A preparation method of o-trifluoromethylbenzamide and its intermediate

Abstract

The invention discloses a preparation method of o-trifluoromethylbenzamide and an intermediate thereof. The invention provides a preparation method of o-trifluoromethylbenzonitrile, which comprises the following steps: in a non-protonic polar solvent, o-bromobenzotrifluoride and cuprous cyanide are subjected to a cyanation substitution reaction as shown below to obtain the o-trifluoromethylbenzonitrile. The invention uses o-trifluoromethylaniline, a byproduct generated when an enterprise produces m-trifluoromethylaniline, as a raw material, explores the potential value of the byproduct, utilizes the byproduct as a resource, has less three wastes, is simple to post-process, and the cuprous bromide, a byproduct generated during the preparation process, can be recycled.

Description

Technical Field

[0001] The invention relates to a preparation method of o-trifluoromethylbenzamide and an intermediate thereof. Background Art

[0002] o-Trifluoromethylbenzamide is a white solid and an important fluorine-containing fine chemical intermediate. There are few reports on the synthesis of o-trifluoromethylbenzamide in domestic and foreign literature. At present, the method for synthesizing this intermediate mainly uses o-trifluoromethylbenzoic acid as a raw material, and reacts with thionyl chloride to obtain o-trifluoromethylbenzoyl chloride, and then reacts with ammonia to obtain o-trifluoromethylbenzamide. The starting raw material o-trifluoromethylbenzoic acid used in this method is expensive, and the acylation reaction and amidation reaction produce a lot of three wastes, which is not conducive to environmental protection. Summary of the invention

[0003] The technical problem to be solved by the present invention is that the raw material price in the existing preparation method is high, and the three wastes generated in the acylation reaction and the amidation reaction are large, which is not conducive to environmental protection. Therefore, the present invention provides a preparation method of o-trifluoromethylbenzamide and its intermediate. The method uses o-trifluoromethylaniline as a raw material, and performs a Sandmeyer bromination reaction with hydrobromic acid and cuprous bromide to generate o-bromotrifluorotoluene, then performs a cyanation substitution reaction with a cyaniding agent to generate o-trifluoromethylbenzonitrile, and finally performs a hydrolysis reaction with hydrogen peroxide to generate o-trifluoromethylbenzamide, with a purity of more than 99.6%. The raw material used in the method is a by-product generated when producing m-trifluoromethylaniline, the three wastes generated in the preparation process are less, and the post-treatment is simple. The cuprous bromide by-product of the bromination reaction can be recycled, which is suitable for industrial production.

[0004] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0005] The present invention provides a method for preparing o-trifluoromethylbenzonitrile, which comprises the following steps: in a non-protonic polar solvent, subjecting o-bromotrifluorotoluene and cuprous cyanide to a cyanation substitution reaction as shown below to obtain the o-trifluoromethylbenzonitrile;

[0006]

[0007] In the cyanation substitution reaction, the aprotic polar solvent may be an amide solvent and / or a sulfoxide solvent; the amide solvent is preferably N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone; the sulfoxide solvent is preferably dimethyl sulfoxide; the aprotic polar solvent may be dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone, such as N,N-dimethylformamide or dimethyl sulfoxide.

[0008] In the cyanation substitution reaction, the reaction temperature may be 140°C to 200°C, preferably 150°C to 190°C.

[0009] In the cyanation substitution reaction, the volume ratio of the aprotic polar solvent to the o-bromotrifluorotoluene can be a conventional volume ratio for such reactions in the art, preferably (1-3):1, more preferably (1-1.5):1, such as 1.1:1 or 1.4:1.

[0010] In the cyanation substitution reaction, the molar ratio of the cuprous cyanide to the o-bromotrifluorotoluene can be (1.0-1.1):1, preferably (1.0-1.06):1, such as 1.03 or 1.06.

[0011] In the cyanation substitution reaction, the reaction temperature may be reflux temperature.

[0012] The cyanation substitution reaction may further include post-treatment, and the post-treatment includes the following steps: suction filtration, distillation, and rectification.

[0013] The preparation method of o-trifluoromethylbenzonitrile may further include the following steps: subjecting a diazonium salt solution of o-trifluoromethylaniline to a bromination reaction with cuprous bromide and hydrobromic acid as shown below to obtain the o-bromotrifluorotoluene;

[0014]

[0015] In the bromination reaction, the diazonium salt solution of o-trifluoromethylaniline is obtained by mixing o-trifluoromethylaniline, hydrobromic acid and sodium nitrite.

[0016] In the bromination reaction, the mixing may further include the following steps: adding sodium nitrite dropwise into a mixed solution A; the mixed solution A is a mixed solution of o-trifluoromethylaniline and hydrobromic acid.

[0017] In the bromination reaction, the dropping temperature can be -5°C to 5°C, preferably 0°C.

[0018] In the bromination reaction, the molar ratio of the sodium nitrite to o-trifluoromethylaniline may be (1.05-1.1):1, for example, 1.05:1 or 1.1:1.

[0019] In the bromination reaction, the sodium nitrite may be an aqueous solution of sodium nitrite, and its mass concentration may be 20% to 40%, for example 30%.

[0020] In the bromination reaction, the mass concentration of the hydrobromic acid may be 30% to 50%, for example 40%.

[0021] In the bromination reaction, the molar ratio of the hydrobromic acid to the o-trifluoromethylaniline may be (3.0-4.0):1, such as 3.5:1 or 3.9:1.

[0022] In the bromination reaction, the molar ratio of the cuprous bromide to the o-trifluoromethylaniline can be (0.15-0.50):1, preferably (0.2-0.4):1, for example 0.2:1.

[0023] In the bromination reaction, the cuprous bromide may be cuprous bromide produced as a byproduct in the cyanidation substitution reaction.

[0024] In the bromination reaction, the molar ratio of the o-trifluoromethylaniline to the hydrobromic acid may be (3-4):1, for example 3.5:1.

[0025] In the bromination reaction, the temperature of the bromination reaction can be room temperature.

[0026] The bromination reaction may further include post-treatment, and the post-treatment includes the following steps: liquid separation, alkali washing, water washing, and distillation.

[0027] The present invention provides a method for preparing o-trifluoromethylbenzamide, which comprises the following steps:

[0028] (1) diazonium salt solution of o-trifluoromethylaniline

[0029] With cuprous bromide and hydrobromic acid, a bromination reaction is carried out as shown below to obtain o-bromotrifluorotoluene as shown below,

[0030]

[0031] (2) in an organic solvent, the o-bromotrifluorotoluene obtained in step (1) and cuprous cyanide are subjected to a cyanation substitution reaction as shown below to obtain o-trifluoromethylbenzonitrile as shown below,

[0032]

[0033] (3) in a solvent, in the presence of a base, subjecting the o-trifluoromethylbenzonitrile obtained in step (2) to a hydrolysis reaction as shown below in the presence of hydrogen peroxide to obtain o-trifluoromethylbenzamide as shown below;

[0034]

[0035] The reaction conditions of the bromination reaction are as described above.

[0036] In the cyanation substitution reaction, the organic solvent is a non-protonic polar solvent.

[0037] The other reaction conditions of the cyanation substitution reaction are as described above.

[0038] In the hydrolysis reaction, the pH of the reaction may be 10-13.

[0039] In the hydrolysis reaction, the mass concentration of the hydrogen peroxide may be 30% to 50%, such as 30% or 50%.

[0040] In the hydrolysis reaction, the molar ratio of the hydrogen peroxide to the o-trifluoromethylbenzonitrile may be (2-3):1, for example 2.5:1.

[0041] In the hydrolysis reaction, the base can be a base commonly used in the art, preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate or potassium carbonate, such as sodium hydroxide.

[0042] In the hydrolysis reaction, the addition time of the hydrogen peroxide can be 4h to 8h, for example 4h to 5h. The hydrolysis reaction is a two-phase reaction, and the reaction requires a certain mass transfer time. If the hydrogen peroxide aqueous solution is added too quickly, the hydrogen peroxide will not have time to react with o-trifluoromethylbenzonitrile and will decompose itself, resulting in a waste of raw materials.

[0043] In the hydrolysis reaction, the reaction temperature may be 30°C to 90°C, such as 30°C to 50°C.

[0044] In the hydrolysis reaction, the solvent may be water. Some of the solvent may be used in combination with the base to form an alkaline solution. The mass concentration of the alkaline solution is preferably 20% to 40%, for example 30%.

[0045] The hydrolysis reaction may further include the following post-processing steps: filtration and drying.

[0046] In the present invention, "room temperature" means "20 to 40°C".

[0047] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0048] The reagents and raw materials used in the present invention are commercially available.

[0049] The positive and progressive effects of the present invention are:

[0050] (1) The present invention provides a method for preparing o-trifluoromethylbenzamide and its intermediates. The present invention uses o-trifluoromethylaniline, a by-product generated when an enterprise produces m-trifluoromethylaniline, as a raw material, explores the potential value of the by-product, and utilizes the by-product as a resource.

[0051] (2) The method of the present invention produces less three wastes and is simple to post-process. The by-product cuprous bromide produced during the preparation process can be recycled. DETAILED DESCRIPTION

[0052] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0053] Example 1

[0054] (1) Sandmeyer bromination reaction

[0055] Preparation of diazonium salt solution: Slowly add 154g of o-trifluoromethylaniline to 500mL of hydrobromic acid (40%) at room temperature with stirring, and cool to 0°C after addition. Slowly add 231g of sodium nitrite solution (30%) to the reaction system with stirring, and add it in 1.5 hours, and keep the reaction temperature below 5°C. Continue stirring for 20 minutes after the addition is completed, and keep warm for use.

[0056] Add 27g of cuprous bromide and 40mL of hydrobromic acid (40%) to a 1L four-necked bottle, stir vigorously at room temperature, add the above diazonium salt solution to the four-necked reaction bottle, and a large amount of gas will be generated by the reaction. Continue stirring for 20 minutes after the diazonium salt solution is added, separate the liquids, recover the hydrobromic acid from the upper aqueous phase, wash the lower organic phase with alkali until it is neutral, wash it with water, and distill it to obtain 195g of o-bromotrifluorotoluene, with a content of 99% and a yield of 90%. 1 H NMR (CDCl3): δ = 7.11-7.18 (m, 2H), 7.36 (d, 1H), 7.48 (d, 1H).

[0057] (2) Cyanide substitution reaction

[0058] Dissolve 90g of the prepared o-bromotrifluorotoluene in 80mL of N,N-dimethylformamide, add 37g of cuprous cyanide, stir, heat and reflux for 8h, cool to room temperature after the reaction is completed, filter with suction, the filter cake is the by-product cuprous bromide, and the filtrate is distilled, rectified and desolventized to obtain 65g of colorless liquid o-trifluoromethylbenzonitrile, with a content of 99.7% and a yield of 95%. 1 H NMR (CDCl3): δ = 7.11-7.17 (m, 2H), 7.36-7.49 (m, 2H).

[0059] (3) Hydrolysis reaction

[0060] Add 84g of the prepared o-trifluoromethylbenzonitrile into a four-necked flask, slowly drop 139g (30%) of hydrogen peroxide aqueous solution into the flask under stirring, adjust the pH of the reaction system to 10-13 with (30%) sodium hydroxide aqueous solution during the reaction, the reaction is exothermic, and the reaction temperature is controlled at 30-50°C. After about 5 hours of dropping of the hydrogen peroxide aqueous solution, a large amount of white needle-shaped crystals are generated in the reaction. Stop the reaction, filter, and dry the filter cake to obtain 91g of white solid o-trifluoromethylbenzamide, with a content of 99.6% and a yield of 98%. 1 H NMR (CDCl3): δ = 5.86 (b, 2H), 7.54-7.62 (m, 2H), 7.72 (d, 2H).

[0061] Example 2

[0062] (1) Sandmeyer bromination reaction

[0063] Preparation of diazonium salt solution: Slowly add 154g of o-trifluoromethylaniline to 550mL of hydrobromic acid (40%) at room temperature with stirring, and cool to 0°C after addition. Slowly add 242g of sodium nitrite solution (30%) to the reaction system with stirring, and add it over 2h, and keep the reaction temperature below 5°C. Continue stirring for 30min after the addition is complete, and keep warm for later use.

[0064] Add 28g of cuprous bromide, the byproduct of the cyanidation substitution reaction in Example 1, and 40mL of hydrobromic acid (40%) to a 1L four-necked bottle, stir vigorously at room temperature, add the above diazonium salt solution to the four-necked reaction bottle, and a large amount of gas is generated by the reaction. After the diazonium salt solution is added, continue to stir for 25min, separate the liquids, recover the hydrobromic acid from the upper aqueous phase, wash the lower organic phase with alkali to neutrality, wash with water, and distill to obtain 193g of o-bromotrifluorotoluene, with a content of 99% and a yield of 89%.

[0065] (2) Cyanide substitution reaction

[0066] Dissolve 90 g of the prepared o-bromotrifluorotoluene in 60 mL of dimethyl sulfoxide, add 38 g of cuprous cyanide, stir, heat and reflux for 6 h, cool to room temperature after the reaction is complete, filter with suction, the filter cake is the by-product cuprous bromide, and the filtrate is distilled and rectified to obtain 65.7 g of colorless liquid o-trifluoromethylbenzonitrile, with a content of 99.8% and a yield of 96%;

[0067] (3) Hydrolysis reaction

[0068] 84g of the prepared o-trifluoromethylbenzonitrile was added into a four-necked flask, and 85g (50%) aqueous hydrogen peroxide solution was slowly added dropwise into the flask under stirring. During the reaction, the pH of the reaction system was adjusted to 10-13 with (30%) aqueous sodium hydroxide solution. The reaction was exothermic, and the reaction temperature was controlled at 30-50°C. The addition of the aqueous hydrogen peroxide solution was completed in about 4 hours, and a large amount of white needle-shaped crystals were generated in the reaction. The reaction was stopped, filtered, and the filter cake was dried to obtain 91g of white solid o-trifluoromethylbenzamide, with a content of 99.6% and a yield of 98%.

[0069] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions and improvements made within the spirit and principle of the present invention are included in the protection scope of the present invention.

Claims

1. A method for preparing o-trifluoromethylbenzonitrile, characterized in that: The method comprises the following steps: in a non-protonic polar solvent, performing a cyanation substitution reaction as shown below on o-bromotrifluorotoluene and cuprous cyanide to obtain the o-trifluoromethylbenzonitrile, wherein the molar ratio of the cuprous cyanide to the o-bromotrifluorotoluene is (1.03-1.06):1; The aprotic polar solvent is an amide solvent and / or a sulfoxide solvent; The amide solvent is N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone; The sulfoxide solvent is dimethyl sulfoxide; The reaction temperature is 140°C to 200°C; The volume ratio of the aprotic polar solvent to the o-bromotrifluorotoluene is (1-3):

1.

2. The method for preparing o-trifluoromethylbenzonitrile according to claim 1, wherein The cyanation substitution reaction also includes post-treatment, which includes the following steps: suction filtration, distillation and rectification.

3. The method for preparing o-trifluoromethylbenzonitrile according to claim 1, characterized in that: The cyanation substitution reaction satisfies one or more of the following conditions: (1) The aprotic polar solvent is dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone; (2) The reaction temperature is 150°C to 190°C; The volume ratio of the aprotic polar solvent described in (3) to the o-bromotrifluorotoluene is (1-1.5):

1.

4. The method for preparing o-trifluoromethylbenzonitrile according to claim 1, wherein The cyanation substitution reaction satisfies one or more of the following conditions: (1) The aprotic polar solvent is N,N-dimethylformamide or dimethyl sulfoxide; (2) the volume ratio of the aprotic polar solvent to the o-bromotrifluorotoluene is 1.1:1 or 1.4:1; The molar ratio of the cuprous cyanide described in (3) to the o-bromotrifluorotoluene described is 1.03 or 1.

06.

5. The method for preparing o-trifluoromethylbenzonitrile according to claim 1, characterized in that: The method further comprises the following steps: subjecting a diazonium salt solution of o-trifluoromethylaniline to a bromination reaction with cuprous bromide and hydrobromic acid as shown below to obtain the o-bromotrifluorotoluene; 6. The method for preparing o-trifluoromethylbenzonitrile according to claim 5, characterized in that: The diazonium salt solution of o-trifluoromethylaniline is obtained by mixing o-trifluoromethylaniline, hydrobromic acid and sodium nitrite.

7. The method for preparing o-trifluoromethylbenzonitrile according to claim 6, characterized in that: The bromination reaction satisfies one or more of the following conditions: (1) The mixing further comprises the following steps: adding sodium nitrite dropwise into the mixed solution A; the mixed solution A is a mixed solution of o-trifluoromethylaniline and hydrobromic acid; the temperature of the adding dropwise is -5°C to 5°C; (2) The molar ratio of sodium nitrite to o-trifluoromethylaniline is (1.05-1.1):1; (3) The sodium nitrite is an aqueous solution of sodium nitrite, and its mass concentration is 20% to 40%; (4) The mass concentration of the hydrobromic acid is 30% to 50%; (5) The molar ratio of the hydrobromic acid to the o-trifluoromethylaniline is (3.0-4.0):1; (6) The molar ratio of the cuprous bromide to the o-trifluoromethylaniline is (0.15-0.50):1; (7) The cuprous bromide is cuprous bromide generated in a cyanidation substitution reaction; (8) The molar ratio of the o-trifluoromethylaniline to the hydrobromic acid is (3-4):1; (9) The temperature of the bromination reaction is room temperature, and the room temperature is 20 to 40° C.; The bromination reaction described in (10) further includes post-treatment, and the post-treatment includes the following steps: liquid separation, alkali washing, water washing, and distillation.

8. The method for preparing o-trifluoromethylbenzonitrile according to claim 7, characterized in that: The bromination reaction satisfies one or more of the following conditions: (1) The mixing further comprises the following steps: adding sodium nitrite dropwise into the mixed solution A; the mixed solution A is a mixed solution of o-trifluoromethylaniline and hydrobromic acid; the temperature of the adding dropwise is 0°C; (2) The molar ratio of sodium nitrite to o-trifluoromethylaniline is 1.05:1 or 1.1:1; (3) The sodium nitrite is an aqueous solution of sodium nitrite, and its mass concentration is 30%; (4) The mass concentration of the hydrobromic acid is 40%; (5) The molar ratio of the hydrobromic acid to the o-trifluoromethylaniline is 3.5:1 or 3.9:1; (6) The molar ratio of the cuprous bromide to the o-trifluoromethylaniline is (0.2-0.4):1; The molar ratio of the o-trifluoromethylaniline described in (7) to the hydrobromic acid is 3.5:

1.

9. The method for preparing o-trifluoromethylbenzonitrile according to claim 8, characterized in that: The molar ratio of the cuprous bromide to the o-trifluoromethylaniline is 0.2:

1.

10. A method for preparing o-trifluoromethylbenzamide, characterized in that: It includes the following steps: (1) A diazonium salt solution of o-trifluoromethylaniline is subjected to a bromination reaction with cuprous bromide and hydrobromic acid as shown below to obtain o-bromotrifluorotoluene as shown below, (2) In a non-protonic polar solvent, the o-bromotrifluorotoluene obtained in step (1) and cuprous cyanide are subjected to a cyanation substitution reaction as shown below to obtain o-trifluoromethylbenzonitrile as shown below, The molar ratio of the cuprous cyanide to the o-bromotrifluorotoluene is (1.03-1.06):1; The aprotic polar solvent is an amide solvent and / or a sulfoxide solvent; The amide solvent is N,N-dimethylformamide, N,N-dimethylacetamide or N-methylpyrrolidone; The sulfoxide solvent is dimethyl sulfoxide; The reaction temperature is 140°C to 200°C; The volume ratio of the aprotic polar solvent to the o-bromotrifluorotoluene is (1-3):1; (3) in a solvent, in the presence of a base, subjecting the o-trifluoromethylbenzonitrile obtained in step (2) to a hydrolysis reaction as shown below in the presence of hydrogen peroxide to obtain o-trifluoromethylbenzamide as shown below; 11. The method for preparing o-trifluoromethylbenzamide according to claim 10, characterized in that: The preparation method meets one or two of the following conditions: (1) The reaction conditions of the bromination reaction are as described in claim 6, 7, 8 or 9; And other reaction conditions of the cyanation substitution reaction (2) are as described in any one of claims 2 to 4.

12. The method for preparing o-trifluoromethylbenzamide according to claim 10 or 11, characterized in that: The preparation method meets one or more of the following conditions: (1) In the hydrolysis reaction, the pH of the reaction is 10 to 13; (2) In the hydrolysis reaction, the mass concentration of hydrogen peroxide is 30% to 50%; (3) In the hydrolysis reaction, the molar ratio of the hydrogen peroxide to the o-trifluoromethylbenzonitrile is (2-3):1; (4) In the hydrolysis reaction, the base is lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate or potassium carbonate; (5) In the hydrolysis reaction, the hydrogen peroxide is added for 4 to 8 hours; (6) In the hydrolysis reaction, the reaction temperature is 30°C to 90°C; (7) In the hydrolysis reaction, the solvent is water; The hydrolysis reaction described in (8) further comprises the following post-treatment steps: filtration and drying.

13. The method for preparing o-trifluoromethylbenzamide according to claim 12, characterized in that: The preparation method meets one or more of the following conditions: (1) In the hydrolysis reaction, the mass concentration of hydrogen peroxide is 30% or 50%; (2) In the hydrolysis reaction, the molar ratio of the hydrogen peroxide to the o-trifluoromethylbenzonitrile is 2.5:1; (3) In the hydrolysis reaction, the base is sodium hydroxide; (4) In the hydrolysis reaction, the hydrogen peroxide is added for 4 to 5 hours; In the hydrolysis reaction described in (5), the reaction temperature is 30°C to 50°C.

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