A method for preparing 4,4'-difluorobenzophenone from 4-chlorofluorobenzene

Abstract

The present invention relates to a method for preparing 4,4'-difluorobenzophenone from 4-chlorofluorobenzene, which comprises the following steps: (1) Using 4-chlorofluorobenzene as the starting material, reacting with magnesium chips in a solvent to prepare a 4-fluorophenylmagnesium chloride solution; (2) Adding the 4-fluorophenylmagnesium chloride solution to a triphosgene solution, and reacting to obtain the target product 4,4'-difluorobenzophenone. In the present invention, the ketone carbonyl group is introduced through triphosgene, the reaction conditions are mild, the Friedel-Crafts reaction or diazotization reaction can be avoided, the use of aluminum trichloride or the generation of diazonium salts with explosion hazards can be avoided, the environmental pollution is small, the operation is safe and simple, and there is no corrosion to the equipment; the starting material 4-chlorofluorobenzene used has a wide source and low cost; the present invention has high yield and repeatability and is easy to be industrially produced.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and particularly relates to a method for preparing 4,4'-difluorobenzophenone from 4-chlorofluorobenzene. Background Art

[0002] 4,4'-Difluorobenzophenone, with the English name 4,4'-Difluorobenzophenone, abbreviated as DFBP, is the main monomer for synthesizing aromatic thermoplastic special engineering plastics (such as polyetheretherketone, polyetherketone, etc.), and is used to manufacture important components in aerospace, automobiles, etc. At the same time, DFBP is also an important pharmaceutical intermediate, used for synthesizing novel and potent cerebrovascular dilating drugs such as flunarizine and the anti-type 2 diabetes drug degliptin.

[0003] In recent years, in-depth research has been carried out on the synthesis process of DFBP at home and abroad, and numerous synthesis processes of DFBP have been developed. According to the principles of various synthesis routes, they can be roughly divided into methods such as Friedel-Crafts reaction method, catalytic carbonylation method, and fluorination method of 4,4'-disubstituted benzophenone.

[0004] However, the existing synthesis methods all have some deficiencies. For example, most synthesis methods use toxic and harmful reagents such as chlorine gas or hydrofluoric acid, which pollute the environment. In addition, the Friedel-Crafts reaction method requires a large amount of catalysts such as aluminum trichloride, and a large amount of hydrogen chloride gas is generated during the reaction and post-treatment process, which seriously corrodes the production equipment. The fluorination method of 4,4'-disubstituted benzophenone often needs to go through a diazotization reaction, and the generated diazonium salts are dangerous to explode.

[0005] Therefore, the current synthesis method of 4,4'-difluorobenzophenone still needs to be further improved. Summary of the Invention

[0006] The purpose of the present invention is to overcome the above technical deficiencies, provide a method for preparing 4,4'-difluorobenzophenone from 4-chlorofluorobenzene, and solve the technical problems of serious environmental pollution or high danger during the synthesis of 4,4'-difluorobenzophenone in the prior art.

[0007] To achieve the above technical purpose, the technical solution provided by the present invention is:

[0008] In the first aspect, the present invention provides a method for preparing 4,4'-difluorobenzophenone from 4-chlorofluorobenzene, comprising the following steps:

[0009] (1) Using 4-chlorofluorobenzene as the starting material, reacting with magnesium chips in a solvent to prepare a 4-fluorophenylmagnesium chloride solution;

[0010] (2) Adding the 4-fluorophenylmagnesium chloride solution to a triphosgene solution, and reacting to obtain the target product 4,4'-difluorobenzophenone.

[0011] Compared with the prior art, the beneficial effects of the present invention include:

[0012] In the present invention, the ketone carbonyl group is introduced by triphosgene, and the reaction conditions are mild. It can avoid Friedel-Crafts reaction or diazotization reaction, avoid using aluminum trichloride or generating diazonium salts with explosion hazards, cause little environmental pollution, is safe and simple to operate, and has no corrosion to equipment; the raw material 4-chlorofluorobenzene used has a wide source and low cost; the present invention has high yield and repeatability and is easy to industrialize. Description of the Drawings

[0013] Figure 1 1H NMR spectrum of 4,4'-difluorobenzophenone prepared in Example 1 of the present invention;

[0014] Figure 2 13C NMR spectrum of 4,4'-difluorobenzophenone prepared in Example 1 of the present invention;

[0015] Figure 3 Liquid phase spectrum of 4,4'-difluorobenzophenone prepared in Example 1 of the present invention. Detailed Embodiments

[0016] In order to make the objectives, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0017] A method for preparing 4,4'-difluorobenzophenone from 4-chlorofluorobenzene according to the present invention comprises the following steps:

[0018] (1) Using 4-chlorofluorobenzene as the starting material, reacting with magnesium chips to prepare 4-fluorophenylmagnesium chloride;

[0019] (2) Adding the 4-fluorophenylmagnesium chloride solution to the solution of triphosgene, and reacting to obtain the target product 4,4'-difluorobenzophenone.

[0020] The preparation method of 4,4'-difluorobenzophenone according to the present invention has the following reaction synthesis route:

[0021]

[0022] Among them, the possible mechanism of the second-step reaction is as shown in the following synthesis route:

[0023]

[0024] Preferably, for the 4-fluorophenylmagnesium chloride in step (1), its preparation method includes,

[0025] 4-chlorofluorobenzene and magnesium shavings are added to organic solvent A, and the reaction is initiated under the action of an initiator, and heated under reflux to prepare 4-fluorophenylmagnesium chloride.

[0026] Further preferably, the molar ratio of 4-chlorofluorobenzene to magnesium shavings is 1:(1-3), preferably 1:(1.2-1.5), more preferably 1:1.2, that is, the magnesium shavings are in excess, which is beneficial to the full reaction of 4-chlorofluorobenzene and the excess magnesium shavings are easy to separate.

[0027] Further preferably, organic solvent A is anhydrous tetrahydrofuran; the molar volume ratio of 4-chlorofluorobenzene to anhydrous tetrahydrofuran is (60-100) mmol:100 mL.

[0028] Further preferably, the initiator is iodine; the addition amount of iodine is 0.1%-0.3% of the mass of 4-chlorofluorobenzene.

[0029] Further preferably, the reaction temperature for initiating the reaction is 20-80 °C, more preferably 55-65 °C.

[0030] Further preferably, the reaction time for initiating the reaction is 2-6 h.

[0031] Preferably, in step (2), the 4-fluorophenylmagnesium chloride solution is added dropwise to the solution of triphosgene, and the target product 4,4'-difluorobenzophenone is obtained; the molar ratio of triphosgene to 4-fluorophenylmagnesium chloride is (0.2-1):1, further preferably (0.3-0.5):1, more preferably 0.4:1.

[0032] Preferably, in step (2), the reaction temperature is -80-0 °C, further preferably -40 °C to -10 °C; more preferably -40 °C.

[0033] Preferably, after dropping the 4-fluorophenylmagnesium chloride solution in step (2), the temperature is kept at -80-0 °C and the reaction is continued for 5-12 hours (during this process, when the peak area of the product 4,4'-difluorobenzophenone in the reaction solution no longer increases detected by GC, the reaction is stopped).

[0034] Preferably, in step (2), the triphosgene solution is prepared by dissolving triphosgene in organic solvent B, and organic solvent B is tetrahydrofuran, ether, methyl tert-butyl ether, n-hexane or toluene, etc.; organic solvent B is more preferably tetrahydrofuran.

[0035] Preferably, the concentration of the triphosgene solution in step (2) is 0.05-0.5 g / mL.

[0036] Preferably, after the reaction of 4-fluorophenylmagnesium chloride and triphosgene in step (2), the following post-treatment is also included:

[0037] After the reaction was completed, saturated ammonium chloride aqueous solution was slowly added to the reaction solution to quench the reaction. The temperature was raised to 20 - 25 °C, and after stirring for 5 minutes, the mixture was allowed to stand for liquid separation. The upper organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 mL × 2);

[0038] The organic phases were combined, dried over anhydrous sodium sulfate, and after filtering off the desiccant, the obtained organic phase was concentrated under reduced pressure using a rotary evaporator. The residue was recrystallized from ethanol to obtain 4,4'-difluorobenzophenone.

[0039] The present invention will be further described in detail below through specific examples.

[0040] Example 1:

[0041] (1) Preparation of 4-fluorophenylmagnesium chloride (tetrahydrofuran solution)

[0042] 2.3 g (96 mmol, 1.2 eq) of magnesium chips and 2 grains of elemental iodine (about 20 mg) were added to a 100 mL reaction flask. Anhydrous tetrahydrofuran (40 mL) was added to a solution of 10.4 g (80 mmol, 1.0 eq) of 4-chlorofluorobenzene, and after mixing evenly, it was poured into a constant pressure dropping funnel. Under nitrogen protection, the above 4-chlorofluorobenzene mixture (5 mL) was added dropwise to a 250 mL reaction flask, and the temperature was raised to 55 °C. When the color of the reaction solution changed from brown to colorless, it indicated that the reaction was initiated. The remaining mixture was continuously added dropwise at 55 °C. After dropping, the temperature was controlled at 55 °C and the reaction was carried out for 3 hours (only a small amount of magnesium chips remained);

[0043] Anhydrous tetrahydrofuran was added to the reaction solution to make the total volume 50 mL, and after stirring evenly, it was cooled to room temperature to obtain a 4-fluorophenylmagnesium chloride solution for standby.

[0044] (2) Preparation of 4,4'-difluorobenzophenone

[0045] 9.5 g (32 mmol, 0.4 eq) of triphosgene was added to a 250 mL reaction flask, and anhydrous tetrahydrofuran (50 mL) was added. After cooling to -40 °C, under nitrogen protection, the 4-fluorophenylmagnesium chloride solution obtained in (1) was added dropwise through a constant dropping funnel. After dropping, the temperature was controlled at -40 °C and stirring was continued for 12 hours;

[0046] 50 mL of saturated ammonium chloride aqueous solution was slowly added to the reaction solution to quench the reaction. The temperature was raised to 20 - 25 °C, and after stirring for 5 minutes, the mixture was allowed to stand for liquid separation. The upper organic phase was separated, and the aqueous phase was extracted with ethyl acetate (100 mL × 2);

[0047] The organic phases were combined, dried over anhydrous sodium sulfate, and after filtering off the desiccant, the obtained organic phase was concentrated under reduced pressure using a rotary evaporator. The residue was recrystallized from ethanol to obtain 7.9 g of 4,4'-difluorobenzophenone.

[0048] The total yield of 4,4'-difluorobenzophenone prepared by a two-step reaction is 90.5% based on 4-chlorofluorobenzene.

[0049] Figure 1 This is the 1H NMR spectrum of the 4,4'-difluorobenzophenone prepared in this example; 1 H NMR(400MHz,Chloroform-d)δ7.81(dd,J=8.8,5.4Hz,4H),7.16(t,J=8.6Hz,4H).

[0050] Figure 2 This is the 13C NMR spectrum of the 4,4'-difluorobenzophenone prepared in this example; 13 C NMR(101MHz,CDCl3)δ193.9,166.8,164.3,133.8,132.7,132.6,115.8,115.6,77.2.

[0051] From Figure 1 、 Figure 2 The NMR spectral data, it can be judged that the final product synthesized in the present invention is indeed 4,4'-difluorobenzophenone.

[0052] Figure 3 This is the liquid phase chromatogram of the 4,4'-difluorobenzophenone prepared in this example; From Figure 3 The liquid phase chromatogram, it can be seen that the purity of the 4,4'-difluorobenzophenone prepared in Example 1 of the present invention is 99.91%, indicating that the purity of the target product synthesized in the present invention is high.

[0053] Example 2:

[0054] The difference from Example 1 is only that in step (2), 23.7 g (80 mol, 1.0 eq) of triphosgene was added to obtain 6.6 g of 4,4'-difluorobenzophenone. The total yield of 4,4'-difluorobenzophenone in the two-step reaction is 75.6% based on 4-chlorofluorobenzene.

[0055] It can be seen from Example 1 and Example 2 that when the amount of triphosgene used is too large, the total yield of 4,4'-difluorobenzophenone will decrease, indicating that the amount of triphosgene used has an impact on the total yield of the target product; Considering from the aspects of cost and yield, the molar ratio of triphosgene to 4-fluorophenylmagnesium chloride in the present invention is (0.2 - 1):1, further preferably (0.3 - 0.5):1, and more preferably 0.4:1.

[0056] Example 3:

[0057] The difference from Example 1 is only that the reaction temperature in step (2) is -10°C, and 7.75 g of 4,4'-difluorobenzophenone is obtained. Based on 4-chlorofluorobenzene, the total yield of 4,4'-difluorobenzophenone in the two-step reaction is 88.8%.

[0058] Comparative Example 1:

[0059] The difference from Example 1 is only that the reaction temperature in step (2) is 25°C, and 5.4 g of 4,4'-difluorobenzophenone is obtained. Based on 4-chlorofluorobenzene, the total yield of 4,4'-difluorobenzophenone in the two-step reaction is 61.9%.

[0060] By changing the temperature in Example 1, Example 3, and Comparative Example 1 above, it can be seen that as the temperature rises, the yield of the final product obtained decreases; at the same time, when the temperature further decreases below -40°C, the equipment requirements are high, the energy consumption is high, and the reaction rate decreases. Considering comprehensively, the reaction temperature in step (2) of the present invention is further preferably -40°C to -10°C.

[0061] Comparative Example 2:

[0062] The difference from Example 1 is only that in step (2), the tetrahydrofuran solution of triphosgene is added dropwise to the 4-fluorophenylmagnesium chloride tetrahydrofuran solution obtained in step (1) through a constant-pressure dropping funnel, and 5.3 g of 4,4',4”-trifluorotriphenylmethanol is obtained, with a two-step yield of 63.2%. 4,4'-Difluorobenzophenone is not obtained.

[0063] It can be seen from Comparative Example 2 that when the tetrahydrofuran solution of triphosgene is added dropwise to the Grignard reagent, the Grignard reagent in the system is always in an excessive state. Therefore, the generated 4,4'-difluorobenzophenone will continue to react with the excessive Grignard reagent to generate 4,4',4”-trifluorotriphenylmethanol, indicating that the feeding order and raw material concentration have a significant impact on the product type, which may lead to side reactions or even the complete failure to generate the target product. Therefore, during the feeding of this step reaction, the Grignard reagent should always be in a non-excessive state, that is, the Grignard reagent is added dropwise to the tetrahydrofuran solution of triphosgene.

[0064] In summary, the present invention discloses a method for preparing 4,4'-difluorobenzophenone from 4-chlorofluorobenzene. Using 4-chlorofluorobenzene as the starting material, it reacts with magnesium chips to prepare 4-fluorophenylmagnesium chloride; the 4-fluorophenylmagnesium chloride solution is added dropwise to the solution of triphosgene to obtain the target product 4,4'-difluorobenzophenone. It has the following advantages:

[0065] (1) By introducing the ketone carbonyl group through triphosgene, the Friedel-Crafts reaction or diazotization reaction can be avoided, the use of aluminum trichloride or the generation of diazonium salts with explosion hazards can be avoided, the environmental pollution is small, and the operation is safe and simple;

[0066] (2) The raw material 4-chlorofluorobenzene used is a by-product recovered from the wastewater of a mature process, with low cost. The reaction conditions of the present invention are mild, the operation is simple and safe and controllable, the yield and repeatability are high, and it is easy to be industrially produced.

[0067] (3) The total yield of the two steps can reach over 88%, and the purity is over 99.9%.

[0068] Therefore, the reaction conditions of the present invention are mild, the operation is simple and safe and controllable, the yield and repeatability are high, and it is easy to be industrially produced.

[0069] The specific embodiments of the present invention described above do not constitute a limitation on the protection scope of the present invention. Any other corresponding changes and deformations made according to the technical concept of the present invention shall be included in the protection scope of the claims of the present invention.

Claims

1. A method for preparing 4,4'-difluorobenzophenone from 4-chlorofluorobenzene, characterized in that, It includes the following steps: (1) Using 4-chlorofluorobenzene as the starting material, reacting with magnesium chips in a solvent to prepare a 4-fluorophenylmagnesium chloride solution; (2) Adding the 4-fluorophenylmagnesium chloride solution to a triphosgene solution, and reacting to obtain the target product 4,4'-difluorobenzophenone; In step (2), the molar ratio of triphosgene to 4-fluorophenylmagnesium chloride is (0.2 - 1):1; In step (2), the 4-fluorophenylmagnesium chloride solution is added dropwise to the triphosgene solution; after the addition is completed, the reaction is carried out for 5 - 12 hours; In step (2), the reaction temperature is -80°C to 0°C.

2. The method for preparing 4,4'-difluorobenzophenone from 4-chlorofluorobenzene according to claim 1, characterized in that, Step (1) specifically includes: 4-chlorofluorobenzene and magnesium chips are in organic solvent A, and under the action of an initiator, they are heated and refluxed to prepare a 4-fluorophenylmagnesium chloride solution.

3. The method for preparing 4,4'-difluorobenzophenone from 4-chlorofluorobenzene according to claim 2, characterized in that, The organic solvent A is anhydrous tetrahydrofuran; the initiator is iodine.

4. The method for preparing 4,4'-difluorobenzophenone from 4-chlorofluorobenzene according to any one of claims 1-3, characterized in that, The molar ratio of the 4-chlorofluorobenzene to the magnesium chips is 1:(1 - 3); the reaction temperature of the 4-chlorofluorobenzene and the magnesium chips is 20 - 80°C, and the reaction time is 2 - 6 h.

5. The method for preparing 4,4'-difluorobenzophenone from 4-chlorofluorobenzene according to claim 1, characterized in that, In step (2), the triphosgene solution is prepared by dissolving triphosgene in organic solvent B. The organic solvent B is tetrahydrofuran, ether, methyl tert-butyl ether, n-hexane or toluene; the concentration of the triphosgene solution is 0.05 - 0.5 g / mL.

6. The method for preparing 4,4'-difluorobenzophenone from 4-chlorofluorobenzene according to claim 1, wherein After the reaction in step (2), it also includes quenching, separation, drying, concentration and recrystallization to obtain pure-phase 4,4'-difluorobenzophenone.

7. The method for preparing 4,4'-difluorobenzophenone from 4-chlorofluorobenzene according to claim 1, characterized in that, The reactions in step (1) and step (2) are both carried out under a protective atmosphere.

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