阅读说明：本技术 一种邻三氟甲基苯甲酰胺的制备方法 (Preparation method of o-trifluoromethyl benzamide ) 是由 潘强彪 陈静华 谢四维 李俊奇 于 2021-10-22 设计创作，主要内容包括：本发明公开了一种邻三氟甲基苯甲酰胺的制备方法。该制备方法包括如下步骤：(1)在有机溶剂中,将邻硝基三氟甲苯和氟化盐进行如下所示的脱硝氟代反应,得到邻氟三氟甲苯；(2)在有机溶剂中,将邻氟三氟甲苯和氰基化试剂进行如下所示的脱氟氰代反应,得到邻三氟甲基苯腈；(3)在碱存在下,将邻三氟甲基苯腈、过氧化氢进行如下所示的水解反应。该制备方法后处理简单,产物纯度高,杂质少,收率高。(The invention discloses a preparation method of o-trifluoromethyl benzamide. The preparation method comprises the following steps: (1) 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; (2) in an organic solvent, carrying out the defluorination cyanation reaction shown in the specification on ortho-fluorobenzotrifluoride and a cyanation reagent to obtain ortho-trifluoromethylbenzonitrile; (3) in the presence of a base, o-trifluoromethylbenzonitrile and hydrogen peroxide are subjected to the following reactionHydrolysis reaction of (3). The preparation method has the advantages of simple post-treatment, high product purity, less impurities and high yield.)

1. The preparation method of o-fluorobenzotrifluoride is characterized by comprising 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;

2. the method according to claim 1, wherein the denitration fluorination reaction satisfies one or more of the following conditions:

the condition 1, the organic solvent is 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 ether solvent is preferably tetrahydrofuran; the amide solvent is preferably one or more of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone and hexamethylphosphoramide; the sulfone solvent is preferably dimethyl sulfoxide and/or sulfolane;

condition 2, the fluoride salt is one or more of sodium fluoride, potassium fluoride, cesium fluoride, tetramethylammonium fluoride, and tetrabutylammonium fluoride;

the molar volume of the o-nitrobenzotrifluoride and the organic solvent is 1-3 mol/L under the condition of 3;

under the condition 4, the molar ratio of the fluoride salt to the o-nitrobenzotrifluoride is 1.0-2.5: 1;

and 5, reacting at the reaction temperature of 25-250 ℃.

3. The method according to claim 2, wherein the denitration fluorination reaction satisfies one or more of the following conditions:

condition 1, the organic solvent is N, N-dimethylformamide and/or sulfolane;

the fluoride salt is tetramethylammonium fluoride and/or potassium fluoride under the condition 2;

the molar volume of the o-nitrobenzotrifluoride and the organic solvent is 2-2.5 mol/L under the condition of 3;

under the condition 4, the molar ratio of the fluoride salt to the o-nitrobenzotrifluoride is 1.3-2.0: 1;

and 5, the reaction temperature of the reaction is 110-210 ℃.

4. The preparation method of o-trifluoromethylbenzonitrile is characterized by comprising the following steps:

(1) the preparation method of ortho-fluorobenzotrifluoride according to any one of claims 1-3, preparing ortho-fluorobenzotrifluoride;

(2) in an organic solvent, carrying out the defluorination cyanation reaction shown in the specification on ortho-fluorobenzotrifluoride and a cyanation reagent to obtain ortho-trifluoromethylbenzonitrile;

5. the process for producing o-trifluoromethylbenzonitrile according to claim 4, wherein the dehydrofluorination reaction satisfies one or more of the following conditions:

the condition 1, the organic solvent is 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 ether solvent is preferably tetrahydrofuran; the amide solvent is preferably one or more of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone and hexamethylphosphoramide; the sulfone solvent is preferably dimethyl sulfoxide and/or sulfolane;

the cyanation reagent is sodium cyanide or potassium cyanide under the condition 2;

the condition 3 is that the molar volume of the o-fluorotrifluorotoluene and the organic solvent is 1-3 mol/L;

the molar ratio of the cyanation reagent to the o-fluorobenzotrifluoride is 1.0-2.0: 1 under the condition 4;

and 5, reacting at the reaction temperature of 50-200 ℃.

6. The process for producing o-trifluoromethylbenzonitrile according to claim 5, wherein the dehydrofluorination reaction satisfies one or more of the following conditions:

the condition 1, the organic solvent is N, N-dimethylformamide;

the molar volume of the o-fluorotrifluorotoluene and the organic solvent is 2-2.5 mol/L under the condition 2;

the molar ratio of the cyanation reagent to the o-fluorobenzotrifluoride is 1.1-1.6: 1 under the condition of 3;

condition 4, the reaction temperature of the reaction is 90 ℃ to 120 ℃, for example, 100 ℃.

7. The preparation method of o-trifluoromethyl benzamide is characterized by comprising the following steps:

(1) preparing ortho-trifluoromethyl benzonitrile according to the method for preparing ortho-trifluoromethyl benzonitrile as claimed in any of claims 4 to 6;

(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;

8. the process for the preparation of ortho-trifluoromethylbenzamide according to claim 7, wherein the hydrolysis reaction satisfies one or more of the following conditions:

in the condition 1, the mass concentration of the hydrogen peroxide is 27 to 50 percent, such as 30 percent;

condition 2, the molar ratio of hydrogen peroxide to ortho-trifluoromethylbenzonitrile is 2.0 to 3.0:1, such as 2.5 to 2.8: 1;

condition 3, the base is one of sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide, for example, sodium hydroxide;

the condition 4 is that the pH of the reaction solution of the reaction is 10-13, such as 11-12;

the reaction temperature is 30-90 ℃, for example, 40-50 ℃;

condition 6, the solvent is water; part of the solvent may be used with the base to form a base solution; the alkali solution preferably has a mass concentration of 5% to 30%, for example 20%.

9. The preparation method of o-trifluoromethyl benzamide is characterized by comprising the following steps:

(1) in an organic solvent, carrying out the defluorination cyanation reaction shown in the specification on ortho-fluorobenzotrifluoride and a cyanation reagent to obtain ortho-trifluoromethylbenzonitrile;

(2) in the presence of alkali, o-trifluoromethylbenzonitrile and hydrogen peroxide are subjected to hydrolysis reaction as shown below;

the conditions of the defluorination cyanation reaction are as defined in any one of claims 4 to 6; the conditions for the hydrolysis reaction are as defined in claim 7 or 8.

10. The preparation method of o-trifluoromethylbenzonitrile is characterized by comprising the following steps: in an organic solvent, carrying out the defluorination cyanation reaction shown in the specification on ortho-fluorobenzotrifluoride and a cyanation reagent to obtain ortho-trifluoromethylbenzonitrile;

the conditions for the decafluorocyanation reaction are as defined in any one of claims 4 to 6.

Technical Field

The invention relates to a preparation method of o-trifluoromethyl benzamide.

Background

The o-trifluoromethyl benzamide is a white solid and is an important fluorine-containing fine chemical intermediate. The synthesis method of the o-trifluoromethyl benzamide has few domestic and foreign literature reports, the existing method for synthesizing the intermediate mainly uses o-trifluoromethyl benzoic acid as a raw material, the o-trifluoromethyl benzoyl chloride is obtained by acylation reaction of the o-trifluoromethyl benzoic acid and thionyl chloride, and then the o-trifluoromethyl benzamide is obtained by amidation reaction of the o-trifluoromethyl benzoic acid and ammonia.

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.