A preparation method of m-nitrobenzonitrile and its application

Abstract

The present invention relates to the field of organic synthesis, in particular to the field of IPC C07D213, and more specifically to a method for preparing m-nitrobenzonitrile and its application. Using m-nitrobenzoic acid as a raw material, acyl chloride, amidation and dehydration reactions are carried out in a microchannel reactor to obtain m-nitrobenzonitrile. Compared with the traditional process, the method greatly shortens the reaction time, improves the safety of the reaction process and the yield of the reactant, and has low raw material price and high economic efficiency.

Description

Technical Field

[0001] The invention relates to the field of organic synthesis, in particular to the field of IPC C07D213, and more specifically to a preparation method of m-nitrobenzonitrile and application thereof. Background Art

[0002] Meta-nitrobenzonitrile is an organic compound, which is mostly used as an intermediate for medicine and pesticides, and can also be used as an organic synthesis intermediate to synthesize pharmaceutical chemicals such as imidazolinone hydrochloride and imidazolinone dipropionate. However, its high price limits its application.

[0003] There are few reports on the preparation of m-nitrobenzonitrile in the prior art. A patent application document with application publication number CN106883147A discloses a method for preparing pentafluorobenzonitrile, using 2,6-dichloro-3-fluoroacetophenone as a raw material, and preparing pentafluorobenzonitrile through nitrilation, chlorination and fluorination. Although the preparation method has a high product yield, it takes a long time, which limits its application.

[0004] CN109320433A discloses a method for preparing 4-trifluoromethylbenzonitrile, using 4-trifluoromethylchlorobenzene as a raw material, and using cheap and readily available 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene as a ligand, and using a small amount of catalyst. Although the preparation method has certain economical efficiency, the preparation time is too long and the yield is not high.

[0005] Therefore, it is necessary to develop a method for preparing m-nitrobenzonitrile, which has a short preparation time, a high yield, and a low raw material price, and has certain economy. Summary of the invention

[0006] In order to solve the above problems, the first aspect of the present invention provides a method for preparing m-nitrobenzonitrile, comprising the following steps:

[0007] S1. dissolving m-nitrobenzoic acid and the halide in polar solvents to obtain m-nitrobenzoic acid solution and halide solution;

[0008] S2. Setting the reaction temperature of the microchannel reactor;

[0009] S3. The volume flow rate of the m-nitrobenzoic acid solution was adjusted by a flow pump to 20-30 mL / min, the volume flow rate of the halide solution was 25-35 mL / min, and the volume flow rate of the nitrogen-containing organic matter was 0.01-0.05 mL / min. After the reaction time was 80-200 s, the feed was stopped;

[0010] S4. After the temperature in the microchannel reactor is reduced to 0-5 ° C, ammonia is introduced into the microchannel reactor at a flow rate of 25-35 mL / min until the pH value in the microchannel reactor is 7-9, and the ammonia is stopped;

[0011] S5. Raise the reaction temperature of the microchannel reactor to 80-150 ° C, continue to introduce the halide solution into the microchannel reactor, react for 5-20 minutes, and then cool to 20-30 ° C;

[0012] S6. The reaction product mixture in step S5 is taken out, the pH value is adjusted to 7-8 with sodium hydroxide aqueous solution, and then distilled and desolventized to obtain m-nitrobenzonitrile solid.

[0013] In the amidation reaction of step S4, the applicant found that the introduction of ammonia can make the reaction proceed quickly while also improving the yield of amide. This may be due to the fact that on the one hand, ammonia can be dissolved in chloroform, making the environment weakly alkaline, m-nitrobenzoyl chloride reacts with ammonia under alkaline conditions, and amino replaces the chlorine atom on m-nitrobenzoyl chloride to generate m-nitrobenzamide, on the other hand, because ammonia can react with the generated hydrogen chloride, the equilibrium is urged to move forward, thereby accelerating the rate of generating m-nitrobenzamide. However, the amidation reaction is an exothermic reaction, and the temperature rise will cause ammonia to escape, and it is impossible to react with m-nitrobenzoyl chloride, so a microchannel reactor is selected to react, and the temperature is controlled at 0-5°C. During the reaction, even if it is an exothermic reaction, the microchannel reactor can quickly conduct the heat released by the reaction, which will not affect the reaction, thereby improving the yield of m-nitrobenzamide.

[0014] Preferably, the halogenated compound in step 1 contains at least two halogen elements; the halogenated compound is one or more of 4-iodotoluenetrifluoromethane, thionyl chloride, 3,4-dichlorophenylacetic acid, 2-chloro-6-fluorophenylacetic acid, 2-bromo-4-fluoro-6-nitrotoluene, and 1-bromo-2,4,5-trichlorobenzene; and more preferably, thionyl chloride.

[0015] Preferably, the polar solvent in step S1 is one or more of formamide, acetonitrile, chloroform, dichloromethane, ether, ethanol, methanol, carbon tetrachloride, ethyl bromide, and tetrahydrofuran; more preferably, it is chloroform.

[0016] Preferably, the molar ratio of the m-nitrobenzoic acid solution to the halide solution in step S1 is 1:(1-5); further preferably, it is 1:(1-3); further preferably, it is 1:2.

[0017] Preferably, the reaction temperature in step S2 is 100-140°C; more preferably, it is 120°C.

[0018] The acyl chloride reaction is an endothermic reaction. The higher the temperature, the faster the reaction rate. However, too high a temperature will affect the generation rate of m-nitrobenzoyl chloride. This may be because too high a temperature will cause the halide to decompose, thereby failing to react with the acid, affecting the occurrence of the acyl chloride reaction. The applicant has found that when the temperature is 100-140°C, the reaction rate is fast and the yield of m-nitrobenzoyl chloride is high.

[0019] Preferably, the nitrogen atom in the nitrogen-containing organic matter in step S3 is connected to at least two non-hydrogen atom substituent groups; the nitrogen-containing organic matter is one or more of pyridine, N,N-diethylethylamine, tetrabutylammonium hydrogen sulfate, tributylamine, benzyltriethylammonium chloride, trioctylmethylammonium chloride, tetrabutylammonium chloride, and tetradecyltrimethylammonium chloride; further preferably, it is N,N-diethylethylamine.

[0020] Preferably, the amount of the nitrogen-containing organic substance is 0.1-1% of m-nitrobenzoic acid; more preferably, it is 0.5%.

[0021] In the process of preparing m-nitrobenzoyl chloride using m-nitrobenzoic acid and thionyl chloride, the required reaction time is often two hours or more. The applicant found that adding a certain amount of N, N-diethylethylamine as a nitrogen-containing organic matter during the reaction, and reacting in a microchannel reactor can greatly shorten the reaction time. This may be due to the fact that on the one hand, the specific surface area of ​​the fluid in the microchannel reactor is 2-4 orders of magnitude higher than that of the traditional reactor, which improves the efficiency of the heat exchange between the fluid and the wall in the microchannel reactor, thereby accurately controlling the reaction temperature and accelerating the reaction rate of the fluid. On the other hand, N, N-diethylethylamine is selected as a nitrogen-containing organic matter, and the electron induction on the nitrogen atom in N, N-diethylethylamine can not only activate the carboxyl group on m-nitrobenzoic acid, reduce the activation energy of the reaction, but also promote the chlorine atom on thionyl chloride to easily attack the hydroxyl group on m-nitrobenzoic acid, and nucleophilic substitution occurs, thereby accelerating the reaction and facilitating the generation of m-nitrobenzoyl chloride. However, its addition amount should not be too much, and adding too much will react with the raw material m-nitrobenzoic acid, affecting the yield of nitrobenzoyl chloride in the reaction. When the amount of the nitrogen-containing organic matter is 0.1-1% of the m-nitrobenzoic acid, the reaction time can be greatly shortened while the yield of m-nitrobenzoyl chloride can be guaranteed.

[0022] The second aspect of the present invention provides m-nitrobenzonitrile prepared by the m-nitrobenzonitrile preparation method as described above.

[0023] The present invention selects m-nitrobenzoic acid as raw material, and microchannel reactor as reaction device, and the reaction time is short, the prepared m-nitrobenzonitrile yield is high, and the economic benefit is good. The m-nitrobenzoic acid is cheap, and it is selected to prepare the expensive m-nitrobenzonitrile, which has very high economic benefit, and the reaction is carried out in the microchannel reactor, and the operation is simple, on the one hand, the thermal effect problems such as local overheating and uneven heat transfer in the reaction process of the reactant are avoided, the generation of side reactions is avoided, and the yield is improved, on the other hand, the reaction time and the reaction process are precisely controllable, and the reaction process is controlled by controlling the raw material flow rate, so that its chemical reaction rate is close to its reaction kinetics limit, and a fast and efficient reaction is achieved, in addition, because the microchannel reactor has a good heat conduction effect, the explosive reaction can be effectively controlled, and the safety of the reaction process is improved, and the microchannel reactor has a high yield, and the waste of raw materials can be reduced as much as possible, and the production cost is effectively reduced, and the economic benefit is further increased.

[0024] Beneficial effects:

[0025] 1. The present invention reduces the cost by selecting cheap m-nitrobenzoic acid as a raw material, has certain economy, and is conducive to realizing its large-scale production.

[0026] 2. By selecting a microchannel reactor as the reaction device, the fluid channel in the microchannel reactor is at the level of 10μm-3㎜, the specific surface area of ​​the fluid is increased, and the reactants in the microchannel can exchange heat with the wall efficiently, and the reaction temperature is accurately controlled. On the one hand, local overheating of the reactants during the reaction process is avoided, which will lead to incomplete reaction and low safety. On the other hand, the reaction time and reaction process are accurately controlled, the yield of m-nitrobenzonitrile is improved, the waste of raw materials is reduced, and the economic benefits are further increased.

[0027] 3. Introducing ammonia into the amidation reaction can, on the one hand, generate m-nitrobenzamide, thereby increasing the yield of m-nitrobenzamide; on the other hand, it can promote the forward shift of the equilibrium and accelerate the reaction rate.

[0028] 4. By controlling the temperature of the chlorination reaction to 100-140°C, the decomposition of the halide can be avoided while promoting the reaction, thereby further improving the reaction efficiency and the yield of m-nitrobenzoyl chloride.

[0029] 5. By adding a certain amount of N,N-diethylethylamine as a nitrogen-containing organic matter during the amidation reaction and reacting in a microchannel reactor, not only can the reaction temperature be accurately controlled and the reaction rate of the fluid be accelerated, but the activation energy of the reaction can also be reduced, thereby accelerating the reaction and greatly shortening the amidation reaction time. DETAILED DESCRIPTION

[0030] Example

[0031] Example 1

[0032] Embodiment 1 provides a method for preparing m-nitrobenzonitrile, comprising the following steps:

[0033] S1. Dissolve 20.04 g of m-nitrobenzoic acid in 500 ml of a polar solvent to obtain a m-nitrobenzoic acid solution, and dissolve 57.1 g of a halide in 1000 ml of a polar solvent to obtain a halide solution;

[0034] S2. Set the reaction temperature of the microchannel reactor to 120 ° C;

[0035] S3. Use a flow pump to adjust the volume flow rate of the m-nitrobenzoic acid solution to 25 mL / min, the volume flow rate of the halide solution to 30 mL / min, and the volume flow rate of the nitrogen-containing organic matter to 0.03 mL / min. The three solutions are simultaneously introduced into the microchannel reactor. When the m-nitrobenzoic acid solution is passed through, the feed is stopped and the reaction is continued for 150 s;

[0036] S4. After the temperature in the microchannel reactor was lowered to 2 ° C, ammonia was introduced into the microchannel reactor at a flow rate of 30 mL / min until the pH value in the microchannel reactor reached 8, and the ammonia was stopped;

[0037] S5. Raise the reaction temperature of the microchannel reactor to 110 ° C, continue to pass the halide solution into the microchannel reactor at a volume flow rate of 30 mL / min, and react for 15 min after completion of the reaction, and cool to 25 ° C;

[0038] S6. The reaction product mixture in step S5 is taken out, the pH value is adjusted to 7.5 with sodium hydroxide aqueous solution, and then distilled to obtain m-nitrobenzonitrile solid.

[0039] The polar solvent is chloroform.

[0040] The halogenated compound is thionyl chloride.

[0041] The nitrogen-containing organic substance is N,N-diethylethylamine; the volume of the N,N-diethylethylamine is 0.08 ml.

[0042] The concentration of sodium hydroxide in the sodium hydroxide aqueous solution is 40 wt %.

[0043] The yield of the obtained m-nitrobenzonitrile is 99.1% (based on m-nitrobenzoic acid), and the preparation time of m-nitrobenzonitrile from m-nitrobenzoic acid is 70 min.

[0044] Example 2

[0045] Example 2 provides a method for preparing m-nitrobenzonitrile, and the specific implementation method is the same as that of Example 1. The difference is that the microchannel reaction temperature in step S2 is 100°C.

[0046] The yield of the obtained m-nitrobenzonitrile is 98.5% (based on m-nitrobenzoic acid), and the preparation time of m-nitrobenzonitrile from m-nitrobenzoic acid is 70 min.

[0047] Example 3

[0048] Example 3 provides a method for preparing m-nitrobenzonitrile, and the specific implementation method is the same as that of Example 1. The difference is that no nitrogen-containing organic matter is added.

[0049] The yield of the obtained m-nitrobenzonitrile is 95.2% (based on m-nitrobenzoic acid), and the preparation time of m-nitrobenzonitrile from m-nitrobenzoic acid is 70 min.

[0050] Example 4

[0051] Example 4 provides a method for preparing m-nitrobenzonitrile, and the specific implementation method is the same as that of Example 1. The difference is that the reaction temperature in step S2 is 160°C.

[0052] The yield of the obtained m-nitrobenzonitrile is 90.8% (based on m-nitrobenzoic acid), and the preparation time of m-nitrobenzonitrile from m-nitrobenzoic acid is 70 min.

Claims

1. A method for preparing m-nitrobenzonitrile, characterized in that: The steps include: S1. dissolving m-nitrobenzoic acid and the halide in polar solvents to obtain m-nitrobenzoic acid solution and halide solution; S2. Setting the reaction temperature of the microchannel reactor; S3. Use a flow pump to adjust the volume flow rate of m-nitrobenzoic acid solution, halide solution and nitrogen-containing organic matter, and stop feeding the raw material after the reaction time of 80-200s; S4. After the temperature in the microchannel reactor is reduced to 0-5 ° C, ammonia is introduced into the microchannel reactor at a flow rate of 25-35 mL / min until the pH value in the microchannel reactor is 7-9, and the ammonia is stopped; S5. Raise the reaction temperature of the microchannel reactor to 80-150 ° C, continue to introduce the halide solution into the microchannel reactor, react for 5-20 minutes, and then cool to 20-30 ° C; S6. The reaction product mixture in step S5 is taken out, the pH value is adjusted to 7-8 by aqueous sodium hydroxide solution, and the solid m-nitrobenzonitrile is obtained by distillation and desolventization; The polar solvent in step S1 is one or more of formamide, acetonitrile, chloroform, dichloromethane, ether, ethanol, methanol, carbon tetrachloride, ethyl bromide, and tetrahydrofuran; The reaction temperature in step S2 is 100-140°C; The volume flow rate of the m-nitrobenzoic acid solution is 20-30 mL / min, the volume flow rate of the halide solution is 25-35 mL / min, and the volume flow rate of the nitrogen-containing organic matter is 0.01-0.05 mL / min.

2. A method for preparing m-nitrobenzonitrile according to claim 1, characterized in that: The halogenated compound in step 1 contains at least two halogen elements.

3. A method for preparing m-nitrobenzonitrile according to claim 2, characterized in that, The halogenated compound containing at least two halogen elements is selected from one or more of 4-iodobenzotrifluoromethane, thionyl chloride, 3,4-dichlorophenylacetic acid, 2-chloro-6-fluorophenylacetic acid, 2-bromo-4-fluoro-6-nitrotoluene, and 1-bromo-2,4,5-trichlorobenzene.

4. A method for preparing m-nitrobenzonitrile according to claim 1, characterized in that, The molar ratio of the m-nitrobenzoic acid solution to the halide solution in step S1 is 1:(1-5).

5. A method for preparing m-nitrobenzonitrile according to claim 1, characterized in that: In step S3, the nitrogen atom in the nitrogen-containing organic compound is connected to at least two non-hydrogen atom substituent groups.

6. A method for preparing m-nitrobenzonitrile according to claim 5, characterized in that, The nitrogen-containing organic matter is one or more of pyridine, N,N-diethylethylamine, tetrabutylammonium hydrogen sulfate, tributylamine, benzyltriethylammonium chloride, trioctylmethylammonium chloride, tetrabutylammonium chloride, and tetradecyltrimethylammonium chloride.