Method for synthesizing 4, 4 '-difluorobenzophenone from 4-nitro-4'-chlorobenzophenone

Abstract

The invention discloses a method for synthesizing 4, 4 '-difluorobenzophenone by using 4-nitro-4'-chlorobenzophenone. The synthesis method of the 4, 4 '-difluorobenzophenone comprises the following steps: S1, carrying out substitution reaction on 4-nitro-4'-chlorobenzophenone and a fluorinating reagent to obtain 4-nitro-4 '-fluorobenzophenone; s2, the 4-nitro-4 '-fluorobenzophenone is subjected to a nitro reduction reaction, and 4-amino-4'-fluorobenzophenone is obtained; and S3, salifying the 4-amino-4 '-fluorobenzophenone and anhydrous hydrogen fluoride, carrying out a diazotization reaction under the action of sodium nitrite, and heating to carry out a cracking reaction after the reaction is finished, thereby obtaining the 4, 4'-difluorobenzophenone. According to the method, the reaction selectivity is improved, side reactions are reduced, and the product purity and yield are improved.

Description

Technical Field

[0001] This invention relates to the field of organic compound synthesis technology, and in particular to a method for synthesizing 4,4′-difluorobenzophenone from 4-nitro-4′-chlorobenzophenone. Background Technology

[0002] 4,4′ Difluorobenzophenone (4,4′) difluorobenzophe none, abbreviated as 4,4′ DFBP is a key intermediate in the preparation of the engineering plastic polyetheretherketone (PEEK). 4,4′ Difluorobenzophenone is a pharmaceutical intermediate mainly used in the production of the potent cerebral vasodilator "flubenzuron" and the new drug "Ducroxine" for the treatment of Alzheimer's disease. Therefore, researching synthetic methods with stable production, safety, reliability, high yield, and high product purity is of great significance.

[0003] CN106045828A discloses a method for preparing 4,4′-difluorobenzophenone, which involves first reacting p-fluorotrichlorotoluene with fluorobenzoyl in the presence of aluminum trichloride as a catalyst, followed by hydrolysis to obtain 4,4′-difluorobenzophenone. Traditional production processes use anhydrous aluminum chloride as a catalyst in the Friedel-Crafts acylation reaction, generating large amounts of aluminum chloride wastewater during the reaction. Furthermore, this reaction process has low selectivity, is prone to isomerization side reactions, and the products are difficult to separate, increasing the difficulty of post-processing and thus reducing yield and purity.

[0004] The traditional diazotization method uses 4,4′ Diaminodiphenylmethane reacts with sodium nitrite in hydrogen fluoride at low temperature to undergo a diazotization reaction, yielding a diazo compound, which is then oxidized with nitric acid at low temperature to obtain the final product. The reaction formula is as follows:

[0005] However, this method uses 4,4′ During the diazotization reaction of diaminodiphenylmethane, fluoride ions are easily released due to factors such as reaction temperature and reaction time during the cracking process, generating 4-fluorobenzophenone impurities. The presence of this impurity will have a wide molecular weight distribution in the preparation of downstream products (such as polyether ether ketone), thus affecting their mechanical and thermal properties. Moreover, this impurity cannot be effectively removed by conventional purification processes such as distillation and recrystallization, and its generation can only be controlled through the reaction process.

[0006] Therefore, how to improve 4,4′ Improving the selectivity of the reaction in the synthesis of difluorobenzophenone, reducing the occurrence of side reactions, and increasing the product yield and purity are of great research significance. Summary of the Invention

[0007] The purpose of this invention is to provide a method for synthesizing 4,4′-difluorobenzophenone from 4-nitro-4′-chlorobenzophenone. This method improves the selectivity of the reaction, reduces the occurrence of side reactions, and increases the product yield and purity.

[0008] To achieve the above objectives, the present invention adopts the following technical solution: This invention provides a method for synthesizing 4,4′-difluorobenzophenone, comprising the following steps: S1, 4-nitro-4′-chlorobenzophenone undergoes a substitution reaction with a fluorinating agent to give 4-nitro-4′-fluorobenzophenone; S2, 4-nitro-4′-fluorobenzophenone undergoes a nitro reduction reaction to yield 4-amino-4′-fluorobenzophenone; S3,4-amino-4′-fluorobenzophenone reacts with anhydrous hydrogen fluoride to form a salt, which is then subjected to a diazotization reaction under the action of sodium nitrite. After the reaction is completed, the temperature is raised to carry out a cracking reaction to obtain 4,4′-difluorobenzophenone.

[0009] According to an embodiment of the present invention, the fluorinating agent is potassium fluoride, and the molar ratio of 4-nitro-4′-chlorobenzophenone to potassium fluoride is 1:(1-5).

[0010] According to an embodiment of the present invention, the substitution reaction is carried out in a solvent; The solvent is selected from one or more of gamma-butyrolactone, sulfolane, diethylene glycol monobutyl ether, diethylene glycol acetate, diethylene glycol butyl ether acetate, tributyl borate, N-methylpyrrolidone, and ethyl benzoate. The molar ratio of 4-nitro-4′-chlorobenzophenone to the solvent is 1:(5-20).

[0011] According to an embodiment of the present invention, the temperature of the substitution reaction is 150–200°C, and the reaction time is 5–8 hours.

[0012] According to an embodiment of the present invention, the nitro reduction reaction is achieved by heating 4-nitro-4′-fluorobenzophenone in the presence of water, ammonium chloride and reduced iron powder.

[0013] Furthermore, the molar ratio of 4-nitro-4′-fluorobenzophenone to ammonium chloride is 1:(1.1-3).

[0014] The molar ratio of 4-nitro-4′-fluorobenzophenone to the reduced iron powder is 1:(1.1-3).

[0015] The molar ratio of 4-nitro-4′-fluorobenzophenone to water is 1:(20-40).

[0016] Furthermore, the nitro reduction reaction is carried out at a temperature of 90–100°C for a reaction time of 4–8 hours.

[0017] According to an embodiment of the present invention, the molar ratio of 4-amino-4′-fluorobenzophenone to anhydrous hydrogen fluoride is 1:(5-40).

[0018] The molar ratio of 4-amino-4′-fluorobenzophenone to sodium nitrite is 1:(1.0~1.1).

[0019] According to an embodiment of the present invention, the temperature of the diazotization reaction is -5℃ to 20℃, and the reaction time is 6 to 10 hours. Further, the diazotization reaction is performed as follows: 4-amino-4′-fluorobenzophenone and anhydrous hydrogen fluoride are first reacted with stirring at 10 to 20℃ for 3 to 5 hours, and then sodium nitrite is added and reacted at -5℃ to -2℃ for 3 to 5 hours.

[0020] According to an embodiment of the present invention, the temperature of the pyrolysis reaction is 10–60°C, and the reaction time is 12–24 hours.

[0021] The present invention has the following beneficial effects: (1) The synthesis method of the present invention improves reaction selectivity, reduces the occurrence of side reactions, and improves product purity and yield.

[0022] (2) The synthesis method of the present invention reduces the emission of wastewater and waste gas, and to a large extent realizes clean and green production. Attached Figure Description

[0023] Figure 1 This is a synthetic route diagram of 4,4′-difluorobenzophenone of the present invention. Detailed Implementation

[0024] As described in the background section, the traditional 4,4' The synthesis of difluorobenzophenone has low selectivity and easily produces byproducts, particularly concerning the 4,4′ end. The yield and purity of difluorobenzophenone synthesis are adversely affected.

[0025] In view of this, the first part, such as Figure 1 The synthetic route shown in the diagram provides a method for synthesizing 4,4′-difluorobenzophenone, comprising the following steps: S1, 4-nitro-4′-chlorobenzophenone undergoes a substitution reaction with a fluorinating agent to obtain 4-nitro-4′-fluorobenzophenone; S2, 4-nitro-4′-fluorobenzophenone undergoes a nitro reduction reaction to obtain 4-amino-4′-fluorobenzophenone; S3, 4-amino-4′-fluorobenzophenone forms a salt with anhydrous hydrogen fluoride, and then undergoes a diazotization reaction under the action of sodium nitrite. After the reaction is completed, the temperature is raised to carry out a pyrolysis reaction to obtain 4,4′-difluorobenzophenone.

[0026] Based on the above technical solution, this invention uses 4-nitro-4′-chlorobenzophenone as the starting material and replaces it with a fluorinating reagent to generate 4-nitro-4′-fluorobenzophenone. Specifically, it first determines the fluoride ion at one end through halogen exchange, and then generates the product through a diazotization process. The entire process exhibits high reaction selectivity, avoids isomer side reactions, prevents isomer formation, and improves product yield and purity. Furthermore, by generating 4-amino-4′-fluorobenzophenone before the diazotization reaction, this invention avoids directly using 4,4′-fluorobenzophenone. During the diazotization reaction of diaminodiphenylmethane, factors such as reaction temperature and reaction time during the cracking process can lead to the shedding of fluoride ions, generating 4-fluorobenzophenone impurities. This invention aims to avoid the impact of these impurities on the performance of downstream products (such as polyetheretherketone). By first completing the fluorine substitution, this invention avoids the generation of byproducts that occur when subsequent simultaneous fluorine substitution at both ends is performed.

[0027] According to embodiments of the present invention, the fluorinating agent is potassium fluoride, and the molar ratio of 4-nitro-4′-chlorobenzophenone to potassium fluoride is 1:(1-5), preferably 1:(2.5-5), including but not limited to 1:2.5 and 1:5. Excess potassium fluoride can improve the conversion rate of 4-nitro-4′-chlorobenzophenone.

[0028] According to an embodiment of the present invention, the substitution reaction is carried out in a solvent; the solvent is selected from one or more of gamma-butyrolactone, sulfolane, diethylene glycol monobutyl ether, diethylene glycol acetate, diethylene glycol butyl ether acetate, tributyl borate, N-methylpyrrolidone, and ethyl benzoate. The molar ratio of 4-nitro-4'-chlorobenzophenone to the solvent is 1:(5-20), preferably 1:(15-20), and more preferably 1:15. When the amount of solvent is small, the probability of collisions between reactant molecules and product molecules increases, leading to an increase in side reactions; while when the amount of solvent is large, the reaction rate decreases, thereby affecting the product yield and increasing the recovery cost.

[0029] According to an embodiment of the present invention, the substitution reaction is carried out at a temperature of 150–200°C for 5–8 hours, preferably at 150–170°C for 6–8 hours, and more preferably at 170°C for 6 hours. Both excessively low and excessively high reaction temperatures are detrimental to the conversion of 4-nitro-4′-chlorobenzophenone, because a low reaction temperature reduces the reaction rate, while an excessively high reaction temperature leads to overly vigorous reactions and the generation of byproducts.

[0030] According to an embodiment of the present invention, in step S1, the method further includes a purification step after the substitution reaction; the purification step may employ at least one purification method such as filtration, distillation, washing, recrystallization, etc., to obtain high-purity 4-nitro-4′-fluorobenzophenone. As an example, after the reaction is completed, the reaction solution is filtered, the solvent is distilled off under reduced pressure, and the product is then washed, recrystallized, and dried to obtain 4-nitro-4′-fluorobenzophenone.

[0031] According to an embodiment of the present invention, in step S2, the nitro reduction reaction is achieved by heating 4-nitro-4′-fluorobenzophenone in the presence of water, ammonium chloride and reduced iron powder.

[0032] According to an embodiment of the present invention, in step S2, the molar ratio of 4-nitro-4′-fluorobenzophenone to ammonium chloride is 1:(1.1-3), preferably 1:(1.5-3), including but not limited to 1:1.5 and 1:3. Excess ammonium chloride can improve the conversion rate of 4-nitro-4′-fluorobenzophenone.

[0033] Furthermore, the molar ratio of 4-nitro-4′-fluorobenzophenone to the reduced iron powder is 1:(1.1-3), preferably 1:(1.5-3), including but not limited to 1:1.5 and 1:3. Excessive reduced iron powder is beneficial for the complete reduction reaction. When the amount of iron powder is too small, the reaction is incomplete, intermediates accumulate, byproducts increase, and the yield decreases. When the amount of iron powder is excessive, post-processing becomes more difficult and costs increase.

[0034] Furthermore, the molar ratio of 4-nitro-4′-fluorobenzophenone to water is 1:(20-40), preferably 1:(36-40), including but not limited to 1:36.1 and 1:40. Excess water allows the raw materials to dissolve better in the solvent, thereby increasing the reaction rate.

[0035] Furthermore, the nitro reduction reaction is carried out at a temperature of 90–100°C for 4–8 hours, preferably at 95°C for 5 hours. If the reaction temperature is too low, according to reaction kinetics, the reaction will be slow or even halted, resulting in a large amount of residual raw materials and a low yield; if the temperature is too high, byproducts will surge, and the product purity and yield will plummet.

[0036] According to an embodiment of the present invention, in step S2, the method further includes a purification step after the reduction reaction; the purification step may employ at least one purification method such as extraction, layering, washing, distillation, or crystallization to remove reaction byproducts and obtain 4-amino-4′-fluorobenzophenone with higher purity. The extraction solvent may be an organic solvent such as acetone, dichloromethane, chloroform, or toluene. As an example, after the reaction is completed, the reaction solution is cooled to room temperature, chloroform is added for extraction and layering, the solvent is distilled, and the resulting product is washed, recrystallized, and dried to obtain 4-amino-4′-fluorobenzophenone.

[0037] According to embodiments of the present invention, the molar ratio of 4-amino-4′-fluorobenzophenone to anhydrous hydrogen fluoride is 1:(5-40), preferably 1:(10-30), more preferably 1:(15-25), and even more preferably 1:(19-25), including but not limited to 1:19, 1:15, or 1:25. The inventors have found that a smaller amount of hydrogen fluoride results in a more vigorous cracking reaction, leading to increased side reactions and a decrease in product purity and yield. Conversely, an excessive amount of hydrogen fluoride also reduces product purity and yield.

[0038] According to embodiments of the present invention, the molar ratio of 4-amino-4′-fluorobenzophenone to sodium nitrite is 1:(1.0 to 1.1), preferably 1:(1.01 to 1.07), more preferably 1:(1.02 to 1.05), including but not limited to 1:1.02, 1:1.03, and 1:1.05. The inventors have found that a portion of sodium nitrite needs to be in excess to ensure product yield, possibly due to localized overheating during the reaction causing the decomposition of sodium nitrite.

[0039] According to an embodiment of the present invention, the diazotization reaction is carried out at a temperature of -5°C to 20°C for 6 to 10 hours. Specifically, the diazotization reaction is performed as follows: 4-amino-4′-fluorobenzophenone is first reacted with anhydrous hydrogen fluoride at 10 to 20°C with stirring for 3 to 5 hours, and then the temperature is lowered to -5°C to -2°C before adding sodium nitrite and reacting for another 3 to 5 hours. As an example, 4-amino-4′-fluorobenzophenone is first reacted with anhydrous hydrogen fluoride at 10 to 20°C with stirring for 4 to 5 hours (e.g., 4 hours or 5 hours), and then the temperature is lowered to -5°C to -2°C (e.g., -2°C or -5°C) before adding sodium nitrite and reacting for another 4 hours. The inventors have found that the diazotization reaction temperature also affects the yield and purity of 4,4′-difluorobenzophenone, with -2°C being preferred. A lower diazotization reaction temperature results in a slower reaction, incomplete reaction, and ultimately affects the product yield.

[0040] According to embodiments of the present invention, the temperature of the pyrolysis reaction is 10–60°C, and the reaction time is 12–24 hours, preferably 30–60°C, more preferably 50–60°C, and even more preferably 50°C. The specific temperature can be adjusted according to the required yield and purity. When the reaction is carried out at 50°C for 20 hours, both the yield and purity reach their maximum. The inventors have found that when the pyrolysis temperature is too low, the pyrolysis reaction is slow or even stops, resulting in a sharp drop in product yield; while when the pyrolysis temperature is too high, side reactions increase, and both yield and purity decrease. In this invention, the diazotization reaction and the pyrolysis reaction are carried out in a one-pot reaction, that is, after the diazotization reaction, no post-treatment process is performed before the pyrolysis reaction. No reaction solvent is added in this reaction process; instead, anhydrous hydrogen fluoride is used as the reaction solvent.

[0041] According to an embodiment of the present invention, in step S3, the method further includes a purification step after the pyrolysis reaction; the purification step can be carried out by at least one of filtration, extraction, washing with water, crystallization, and distillation, wherein the extraction solvent can be an organic solvent such as acetone, petroleum ether, xylene, or toluene. As an example, after the reaction is completed, petroleum ether, toluene, or xylene is added for extraction, followed by layering, solvent removal, washing with water, and recrystallization to obtain 4,4′-difluorobenzophenone.

[0042] The present invention will now be described in further detail with reference to specific embodiments. The given embodiments are merely illustrative of the invention and not intended to limit its scope. The embodiments provided below can serve as a guide for further improvements by those skilled in the art and do not constitute a limitation on the invention in any way.

[0043] Unless otherwise specified, the methods used in the following embodiments are conventional methods, performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Unless otherwise specified, the materials and reagents used in the following embodiments are commercially available.

[0044] Example 1 4-Nitro-4′-chlorobenzophenone was synthesized according to the dosages and reaction conditions in Table 1. The specific operation was as follows: 58.0 g (1.0 mol) potassium fluoride, 261.6 g (1.0 mol) 4-nitro-4′-chlorobenzophenone, and 1800 g (15.0 mol) sulfolane were added sequentially to a 3 L three-necked reactor equipped with a stirrer, thermometer, and reflux condenser. Stirring was started and the temperature was raised to 170 °C. The reaction was maintained at this temperature for 6 h, then cooled to room temperature. The mixture was filtered, and the solvent was distilled off under reduced pressure. The product was then washed, recrystallized, and dried to obtain 4-nitro-4′-fluorobenzophenone (Ⅰ). The yields of 4-nitro-4′-fluorobenzophenone are shown in Table 1.

[0045] Example 2 The difference from Example 1 is that the molar ratio of 4-nitro-4′-chlorobenzophenone to potassium fluoride was adjusted to 1:2.5, while the rest was the same as in Example 1. The amounts of raw materials, reaction conditions, and yields are shown in Table 1.

[0046] Example 3 The difference from Example 1 is that the molar ratio of 4-nitro-4′-chlorobenzophenone to potassium fluoride was adjusted to 1:5, while the rest was the same as in Example 1. The amounts of raw materials, reaction conditions, and yields are shown in Table 1.

[0047] Example 4 The difference from Example 2 is that the molar ratio of 4-nitro-4′-chlorobenzophenone to solvent was adjusted to 1:5, while the rest was the same as in Example 2. The amounts of raw materials, reaction conditions, and yields are shown in Table 1.

[0048] Example 5 The difference from Example 2 is that the molar ratio of 4-nitro-4′-chlorobenzophenone to solvent was adjusted to 1:20, while the rest was the same as in Example 2. The amounts of raw materials, reaction conditions, and yields are shown in Table 1.

[0049] Example 6 The difference from Example 2 is that the reaction temperature was adjusted to 150°C and the reaction time was adjusted to 8 hours, while the rest was the same as in Example 2. The amount of raw materials, reaction conditions and yield are shown in Table 1.

[0050] Example 7 The difference from Example 2 is that the reaction temperature was adjusted to 200°C and the reaction time was adjusted to 5 hours; otherwise, the results were the same as in Example 2. The amounts of raw materials, reaction conditions, and yields are shown in Table 1.

[0051] Comparative Example 1 The difference from Example 2 is that the reaction temperature was adjusted to 145°C and the reaction time was adjusted to 8 hours, while the rest was the same as in Example 2. The amount of raw materials, reaction conditions and yield are shown in Table 1.

[0052] Comparative Example 2 The difference from Example 2 is that the reaction temperature was adjusted to 205°C and the reaction time was adjusted to 5 hours; otherwise, it was the same as Example 2. The amounts of raw materials, reaction conditions, and yields are shown in Table 1.

[0053] Table 1 Comparison of data from examples with different feed ratios and reaction temperatures in step S1

[0054] As can be seen from Table 1, when the amount of fluorinating agent (potassium fluoride) increases to a certain level, the product yield remains almost unchanged. When the amount of solvent is small, the probability of collisions between reactant molecules and product molecules increases, leading to an increase in side reactions. When the amount of solvent is large, the reaction rate decreases, thus affecting the product yield and increasing the recovery cost. When the reaction temperature is too low, the reaction rate decreases, while when the reaction temperature is too high, the reaction is too vigorous and easily produces byproducts. Therefore, the reaction conditions and feed ratio in Example 3 are the optimal process conditions for reaction step S1, and the obtained 4-nitro-4′-fluorobenzophenone (Ⅰ) is used in step S2.

[0055] Example 8 4-Amino-4′-fluorobenzophenone was synthesized according to the dosages and reaction conditions in Table 2. The specific operation was as follows: 650 g of water, 80.3 g (1.5 mol) of ammonium chloride, and 84 g (1.5 mol) of reduced iron powder were added sequentially to a 3 L three-necked reactor equipped with a stirrer, thermometer, and reflux condenser. The temperature was initially raised to 95 °C with stirring, and 245.2 g (1.0 mol) of 4-nitro-4′-fluorobenzophenone was slowly added. The reaction was maintained at this temperature for 5 hours. After the reaction was completed, the temperature was lowered to room temperature, and chloroform was added for extraction and separation. After solvent distillation, the resulting product was washed, recrystallized, and dried to obtain 4-amino-4′-fluorobenzophenone (II). The yields of 4-amino-4′-fluorobenzophenone are shown in Table 2.

[0056] Example 9 The difference from Example 8 is that the molar ratio of 4-nitro-4′-fluorobenzophenone to ammonium chloride was adjusted to 1:1.1, while the rest was the same as in Example 8. The amounts of raw materials, reaction conditions, and yields are shown in Table 2.

[0057] Example 10 The difference from Example 8 is that the molar ratio of 4-nitro-4′-fluorobenzophenone to ammonium chloride was adjusted to 1:3, while the rest was the same as in Example 8. The amounts of raw materials, reaction conditions, and yields are shown in Table 2.

[0058] Example 11 The difference from Example 8 is that the molar ratio of 4-nitro-4′-fluorobenzophenone to reduced iron powder was adjusted to 1:1.1, while the rest was the same as in Example 8. The amounts of raw materials, reaction conditions, and yields are shown in Table 2.

[0059] Example 12 The difference from Example 8 is that the molar ratio of 4-nitro-4′-fluorobenzophenone to reduced iron powder was adjusted to 1:3, while the rest was the same as in Example 8. The amounts of raw materials, reaction conditions, and yields are shown in Table 2.

[0060] Example 13 The difference from Example 8 is that the molar ratio of 4-nitro-4′-fluorobenzophenone to water was adjusted to 1:20, while the rest was the same as in Example 8. The amounts of raw materials, reaction conditions, and yields are shown in Table 2.

[0061] Example 14 The difference from Example 8 is that the molar ratio of 4-nitro-4′-fluorobenzophenone to water was adjusted to 1:40, while the rest was the same as in Example 8. The amounts of raw materials, reaction conditions, and yields are shown in Table 2.

[0062] Example 15 The difference from Example 8 is that the reaction temperature was adjusted to 90°C and the reaction time was adjusted to 8 hours, while the rest was the same as Example 8. The amount of raw materials, reaction conditions and yield are shown in Table 2.

[0063] Example 16 The difference from Example 8 is that the reaction temperature was adjusted to 100°C and the reaction time was adjusted to 4 hours; otherwise, it was the same as Example 8. The amounts of raw materials, reaction conditions, and yields are shown in Table 2.

[0064] Comparative Example 3 The difference from Example 8 is that the molar ratio of 4-nitro-4′-fluorobenzophenone to reduced iron powder was adjusted to 1:1.0, while the rest was the same as in Example 8. The amounts of raw materials, reaction conditions, and yields are shown in Table 2.

[0065] Comparative Example 4 The difference from Example 8 is that the reaction temperature was adjusted to 75°C, otherwise it is the same as Example 8. The amount of raw materials, reaction conditions and yield are shown in Table 2.

[0066] Comparative Example 5 The difference from Example 8 is that the molar ratio of 4-nitro-4′-fluorobenzophenone to water was adjusted to 1:15 and the reaction temperature was adjusted to 105°C; otherwise, it was the same as Example 8. The amounts of raw materials, reaction conditions, and yields are shown in Table 2.

[0067] Table 2 Comparison of data from examples with different feed ratios and reaction temperatures in step S2

[0068] As shown in Table 2, the ratio of each material fed in step S2 is crucial to the reaction. The reaction temperature also determines the reaction time and product yield. Insufficient ammonium chloride slows the reaction rate and results in incomplete reaction; excessive amounts lead to a violent reaction, wasting solvent and increasing costs. The amount of iron powder directly affects the product yield. Insufficient iron powder leads to incomplete reaction, accumulation of intermediates, increased byproducts, and decreased yield. Excessive iron powder increases the difficulty of post-processing and costs. According to reaction kinetics, excessively low reaction temperatures result in slow or even halted reactions, with large amounts of raw materials remaining and low yields. Excessively high temperatures lead to a surge in byproducts and a sharp drop in yield. Based on the above experimental results, Example 8 shows the optimal process conditions for S2, and the obtained 4-amino-4′-fluorobenzophenone (II) is used in step S3.

[0069] Example 17 4,4′-Difluorobenzophenone was synthesized according to the dosages and reaction conditions in Table 3. The specific procedures were as follows: 1160 g (58 mol) of anhydrous hydrogen fluoride and 645 g (3.0 mol) of 4-amino-4′-fluorobenzophenone were added to a 3L carbon steel reactor equipped with a stirrer, thermometer, and reflux condenser. The mixture was stirred at 10-20℃ for 4 h. The temperature inside the reactor was then lowered to -5℃, and 211 g (3.06 mol) of sodium nitrite was slowly added. After reacting for 4 h, the temperature was slowly increased to 50℃ for a cracking reaction. After 20 h, the reaction was completed. The mixture was cooled to room temperature and extracted with petroleum ether. After separation, solvent removal, washing with water, and recrystallization yielded white crystalline 4,4′-difluorobenzophenone (III). The yields of 4,4′-difluorobenzophenone are shown in Table 3.

[0070] Example 18 The difference from Example 17 is that the molar ratio of 4-amino-4′-fluorobenzophenone to anhydrous hydrogen fluoride was adjusted to 1:15, while the rest was the same as in Example 17. The amounts of raw materials, reaction conditions, and yields are shown in Table 3.

[0071] Example 19 The difference from Example 17 is that the molar ratio of 4-amino-4′-fluorobenzophenone to anhydrous hydrogen fluoride was adjusted to 1:25, while the rest was the same as in Example 17. The amounts of raw materials, reaction conditions, and yields are shown in Table 3.

[0072] Example 20 The difference from Example 17 is that the molar ratio of 4-amino-4′-fluorobenzophenone to sodium nitrite was adjusted to 1:1.03, while the rest was the same as in Example 17. The amounts of raw materials, reaction conditions, and yields are shown in Table 3.

[0073] Example 21 The difference from Example 17 is that the molar ratio of 4-amino-4′-fluorobenzophenone to sodium nitrite was adjusted to 1:1.05, while the rest was the same as in Example 17. The amounts of raw materials, reaction conditions, and yields are shown in Table 3.

[0074] Example 22 The difference from Example 17 is that the diazotization reaction temperature was adjusted to -2°C, while the rest is the same as Example 17. The amounts of raw materials, reaction conditions, and yields are shown in Table 3.

[0075] Example 23 The difference from Example 22 is that the stirring time was adjusted to 5 hours, while the rest is the same as Example 22. The amount of raw materials, reaction conditions and yield are shown in Table 3.

[0076] Example 24 The difference from Example 22 is that the diazotization reaction time was adjusted to 5 hours and the pyrolysis reaction time was adjusted to 24 hours; otherwise, the process was the same as in Example 22. The feedstock amounts, reaction conditions, and yields are shown in Table 3.

[0077] Example 25 The difference from Example 22 is that the molar ratio of 4-amino-4′-fluorobenzophenone to anhydrous hydrogen fluoride was adjusted to 1:5, while the rest was the same as in Example 22. The amounts of raw materials, reaction conditions, and yields are shown in Table 3.

[0078] Example 26 The difference from Example 22 is that the molar ratio of 4-amino-4′-fluorobenzophenone to anhydrous hydrogen fluoride was adjusted to 1:40, and the pyrolysis temperature was adjusted to 40°C; otherwise, it was the same as Example 22. The amounts of raw materials, reaction conditions, and yields are shown in Table 3.

[0079] Example 27 The difference from Example 22 is that the molar ratio of 4-amino-4′-fluorobenzophenone to sodium nitrite was adjusted to 1:1, while the rest was the same as in Example 22. The amounts of raw materials, reaction conditions, and yields are shown in Table 3.

[0080] Example 28 The difference from Example 22 is that the molar ratio of 4-amino-4′-fluorobenzophenone to sodium nitrite was adjusted to 1:1.1, while the rest was the same as in Example 22. The amounts of raw materials, reaction conditions, and yields are shown in Table 3.

[0081] Example 29 The difference from Example 22 is that the pyrolysis temperature was adjusted to 10°C and the pyrolysis time was adjusted to 24 hours, while the rest were the same as in Example 22. The amount of raw materials, reaction conditions and yield are shown in Table 3.

[0082] Example 30 The difference from Example 29 is that the pyrolysis temperature was adjusted to 30°C and the pyrolysis time was adjusted to 24 hours; otherwise, it was the same as Example 22. The feed amounts, reaction conditions, and yields are shown in Table 3.

[0083] Example 31 The difference from Example 22 is that the pyrolysis temperature was adjusted to 60°C, while the rest is the same as in Example 22. The feed amounts, reaction conditions, and yields are shown in Table 3.

[0084] Comparative Example 6 The difference from Example 22 is that the pyrolysis temperature was adjusted to 5°C and the pyrolysis time was adjusted to 24 hours, while the rest was the same as Example 22. The amount of raw materials, reaction conditions and yield are shown in Table 3.

[0085] Comparative Example 7 The difference from Example 22 is that the pyrolysis temperature was adjusted to 65°C, while the rest is the same as in Example 22. The feed amounts, reaction conditions, and yields are shown in Table 3.

[0086] Table 3 Comparison of data from examples with different feed ratios and reaction temperatures in step S3

[0087] Table 3 shows that the amounts of anhydrous hydrogen fluoride and sodium nitrite in step S3 directly affect the yield and purity of the final product, 4,4′-difluorobenzophenone. When the amount of anhydrous hydrogen fluoride is too low, the pyrolysis reaction becomes more vigorous, resulting in more byproducts. Conversely, when the amount of solvent is too high, the reaction rate decreases, and the pyrolysis temperature cannot be reached, leading to a reduction in both the product yield and purity. A low diazotization reaction temperature results in a slow and incomplete reaction, ultimately affecting the product yield. A pyrolysis temperature that is too low slows or even halts the pyrolysis reaction, causing a sharp drop in product yield. Conversely, a high pyrolysis temperature increases side reactions, leading to a decrease in both yield and purity, while also increasing the amount of tar, making post-processing more difficult. With appropriate process conditions, a high-quality product with a purity exceeding 99.90% can be obtained.

[0088] The present invention has been described in detail above. Those skilled in the art will recognize that the invention can be practiced in a wide range of ways with equivalent parameters, concentrations, and conditions without departing from its spirit and scope. While specific embodiments have been provided, it should be understood that further modifications can be made to the invention. In summary, according to the principles of the invention, this application is intended to include any changes, uses, or improvements to the invention, including modifications made using conventional techniques known in the art that depart from the scope disclosed herein.

Claims

1. A method for synthesizing 4,4′-difluorobenzophenone, characterized in that, Includes the following steps: S1, 4-nitro-4′-chlorobenzophenone undergoes a substitution reaction with a fluorinating agent to give 4-nitro-4′-fluorobenzophenone; S2, 4-nitro-4′-fluorobenzophenone undergoes a nitro reduction reaction to yield 4-amino-4′-fluorobenzophenone; S3,4-amino-4′-fluorobenzophenone reacts with anhydrous hydrogen fluoride to form a salt, which is then subjected to a diazotization reaction under the action of sodium nitrite. After the reaction is completed, the temperature is raised to carry out a cracking reaction to obtain 4,4′-difluorobenzophenone.

2. The method for synthesizing 4,4'-difluorobenzophenone according to claim 1, characterized in that: The fluorinating agent is potassium fluoride, and the molar ratio of 4-nitro-4′-chlorobenzophenone to potassium fluoride is 1:(1-5).

3. The method for synthesizing 4,4′-difluorobenzophenone according to any one of claims 1-2, characterized in that: The substitution reaction is carried out in a solvent; And / or, the solvent is selected from one or more of gamma-butyrolactone, sulfolane, diethylene glycol monobutyl ether, diethylene glycol acetate, diethylene glycol butyl ether acetate, tributyl borate, N-methylpyrrolidone, and ethyl benzoate. And / or, the molar ratio of 4-nitro-4′-chlorobenzophenone to the solvent is 1:(5-20).

4. The method for synthesizing 4,4′-difluorobenzophenone according to any one of claims 1-3, characterized in that: The substitution reaction is carried out at a temperature of 150–200°C for 5–8 hours.

5. The method for synthesizing 4,4′-difluorobenzophenone according to any one of claims 1-4, characterized in that: The nitro reduction reaction is achieved by heating 4-nitro-4′-fluorobenzophenone in the presence of water, ammonium chloride, and reduced iron powder.

6. The method for synthesizing 4,4'-difluorobenzophenone according to claim 5, characterized in that: The molar ratio of 4-nitro-4′-fluorobenzophenone to ammonium chloride is 1:(1.1~3). And / or, the molar ratio of 4-nitro-4′-fluorobenzophenone to the reduced iron powder is 1:(1.1-3). And / or, the molar ratio of 4-nitro-4′-fluorobenzophenone to water is 1:(20-40).

7. The method for synthesizing 4,4′-difluorobenzophenone according to any one of claims 5-6, characterized in that: The nitro reduction reaction is carried out at a temperature of 90–100°C for 4–8 hours.

8. The method for synthesizing 4,4′-difluorobenzophenone according to any one of claims 1-7, characterized in that: The molar ratio of 4-amino-4′-fluorobenzophenone to anhydrous hydrogen fluoride is 1:(5-40). And / or, the molar ratio of 4-amino-4′-fluorobenzophenone to sodium nitrite is 1:(1.0 to 1.1).

9. The method for synthesizing 4,4′-difluorobenzophenone according to any one of claims 1-8, characterized in that: The diazotization reaction is carried out at a temperature of -5℃ to 20℃ for 6 to 10 hours. Further, the diazotization reaction is carried out as follows: 4-amino-4′-fluorobenzophenone and anhydrous hydrogen fluoride are first stirred and reacted at 10 to 20℃ for 3 to 5 hours, and then sodium nitrite is added and reacted at -5℃ to -2℃ for 3 to 5 hours.

10. The method for synthesizing 4,4′-difluorobenzophenone according to any one of claims 1-9, characterized in that: The pyrolysis reaction is carried out at a temperature of 10–60°C for 12–24 hours.

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