Preparation method of m-trifluoromethyl acetophenone

Abstract

The invention discloses a preparation method of m-(trifluoromethyl) acetophenone. The technical problem to be solved by the invention is to overcome the defects of expensive reagents, more reaction steps, low yield, high safety risk, more three wastes, difficulty in large-scale industrial production and the like in the preparation of the 3-trifluoromethyl acetophenone by the existing synthesis method. The invention provides the preparation method of the 3-trifluoromethyl acetophenone. The preparation method provided by the invention has the advantages of easily available raw materials, mild reaction conditions, high product yield and purity, convenience in operation, safety, environment friendliness and suitability for industrial production.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic chemistry, in particular to a preparation method of m-trifluoromethylacetophenone. BACKGROUND

[0002] M-trifluoromethylacetophenone is an important intermediate of organic fluorides, which is widely used in the fields of medicine, pesticide, chemical industry, etc. Its molecular formula is C9H7F3O, and the relative molecular mass is 188.15.

[0003] M-trifluoromethylacetophenone is a colorless or light yellow liquid, which is mainly used in the fields of pesticide, medicine, liquid crystal material, etc. It is not only a key intermediate for synthesizing methoxy propenoate compounds, but also an important raw material for synthesizing medicine and dyes.

[0004] M-trifluoromethylacetophenone is also a key intermediate of triflumizole. The compound contains trifluoromethyl, and the trifluoromethyl containing C-F bond has high fat solubility, high electronegativity, good metabolic stability and bioavailability, and is widely used in drugs, pesticides and functional materials. In addition, some compounds containing trifluoromethyl also have the effect of stimulant or sedative.

[0005] According to the reports at home and abroad, the current preparation methods of m-trifluoromethylacetophenone mainly include the following methods:

[0006] ①In the patent document CN118388332A, 2-chloro-5-(trifluoromethyl)acetophenone is used as raw material, methanol is used as solvent, sodium carbonate and expensive palladium-carbon are used as catalyst, and high-pressure hydrogenation dechlorination is carried out to obtain 2-bromo-5-fluorotoluene. The reaction effect of this method is good, but the catalyst is expensive, and the raw material is difficult to obtain.

[0007]

[0008] ②In the patent document CN102690180B, trifluorotoluene is used as raw material, cuprous chloride, n-butyllithium and acetyl chloride are added under ultra-low temperature conditions to carry out acylation reaction, then the pH is adjusted by inorganic acid, and finally the target product is obtained by rectification. The reaction conditions of this method are harsh, the reagent n-butyllithium is expensive, the waste treatment has high pollution risk, and it is not suitable for industrial large-scale production.

[0009]

[0010] ③The patent CN101161621A reports that halogenated trifluorotoluene is used as raw material, such as m-chlorotrifluorotoluene, which is reacted with vinyl ether (vinyl butyl ether) in the presence of palladium acetate, Styrene-DVB (D301 R) resin and dimethyl sulfoxide to obtain m-trifluoromethylacetophenone. The subsequent separation of this method is difficult, and the economic efficiency and safety of industrialization are insufficient.

[0011]

[0012] J. Am. Chem. Soc. 1948, 70, 12, 4020-4023 reported that m-trifluoromethylbenzonitrile reacted with Grignard reagent methylmagnesium bromide / methylmagnesium iodide in ethyl ether solvent to form m-trifluoromethylacetophenone.

[0013] It can be seen that the preparation method of m-trifluoromethylacetophenone in the prior art has the defects of expensive reagents, difficult post-treatment, great pollution risk of waste treatment, limited large-scale process production, low reaction yield and complicated steps, which need to be solved urgently. SUMMARY

[0014] The technical problem to be solved by the present application is to overcome the defects of the prior art, such as expensive reagents, multiple reaction steps, low yield, high safety risk, much waste, and difficult large-scale industrial production, and to provide a preparation method of m-trifluoromethylacetophenone. The preparation method provided by the present application has the advantages of easy raw materials, mild reaction conditions, high yield and purity of the product, convenient operation, safety and environmental protection, and is suitable for industrial production.

[0015] The present application solves the above technical problems by the following technical solutions.

[0016] The present application provides a preparation method of m-trifluoromethylacetophenone, which comprises the following steps:

[0017] In a solvent, an organometallic reagent is subjected to a nucleophilic addition reaction with m-trifluoromethylbenzonitrile in the presence of a catalyst to obtain m-trifluoromethylacetophenone;

[0018] .

[0019] The solvent can be a conventional solvent for such reactions in the art, preferably an ether solvent. The ether solvent is preferably selected from one or more of ethyl ether, tetrahydrofuran and 2-methyltetrahydrofuran, more preferably 2-methyltetrahydrofuran.

[0020] The molar volume ratio of the m-trifluoromethylbenzonitrile to the solvent is preferably 1:(0.1-1) mol / L, more preferably 1:(0.1-0.3) mol / L, for example 1:0.17 mol / L.

[0021] The catalyst is preferably a metal halide, further preferably LiCl or ZnCl2, for example anhydrous LiCl, anhydrous ZnCl2, a tetrahydrofuran solution of ZnCl2 or a methyltetrahydrofuran solution of ZnCl2, more preferably anhydrous LiCl or anhydrous ZnCl2.

[0022] The molar ratio of the catalyst to the m-trifluoromethylbenzonitrile is preferably (0.01-0.3): 1, more preferably (0.05-0.2): 1, for example 0.01:1, 0.02:1, 0.03:1, 0.05:1, 0.1:1 or 0.2:1.

[0023] The organometallic reagent can be a conventional organometallic reagent for such a reaction, and is preferably a methyl lithium reagent or a methyl Grignard reagent, for example methyl lithium, methyl magnesium chloride, methyl magnesium bromide or methyl magnesium iodide.

[0024] The molar ratio of the organometallic reagent to the m-trifluoromethylbenzonitrile is preferably (1-3): 1, more preferably (1.1-2): 1, for example 1.3:1, 1.5:1 or 1.6:1.

[0025] The organometallic reagent is preferably dissolved in the solvent (reaction solvent of the present application) and added in the form of an organometallic reagent solution by dropwise addition. The concentration of the organometallic reagent solution is preferably 1-10 mol / L, further preferably 2-6 mol / L, for example 2 mol / L, 3 mol / L or 6 mol / L.

[0026] The catalyst and the organometallic reagent are preferably selected from any of the following combinations:

[0027] Combination 1: anhydrous LiCl and methyl magnesium chloride;

[0028] Combination 2: anhydrous LiCl and methyl magnesium bromide;

[0029] Combination 3: anhydrous LiCl and methyl magnesium iodide;

[0030] Combination 4: anhydrous LiCl and methyl lithium;

[0031] Combination 5: anhydrous ZnCl2and methyl magnesium chloride.

[0032] In the combination 1, combination 2, combination 3 and combination 4, the molar ratio of the catalyst to the organometallic reagent is preferably 1:(5-25), further preferably 1:(10-20), for example 1:15.

[0033] In the combination 5, the molar ratio of the catalyst to the organometallic reagent is preferably 1:(5-15), further preferably 1:(6-8), for example 1:7.5.

[0034] The feeding temperature of the nucleophilic addition reaction can be -15 to 0°C, preferably -5 to 0°C, for example -5°C.

[0035] The reaction temperature of the nucleophilic addition reaction can be 50-80°C, preferably 65-80°C, for example 75°C.

[0036] The progress of the nucleophilic addition reaction can be monitored by using the conventional detection method in the art, and GC is preferred in the present application. The end point of the progress of the nucleophilic addition reaction is that the content of the m-trifluoromethylbenzonitrile in the reaction solution is less than 0.05% (area normalization).

[0037] The preparation method preferably comprises the following steps:

[0038] The nucleophilic addition reaction is carried out by sequentially adding the catalyst and the organometallic reagent to the mixed solution of the m-trifluoromethylbenzonitrile and the solvent.

[0039] The preparation method more preferably comprises the following steps:

[0040] The nucleophilic addition reaction is carried out by sequentially adding the catalyst and the mixed solution of the organometallic reagent and the solvent under temperature control to the mixed solution of the m-trifluoromethylbenzonitrile and the solvent.

[0041] The temperature control can be controlled to be -15-5°C, preferably -15-0°C, more preferably -5-0°C, for example -5°C.

[0042] The nucleophilic addition reaction can further comprise post-treatment after the reaction. The post-treatment can be the conventional post-treatment method for such reactions in the art, and the present application preferably comprises the following steps:

[0043] After the nucleophilic addition reaction, the solvent is recovered, a hydrolysis reaction is carried out, the phases are separated, the oil phase is washed with alkali, the phases are separated again, the oil phase is rectified, and the m-trifluoromethylacetophenone is obtained.

[0044] In the post-treatment, the recovery of the solvent can be the conventional recovery operation for such reactions in the art.

[0045] In the post-treatment, the hydrolysis reaction is preferably carried out under acidic conditions. The acidic conditions are preferably obtained by adding an acidic reagent.

[0046] In the hydrolysis reaction, the acidic reagent can be the acidic reagent commonly used in the post-treatment of such reactions in the art, preferably a hydrochloric acid solution and / or a sulfuric acid solution, and further preferably a hydrochloric acid solution.

[0047] In the hydrochloric acid solution, the mass fraction of hydrochloric acid is preferably 15%-25%, for example 20%.

[0048] The molar volume ratio of the m-trifluoromethylbenzonitrile to the acidic reagent is preferably 3-7 mol / L, further preferably 5-6 mol / L, for example 5.8 mol / L.

[0049] The temperature of the hydrolysis reaction can be the temperature conventional for such reactions in the art, preferably 70-80°C.

[0050] The progress of the hydrolysis reaction can be monitored by conventional methods in the art, generally taking the disappearance of the starting material or the lack of further reaction as the end point of the reaction; the reaction time of the hydrolysis reaction can be 3-10h, preferably 4-8h, for example 5-6h.

[0051] In the post-treatment, the phase separation operation can be the phase separation operation conventional for such reactions in the art.

[0052] In the post-treatment, the basic reagent added in the alkali washing can be the basic solution commonly used in the post-treatment of such reactions in the art, preferably saturated sodium bicarbonate solution, sodium carbonate solution, sodium hydroxide solution or potassium hydroxide solution, further preferably saturated sodium bicarbonate solution. The alkali washing is preferably terminated when the pH of the oil phase is 7-10. The amount of the saturated sodium bicarbonate solution is preferably 1-5 times the mass of the oil phase, more preferably 1-3 times the mass of the oil phase.

[0053] The operation of the present application is not explicitly limited in temperature, generally being carried out at room temperature (0-40°C, preferably 10-30°C).

[0054] On the basis of not violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined, i.e. obtaining each preferred example of the present application.

[0055] The reagents and raw materials used in the present application are commercially available.

[0056] The positive progress effect of the present application is in that:

[0057] (1) the reaction condition is mild and the operation is simple;

[0058] (2) the use of catalyst improves the reaction conversion rate;

[0059] (3) the use of hydrolysis reaction for post-treatment improves the yield and purity of the product;

[0060] (4) the use of less expensive reagents and raw materials is safe and environmentally friendly. DETAILED DESCRIPTION

[0061] The present application will be further illustrated by the following examples, but the present application is not limited in the scope of the examples. The experimental methods not specified in the following examples are selected according to the conventional methods and conditions, or according to the instructions of the goods.

[0062] The parameters of the GC detection method in the following examples are as follows:

[0063]

[0064] Example 1

[0065]

[0066] In a 500 mL flask, 100 mL of 2-methyltetrahydrofuran and 100 g of m-trifluoromethylbenzonitrile (0.58 mol) were added with stirring. The mixture was cooled to -5 °C, and anhydrous LiCl (0.05 mol, 2.1 g) was added. Then, methylmagnesium chloride (0.75 mol, 251 mL, 3 M 2-methyltetrahydrofuran solution) was added dropwise. After the addition was complete, the mixture was stirred for 0.5 h, heated to reflux (75 °C), and the solvent was recovered. The mixture was cooled to room temperature, and 100 mL of 20% HCl solution was added. The mixture was heated to 75 °C, stirred for 6 h, cooled, and the phases were separated. The oil phase was washed with 50 mL of saturated sodium bicarbonate solution, and phase separation was continued. The resulting oil phase was distilled to obtain 101.2 g of m-trifluoromethylacetophenone, with a GC purity of 99.5% and a yield of 92%. 1 H NMR (600 MHz, CDCl3) 8.19 (s, 1H), 8.12 (d, 1H), 7.80 (d,1H), 7.60 (t,1H), 2.63 (s, 3H) ppm.

[0067] Example 2

[0068]

[0069] In a 500 mL flask, 100 mL of 2-methyltetrahydrofuran and 100 g of m-trifluoromethylbenzonitrile (0.58 mol) were added with stirring. The mixture was cooled to -5 °C, and anhydrous LiCl (0.05 mol, 2.1 g) was added. Methylmagnesium bromide (0.75 mol, 250 mL, 3 M 2-methyltetrahydrofuran solution) was then added dropwise. After the addition was complete, the mixture was stirred for 0.5 h, heated to reflux (75 °C), and the solvent was recovered. The mixture was cooled to room temperature, and 100 mL of 20% HCl solution was added. The mixture was heated to 75 °C, stirred for 5 h, cooled, and the phases were separated. The oil phase was washed with 50 mL of saturated sodium bicarbonate solution, and the phases were separated again. The resulting oil phase was distilled to obtain 100.1 g of m-trifluoromethylacetophenone with a GC purity of 99.4% and a yield of 91%.

[0070] Example 3

[0071]

[0072] In a 500 mL flask, 100 mL of 2-methyltetrahydrofuran and 100 g of m-trifluoromethylbenzonitrile (0.58 mol) were added with stirring. The mixture was cooled to -5 °C, and anhydrous LiCl (0.05 mol, 2.1 g) was added. Methylmagnesium iodide (0.75 mol, 125 mL, 6 M 2-methyltetrahydrofuran solution) was then added dropwise. After the addition was complete, the mixture was stirred for 0.5 h, heated to reflux (75 °C), and the solvent was recovered. The mixture was cooled to room temperature, and 100 mL of 20% HCl solution was added. The mixture was heated to 75 °C, stirred for 5 h, cooled, and the phases were separated. The oil phase was washed with 50 mL of saturated sodium bicarbonate solution, and the phases were separated again. The resulting oil phase was distilled to obtain 97.9 g of m-trifluoromethylacetophenone with a GC purity of 99.2% and a yield of 89%.

[0073] Example 4

[0074]

[0075] In a 500 mL flask, 100 mL of 2-methyltetrahydrofuran and 100 g of m-trifluoromethylbenzonitrile (0.58 mol) were added with stirring. The mixture was cooled to -5 °C, and anhydrous LiCl (0.05 mol, 2.1 g) was added. Methyllithium (0.75 mol, 375 mL, 2 M 2-methyltetrahydrofuran solution) was then added dropwise. After the addition was complete, the mixture was stirred for 0.5 h, heated to reflux (75 °C), and the solvent was recovered. The mixture was cooled to room temperature, and 100 mL of 20% HCl solution was added. The mixture was heated to 75 °C, stirred for 5 h, cooled, and the phases were separated. The oil phase was washed with 50 mL of saturated sodium bicarbonate solution, and the phases were separated again. The resulting oil phase was distilled to obtain 101.4 g of m-trifluoromethylacetophenone with a GC purity of 99.4% and a yield of 92.4%.

[0076] Example 5

[0077]

[0078] In a 500 mL flask, 100 mL of 2-methyltetrahydrofuran and 100 g of m-trifluoromethylbenzonitrile (0.58 mol) were added with stirring. The mixture was cooled to -5 °C, and anhydrous ZnCl2 (0.1 mol, 13.6 g) was added. Methylmagnesium chloride (0.75 mol, 251 mL, 3 M 2-methyltetrahydrofuran solution) was then added dropwise. After the addition was complete, the mixture was stirred for 0.5 h, heated to reflux (75 °C), and the solvent was recovered. The mixture was cooled to room temperature, and 100 mL of 20% HCl solution was added. The mixture was heated to 75 °C, stirred for 5 h, cooled, and the phases were separated. The oil phase was washed with 50 mL of saturated sodium bicarbonate solution, and the phases were separated again. The resulting oil phase was distilled to obtain 100.1 g of m-trifluoromethylacetophenone with a GC purity of 99.6% and a yield of 91.4%.

Claims

1. A method for preparing m-trifluoromethylacetophenone, comprising the following steps: In a solvent, in the presence of a catalyst, an organometallic reagent undergoes a nucleophilic addition reaction with m-trifluoromethylbenzonitrile to yield m-trifluoromethylacetophenone. 。 2. The preparation method according to claim 1, characterized in that, It meets one or more of the following conditions: (1) The solvent is an ether solvent; (2) The molar volume ratio of the m-trifluoromethylbenzonitrile to the solvent is 1:(0.1~1)mol / L; (3) The catalyst is a metal halide; (4) The molar ratio of the catalyst to the m-trifluoromethylbenzonitrile is (0.01~0.3):1; (5) The organometallic reagent is a methyllithium reagent or a methyl Grignard reagent; (6) The molar ratio of the organometallic reagent to the m-trifluoromethylbenzonitrile is (1~3):1; (7) The organometallic reagent is dissolved in the solvent and added dropwise in the form of an organometallic reagent solution; (8) The feeding temperature of the nucleophilic addition reaction is -15~0℃; (9) The reaction temperature of the nucleophilic addition reaction is 50~80℃.

3. The preparation method according to claim 2, characterized in that, It meets one or more of the following conditions: (1) The ether solvent is selected from one or more of diethyl ether, tetrahydrofuran and 2-methyltetrahydrofuran, preferably 2-methyltetrahydrofuran; (2) The molar volume ratio of the m-trifluoromethylbenzonitrile to the solvent is 1:(0.1~0.3)mol / L, preferably 1:0.17mol / L; (3) The catalyst is LiCl or ZnCl2, for example, anhydrous LiCl, anhydrous ZnCl2, a tetrahydrofuran solution of ZnCl2 or a methyltetrahydrofuran solution of ZnCl2, more preferably anhydrous LiCl or anhydrous ZnCl2; (4) The molar ratio of the catalyst to the m-trifluoromethylbenzonitrile is (0.05~0.2):1, preferably 0.01:1, 0.02:1, 0.03:1, 0.05:1, 0.1:1 or 0.2:1; (5) The organometallic reagent is methyllithium, methylmagnesium chloride, methylmagnesium bromide or methylmagnesium iodide; (6) The molar ratio of the organometallic reagent to the m-trifluoromethylbenzonitrile is (1.1-2):1, preferably 1.3:1, 1.5:1 or 1.6:1; (7) The concentration of the organometallic reagent solution is 1~10 mol / L, more preferably 2~6 mol / L, for example 2 mol / L, 3 mol / L or 6 mol / L; (8) The feeding temperature of the nucleophilic addition reaction is -5~0℃, for example -5℃; (9) The reaction temperature of the nucleophilic addition reaction is 65~80℃, for example 75℃.

4. The preparation method according to claim 3, characterized in that, The catalyst and the organometallic reagent are selected from any combination of the following: Combination 1: Anhydrous LiCl and methylmagnesium chloride; Combination 2: Anhydrous LiCl and methyl magnesium bromide; Combination 3: Anhydrous LiCl and methylmagnesium iodide; Combination 4: Anhydrous LiCl and methyllithium; Combination 5: Anhydrous ZnCl2 and methyl magnesium chloride.

5. The preparation method according to claim 4, characterized in that, It satisfies any of the following conditions: (1) In combination 1, combination 2, combination 3 and combination 4, the molar ratio of the catalyst to the organometallic reagent is 1:(5~25), more preferably 1:(10-20), for example 1:15; (2) In combination 5, the molar ratio of the catalyst to the organometallic reagent is 1:(5~15), more preferably 1:(6~8), for example 1:7.

5.

6. The preparation method according to claim 1, characterized in that, It includes the following steps: A nucleophilic addition reaction is carried out by sequentially adding a catalyst and an organometallic reagent to a mixed solution of m-trifluoromethylbenzonitrile and solvent. Preferably, it includes the following steps: A nucleophilic addition reaction was carried out by adding a catalyst and a mixture of organometallic reagent and solvent in sequence to a mixed solution of m-trifluoromethylbenzonitrile and solvent under temperature control. Preferably, the temperature control is -15~5℃, more preferably -15~0℃, and even more preferably -5~0℃, for example -5℃.

7. The preparation method according to claim 1, characterized in that, The nucleophilic addition reaction is followed by post-processing. Preferably, the post-processing includes the following steps: After the nucleophilic addition reaction is completed, the solvent is recovered, hydrolysis reaction is performed, phase separation is carried out, the oil phase is washed with alkali, phase separation is carried out again, and the oil phase is distilled to obtain m-trifluoromethylacetophenone.

8. The preparation method according to claim 7, characterized in that, It meets one or more of the following conditions: (1) The hydrolysis reaction is carried out under acidic conditions; preferably, the acidic conditions are obtained by adding an acidic reagent; (2) The temperature of the hydrolysis reaction is 70~80℃; (3) The reaction time of the hydrolysis reaction is 3~10h.

9. The preparation method according to claim 8, characterized in that, It meets one or more of the following conditions: (1) The acidic reagent is a hydrochloric acid solution and / or a sulfuric acid solution, with hydrochloric acid solution being more preferred; (2) The molar volume ratio of the m-trifluoromethylbenzonitrile to the acidic reagent is 3~7 mol / L, more preferably 5~6 mol / L, for example 5.8 mol / L; (3) The reaction time of the hydrolysis reaction is 4~8h.

10. The preparation method according to claim 9, characterized in that, It meets one or two of the following conditions: (1) When the acidic reagent is a hydrochloric acid solution, the mass fraction of hydrochloric acid in the hydrochloric acid solution is 15%~25%, for example, 20%; (2) The reaction time of the hydrolysis reaction is 5-6 hours.

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