not particularly limited.
The drying method of the present invention is not particularly limited, and any method for drying known to those skilled in the art may be used, for example, vacuum drying, air-blast drying, normal pressure and normal pressure or freeze drying, and the drying temperature may be adjusted according to the actual process conditions, for example, 50 ℃, 60 ℃, 70 ℃, 80 ℃ or 100 ℃ may be used.
Compared with the prior art, the invention has at least the following beneficial effects:
(1) The preparation method of the 2, 6-difluorobenzamide provided by the invention does not generate mixed waste salt, and the production flow is simpler;
(2) The hydrogen chloride in the tail gas generated by the reaction of the preparation method of the 2, 6-difluorobenzamide provided by the invention can be recycled as a by-product acid, the atom utilization rate is high, and the resource utilization is realized;
(3) The preparation method of the 2, 6-difluorobenzamide provided by the invention has high reaction efficiency, wherein the purity of the 2, 6-difluorobenzonitrile is more than or equal to 95wt%, the yield is more than or equal to 75wt%, the purity of the 2, 6-difluorobenzonitrile is more than or equal to 99wt% under the better condition, the yield is more than or equal to 88wt%, the cost is low, and the market competitiveness of the 2, 6-difluorobenzamide is improved.
Detailed Description
For the purpose of facilitating an understanding of the present invention, the present invention will now be described by way of examples. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitation of the present invention.
1. Examples of the embodiments
Example 1
This example provides a method for preparing 2, 6-difluorobenzamide, comprising the steps of:
(1) Firstly, cooling a polytetrafluoroethylene storage tank to 10 ℃, slowly introducing hydrogen fluoride gas into the polytetrafluoroethylene storage tank with heat insulation through the steel tank to liquefy the hydrogen fluoride, and measuring the weight of the hydrogen fluoride; quantitatively transferring to a polytetrafluoroethylene dropping funnel with heat preservation, and preserving heat at 10 ℃ for later use;
adding 50g (0.288 mol) of 99% 2, 6-dichlorobenzonitrile and 147g of sulfolane into a fluorination reaction kettle, heating to 220 ℃, slowly dropwise adding 16.12g (0.806 mol) of hydrogen fluoride liquid weighed by heat preservation in advance while stirring, wherein the dropwise adding time is 5 hours, and after the dropwise adding is finished, preserving the heat for 2 hours to carry out reaction;
in the reaction process, introducing the tail gas of the reaction into a polytetrafluoroethylene flask which can resist the corrosion of hydrogen fluoride liquid, placing the flask in a cooling device, and mechanically applying the trapped hydrogen fluoride to the reaction in the next batch of step (1); the uncooled hydrogen chloride gas is absorbed and enriched by secondary water and is converted into a secondary acid;
after the reaction is finished, carrying out negative pressure of 1.0kPa by using a vacuum oil pump, collecting the fraction of 2, 6-difluorobenzonitrile within the range of 75-85 ℃, and mechanically applying the residual solvent in the kettle and the unreacted raw materials to the reaction of the next batch of step (1);
(2) Adding 30g (0.214 mol) of 2, 6-difluorobenzonitrile obtained in the step (1) and 25.62g (0.128 mol) of 20% sodium hydroxide solution into a four-neck flask with a stirring function, a thermometer and a reflux condenser, heating to 50 ℃, dropwise adding 72.61g (0.641 mol) of 30wt% hydrogen peroxide under the stirring function, dropwise adding for 3h, and preserving heat for 2h to perform hydrolysis reaction;
after the reaction is finished, the temperature is reduced to 25 ℃,10wt% hydrochloric acid is added to adjust the pH value to be neutral (about 7.0), the mixture is stirred for 1.5h under the condition of heat preservation, the temperature is reduced, the filtration is carried out, water is added to wash a filter cake, and the filter cake is dried to obtain a 2, 6-difluorobenzamide solid product.
Examples 2 to 10
The reaction temperature and the molar ratio of hydrogen fluoride to 2, 6-dichlorobenzonitrile in step (1) were changed, and the rest of the experimental conditions were the same as in example 1, and the specific conditions and the product yield and purity of 2, 6-difluorobenzonitrile were as shown in Table 1.
TABLE 1
Examples 11 to 13
The reaction solvent and the reaction temperature in the step (1) were changed while keeping the same molar ratio and the rest the same as in example 1, and the specific conditions and the product yield and purity of 2, 6-difluorobenzonitrile were as shown in Table 2.
TABLE 2
Examples 14 to 20
The molar ratio of 2, 6-difluorobenzonitrile to sodium hydroxide and hydrogen peroxide in step (2) was changed, and the rest of the experimental conditions were the same as in example 1, and the specific conditions and the product yield and purity of 2, 6-difluorobenzamide are shown in table 3.
TABLE 3
Examples 21 to 23
The hydrolysis temperature in the step (2) was changed, and the remaining reaction conditions were the same as in example 1, and the specific conditions and the product yield and purity of 2, 6-difluorobenzamide were as shown in Table 4.
TABLE 4
Example 24
This example provides a method for preparing 2, 6-difluorobenzamide, comprising the steps of:
(1) Firstly, cooling a polytetrafluoroethylene storage tank to 3 ℃, slowly introducing hydrogen fluoride gas into the polytetrafluoroethylene storage tank with heat insulation through a steel cylinder to liquefy the hydrogen fluoride, and measuring the weight of the hydrogen fluoride; quantitatively transferring the mixture into a polytetrafluoroethylene dropping funnel with heat insulation, and insulating the mixture at 3 ℃ for later use;
adding 50g (0.288 mol) of 99% 2, 6-dichlorobenzonitrile and 147g of sulfolane into a fluorination reaction kettle, heating to 230 ℃, slowly dropwise adding 16.12g (0.806 mol) of hydrogen fluoride liquid weighed by heat preservation in advance while stirring, wherein the dropwise adding time is 8h, and after the dropwise adding is finished, preserving the heat for 4h to carry out reaction;
in the reaction process, introducing the tail gas of the reaction into a polytetrafluoroethylene flask which can resist the corrosion of hydrogen fluoride liquid, placing the flask in a cooling device, and mechanically applying the trapped hydrogen fluoride to the reaction in the next batch of step (1); the uncooled hydrogen chloride gas is absorbed and enriched by secondary water and is converted into a by-product acid;
after the reaction is finished, carrying out negative pressure to 1.5kPa by using a vacuum oil pump, collecting the fraction of 2, 6-difluorobenzonitrile within the range of 80-90 ℃, and mechanically applying the residual solvent and the unreacted raw materials in the kettle to the reaction of the next batch of step (1);
(2) Adding 2, 6-difluorobenzonitrile 30g and 3062 g of sodium hydroxide solution with weight percent in the step (1) into a four-neck flask with a stirring thermometer and a reflux condenser, heating to 60 ℃, dropwise adding 72.61g of 35% hydrogen peroxide under the stirring action, dropwise adding for 1h, and preserving heat for 4h to perform hydrolysis reaction;
after the reaction is finished, the temperature is reduced to 20 ℃, 15wt% hydrochloric acid is added to adjust the pH value to be neutral (about 6.8), the temperature is kept and the stirring is carried out for 2 hours, the temperature is reduced, the filtration is carried out, water is added to wash a filter cake, and the 2, 6-difluorobenzamide solid product is obtained after the drying.
Example 25
This example provides a method for preparing 2, 6-difluorobenzamide, comprising the steps of:
(1) Firstly, cooling a polytetrafluoroethylene storage tank to 5 ℃, introducing hydrogen fluoride gas into the polytetrafluoroethylene storage tank with heat insulation through the steel tank to liquefy the hydrogen fluoride, and measuring the weight of the hydrogen fluoride; quantitatively transferring to a polytetrafluoroethylene dropping funnel with heat preservation, and preserving heat at 5 ℃ for later use;
adding 50g (0.288 mol) of 99% 2, 6-dichlorobenzonitrile and 147g of sulfolane into a fluorination reaction kettle, heating to 220 ℃, slowly dropwise adding 16.12g (0.806 mol) of hydrogen fluoride liquid weighed by heat preservation in advance while stirring, wherein the dropwise adding time is 3 hours, and after the dropwise adding, preserving the heat for 4 hours to carry out reaction;
in the reaction process, introducing the tail gas of the reaction into a polytetrafluoroethylene flask which can resist the corrosion of hydrogen fluoride liquid, placing the flask in a cooling device, and mechanically applying the trapped hydrogen fluoride to the reaction in the next batch of step (1); the uncooled hydrogen chloride gas is absorbed and enriched by secondary water and is converted into a by-product acid;
after the reaction is finished, carrying out negative pressure of 0.5kPa by using a vacuum oil pump, collecting the fraction of 2, 6-difluorobenzonitrile at the temperature of between 70 and 80 ℃, and mechanically applying the residual solvent and the unreacted raw materials in the kettle to the reaction of the next step (1);
(2) Adding 30g of 2, 6-difluorobenzonitrile and 25.62g of 10wt% sodium hydroxide solution obtained in the step (1) into a four-neck flask with a stirring thermometer and a reflux condenser, heating to 30 ℃, dropwise adding 72.61g of 20wt% hydrogen peroxide under the stirring action, dropwise adding for 6 hours, and preserving heat for 1 hour to perform hydrolysis reaction;
after the reaction is finished, the temperature is reduced to 25 ℃, 7wt% hydrochloric acid is added to adjust the pH value to be neutral (about 7.3), the temperature is kept and the stirring is carried out for 1h, the temperature is reduced and the filtration is carried out, water is added to wash a filter cake, and the 2, 6-difluorobenzamide solid product is obtained after drying.
The product yields and purities of 2, 6-difluorobenzonitrile and 2, 6-difluorobenzamide in example 1 and examples 24 to 25 are shown in Table 5.
TABLE 5
Example 26
This example provides a process for preparing 2, 6-difluorobenzamide, which is the same as in example 1 except that hydrogen fluoride gas is slowly introduced in step (1).
Compared with the method of directly introducing the hydrogen fluoride gas into the reactor in example 26, the method of liquefying the hydrogen fluoride in example 1 and then slowly adding the hydrogen fluoride dropwise in example 1 has the advantages that the liquefied hydrogen fluoride in example 1 can be fully contacted and reacted with the organic solvent and the 2, 6-dichlorobenzonitrile, the reaction yield and the effect are better, and the continuous introduction of the gas phase promotes the discharge of the introduced hydrogen fluoride gas in example 26, so that the consumption of the hydrogen fluoride is increased. The amount of hydrogen fluoride used was 46.08g (2.304 mol) in terms of 50g (0.288 mol) of 2, 6-dichlorobenzonitrile charged, and the utilization rate of hydrogen fluoride was reduced from 71.4wt% in example 1 to 25wt% in example 26 in terms of the amount of hydrogen fluoride charged, thereby showing that the present invention improves the utilization rate of hydrogen fluoride by adding it in the form of liquid-phase hydrogen fluoride.
2. Comparative example
Comparative example 1
This comparative example provides a production method of 2, 6-difluorobenzamide, which is the same as in example 1 except that hydrogen fluoride in step (1) is replaced with a potassium fluoride solid, and specifically, which comprises the steps of:
(1) Adding 50g (0.288 mol) of 99wt% 2, 6-dichlorobenzonitrile, 46.36g of 99wt% potassium fluoride and 147g of sulfolane into a reaction kettle, heating to 220 ℃, and keeping the temperature for reaction for 7 hours;
after the reaction is finished, filtering the reaction materials, washing a filter cake by 14.7g of sulfolane, combining washing liquid and reaction liquid, carrying out negative pressure of 0.3kPa by using a vacuum oil pump, collecting 34.7g of 2, 6-difluorobenzonitrile with the content of 98 percent and the yield of 85.1 percent within the range of 70-80 ℃, and mechanically applying the residual solvent and the unreacted raw materials after simple distillation to the reaction of the next step (1);
(2) Adding 30.4g of 2, 6-difluorobenzonitrile obtained in the step (1) and 25.62g (0.128 mol) of 20% sodium hydroxide solution into a four-neck flask with a stirring thermometer and a reflux condenser, heating to 50 ℃, dropwise adding 72.61g (0.641 mol) of 30wt% hydrogen peroxide under the stirring action, dropwise adding for 3h, and preserving heat for 2h to perform hydrolysis reaction;
after the reaction is finished, the temperature is reduced to 25 ℃,10wt% hydrochloric acid is added to adjust the pH value to be neutral (about 7.0), the temperature is kept and the stirring is carried out for 1.5h, the temperature is reduced and the filtration is carried out, water is added to wash a filter cake, and the 2, 6-difluorobenzamide solid 30.9g, the content is 99wt% and the yield is 91.1wt% is obtained after the drying.
Comparing example 1 with example 1, it can be seen that, in comparative example 1, potassium fluoride solid reagent is used as reactant, and after the reaction, filtration is needed to collect 2, 6-difluorobenzonitrile, so that not only is mixed waste salt generated and the subsequent treatment is difficult, but also the content and yield of 2, 6-difluorobenzamide in the product of example 1 are higher than those in comparative example 1.
The purity of the product is tested by a gas chromatography normalization analysis method.
The following points can be seen from tables 1 to 5:
(1) It can be seen from the comprehensive examples 1 to 26 that the preparation method of 2, 6-difluorobenzamide provided by the invention improves the atom utilization rate of the reaction by using hydrogen fluoride as a reaction raw material, can produce acid by-product, effectively reduces the production cost of the product, and improves the market competitiveness of the product; wherein the purity of the 2, 6-difluorobenzonitrile is more than or equal to 95wt%, the yield is more than or equal to 75wt%, and under the better condition, the purity of the 2, 6-difluorobenzonitrile is more than or equal to 99wt%, and the yield is more than or equal to 88wt%;
(2) It can be seen from the combination of example 1 and examples 21 to 23 that the hydrolysis temperature in example 1 was 50 ℃, the content of 2, 6-difluorobenzamide in the product of example 1 was 99.87wt% and the yield was 91.2wt% compared to the hydrolysis temperatures in examples 21 to 23 of 30 ℃,40 ℃ and 60 ℃, respectively, whereas the purity and yield of the products in examples 21 to 23 were inferior to those in example 1, thereby showing that the present invention significantly improves the purity and yield of the products by controlling the hydrolysis temperature within a specific range;
(3) It can be seen from the combination of example 1 and examples 18 to 20 that the molar ratios of the base to 2, 6-difluorobenzonitrile in example 1 and example 18 were 0.6 and 2.0, respectively, while the molar ratios in examples 19 to 20 were 0.3 and 4.0, respectively, the contents of 2, 6-difluorobenzamide in example 1 and example 18 were 99.87wt% and 98.63wt%, respectively, and the yields were 91.2wt% and 85.5wt%, respectively, while the contents of 2, 6-difluorobenzamide in examples 19 to 20 were 98.51wt% and 97.97wt%, respectively, and the yields were 85.1wt% and 83.2wt%, respectively, thereby showing that the present invention is capable of further improving the purity and the yield of the product by further controlling the molar ratio of the base to 2, 6-difluorobenzonitrile to be in the range of 0.6 to 2.0;
(4) From the results of examples 14 to 17, it can be seen that the molar ratios of hydrogen peroxide to 2, 6-difluorobenzonitrile in examples 14 to 15 are 4.0 and 2.0, respectively, and the contents of 2, 6-difluorobenzamide in examples 14 to 15 are 99.61wt% and 98.97wt%, respectively, and the yields are 89.3wt% and 85.4wt%, respectively, compared to the molar ratios of 1.0 and 5.0 in examples 16 to 17, while the contents of 2, 6-difluorobenzamide in examples 16 to 17 are 98.91wt% and 98.89wt%, respectively, and the yields are 82.1wt% and 85.1wt%, respectively, thereby showing that the present invention can improve the yield and purity of the product by further controlling the molar ratio of hydrogen peroxide to 2, 6-difluorobenzonitrile within the range of 2 to 4;
(5) It can be seen from the combination of examples 5 to 6 and examples 9 to 10 that the molar ratio of hydrogen fluoride to 2, 6-dichlorobenzonitrile in examples 5 to 6 was 2.5 and 3.0, respectively, and the content of 2, 6-difluorobenzonitrile in examples 5 to 6 was 98.4wt% and 98.7wt%, and the yield was 88.5wt% and 89.2wt%, respectively, compared to the molar ratio of 2.0 and 4.0 in examples 9 to 10, whereas the content of 2, 6-difluorobenzonitrile in examples 9 to 10 was 98.0wt% and 98.1wt%, and the yield was 87.7wt% and 88.2wt%, respectively, thereby showing that the present invention is able to more improve the yield and purity of 2, 6-difluorobenzonitrile as an intermediate product by further controlling the molar ratio of hydrogen fluoride to 2, 6-dichlorobenzonitrile to be in the range of 2.5 to 3.0;
(6) It can be seen from the combination of examples 3 to 4 and examples 7 to 8 that the reaction temperatures in examples 3 to 4 were 170 ℃ and 195 ℃, respectively, and the 2, 6-difluorobenzonitrile contents in examples 3 to 4 were 98.2wt% and 98.3wt%, respectively, and the yields were 88.5wt% and 88.9wt%, respectively, compared to the temperatures in examples 7 to 8 of 150 ℃ and 250 ℃, respectively, whereas the 2, 6-difluorobenzonitrile contents in examples 7 to 8 were 97.7wt% and 98.12wt%, respectively, and the yields were 86.9wt% and 87.9wt%, respectively, thereby showing that the present invention can better improve the yield and purity of the intermediate 2, 6-difluorobenzonitrile by controlling the reaction temperature of hydrogen fluoride with 2, 6-dichlorobenzonitrile within a specific range.
In conclusion, the preparation method of 2, 6-difluorobenzamide provided by the invention can improve the purity and yield of the intermediate product 2, 6-difluorobenzonitrile and the final product 2, 6-difluorobenzamide, wherein the purity of the 2, 6-difluorobenzonitrile is more than or equal to 95wt%, the yield is more than or equal to 75wt%, the purity of the 2, 6-difluorobenzonitrile is more than or equal to 99wt% under better conditions, the yield is more than or equal to 88wt%, no mixed waste salt is generated, and the process flow is simple.
The applicant states that the present invention is illustrated by the above examples to show the detailed process equipment and process flow of the present invention, but the present invention is not limited to the above detailed process equipment and process flow, i.e. it does not mean that the present invention must rely on the above detailed process equipment and process flow to be implemented. It should be understood by those skilled in the art that any modifications of the present invention, equivalent substitutions of the raw materials of the product of the present invention, and the addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (33)
1. A preparation method of 2, 6-difluorobenzamide is characterized by comprising the following steps:
(1) Mixing 2, 6-dichlorobenzonitrile and an organic solvent, heating to the reaction temperature, preserving the temperature, dropwise adding a hydrogen fluoride liquid, continuously preserving the temperature after dropwise adding, and reacting to obtain 2, 6-difluorobenzonitrile; the temperature of the hydrogen fluoride liquid is 2-10 ℃; the molar ratio of the hydrogen fluoride to the 2, 6-dichlorobenzonitrile is 2.0 to 4.0; the reaction time is 4-12 h; after the reaction, under the condition of negative pressure, collecting the fraction of the 2, 6-difluorobenzonitrile; the organic solvent comprises any one or the combination of at least two of N-N dimethylformamide, N-N dimethylacetamide or sulfolane;
(2) And hydrolyzing the 2, 6-difluorobenzonitrile to obtain the 2, 6-difluorobenzamide.
2. The method according to claim 1, wherein the temperature of the reaction in the step (1) is 150 to 250 ℃.
3. The method according to claim 1, wherein the temperature of the reaction in the step (1) is 170 to 220 ℃.
4. The process according to claim 1, wherein the molar ratio of hydrogen fluoride to 2, 6-dichlorobenzonitrile is from 2.5 to 3.0.
5. The production method according to claim 1, wherein the negative pressure in the step (1) is 0.5 to 1.5kPa.
6. The method according to claim 1, wherein the fraction at 70 to 90 ℃ is collected in the step (1).
7. The method according to claim 1, wherein the off-gas of the reaction in step (1) is cooled to trap hydrogen fluoride.
8. The production method according to claim 7, wherein the hydrogen fluoride trapped in step (1) is applied to the reaction in step (1).
9. The method according to claim 8, wherein the gas that is not condensed in the cooling in the step (1) is absorbed in a liquid phase to obtain a by-product.
10. The preparation method according to claim 1, wherein the hydrolysis in the step (2) comprises a hydrolysis reaction of 2, 6-difluorobenzonitrile with hydrogen peroxide under catalysis of an alkali source to prepare a reaction product containing 2, 6-difluorobenzamide.
11. The method according to claim 10, wherein the alkali source is a solution containing sodium hydroxide.
12. The method according to claim 11, wherein the concentration of the sodium hydroxide-containing solution is 10 to 30wt%.
13. The method of claim 10, wherein the molar ratio of base in the base source to 2, 6-difluorobenzonitrile is from 0.3 to 4.
14. The method according to claim 13, wherein the molar ratio of the base in the alkali source to the 2, 6-difluorobenzonitrile is from 0.6 to 2.0.
15. The preparation method of claim 10, wherein the molar ratio of the hydrogen peroxide to the 2, 6-difluorobenzonitrile is 1 to 5.
16. The preparation method of claim 15, wherein the molar ratio of the hydrogen peroxide to the 2, 6-difluorobenzonitrile is 2 to 4.
17. The preparation method of claim 10, wherein the concentration of the hydrogen peroxide is 20-35 wt%.
18. The method of claim 10, wherein the hydrolysis reaction is carried out at a temperature of 30 to 60 ℃.
19. The method of claim 18, wherein the hydrolysis reaction is carried out at a temperature of 45 to 55 ℃.
20. The method according to claim 19, wherein the hydrolysis reaction is carried out for a period of 2 to 10 hours.
21. The method of claim 10, wherein step (2) comprises: mixing an alkali source and 2, 6-difluorobenzonitrile, heating to the temperature of hydrolysis reaction, preserving heat, dropwise adding hydrogen peroxide, and continuously preserving heat after dropwise adding is finished to prepare a reaction product containing the 2, 6-difluorobenzamide.
22. The production method according to claim 21, wherein the length of the dropwise addition is 1 to 6 hours.
23. The method of claim 21, wherein the period of the continuous incubation is 1 to 4 hours.
24. The preparation method according to claim 10, wherein the reaction product in step (2) is subjected to temperature reduction, pH adjustment and solid-liquid separation in sequence to obtain 2, 6-difluorobenzamide.
25. The method of claim 24, wherein the temperature is reduced to a temperature of 20 to 30 ℃.
26. The method of claim 24, wherein the pH adjustment comprises: adding acid, keeping the temperature and stirring to adjust the pH value.
27. The method of claim 26, wherein the acid comprises hydrochloric acid.
28. The method of claim 27, wherein the hydrochloric acid has a concentration of 7 to 15wt%.
29. The preparation method of claim 26, wherein the stirring at the constant temperature is carried out for 1 to 2 hours.
30. The method according to claim 26, wherein the pH is adjusted to 6.0 to 8.0.
31. The method of claim 24, wherein the solid-liquid separation comprises suction filtration at reduced temperature.
32. The method of claim 31, further comprising washing and drying after the solid-liquid separation.
33. The method of claim 1, comprising the steps of:
(1) Mixing 2, 6-dichlorobenzonitrile and an organic solvent, heating to 150-250 ℃, storing hydrogen fluoride to an environment of 2-10 ℃, preserving heat, slowly dripping hydrogen fluoride liquid for 3-8 h, keeping the molar ratio of the hydrogen fluoride to the 2, 6-dichlorobenzonitrile at 2.0-4.0, and continuing preserving heat for 1-4 h after dripping is finished, and reacting; in the reaction process, cooling the tail gas of the reaction, trapping hydrogen fluoride, mechanically applying the trapped hydrogen fluoride to the reaction in the step (1), and absorbing uncondensed gas in the cooling process by water to obtain a by-product acid;
after the reaction is finished, collecting the fraction of 2, 6-difluorobenzonitrile at 70-90 ℃ under the negative pressure condition of 0.5-1.5 kPa;
(2) Mixing 10-30 wt% of sodium hydroxide-containing solution and 2, 6-difluorobenzonitrile, heating to 30-60 ℃, keeping the temperature, dropwise adding 20-35 wt% of hydrogen peroxide for 1-6 h, keeping the molar ratio of the hydrogen peroxide to the 2, 6-difluorobenzonitrile at 1-5, continuously keeping the temperature for 1-4 h after dropwise adding, preparing a reaction product containing the 2, 6-difluorobenzamide, cooling the reaction product to 20-30 ℃, adding 7-15 wt% of hydrochloric acid, keeping the temperature, stirring for 1-2 h, adjusting the pH value to 6.8-7.2, and sequentially carrying out solid-liquid separation, washing and drying to obtain the 2, 6-difluorobenzamide.
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