CN112939782B - Preparation method of fluorine-containing aryl compound - Google Patents

Abstract

The invention relates to the field of organic synthesis, in particular to a preparation method of a fluorine-containing aryl compound. The present invention provides a process for preparing a compound of formula 1, comprising: fluorination reaction: the compound of formula 2 is reacted with an alkali metal fluoride in the presence of a phase transfer catalyst to obtain the compound of formula 1. According to the preparation method of the fluorine-containing aryl compound, a reaction system does not include a solvent, the boiling point of the phase transfer catalyst is higher, no solvent interference exists during rectification or short steaming after the reaction is finished, the distillation yield is high, and the product purity is good.

Description

A kind of preparation method of fluorine-containing aryl compound

technical field

The invention relates to the field of organic synthesis, in particular to a preparation method of a fluorine-containing aryl compound.

Background technique

Fluorine-containing aryl compounds are important intermediates for some pesticides, medicines and materials. After the introduction of fluorine atoms into aromatic compounds, the physical and chemical properties of the compounds can be significantly changed, and even aromatic compounds can produce many new and special functions. Its efficacy and duration of action are also longer.

There are several methods for fluorine-containing aromatic compounds: 1) Direct fluorine substitution reaction. Aromatic hydrocarbons are directly fluorinated by using fluorine gas, generally by diluting fluorine gas with nitrogen or argon gas, and passing it into an inert solvent for aromatic hydrocarbons at a lower temperature to carry out the reaction. Due to the high activity of fluorine gas, the direct fluorination reaction is not easy to control, there are many side reactions, and the reaction conditions and the requirements for the reaction equipment are relatively harsh, so the direct fluorination reaction of fluorine gas to prepare fluorine-containing aromatic compounds is not widely used. 2) Balz-Schiemann diazotization method. The method takes an aromatic primary amine as a raw material, diazotizes nitrous acid to form an aromatic amine diazonium salt, and then reacts the diazonium salt with HBF ₂ to generate an insoluble fluoroborate diazonium salt, and the fluoroborate diazonium salt is dried In addition to water, it is heated and decomposed to generate fluorine-containing aromatic compounds. When the method heats the diazonium salt, it decomposes to generate a large amount of toxic gas, and during the decomposition, there is a risk of exothermic series, and its application is greatly limited. 3) Halogen exchange fluorine. The method is to use alkali metal fluorides (eg KF, NaF, CsF) for halogen exchange with other halogens (chlorine, bromine, iodine) on the benzene ring. The method generally uses high-boiling point solvents such as DMF, DMSO, NMP and sulfolane as the reaction solvent, and these solvents are often close to the target product in boiling point. In actual production, it is difficult to separate the product and the solvent when the product is separated by rectification, the product purity is difficult to improve, and the yield is difficult to separate. On the low side, it is difficult to recover and apply the solvent.

SUMMARY OF THE INVENTION

In view of the above-mentioned shortcomings of the prior art, the purpose of the present invention is to provide a preparation method of a fluorine-containing aryl compound for solving the problems in the prior art.

To achieve the above purpose and other related purposes, the present invention provides a preparation method of the compound of formula 1, comprising:

Fluorination reaction: the compound of formula 2 is reacted with an alkali metal fluoride in the presence of a phase transfer catalyst to prepare the compound of formula 1, and the reaction equation is as follows:

In formula 1, R ₁ is selected from nitro, cyano, acid fluoride, H, F;

R ₂ is selected from nitro, cyano, acid fluoride, H, F;

R ₃ is selected from nitro, cyano, acid fluoride, H, F;

R ₄ is selected from nitro, cyano, acid fluoride, H, F;

R ₅ is selected from nitro, cyano, acid fluoride, H, F;

And at least one of R ₁ , R ₂ , R ₃ , R ₄ and R ₅ is a nitro group, a cyano group, or an acid fluoride;

In formula 2, X is selected from Cl, Br;

R ₁ ' is selected from nitro, cyano, acid chloride, acid fluoride, H, Cl, Br, F;

R ₂ ' is selected from nitro, cyano, acid chloride, acid fluoride, H, Cl, Br, F;

R ₃ ' is selected from nitro, cyano, acid chloride, acid fluoride, H, Cl, Br, F;

R ₄ ' is selected from nitro, cyano, acid chloride, acid fluoride, H, Cl, Br, F;

R ₅ ' is selected from nitro, cyano, acid chloride, acid fluoride, H, Cl, Br, F;

And at least one group in R ₁ ', R ₂ ', R ₃ ', R ₄ ', R ₅ ' is nitro, cyano, acid chloride, acid fluoride;

When R ₁ ', R ₂ ', R ₃ ', R ₄ ', and R ₅ ' are each independently selected from Cl or Br, their corresponding R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from F;

When R ₁ ', R ₂ ', R ₃ ', R ₄ ', and R ₅ ' are each independently selected from acid chlorides, their corresponding R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from acid chlorides. Acyl fluoride;

When R ₁ ', R ₂ ', R ₃ ', R ₄ ', R ₅ ' are each independently selected from nitro, cyano, acid fluoride, H, F, the corresponding R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ remain unchanged.

In some embodiments of the present invention, in formula 1, R ₁ is selected from nitro, cyano, acid fluoride, H, F;

R ₂ is selected from H, F;

R ₃ is selected from nitro, cyano, acid fluoride, H, F;

R ₄ is selected from H, F;

R ₅ is selected from nitrates H, F;

And at least one of R ₁ and R ₃ is a nitro group, a cyano group, or an acid fluoride;

In formula 2, X is selected from Cl;

R ₁ ' is selected from nitro, cyano, acid chloride, H, Cl, F;

R ₂ ' is selected from H, Cl, F;

R ₃ ' is selected from nitro, cyano, acid chloride, H, Cl, F;

R ₄ ' is selected from H, Cl, F;

R ₅ ' is selected from H, Cl, F;

And at least one group in R ₁ ', R ₃ ' is nitro, cyano, acid chloride;

When R ₁ ', R ₂ ', R ₃ ', R ₄ ', and R ₅ ' are each independently selected from Cl, their corresponding R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from F;

When R ₁ ', R ₂ ', R ₃ ', R ₄ ', and R ₅ ' are each independently selected from acid chlorides, their corresponding R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from acid chlorides. Acyl fluoride;

When R ₁ ', R ₂ ', R ₃ ', R ₄ ', R ₅ ' are each independently selected from nitro, cyano, H, F, the corresponding R ₁ , R ₂ , R ₃ , R ₄ , R ₅ remains unchanged.

In some embodiments of the invention, the reaction is carried out in the absence of a solvent.

In some embodiments of the present invention, the alkali metal fluoride is selected from potassium fluoride and/or sodium fluoride.

In some embodiments of the present invention, the molar ratio of the alkali metal fluoride to the compound of formula 2 is 1-8:1.

In some embodiments of the present invention, the phase transfer catalyst is selected from crown ethers, preferably selected from a combination of one or more of 18-crown-6 and 15-crown-5.

In some embodiments of the present invention, the weight ratio of the phase transfer catalyst to the compound of formula 2 is 0.1-3:1.

In some embodiments of the invention, the reaction is carried out under anhydrous conditions.

In some embodiments of the present invention, the reaction temperature is 70-180°C.

In some embodiments of the present invention, the post-treatment of the reaction includes: beating, solid-liquid separation, and the compound of formula 1 can be prepared by purifying the obtained liquid phase.

In some embodiments of the present invention, the purification method specifically includes recrystallization and/or rectification.

In some embodiments of the invention, at least a portion of the liquid phase purification residue is used as a phase transfer catalyst in the fluorination reaction.

In some embodiments of the present invention, the solid phase obtained by the solid-liquid separation comprises an alkali metal halide.

Detailed ways

In order to make the purpose, technical solutions and beneficial technical effects of the present invention clearer, the present invention will be further described in detail below with reference to the embodiments. Those who are familiar with the technology can easily understand other advantages and other advantages of the present invention from the contents disclosed in this specification. effect.

The present invention provides a preparation method of the compound of formula 1, which may include: reacting the compound of formula 2 with an alkali metal fluoride in the presence of a phase transfer catalyst to prepare the compound of formula 1, and the reaction equation is as follows:

In formula 1, R ₁ is selected from nitro, cyano, acid fluoride, H, F;

R ₂ is selected from nitro, cyano, acid fluoride, H, F;

R ₃ is selected from nitro, cyano, acid fluoride, H, F;

R ₄ is selected from nitro, cyano, acid fluoride, H, F;

R ₅ is selected from nitro, cyano, acid fluoride, H, F;

And at least one of R ₁ , R ₂ , R ₃ , R ₄ and R ₅ is a nitro group, a cyano group, or an acid fluoride;

In formula 2, X is selected from Cl, Br;

R ₁ ' is selected from nitro, cyano, acid chloride, acid fluoride, H, Cl, Br, F;

R ₂ ' is selected from nitro, cyano, acid chloride, acid fluoride, H, Cl, Br, F;

R ₃ ' is selected from nitro, cyano, acid chloride, acid fluoride, H, Cl, Br, F;

R ₄ ' is selected from nitro, cyano, acid chloride, acid fluoride, H, Cl, Br, F;

R ₅ ' is selected from nitro, cyano, acid chloride, acid fluoride, H, Cl, Br, F;

And at least one of R ₁ ', R ₂ ', R ₃ ', R ₄ ', and R ₅ ' is a nitro group, a cyano group, an acid chloride, or an acid fluoride.

In the preparation method of the compound of formula 1 provided by the present invention, the reaction is usually a fluorination reaction, and the X group on the aromatic ring of the compound of formula 2 is converted into F in the fluorination reaction, thereby providing the compound of formula 1. In the above fluorination reaction, the positions of R ₁ ', R ₂ ', R ₃ ', R ₄ ' and R ₅ ' in the compound of formula 2 are usually the same as those of R 1 , R ₁ , The positions where the R ₂ , R ₃ , R ₄ , and R ₅ groups are located correspond to. When R ₁ ', R ₂ ', R ₃ ', R ₄ ', and R ₅ ' are each independently selected from Cl or Br, their corresponding R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are each independently is selected from F; when R ₁ ', R ₂ ', R ₃ ', R ₄ ', and R ₅ ' are each independently selected from acid chlorides, the corresponding R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are each independently independently selected from acid fluoride; when R ₁ ', R ₂ ', R ₃ ', R ₄ ', R ₅ ' are independently selected from nitro, cyano, acid fluoride, H, F, the corresponding R ₁ , R ₂ , R ₃ , R ₄ , R ₅ remain unchanged.

In a preferred embodiment of the present invention, in formula 1, R ₁ is selected from nitro, cyano, acid fluoride, H, F;

R ₂ is selected from H, F;

R ₃ is selected from nitro, cyano, acid fluoride, H, F;

R ₄ is selected from H, F;

R ₅ is selected from nitrates H, F;

And at least one of R ₁ and R ₃ is a nitro group, a cyano group, or an acid fluoride;

In formula 2, X is selected from Cl;

R ₁ ' is selected from nitro, cyano, acid chloride, H, Cl, F;

R ₂ ' is selected from H, Cl, F;

R ₃ ' is selected from nitro, cyano, acid chloride, H, Cl, F;

R ₄ ' is selected from H, Cl, F;

R ₅ ' is selected from H, Cl, F;

And at least one group in R ₁ ', R ₃ ' is nitro, cyano, acid chloride;

When R ₁ ', R ₂ ', R ₃ ', R ₄ ', and R ₅ ' are each independently selected from Cl, their corresponding R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from F; when R ₁ ', R ₂ ', R ₃ ', R ₄ ', and R ₅ ' are each independently selected from acid chlorides, their corresponding R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are each independently is selected from acid fluoride; when R ₁ ', R ₂ ', R ₃ ', R ₄ ', R ₅ ' are independently selected from nitro, cyano, H, F, the corresponding R ₁ , R ₂ , R ₃ , R ₄ , R ₅ remain unchanged.

In the preparation method of the compound of formula 1 provided by the present invention, the reaction can usually be carried out in the absence of a solvent, that is, the reaction system basically does not contain the compound of formula 2, alkali metal fluoride and phase transfer catalyst. Other solvents used to disperse the above substances. The preparation method of the compound of formula 1 provided by the present invention uses an aryl halide as a raw material, and reacts with an alkali metal fluoride under the participation of a phase transfer catalyst to prepare a corresponding fluorine-containing aryl compound. After the reaction is finished, the reaction product can be processed by post-processing methods such as solvent beating, solid-liquid separation, etc., and the obtained solid phase can include alkali metal halides (for example, potassium chloride, sodium chloride, etc.), so that by-products can be recovered. The product alkali metal halide, the obtained liquid phase product can be further purified to obtain the compound of formula 1, and the obtained strontium residue during the purification process can be directly applied to the fluorination reaction for catalysis and the reaction speed has no obvious change.

In the preparation method of the compound of formula 1 provided by the present invention, the alkali metal fluoride can be selected from potassium fluoride and/or sodium fluoride, and the amount of the alkali metal fluoride is usually related to the number of halogen atoms of the substrate, for example, The amount of the alkali metal fluoride to be used is generally equal to or in excess of the compound of formula 2. For another example, the molar ratio of the alkali metal fluoride to the compound of formula 2 can be 1-8:1, 1-2:1, 2- 3:1, 3-4:1, 4-5:1, 5-6:1, 6-7:1, or 7-8:1.

In the preparation method of the compound of formula 1 provided by the present invention, the phase transfer catalyst usually has a suitable melting point, so that it can be melted into a liquid in the reaction. To achieve a good solubilization effect, for example, the melting point of the phase transfer catalyst is generally lower than the reaction temperature of the reaction system, and for another example, the melting point of the phase transfer catalyst can generally be ≤50°C. Of course, at this temperature, the phase transfer catalyst still has relatively good stability. The phase transfer catalyst usually has a suitable boiling point, so that interference can be avoided during rectification or short distillation after the reaction, and the product yield and product purity can be improved. For example, the boiling point of the phase transfer catalyst is usually higher than that of the target product. For another example, the boiling point of the phase transfer catalyst may be 110°C or higher, or 115°C or higher. In a specific embodiment of the present invention, the phase transfer catalyst may be selected from crown ethers and the like, and may specifically be 18-crown-6 and 15-crown-5. Crown ethers have relatively better thermal stability, do not need to be added during the entire reaction process, and also have a suitable melting point to aid solubility. In addition, the boiling point of the crown ether is moderate, on the one hand, it can have a good degree of differentiation from the product, and the product can be separated by rectification, and on the other hand, the crown ether can be recovered by vacuum distillation. The amount of the phase transfer catalyst used can be adjusted by those skilled in the art, for example, the weight ratio of the phase transfer catalyst to the compound of formula 2 can be 0.1-3:1, 0.1-0.3:1, 0.3 -0.5:1, 0.5-1:1, 1-1.5:1, 1.5-2:1, 2-2.5:1, or 2.5-3:1, preferably 0.5-1:1.

In the preparation method of the compound of formula 1 provided by the present invention, the fluorination reaction can usually be carried out under anhydrous conditions, and the anhydrous conditions generally mean that the reaction system basically does not contain water. Those skilled in the art can choose a suitable method to provide an anhydrous reaction system. For example, the solvent can be refluxed with water to make the moisture content in the reaction system qualified. For another example, the solvent used in the refluxed water can be benzene. The combination of one or more of solvents, alkane solvents, etc., may specifically be a combination of one or more of benzene, toluene, xylene, cyclohexane, hexane, heptane, petroleum ether, and the like.

In the preparation method of the compound of formula 1 provided by the present invention, the fluorination reaction can usually be carried out under heating conditions, specifically 70-180°C, 70-90°C, 90-110°C, 110-130°C, 130-150°C As for the temperature condition of 150-180 degreeC, 130-150 degreeC may be preferable. Those skilled in the art can appropriately adjust the reaction time according to the reaction progress. Methods for monitoring the reaction progress should be known to those skilled in the art, such as analytical methods such as chromatography, nuclear magnetic resonance, etc. The end point of the reaction is that the raw material substrate basically disappears, and the specific reaction time can be 3 to 10 hours.

In the preparation method of the compound of formula 1 provided by the present invention, the post-treatment of the reaction includes: beating after the reaction, solid-liquid separation, and purification of the obtained liquid phase to obtain the compound of formula 1. Those skilled in the art can select a suitable solvent for beating the product obtained by the reaction. For example, the solvent used in the beating process can usually be one or more of benzene-based solvents, alkane-based solvents, halogenated alkane-based solvents, etc. The combination may specifically be a combination of one or more of benzene, toluene, xylene, cyclohexane, hexane, heptane, petroleum ether, dichloromethane, dichloroethane, and the like.

In the post-treatment process, the solid phase obtained from the solid-liquid separation can usually include alkali metal halides, and the alkali metal halides usually correspond to the reaction raw material alkali metal fluorides. Since X is selected from Cl and Br, the The alkali metal halides are usually alkali metal chlorides and alkali metal bromides, and further, when the alkali metal fluorides are selected from potassium fluoride and sodium fluoride, the generated alkali metal halides are usually corresponding to potassium halides and The halide of sodium, for example, the alkali metal halide may specifically be a combination of one or more of potassium chloride, potassium bromide, sodium chloride, sodium bromide, and the like.

In the post-processing process, the method for purifying the liquid phase obtained by solid-liquid separation may specifically include recrystallization and/or rectification. Before purification, the solvent can be removed, and the removal amount of the solvent can usually be an appropriate amount or completely removed, so as to facilitate subsequent purification treatment. During the rectification process, the target product can be obtained by collecting at a suitable fraction temperature. The remaining residue usually includes a phase transfer catalyst, and at least part of the residue can be used as a phase transfer catalyst in the fluorination reaction, so as to realize the recovery of the phase transfer catalyst. Apply. During the recrystallization process, a suitable solvent can be used to recrystallize the liquid phase obtained from the solid-liquid separation, for example, it can be an alkane solvent, an alcohol solvent, an aromatic hydrocarbon solvent, a ketone solvent, an ester solvent, and an ether solvent. , water, etc., more specifically can be solvents such as hexane, ethanol, methanol, isopropanol, heptane, toluene, acetone, water, ethyl acetate, methyl tert-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, etc. After the solid phase is separated, the remaining residue usually includes a phase transfer catalyst, and at least part of the residue can be used as a phase transfer catalyst in the fluorination reaction, thereby realizing the recovery and application of the phase transfer catalyst. The number of times of applying the residue obtained by at least part of the liquid phase purification as the phase transfer catalyst in the fluorination reaction can usually be multiple times, specifically 5 to 12 times, 5 times, 6 times, 7 times, 8 times, 9 times , 10 times, 11 times, or 12 times.

In the post-treatment process, it may also include purifying at least part of the residue obtained by purifying the liquid phase, so as to recover the phase transfer catalyst. Those skilled in the art can choose a suitable method to recover the phase transfer catalyst in the residue obtained from the liquid phase purification after repeated application (for example, the residue remaining in rectification, the residue remaining in recrystallization, etc.), for example, The phase transfer catalyst can be recovered by distillation, and the cyclic application of the phase transfer catalyst is realized, and the unit consumption is low.

The preparation method of the fluorine-containing aryl compound provided by the present invention does not include a solvent in the reaction system, and the phase transfer catalyst has a relatively high boiling point, no solvent interference during rectification or short distillation after the reaction is completed, the distillation yield is high, and the product purity is good . In addition, in addition to catalyzing, the phase transfer catalyst can also disperse the raw materials in the reaction system, so that the reaction speed of the fluorination reaction can be effectively improved. Compared with the phase transfer catalyst, the reaction speed is increased by more than 5 times, and the unit production capacity is greatly improved; at the same time, the phase transfer catalyst (for example, crown ether, etc.) has good thermal stability, and side reactions such as degradation will not occur at high temperatures, and there is no need to frequently open the kettle to supplement the phase. The catalyst is transferred to advance the reaction. In addition, the preparation method has a fast reaction speed and a small amount of tar in the system. After the reaction, purer by-product potassium chloride or sodium chloride can be obtained by beating and filtering operations, which can be recovered by a professional recycling company, while the traditional The by-products obtained from the process contain a lot of tar, which is difficult to recycle, which greatly reduces the output of solid waste. The tantalum residues after distillation and recrystallization are mainly crown ethers, which can be directly applied to the fluorination reaction for many times. , greatly reduces the raw material cost of the reaction and the output of the three wastes, and the distillation residue after repeated application can recover crown ether by short distillation, which realizes the cyclic application of crown ether, and the unit consumption is low. At the same time, the boiling point of crown ether is higher, and compared with conventional fluorinated solvents (NMP, sulfolane, etc.), it has a good degree of discrimination with the target product, and it can be easily separated from the product in the rectification operation, which greatly improves the purity and efficiency of the product. Separation yield.

The invention of the present application is further illustrated by the following examples, but the scope of the present application is not limited thereby.

Example 1

Preparation of 2,4,5-trifluoronitrobenzene:

Add 350.0g 2,4-dichloro-5-fluoronitrobenzene, 175.0g 18-crown-6 and 242.0g anhydrous potassium fluoride to a 1L reaction flask, heat to 140～150℃ and react for 5～10 hours, After the reaction is completed in the middle control, the temperature is lowered, filtered, and the filter cake is slurried with toluene. The organic phases are combined, and the toluene is recovered by short distillation. Yield 85.0%.

The mechanical application of the still residue: after the short steaming, 208 g of the still residue was obtained, to which 350.0 g of 2,4-dichloro-5-fluoro-nitrobenzene and 242.0 g of anhydrous potassium fluoride were added, and the reaction was heated to 140-150° C. for 5- After 10 hours, the temperature was lowered after the middle-controlled reaction was completed, filtered, and the filter cake was slurried with toluene. The organic phases were combined, and the toluene was recovered by short distillation. The vacuum degree was -0.095Mpa. The purity is 99.1%, and the yield is 88.0%.

The residue of the kettle was repeatedly used for the fluorination reaction, and it could be used seven times in total. The relevant product yield and product purity are shown in Table 1.

Table 1

number of applications yield purity 1 92.2% 99.0% 2 90.1% 98.9% 3 91.2% 99.3% 4 88.8% 99.0% 5 88.3% 98.6% 6 87.8% 99.0% 7 86.9% 98.7%

The recovery of crown ether in the still residue: the still residue after being applied repeatedly is distilled in a vacuum degree of 2～3mmHg, and the top temperature 130～140 ℃ fraction is collected to obtain 151.6g of 18-crown-6, with a purity of 97.2% and a recovery rate of 86.3 %.

Example 2

Preparation of 2,4,5-trifluorobenzonitrile:

Add 380.0g 2,4-dichloro-5-fluorobenzonitrile, 95.0g 18-crown-6 and 290.5g anhydrous potassium fluoride to a 1L reaction flask, heat to 120～130℃ and react for 5～10 hours. After the control reaction is completed, lower the temperature, filter, use xylene to make the filter cake, combine the organic phases, short steam to recover xylene 3, vacuum degree -0.095Mpa, collect the top temperature 80～95 ℃ fraction, obtain 289.0g product, HPLC purity 99.2% , the yield is 92.0%. Kettle residue 206g. H ¹ NMR (400 MHz, CDCl ₃ ): δ 6.75-6.82 (m, 1H), δ 7.18-7.28 (m, 1H).

The mechanical application and recovery scheme of the still residue can be carried out with reference to Example 1, and can be applied ten times in total. The relevant applied product yield and product purity are shown in Table 2.

Table 2

number of applications yield purity 1 94.2% 98.7% 2 90.1% 99.4% 3 90.2% 98.8% 4 88.5% 99.0% 5 88.9% 98.6% 6 88.8% 99.2% 7 87.9% 98.7% 8 88.0% 98.5% 9 87.7% 98.8% 10 85.4% 98.9%

The recovery of the crown ether in the still residue: the still residue after being applied repeatedly is distilled in a vacuum degree of 2～3mmHg, the top temperature 130～140 ℃ fraction is collected, 18-crown-6 85.0g is recovered, the purity is 96.1%, and the recovery rate is 90.0 %.

Example 3

Preparation of 2,4,6-trifluorobenzoyl fluoride:

Add 965.0g of 2,4,6-trichlorobenzoyl chloride, 2895.0g of 18-crown-6 and 1380.4g of anhydrous potassium fluoride to a 10L reaction flask, heat to 110～120℃ and react for 10～15 hours. After the reaction is complete, lower the temperature, filter, use dichloromethane to make pulp and filter cake, combine the organic phases, short steam to recover dichloromethane, rectify with a vacuum degree of 45～50mmHg, collect fractions with a top temperature of 85～90°C to obtain 634.1g product, HPLC purity 98.5 %, the yield is 90.0%. The residue of the kettle was 2936.5g. H ¹ NMR (400 MHz, CDCl ₃ ): δ 6.48-6.62 (m, 2H).

The mechanical application and recovery scheme of the still residue can be carried out with reference to Example 1, and can be applied eight times in total, and the relevant applied product yield and product purity are shown in Table 3.

table 3

number of applications yield purity 1 93.2% 98.7% 2 92.1% 99.4% 3 93.2% 98.8% 4 88.5% 98.5% 5 88.9% 98.6% 6 86.7% 99.2% 7 86.9% 98.7% 8 87.0% 99.2%

The recovery of crown ether in the still residue: the still residue after repeated application is distilled at a vacuum degree of 2-3 mmHg, the fraction with a top temperature of 130-140° C. is collected, and 2547.6 g of 18-crown-6 is recovered, with a recovery rate of 88.0%.

Example 4

Preparation of 4-fluoronitrobenzene:

Add 360.0g 4-chloronitrobenzene, 36.0g 18-crown-6 and 172.6g anhydrous potassium fluoride to a 1L reaction flask, heat to 140～150℃ and react for 3～5 hours. Filtration, using dichloroethane to make the filter cake, combining the organic phases, short steaming to recover dichloroethane, vacuum 45-50mmHg distillation, collecting top temperature 75-80 ℃ fractions to obtain 293.4g product, yield 91.0%, HPLC purity 98.8%, still residue 38.6g.

The mechanical application of the still residue and the recovery scheme can be carried out with reference to Example 1, and can be applied mechanically eight times in total, and the product yield and product purity of the relevant mechanical application are as shown in Table 4,

Table 4

number of applications yield purity 1 93.8% 98.7% 2 93.1% 99.4% 3 93.2% 98.4% 4 89.5% 99.3% 5 88.9% 99.6% 6 86.6% 99.2% 7 87.5% 98.7% 8 87.0% 99.0%

The recovery of crown ether in the still residue: the still residue after being applied repeatedly is distilled at a vacuum degree of 2～3mmHg, the fraction with a top temperature of 130～140°C is collected, and 29.6g of 18-crown-6 is recovered, and the recovery rate is 82.2%.

Example 5

Preparation of 2,4-difluoronitrobenzene:

Add 360.0g of 2-fluoro-4-bromonitrobenzene, 360.0g of 15-crown-5 and 123.6g of anhydrous sodium fluoride to a 1L reaction flask, heat to 150～160℃ and react for 3～5 hours, the reaction is controlled in the middle After complete cooling, filter, use cyclohexane to make pulp and filter cake, combine organic phases, short steam to recover cyclohexane, vacuum degree 45～50mmHg distillation, collect top temperature 70～75 ℃ fraction to obtain 234.3g product, yield 90.0%, HPLC purity 99.2%. Still residue 386.1g.

The mechanical application and recovery scheme of the still residue can be carried out with reference to Example 1, and can be applied eight times in total, and the relevant applied product yield and product purity are shown in Table 5.

table 5

The recovery of crown ether in the still residue: the still residue after repeated application is distilled in a vacuum degree of 2～3mmHg, the top temperature 110～120 ℃ fraction is collected, 15-crown-5 315.0g is recovered, and the recovery rate is 87.5%.

Example 6

Preparation of 2,4,6-trifluorobenzoyl fluoride:

Add 500.0g 2,4,-difluoro-6-chlorobenzoyl fluoride, 150.0g 18-crown-6 and 194.1g anhydrous potassium fluoride to a 1L reaction flask, heat to 70-90°C and react for 3-5 After the reaction was completed in the middle of the control, the temperature was lowered, filtered, and the filter cake was pulped with toluene. The organic phases were combined, and the toluene was recovered by short steaming. The vacuum was 45 to 50 mmHg for rectification, and the fractions with a top temperature of 85 to 90 °C were collected to obtain 422.0 g of product, with a yield of 92.2 %, HPLC purity 98.6%. Still residue 168.2g.

The mechanical application of the still residue and the recovery scheme can be carried out with reference to Example 1, and can be applied twelve times in total, and the relevant applied product yield and product purity are shown in Table 6.

Table 6

number of applications yield purity 1 93.8% 99.0% 2 93.0% 99.4% 3 91.2% 98.8% 4 88.9% 98.3% 5 88.9% 98.6% 6 88.6% 98.2% 7 88.5% 99.7% 8 85.0% 98.3% 9 87.6% 98.8% 10 88.5% 98.4% 11 85.0% 98.6% 12 85.4% 98.4%

The recovery of crown ether in the still residue: the still residue after repeated application is distilled at a vacuum degree of 2-3 mmHg, the fraction with a top temperature of 130-140 ℃ is collected, and 140.0 g of 18-crown-6 is recovered, and the recovery rate is 93.3%.

Example 7

Preparation of pentafluorobenzonitrile:

Add 500.0g pentachlorobenzonitrile, 1500.0g 18-crown-6 and 633.0g anhydrous potassium fluoride to a 3L reaction flask, heat to 160～180°C and react for 15～20 hours, cool down after the reaction is completed in the middle control, filter, Use toluene to beat the filter cake, combine the organic phases, short steam to recover toluene, rectify with a vacuum degree of 45-50 mmHg, collect fractions with a top temperature of 100-110° C. to obtain 298.2 g of product, the yield is 85.0%, and the HPLC purity is 99.0%. Still residue 1560.2g.

The mechanical application of the still residue and the recovery scheme can be carried out with reference to Example 1, and can be applied for ten times in total, and the relevant applied product yield and product purity are shown in Table 7.

Table 7

number of applications yield purity 1 88.8% 99.2% 2 87.0% 99.0% 3 87.2% 98.8% 4 88.0% 98.8% 5 86.9% 98.6% 6 86.6% 98.5% 7 85.5% 98.7% 8 86.0% 98.3% 9 87.6% 98.8% 10 83.5% 97.9%

The recovery of crown ether in the still residue: the still residue after repeated application is distilled at a vacuum degree of 2～3mmHg, the fraction with a top temperature of 130～140°C is collected, 18-crown-6 1350.0g is recovered, and the recovery rate is 90.0%.

Example 8

Preparation of 2,4-difluoro-5-nitrobenzonitrile:

Add 400.0g 2-fluoro-4-chloro-5-nitrobenzonitrile, 400.0g 18-crown-6 and 194.1g anhydrous potassium fluoride to a 1L reaction flask, heat to 70～85℃ and react for 5～8 hours , after the reaction is completed in the middle control, lower the temperature, filter, use dichloromethane to make the filter cake, combine the organic phases, short steam to recover dichloromethane, rectify with a vacuum degree of 45～50mmHg, collect the top temperature 125～130 ℃ fraction to obtain 316.5g of product, The yield was 86.2%, and the HPLC purity was 99.0%. The residue of the kettle was 268.2g. H ¹ NMR (400 MHz, CDCl ₃ ): δ 7.10-7.22 (m, 2H), δ 8.45-8.53 (m, 2H).

The mechanical application of the still residue and the recovery scheme can be carried out with reference to Example 1, which can be applied seven times in total, and the relevant applied product yield and product purity are shown in Table 8.

Table 8

number of applications yield purity 1 85.8% 98.9% 2 91.1% 99.4% 3 92.2% 98.4% 4 88.5% 99.0% 5 88.9% 98.6% 6 85.6% 99.2% 7 83.5% 99.1%

The recovery of crown ether in the still residue: the still residue after repeated application is distilled at a vacuum degree of 2～3mmHg, the top temperature 130～140 ℃ fraction is collected, 18-crown-6 350.0g is recovered, and the recovery rate is 87.5%.

Example 9

Preparation of 4,5-difluorophthaloyl fluoride:

Add 360.0g of 4,5-dichlorophthaloyl chloride, 100.0g of 15-crown-5 and 384.6g of anhydrous sodium fluoride to a 1L reaction flask, heat to 110～130℃ and react for 6～15 hours. After the reaction is complete, lower the temperature, filter, use hexane to make the filter cake, combine the organic phases, recycle the hexane by short distillation, distill at a vacuum degree of 25-30 mmHg, collect the fractions with a top temperature of 85-95 ° C to obtain 221.6 g of product, the yield is 81.2%, HPLC Purity 99.0%. 113.6g of residues in the kettle. H ¹ NMR (400 MHz, CDCl ₃ ): δ 7.98-8.12 (m, 2H).

The mechanical application of the still residue and the recovery scheme can be carried out with reference to Example 1, and can be applied mechanically nine times in total, and the relevant mechanically applied product yield and product purity are shown in Table 9.

Table 9

number of applications yield purity 1 80.2% 99.3% 2 87.1% 99.2% 3 86.2% 98.8% 4 87.5% 99.0% 5 86.9% 98.6% 6 85.8% 98.2% 7 83.9% 98.7% 8 80.0% 98.8% 9 78.4% 98.0%

The recovery of crown ether in the still residue: the still residue after being applied repeatedly is distilled at a vacuum degree of 2～3mmHg, the top temperature 110～120 ℃ fraction is collected, 15-crown-5 87.0g is recovered, and the recovery rate is 87.0%.

Example 10

Preparation of 2,4-difluoro-5-nitrobenzoyl fluoride:

Add 400.0g 2-chloro-4-bromo-5-nitrobenzoyl chloride, 200.0g 18-crown-6 and 311.0g anhydrous potassium fluoride to a 1L reaction flask, heat to 130～150℃ and react for 6～8 After the reaction was completed, the temperature was lowered, filtered, and the filter cake was pulped with toluene. The organic phases were combined, and the toluene was recovered by short steaming. The vacuum was 25-30 mmHg for rectification, and the fractions with a top temperature of 90-95 °C were collected to obtain 226.7 g of product, and the yield was 82.6 %, HPLC purity 99.0%. Kettle residue 223.1g. H ¹ NMR (400 MHz, CDCl ₃ ): δ 7.18-7.28 (m, 1H), δ 8.75-8.82 (m, 1H).

The mechanical application and recovery scheme of the still residue can be carried out with reference to Example 1, and can be applied six times in total, and the relevant applied product yield and product purity are shown in Table 10.

Table 10

number of applications yield purity 1 86.2% 99.0% 2 86.1% 98.9% 3 85.2% 98.6% 4 86.8% 99.0% 5 83.3% 98.6% 6 80.8% 98.0%

The recovery of crown ether in the still residue: the still residue after repeated application is distilled in a vacuum degree of 2～3mmHg, the fraction with a top temperature of 130～140℃ is collected, 187.0g of 18-crown-6 is recovered, and the recovery rate is 93.5%.

Example 11

Preparation of 2,3-difluoro-6-nitrobenzonitrile:

Add 360.0g 2-fluoro-3-chloro-6-nitrobenzonitrile, 400.0g 18-crown-6 and 125.2g anhydrous potassium fluoride to a 1L reaction flask, heat to 100～105℃ and react for 5～8 hours , after the reaction is completed in the middle control, lower the temperature, filter, use heptane to beat the filter cake, combine the organic phases, short-steam to recover heptane, distill at a vacuum degree of 15-20 mmHg, collect fractions with a top temperature of 95-100 ℃ to obtain 268.3 g of product, and the yield is 81.2 %, HPLC purity 99.0%. The residue of the kettle was 436.6g. H ¹ NMR (400 MHz, CDCl ₃ ): δ 7.78-7.88 (m, 1H), δ 8.26-8.38 (m, 1H).

The mechanical application and recovery scheme of the still residue can be carried out with reference to Example 1, which can be applied six times in total, and the relevant applied product yield and product purity are shown in Table 11.

Table 11

The recovery of crown ether in the still residue: the still residue after being applied repeatedly is distilled at a vacuum degree of 2～3mmHg, the top temperature 130～140 ℃ fraction is collected, 18-crown-6 387.0g is recovered, and the recovery rate is 96.5%.

Example 12

Preparation of 2,4-difluoro-1,3,5-trinitrobenzene:

Add 282.0g 2,4-dichloro-1,3,5-trinitrobenzene, 282.0g 18-crown-6 and 133.6g anhydrous potassium fluoride to a 1L reaction flask, heat to 70～75℃ for reaction 5 ~8 hours, after the reaction was completed in the middle control, the temperature was lowered, filtered, the filter cake was pulped with toluene, the organic phases were combined, and the toluene was recovered by short steaming, and the obtained residue was recrystallized from ethanol to obtain 186.8 g of product, the yield was 75.1%, and the HPLC purity was 98.0 %. After the crystallization mother liquor was concentrated, 302.9 g of still residue was obtained. H ¹ NMR (400 MHz, CDCl ₃ ): δ 9.50-9.62 (m, 1H).

The mechanical application and recovery scheme of the still residue can be carried out with reference to Example 1, and can be applied five times in total, and the relevant applied product yield and product purity are shown in Table 12.

Table 12

number of applications yield purity 1 76.2% 98.0% 2 86.1% 98.9% 3 85.2% 98.6% 4 86.8% 99.0% 5 83.3% 97.6%

The recovery of crown ether in the still residue: the still residue after being applied repeatedly is distilled at a vacuum degree of 2～3mmHg, the fraction with a top temperature of 130～140°C is collected, and 241.0 g of 18-crown-6 is recovered, and the recovery rate is 85.5%.

Example 13

Preparation of 2,4-difluoro-1,5-dinitrobenzene:

Add 300.0g 2-fluoro-4-chloro-1,3,5-trinitrobenzene, 300.0g 18-crown-6 and 102.7g anhydrous potassium fluoride to a 1L reaction flask, heat to 100～105℃ for reaction After 3 to 6 hours, the temperature was lowered after the mid-control reaction was completed, filtered, and the filter cake was beaten with toluene, and the organic phases were combined, and the toluene was recovered by short distillation, and the vacuum was distilled at 2 to 3 mmHg. The yield was 79.6%, and the HPLC purity was 99.0%. Still residue 316.4g. H ¹ NMR (400 MHz, CDCl ₃ ): δ 7.28-7.38 (m, 1H), δ 8.86-8.98 (m, 1H).

The mechanical application and recovery scheme of the still residue can be carried out with reference to Example 1, which can be applied five times in total, and the relevant applied product yield and product purity are shown in Table 13.

Table 13

number of applications yield purity 1 85.2% 99.0% 2 85.1% 98.7% 3 85.2% 99.3% 4 84.8% 99.0% 5 80.3% 98.6% 6 77.8% 98.8%

The recovery of crown ether in the still residues: the still residues after repeated application are distilled at a vacuum degree of 2～3mmHg, the fractions with a top temperature of 130～140°C are collected, 18-crown-6 261.0g is recovered, and the recovery rate is 87.0%.

Example 14

Preparation of 2,4,5-trifluoronitrobenzene:

Add 350.0g 2,4-dichloro-5-fluoronitrobenzene, 700.0g sulfolane and 242.0g anhydrous potassium fluoride to a 2L reaction flask, heat to 140～150℃ for reaction, open the stopper every three hours and add 3.5g g tetramethyl ammonium chloride, the reaction is controlled by gas chromatography, and the reaction end point is reached in about 30 hours, and a total of 38.5 g of tetramethyl ammonium chloride is used. The product and sulfolane mixed solvent are distilled out by short steaming, and the residue in the kettle is a mixed solid of potassium chloride, potassium fluoride and tar, and the color is black gray, which is treated as solid waste. The short distillation fraction was purified by a rectifying tower to obtain 200.7 g of product with a purity of 97.4% and a yield of 68.1%.

This example is the comparative reaction of Example 1, which is carried out by a conventional fluorination method, that is, using sulfolane as the reaction solvent and tetramethylammonium chloride as the phase transfer catalyst to carry out the fluorination reaction. In the reaction, it is necessary to open the lid several times to add the phase transfer catalyst, and because the product and sulfolane are difficult to separate, the product purity and yield are significantly reduced, and a large amount of inorganic salt and tar mixed solid waste produced by the reaction cannot be recycled.

To sum up, the present invention effectively overcomes various shortcomings in the prior art and has high industrial utilization value.

The above-mentioned embodiments merely illustrate the principles and effects of the present invention, but are not intended to limit the present invention. Anyone skilled in the art can modify or change the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or changes made by those with ordinary knowledge in the technical field without departing from the spirit and technical idea disclosed in the present invention should still be covered by the claims of the present invention.

Claims (6)

1. a preparation method of a compound of formula 1, comprising: Fluorination reaction: the compound of formula 2 is reacted with an alkali metal fluoride in the presence of a phase transfer catalyst to prepare the compound of formula 1, and the reaction equation is as follows:

In formula 1, R ₁ is selected from nitro, cyano, acid fluoride, H, F; R ₂ is selected from nitro, cyano, acid fluoride, H, F; R ₃ is selected from nitro, cyano, acid fluoride, H, F; R ₄ is selected from nitro, cyano, acid fluoride, H, F; R ₅ is selected from nitro, cyano, acid fluoride, H, F; And at least one of R ₁ , R ₂ , R ₃ , R ₄ and R ₅ is a nitro group, a cyano group, or an acid fluoride; In formula 2, X is selected from Cl, Br; R ₁ ' is selected from nitro, cyano, acid chloride, acid fluoride, H, Cl, Br, F; R ₂ ' is selected from nitro, cyano, acid chloride, acid fluoride, H, Cl, Br, F; R ₃ ' is selected from nitro, cyano, acid chloride, acid fluoride, H, Cl, Br, F; R ₄ ' is selected from nitro, cyano, acid chloride, acid fluoride, H, Cl, Br, F; R ₅ ' is selected from nitro, cyano, acid chloride, acid fluoride, H, Cl, Br, F; And at least one group in R ₁ ', R ₂ ', R ₃ ', R ₄ ', R ₅ ' is nitro, cyano, acid chloride, acid fluoride; When R ₁ ', R ₂ ', R ₃ ', R ₄ ', and R ₅ ' are each independently selected from Cl or Br, their corresponding R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from F; When R ₁ ', R ₂ ', R ₃ ', R ₄ ', and R ₅ ' are each independently selected from acid chlorides, their corresponding R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from acid chlorides. Acyl fluoride; When R ₁ ', R ₂ ', R ₃ ', R ₄ ', R ₅ ' are each independently selected from nitro, cyano, acid fluoride, H, F, the corresponding R ₁ , R ₂ , R ₃ , R ₄ , R ₅ remain unchanged; The weight ratio of the phase transfer catalyst to the compound of formula 2 is 0.1-3:1; The phase transfer catalyst is selected from the combination of one or more of 18-crown-6 and 15-crown-5; The reaction is carried out in the absence of a solvent, the reaction temperature is 70-180 ° C, and the reaction time is 3-10 hours; The alkali metal fluoride is selected from potassium fluoride and/or sodium fluoride; The post-treatment of the reaction includes: beating, solid-liquid separation, and the compound of formula 1 can be prepared by purifying the obtained liquid phase; The residue obtained by at least part of the liquid phase purification is used as the phase transfer catalyst in the fluorination reaction, and the number of times of applying the residue as the phase transfer catalyst in the fluorination reaction is 5 to 12 times. 2. The preparation method of the compound of formula 1 according to claim 1, characterized in that, in formula 1, R ₁ is selected from nitro, cyano, acid fluoride, H, F; R ₂ is selected from H, F; R ₃ is selected from nitro, cyano, acid fluoride, H, F; R ₄ is selected from H, F; R ₅ is selected from H, F; And at least one of R ₁ and R ₃ is a nitro group, a cyano group, or an acid fluoride; In formula 2, X is selected from Cl; R ₁ ' is selected from nitro, cyano, acid chloride, H, Cl, F; R ₂ ' is selected from H, Cl, F; R ₃ ' is selected from nitro, cyano, acid chloride, H, Cl, F; R ₄ ' is selected from H, Cl, F; R ₅ ' is selected from H, Cl, F; And at least one group in R ₁ ', R ₃ ' is nitro, cyano, acid chloride; When R ₁ ', R ₂ ', R ₃ ', R ₄ ', and R ₅ ' are each independently selected from Cl, their corresponding R ₁ , R ₂ , R ₃ , R ₄ , and R ₅ are each independently selected from F; When R ₁ ' and R ₃ ' are each independently selected from acid chlorides, their corresponding R ₁ ' and R ₃ are each independently selected from acid fluorides; When R ₁ ', R ₃ ' are independently selected from nitro, cyano, H, F, their corresponding R ₁ , R ₃ remain unchanged; When R ₂ ', R ₄ ', and R ₅ ' are independently selected from H and F, their corresponding R ₂ , R ₄ , and R ₅ remain unchanged. 3 . The method for preparing the compound of formula 1 according to claim 1 , wherein the molar ratio of the alkali metal fluoride to the compound of formula 2 is 1-8:1. 4 . 4. The preparation method of the compound of formula 1 according to claim 1, wherein the reaction is carried out under anhydrous conditions. 5. The preparation method of the compound of formula 1 according to claim 4, wherein the purification method specifically comprises recrystallization and/or rectification. 6 . The method for preparing the compound of formula 1 according to claim 5 , wherein the solid-phase product obtained by the solid-liquid separation comprises an alkali metal halide. 7 .