Disclosure of Invention
In order to solve the problems, the invention provides a method for synthesizing o-trifluoromethyl benzamide. The method takes ortho-nitrobenzotrifluoride as a raw material, carries out denitration and fluorination with fluoride salt to generate ortho-fluorobenzotrifluoride, carries out dehydrofluorination with a cyanation reagent to generate ortho-trifluoromethylbenzonitrile, and finally carries out hydrolysis reaction with hydrogen peroxide to generate the ortho-trifluoromethylbenzamide, wherein the purity is over 99.6 percent, the impurity types are few, and the product quality is stable.
The invention provides a preparation method of o-fluoro benzotrifluoride, which comprises the following steps: in an organic solvent, carrying out denitration and fluorination reaction on ortho-nitrobenzotrifluoride and fluoride salt as shown in the specification to obtain ortho-fluorobenzotrifluoride;
the organic solvent may be an aprotic polar solvent. The aprotic polar solvent can be one or more of a ketone solvent, an ether solvent, an amide solvent and a sulfone solvent. The ketone solvent is preferably acetone. The ethereal solvent is preferably tetrahydrofuran. The amide solvent is preferably one or more of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, and hexamethylphosphoramide, for example, N-dimethylformamide. The sulfone solvent is preferably dimethyl sulfoxide and/or sulfolane.
The fluoride salt may be one or more of sodium fluoride, potassium fluoride, cesium fluoride, tetramethylammonium fluoride and tetrabutylammonium fluoride, such as tetramethylammonium fluoride and/or potassium fluoride.
The organic solvent may be used in an amount conventional in the art for reactions of this type. The molar volume of the o-nitrobenzotrifluoride and the organic solvent can be 1-3 mol/L, such as 2-2.5 mol/L.
The molar ratio of the fluoride salt to the ortho-nitrobenzotrifluoride can be 1.0-2.5: 1, such as 1.3-2.0: 1.
The reaction temperature of the reaction can be 25-250 ℃, for example 110-210 ℃.
The progress of the reaction can be monitored by conventional test methods in the art (e.g., TLC, HPLC, GC, or NMR), and is generally determined as the end point of the reaction when ortho-nitrobenzotrifluoride is no longer reacted. The reaction time of the reaction can be 2.5 to 4 hours.
The reaction may also include the following post-treatment steps: filtration and separation of the product from the filtrate. The separation is preferably by distillation.
The invention also provides a preparation method of o-trifluoromethyl benzonitrile, which comprises the following steps:
(1) preparing o-fluorotrifluorotoluene according to the preparation method of o-fluorotrifluorotoluene;
(2) in an organic solvent, carrying out the defluorination cyanation reaction of the o-fluorobenzotrifluoride and a cyanation reagent as shown in the specification to obtain o-trifluoromethylbenzonitrile;
in the defluorination cyanation reaction, the organic solvent can be an aprotic polar solvent, and the aprotic polar solvent can be one or more of a ketone solvent, an ether solvent, an amide solvent and a sulfone solvent. The ketone solvent is preferably acetone. The ethereal solvent is preferably tetrahydrofuran. The amide solvent is preferably one or more of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, and hexamethylphosphoramide, for example, N-dimethylformamide. The sulfone solvent is preferably dimethyl sulfoxide and/or sulfolane.
In the defluorination cyanation reaction, the cyanation reagent can be sodium cyanide or potassium cyanide.
The organic solvent may be used in an amount conventional in the art for reactions of this type. The molar volume of the o-fluorobenzotrifluoride and the organic solvent can be 1-3 mol/L, such as 2-2.5 mol/L.
In the dehydrofluorination reaction, the molar ratio of the cyanation reagent to the o-fluorobenzotrifluoride may be 1.0-2.0: 1, for example, 1.1-1.6: 1.
The reaction temperature of the dehydrofluorination reaction can be 50-200 ℃, for example 90-120 ℃, and also for example 100 ℃.
The progress of the reaction of the dehydrofluorination can be monitored by a conventional test method in the art (e.g., TLC, HPLC, GC or NMR), and the end point of the reaction is usually determined when ortho-nitrobenzotrifluoride is no longer reacted. The reaction time of the defluorination and cyanation reaction can be 5-6 hours.
The defluorination cyanation reaction can also comprise the following post-treatment steps: filtration and separation of the product from the filtrate. The separation mode is preferably vacuum distillation.
The invention provides a preparation method of o-trifluoromethyl benzamide, which comprises the following steps:
(1) the o-trifluoromethyl benzonitrile is prepared according to the preparation method of the o-trifluoromethyl benzonitrile;
(2) in a solvent, in the presence of alkali, carrying out hydrolysis reaction on ortho-trifluoromethyl benzonitrile and hydrogen peroxide as shown in the specification to obtain ortho-trifluoromethyl benzamide;
in the hydrolysis reaction, the mass concentration of the hydrogen peroxide can be 27-50%, for example 30%.
In the hydrolysis reaction, the molar ratio of the hydrogen peroxide to the o-trifluoromethylbenzonitrile can be 2.0-3.0: 1, for example, 2.5-2.8: 1.
In the hydrolysis reaction, the base may be one conventionally used in the art, and is preferably one of sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide, such as sodium hydroxide. In the hydrolysis reaction, the pH of the reaction solution of the reaction can be 10-13, for example 11-12.
In the hydrolysis reaction, the adding time of the hydrogen peroxide can be 4-8 hours, such as 4.5-5 hours. The hydrolysis reaction is a two-phase reaction, and the reaction requires a certain mass transfer time.
The reaction temperature of the hydrolysis reaction can be 30-90 ℃, for example, 40-50 ℃.
In the hydrolysis reaction, the solvent may be water. Part of the solvent may be used to form an alkaline solution with the base. The alkali solution preferably has a mass concentration of 5% to 30%, for example 20%.
The hydrolysis reaction can also comprise the following post-treatment steps: filtering and drying.
The invention also provides a preparation method of the o-trifluoromethyl benzamide, which comprises the following steps:
(1) in an organic solvent, carrying out the defluorination cyanation reaction of the o-fluorobenzotrifluoride and a cyanation reagent as shown in the specification to obtain o-trifluoromethylbenzonitrile;
(2) in the presence of alkali, o-trifluoromethylbenzonitrile and hydrogen peroxide are subjected to hydrolysis reaction as shown below;
in the above-mentioned dehydrofluorination reaction and the above-mentioned hydrolysis reaction, the respective reaction conditions may be as described above.
The invention also provides a preparation method of the o-trifluoromethyl benzonitrile, which comprises the following steps: in an organic solvent, carrying out the defluorination cyanation reaction of the o-fluorobenzotrifluoride and a cyanation reagent as shown in the specification to obtain o-trifluoromethylbenzonitrile;
in the preparation method of the o-trifluoromethylbenzonitrile, each reaction condition can be as described above.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
(1) the invention provides a preparation method of o-trifluoromethyl benzamide and an intermediate thereof, which takes a byproduct o-nitrobenzotrifluoride generated when an enterprise produces m-nitrobenzotrifluoride as a raw material, exploits the potential value of the byproduct and carries out resource utilization on the byproduct.
(2) The method has the advantages of less three wastes, simple post-treatment, resource utilization of nitrite and fluoride produced in the preparation process, no use of organic solvent when preparing the o-trifluoromethyl benzamide through hydrolysis reaction, oxygen as a byproduct, simple post-treatment and environmental protection.
(3) The prepared o-trifluoromethyl benzamide has high purity, less impurities and high yield.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
In the following examples, DMF represents N, N-dimethylformamide.
Example 1
(1) Denitration fluorination
Adding o-nitrobenzotrifluoride (19.1g,0.10mol), anhydrous tetramethylammonium fluoride (12.1g,0.13mol) and 40mL of DMF (solvent) into a reaction flask, heating to 110 ℃, keeping the temperature for reaction for 2.5h, cooling to room temperature after the reaction is finished, filtering to remove generated potassium nitrite, evaporating 15.6g of colorless oily liquid o-fluorobenzotrifluoride from the filtrate, ensuring the purity to be 99.2 percent, obtaining the yield to be 95.1 percent, and then decompressing and recovering the DMF.
The product obtained was analyzed by GC comparison with a standard compound (purchased ortho-fluorobenzotrifluoride) and the retention time was consistent and was 2.233 min.
The GC analysis method was as follows:
item
|
Parameter(s)
|
Chromatographic column
|
OV-1701
|
Column length x column inner diameter x film thickness
|
30m×0.5mm×0.32μm
|
Vaporization chamber temperature/. degree.C
|
280
|
FID Detector temperature/. degree.C
|
280
|
Column box temperature/. degree.C
|
170
|
Sample size/. mu.L
|
0.1
|
Carrier gas
|
N2 |
Flow of carrier gas/(mL/min)
|
0.6
|
Air flow/(mL/min)
|
300
|
Hydrogen flow/(mL/min)
|
30
|
Split ratio
|
50:1 |
(2) Defluorination of cyanogen
Adding ortho-fluoro benzotrifluoride (16.4g,0.10mol), potassium cyanide (7.2g,0.11mol) and 40mL of DMF (dimethyl formamide) solvent into a reaction flask, heating to 100 ℃, keeping the temperature for 5 hours for reaction, cooling to room temperature after the reaction is finished, filtering to remove the generated potassium fluoride and unreacted potassium cyanide, carrying out vacuum rectification on the filtrate, recovering DMF, and obtaining 16.1g of o-trifluoromethylbenzonitrile as colorless oily liquid, wherein the purity is 99.3%, and the yield is 94.1%.
The prepared product was analyzed by LC comparison with a standard compound (purchased o-trifluoromethylbenzonitrile) and the retention time of both was consistent and was 4.208 min.
The LC analysis method was as follows:
item
|
Parameter(s)
|
Chromatographic column
|
ZORBAX Eclopse XDB-C18(4.6mm*250mm*5μm)
|
Column temperature/. degree.C
|
35
|
Mobile phase
|
Water methanol 30:70(v/v)
|
Flow rate/(mL/min)
|
1.0mL/min
|
Sample size/. mu.L
|
1
|
Detection wavelength/nm
|
254
|
Detection time/min
|
13 |
(3) Hydrolysis
Adding the prepared o-trifluoromethylbenzonitrile (84g,0.49mol) into a flask, slowly dropwise adding 139g of aqueous solution of hydrogen peroxide (30%, 139g,1.23mol) into the flask under stirring, adjusting the pH of a reaction system to 11-12 by using aqueous solution of sodium hydroxide (30%) during reaction, controlling the reaction temperature to 40-50 ℃, and after 5h of dropwise addition of the aqueous solution of hydrogen peroxide, generating a large amount of white needle-shaped crystals. Stopping reaction, filtering, and drying a filter cake to obtain 91g of white solid o-trifluoromethyl benzamide, wherein the purity is 99.6 percent, and the yield is 98 percent.
The product of the preparation was analyzed by LC comparison with a standard compound (purchased o-trifluoromethylbenzamide) and the retention time was consistent with 2.747 min.
The LC analysis method is the same as that in the step (2).
Example 2
(1) Denitration fluorination
Adding o-nitrobenzotrifluoride (19.1g,0.10mol), 11.6g anhydrous potassium fluoride (11.6g,0.20mol) and 50mL solvent sulfolane into a reaction flask, heating to 210 ℃, keeping the temperature for reaction for 4h, cooling to room temperature after the reaction is finished, filtering to remove generated potassium nitrite and unreacted potassium fluoride, evaporating 15.3g of colorless oily liquid o-fluorobenzotrifluoride from the filtrate, ensuring the purity to be 99.0 percent and the yield to be 93.3 percent, and then decompressing and recovering DMF.
The product obtained was analyzed by GC comparison with a standard compound (purchased ortho-fluorobenzotrifluoride) and the retention time was consistent and was 2.233 min.
The GC analysis method was the same as that in step (1) of example 1.
(2) Defluorination of cyanogen
Adding ortho-fluoro benzotrifluoride (16.4g,0.10mol), sodium cyanide (7.8g,0.16mol) and 50mL of DMF (dimethyl formamide) solvent into a reaction flask, heating to 120 ℃, keeping the temperature for reaction for 6h, cooling to room temperature after the reaction is finished, filtering to remove the generated sodium fluoride and unreacted sodium cyanide, carrying out reduced pressure rectification on the filtrate, recovering DMF, and obtaining 16.6g of o-trifluoromethylbenzonitrile as colorless oily liquid, wherein the purity is 99.1%, and the yield is 97.1%.
The prepared product was analyzed by LC comparison with a standard compound (purchased o-trifluoromethylbenzonitrile) and the retention time of both was consistent and was 4.208 min.
The LC analysis method was the same as that in step (2) of example 1.
(3) Hydrolysis
Adding the prepared o-trifluoromethylbenzonitrile (100.8g,0.53mol) into a flask, slowly dropwise adding an aqueous solution of hydrogen peroxide (50%, 100.8g,1.48mol) into the flask under stirring, adjusting the pH of a reaction system to 11-12 by using an aqueous solution of sodium hydroxide (20%) during reaction, controlling the reaction temperature to be 40-50 ℃, and after the dropwise addition of the aqueous solution of hydrogen peroxide is finished for 4.5h, generating a large amount of white needle-shaped crystals. Stopping reaction, filtering, and drying the filter cake to obtain 110.3g of white solid o-trifluoromethyl benzamide, wherein the purity is 99.9 percent and the yield is 99 percent.
The product of the preparation was analyzed by LC comparison with a standard compound (purchased o-trifluoromethylbenzamide) and the retention time was consistent with 2.747 min.
The LC analysis method was the same as that in step (2) of example 1.