Method for synthesizing 2-methyl-3-trifluoromethylaniline using continuous flow microreactor

Abstract

The present invention relates to the field of compound synthesis, and in particular to a method for synthesizing 2-methyl-3-trifluoromethylaniline by using o-methylbenzoic acid as a raw material and a continuous flow microreactor. By using a continuous flow process, compared with an intermittent process using a traditional kettle reactor, the method has the characteristics of high yield, less post-treatment wastewater, low energy consumption and labor costs, low total project cost, and improved production capacity.

Description

Technical Field

[0001] The invention relates to the field of compound synthesis, and in particular to a method for synthesizing 2-methyl-3-trifluoromethylaniline by using o-methylbenzoic acid as a raw material and a continuous flow microreactor. Background Art

[0002] 2-Methyl-3-trifluoromethylaniline (MTA), CAS No. 54396-44-0, is an important pharmaceutical and pesticide intermediate, mainly used in the synthesis of antiseptics, herbicides and veterinary anti-inflammatory drugs, and is also a key intermediate in the synthesis of flunixin meglumine. The synthesis process disclosed in existing literature has certain drawbacks.

[0003] U.S. Patent No. 5,965,735 discloses a synthetic route using m-aminotrifluorotoluene as a starting material, wherein the amino group is first protected with pivaloyl chloride, and then subjected to a synthetic reaction with n-butyl lithium and methyl iodide or dimethyl sulfate at low temperature to obtain a methylated product, and finally the protecting group is removed to obtain the target product. The butyl lithium used in this route is relatively expensive, and the methyl iodide and dimethyl sulfate used are also highly toxic, and the methylation reaction must be carried out at low temperatures, so this route is not suitable for industrial production needs. The synthetic route is as follows:

[0004]

[0005] Chinese patent CN103570558 discloses a synthetic route using 3-amino-4-chlorobenzotrifluoride as the starting material, protecting the amino group with isobutyl chloride, methylating with butyl lithium and dimethyl sulfate, removing the chlorine on the benzene ring by palladium carbon hydrogenation, and then deprotecting to obtain the target product. The method used in this route is not significantly different from that described in US Pat. No. 5965735, and there is an additional step of hydrogenation and dehalogenation. Therefore, this route is not suitable for large-scale industrial production. Its synthetic route is as follows:

[0006]

[0007] U.S. Patent No. 4209424 discloses a synthetic route using 3-amino-4-chlorobenzotrifluoride as the starting material, using DMSO to condense the amino group, then heating and rearrangement, and Raney nickel catalysis to eliminate the chlorine on the benzene ring to obtain the target product. The multi-step reaction of this route needs to be carried out at high temperature, and the overall yield is not very high. Therefore, this route is not suitable for large-scale industrial production. The synthetic route is as follows:

[0008]

[0009] Chinese patent CN108911989 discloses a method of using 2-chloro-3-fluoromethylaniline as a raw material, introducing a methylthio group at the ortho position of the amino group, reacting with sulfonyl chloride to convert the methylthio group into a chloromethyl group, and then removing the chlorine on the benzene ring and the methyl group by palladium-carbon catalytic hydrogenation to obtain the target product. This route uses unpleasant dimethyl sulfide, and the yield of each step is not very high. Therefore, this route is not suitable for large-scale industrial production. The synthetic route is as follows:

[0010]

[0011] Continuous flow reactors are chemical reactions that occur in tiny spaces. The average channel size is 1-3.5 mm, and it contains thousands of tiny channels. Fluids flow in these channels, and the required reactions are required to occur in these channels, increasing the surface contact probability so that the reaction materials can be fully reacted. Microreactors react based on the principle of repeated impacts driven by a high-pressure constant-current pump. The raw material conversion rate is increased by more than 20%, the side reaction impurities are reduced by more than 30%, and the reaction time is shortened to 1.3% of the kettle type, eliminating the amplification effect in the reaction process, achieving full intelligence of chemical reactions, and full automatic production, which is suitable for large-scale continuous production of chemicals. The research and application field of microchannel reaction technology has gradually expanded from micro-processing to a new discipline with an independent concept. Compared with conventional kettle reactions, microreactors have great advantages, with efficient heat transfer capacity, efficient mass transfer capacity, continuous controllable reaction process, small size, low consumption, and high safety.

[0012] The present invention develops a set of continuous flow microreactors and applies the continuous flow microreaction technology to the preparation process of 2-methyl-3-trifluoromethylaniline to solve the problems of low raw material conversion rate, high risk and environmental pollution in the process. Summary of the invention

[0013] Aiming at the technical problems of low raw material conversion rate, high risk, many by-products and environmental pollution in the above-mentioned 2-methyl-3-trifluoromethylaniline autoclave reaction synthesis method, the present invention provides a continuous flow micro-reaction synthesis method of 2-methyl-3-trifluoromethylaniline. By using a continuous flow process, compared with the intermittent process using a traditional autoclave reactor, the method has the characteristics of high yield, less post-treatment wastewater, low energy consumption and labor costs, low total project cost and improved production capacity.

[0014] To achieve the above object, the present invention adopts the following technical solutions:

[0015] The present invention provides a method for synthesizing 2-methyl-3-trifluoromethylaniline using a continuous flow microreactor, comprising:

[0016] Step a: Use metering pumps to pump a sulfuric acid solution of o-toluic acid and nitric acid into a microreactor respectively. When the reaction reaches the end point, the feed liquid enters a post-treatment system to obtain compound A.

[0017]

[0018] Step b: The toluene solution of compound A obtained in step a, sulfur tetrafluoride and hydrogen fluoride gas are pumped into the microreactor by a metering pump, and the reaction solution flows out into a post-processing system to obtain compound B.

[0019]

[0020] Step c: Pumping the ethanol solution of compound B obtained in step b and hydrogen (pressure controlled at 5 to 60 psi) into a microreactor equipped with a palladium carbon filler column, and the reaction solution flows out into a post-processing system to obtain compound MTA.

[0021]

[0022] The sulfuric acid solution in step a is a 15% to 50% sulfuric acid solution. Preferably, the sulfuric acid solution in step a is a 20% sulfuric acid solution.

[0023] The nitric acid solution in step a is a 55% to 65% solution. Preferably, the nitric acid solution in step a is a 60% nitric acid solution.

[0024] The flow rate in the microreactor in step a is 1 ml / min to 50 ml / min.

[0025] In the step a, the flow rate ratio of the sulfuric acid solution of o-toluic acid and nitric acid in the metering pump in the microreactor is 3:1 to 6:1.

[0026] The molar ratio of nitric acid to o-toluic acid in the microreactor in step a is 1:1 to 1.6:1.

[0027] The mass ratio of nitric acid to sulfuric acid in the microreactor in step a is 1:10 to 2:10.

[0028] The reaction temperature in the microreactor of step a is 50° C.-90° C. In some embodiments, the reaction temperature in the microreactor of step a is 60° C. to 85° C.

[0029] The reaction residence time in the microreactor in step a is 10 seconds to 30 minutes. In some embodiments, the reaction residence time in the microreactor in step a is 2 minutes to 10 minutes.

[0030] In the synthesis method of the compound A, after the reaction of step a is completed, post-treatment is optionally performed.

[0031] In some embodiments, a method for synthesizing compound A comprises step a: using a metering pump to pump nitric acid and sulfuric acid solutions of o-toluic acid into a microreactor at a flow rate of 1:3 to 1:6, respectively, the reaction temperature of the microreactor is set to 60°C-80°C, the residence time is 2 min to 10 min, the liquid product is collected, HPLC is used to monitor the reaction completion, and the reaction liquid flows out into a post-treatment system, and optionally post-treated to obtain compound A.

[0032] Step a adopts a continuous flow microreactor synthesis method. Compared with the traditional kettle reaction, its conversion rate is increased from 73% to 94%, avoiding the danger of violent explosion of nitration reaction, reducing isomers from 10% to 3.0%, and significantly reducing post-treatment acidic wastewater.

[0033] The flow rate in the microreactor in step b is 1 ml / min to 50 ml / min, wherein the flow rates of sulfur tetrafluoride and hydrogen fluoride gas are both 1 ml / min to 50 ml / min.

[0034] The reaction temperature in the microreactor of step b is 100° C.-150° C. In some embodiments, the reaction temperature in the microreactor of step b is 80° C. to 130° C.

[0035] The reaction residence time in the microreactor in step b is 10 seconds to 30 minutes.

[0036] In the synthesis method of the compound B, after the reaction of step b is completed, post-treatment is optionally performed. In some embodiments, in the synthesis method of 2-methyl-3-trifluoromethylaniline, post-treatment of step b includes: after the reaction is completed, quenching, extraction, washing, drying, removing solvent, and distilling to obtain compound B.

[0037] In some embodiments, a method for synthesizing 2-methyl-3-trifluoromethylaniline comprises step b: using a metering pump to pump the toluene solution of compound A obtained in step a, sulfur tetrafluoride and hydrogen fluoride (gas control pressure 5 to 30 psi) into a microreactor, respectively, setting the reaction temperature of the microreactor to 100°C-150°C, the residence time to 10 seconds to 30 minutes, collecting liquid products, monitoring the reaction completion by HPLC, and the reaction liquid flows out into a post-processing system, quenching, extraction, washing, drying, removing the organic solvent, and distilling to obtain compound B.

[0038] Step b adopts a continuous flow microreactor synthesis method. Compared with the traditional kettle reaction, its conversion rate is increased from 82% to 93%, the elimination of reaction by-products is reduced from 13% to 2.2%, and the post-treatment acidic wastewater is significantly reduced.

[0039] The flow rate in the microreactor in step c is 1 ml / min to 50 ml / min.

[0040] The reaction temperature in the microreactor of step c is 10° C.-50° C. In some embodiments, the reaction temperature in the microreactor of step c is 20° C.-60° C.

[0041] The reaction residence time in the microreactor in step c is 10 seconds to 30 minutes.

[0042] In the synthesis method of MTA, after the reaction is completed in step c, post-treatment is optionally performed. In some embodiments, in the synthesis method of MTA, post-treatment in step c includes: after the reaction is completed, filtering, removing the organic solvent, and distilling to obtain MTA.

[0043] In some embodiments, a method for synthesizing 2-methyl-3-trifluoromethylaniline comprises step c: using a metering pump to pump the ethanol solution of compound B obtained in step b and hydrogen (controlling the pressure at 5 to 60 psi) into a microreactor equipped with a palladium carbon filler column, respectively, the reaction temperature is set at 20°C-60°C, the residence time is 10 seconds to 10 minutes, the liquid product is collected, and HPLC is used to monitor the reaction completion. After the reaction liquid flows out, it enters a post-processing system, is filtered, the organic solvent is removed, and MTA is obtained by distillation.

[0044] Step c adopts the synthesis method of continuous flow microreactor, which requires lower pressure and is safer than the traditional kettle reaction.

[0045] The method for synthesizing MTA of the present invention comprises at least one of step a, step b, and step c.

[0046] In some embodiments, the synthesis method of 2-methyl-3-trifluoromethylaniline of the present invention comprises step b and step c.

[0047] In some embodiments, the synthesis method of 2-methyl-3-trifluoromethylaniline of the present invention comprises step c.

[0048] In some embodiments, a method for synthesizing 2-methyl-3-trifluoromethylaniline comprises the steps of: a: using a metering pump to pump nitric acid and sulfuric acid solutions of o-toluic acid into a microreactor at a flow rate of 1:3 to 1:6, setting the reaction temperature of the microreactor to 60°C-80°C, the residence time to 2 min to 10 min, collecting liquid products, monitoring the reaction to be complete by HPLC, and entering a post-processing system after the reaction solution flows out, and optionally post-processing to obtain compound A; and b: using a metering pump to pump the toluene solution of compound A obtained in step a, sulfur tetrafluoride and hydrogen fluoride (gas control pressure 5 to 30 psi) into the microreactor, setting the reaction temperature of the microreactor to 1 00℃-150℃, the residence time is 10 seconds to 30min, the liquid product is collected, and the reaction is completed by HPLC monitoring. The reaction liquid flows out and enters the post-processing system, and is quenched, extracted, washed, dried, and the organic solvent is removed and distilled to obtain compound B; step c: using a metering pump to pump the ethanol solution of compound B obtained in step b and hydrogen (control the pressure at 5 to 60psi) into a microreactor equipped with a palladium carbon filling column, respectively, and the reaction temperature is set to 20℃-60℃, the residence time is 10 seconds to 10min, the liquid product is collected, and the reaction is completed by HPLC monitoring. The reaction liquid flows out and enters the post-processing system, and is filtered, the organic solvent is removed, and MTA is distilled to obtain MTA.

[0049] In the technical scheme of the present invention, a continuous flow microreactor is creatively adopted and an improved method is used to synthesize 2-methyl-3-trifluoromethylaniline. By examining the influence of factors such as material molar ratio, reaction residence time, reaction temperature, etc. on yield and purity, the optimal process conditions are determined. The optimized process has the characteristics of high raw material conversion rate, reduced flammable and explosive hazards, reduced three wastes, low energy consumption and labor costs, low total project cost, and improved production capacity.

[0050] In summary, the present invention includes the following beneficial technical effects:

[0051] 1. The present invention provides a method for synthesizing 2-methyl-3-trifluoromethylaniline by a continuous flow microreactor. The continuous flow microreactor is used. Compared with the traditional kettle reaction, in step a, the conversion rate of the reactants is improved, the reaction by-products are eliminated, the risk of overheating and explosion is avoided, and the post-treatment wastewater is reduced; in step b, the risk of acid gas leakage caused by high temperature is reduced, and the post-treatment wastewater is reduced. In step c, the risk of explosion is reduced. At the same time, due to the relatively closed reaction system and efficient mass transfer and heat transfer performance, the continuous flow microreactor can meet the higher requirements of this step based on environmental safety and stable process parameters.

[0052] 2. The present invention provides a continuous flow micro-reaction synthesis method for 2-methyl-3-trifluoromethylaniline. By examining the effects of flow rate ratio, reaction residence time, reaction temperature and other factors on yield and purity, the optimal process conditions are determined. The method has the characteristics of high yield, less post-treatment wastewater, low energy consumption and labor costs, low total project cost and improved production capacity.

[0053] In the description of the present invention, it should be understood that the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of the features. In the description of the present invention, the meaning of "plurality" is two or more, unless otherwise clearly and specifically defined.

[0054] In the description of this specification, the description with reference to the terms "one embodiment", "some embodiments", "example", "specific example", or "some examples" etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art may combine and combine the different embodiments or examples described in this specification and the features of the different embodiments or examples, without contradiction.

[0055] In the present invention, expressions such as "compound A", "compound represented by formula A" and "formula A" refer to the same compound.

[0056] In the present invention, "optionally" or "optionally" means that it may or may not be present; or it may or may not be performed; for example, "optionally adding a reaction solvent to the crude product obtained in step (C)" means that a reaction solvent may or may not be added to the crude product obtained in step (C). DETAILED DESCRIPTION

[0057] In order to enable those skilled in the art to better understand the technical solution of the present invention, some non-limiting embodiments are further disclosed below to further describe the present invention in detail.

[0058] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0059] In the present invention, min means minute; h means hour; g means gram; ml means milliliter; Kg means kilogram.

[0060] In the present invention, HPLC means high performance liquid chromatography.

[0061] Example 1 Preparation of Compound A

[0062]

[0063] 136.15 g of o-toluic acid was dissolved in 280 ml of sulfuric acid and placed in liquid storage bottle A, 52 ml of nitric acid was placed in liquid storage bottle B, the reaction temperature was set to 80°C, the materials in bottles A and B were respectively pumped into the microchannel reactor by two plunger metering pumps at a flow rate of 6:1, the residence time was 2 minutes, the liquid product was collected, and the reaction was monitored to be complete by HPLC. The reaction liquid flowed out and entered the post-treatment system, and was crystallized by adding water, filtered, and washed to obtain compound A with a purity of 99.5% and a yield of 94%.

[0064] Comparative Example 1 Preparation of Compound A

[0065] 136.15g of o-toluic acid was dissolved in 280ml of sulfuric acid and placed in a reaction bottle. 52ml of 65% concentrated nitric acid was added dropwise at 0-5 degrees using a dropping funnel. After the addition was complete, the temperature was slowly raised to 80°C and the reaction was continued for 6 hours. The reaction was monitored by HPLC until it was complete. The reaction solution was crystallized by adding water, filtered, and washed to obtain compound A with a purity of 95.4% and a yield of 73%.

[0066] Example 2 Preparation of Compound B

[0067]

[0068] The toluene solution of compound A obtained in Example 1 was placed in liquid storage bottle A, and the reaction temperature was set to 150° C. The toluene solution of compound A was pumped into the microchannel reactor at a rate of 5 ml / min. The pressure was controlled at 15 psi to pass sulfur tetrafluoride and hydrogen fluoride gases into the microchannel reactor with a residence time of 10 min. The liquid product was collected and the reaction was completed under HPLC monitoring. The reaction liquid flowed out and entered the post-treatment system. After extraction, washing, drying and removal of the organic solvent, it was distilled under reduced pressure to obtain compound 2 B with a purity of 98.5% and a yield of 93%.

[0069] Comparative Example 2 Preparation of Compound B

[0070] The toluene solution of compound A obtained in Example 1 was placed in a high-pressure reaction bottle, the reaction temperature was set to 150°C, sulfur tetrafluoride and hydrogen fluoride gas were introduced, and the reaction was carried out for 4 hours. After cooling to room temperature, the gas was carefully released, the liquid product was collected, and the reaction was monitored by HPLC to be complete. The reaction solution was extracted, washed, dried, and the organic solvent was removed, and then the compound 2 B was obtained by vacuum distillation with a purity of 96.5% and a yield of 82%.

[0071] Example 3 Preparation of 2-methyl-3-trifluoromethylaniline

[0072]

[0073] The compound B obtained in Example 1 was dissolved in 150 ml of ethanol and pumped into a palladium-carbon column at a rate of 1 ml / min. The pressure was controlled at 30 psi and hydrogen was passed into the palladium-carbon column for a residence time of 10 min. The reaction was completed under HPLC monitoring. The reaction solution was concentrated to remove the solvent, and the residue was distilled under reduced pressure to obtain 2-methyl-3-trifluoromethylaniline with a purity of 99.0% and a yield of 86%.

[0074] The method of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein within the content, spirit and scope of the present invention to implement and apply the technology of the present invention. Those skilled in the art can refer to the content of this article and appropriately improve the process parameters. It is particularly important to point out that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention.

Claims

1. A method for synthesizing 2-methyl-3-trifluoromethylaniline using a continuous flow microreactor, comprising the following steps: Step a: using a metering pump to pump a sulfuric acid solution of o-toluic acid and nitric acid into a microreactor respectively, and when the reaction reaches the end point, the feed liquid enters a post-processing system to obtain compound A, Step b: The toluene solution of compound A obtained in step a, sulfur tetrafluoride and hydrogen fluoride gas are pumped into the microreactor by a metering pump, and the reaction solution flows out into a post-processing system to obtain compound B. Step c: Pumping the ethanol solution of compound B obtained in step b and hydrogen into a microreactor equipped with a palladium carbon filler column, wherein the hydrogen pressure is controlled at 5 to 60 psi, and the reaction solution flows out into a post-processing system to obtain compound MTA. in, The reaction temperature in the microreactor of step a is 50° C.-90° C.; the reaction temperature in the microreactor of step b is 100° C.-150° C.; the reaction temperature in the microreactor of step c is 10° C.-50° C.; the flow rate in the microreactors in steps a, b and c is 1 ml / min-50 ml / min.

2. The synthesis method according to claim 1, characterized in that In the step a, the flow rate ratio of the sulfuric acid solution of o-toluic acid and nitric acid in the metering pump in the microreactor is 3:1 to 6:

1.

3. The synthesis method according to any one of claims 1 to 2, characterized in that The reaction residence time in the microreactor is 10 seconds to 30 minutes.

4. A method for synthesizing 2-methyl-3-trifluoromethylaniline, comprising the steps of: a: using a metering pump to pump nitric acid and sulfuric acid solutions of o-toluic acid into a microreactor at a flow rate of 1:3 to 1:6, setting the reaction temperature of the microreactor to 60°C-80°C, the residence time to 2 min to 10 min, collecting liquid products, monitoring the reaction completion by HPLC, and entering a post-treatment system after the reaction liquid flows out, and optionally post-treating to obtain compound A; and b: using a metering pump to pump the toluene solution of compound A obtained in step a, sulfur tetrafluoride and hydrogen fluoride into the microreactor, wherein the sulfur tetrafluoride and hydrogen fluoride gases are controlled at a pressure of 5 to 30 psi, and setting the reaction temperature of the microreactor to 1 00℃-150℃, the residence time is 10 seconds to 30min, the liquid product is collected, HPLC monitors the reaction to be complete, the reaction liquid flows out and enters the post-processing system, quenches, extracts, washes, dries, removes the organic solvent, and distills to obtain compound B; step c: using a metering pump to pump the ethanol solution of compound B obtained in step b and hydrogen into a microreactor equipped with a palladium carbon filler column, wherein the hydrogen controls the pressure of 5 to 60psi, the reaction temperature is set to 20℃-60℃, the residence time is 10 seconds to 10min, the liquid product is collected, HPLC monitors the reaction to be complete, the reaction liquid flows out and enters the post-processing system, is filtered, removes the organic solvent, and distills to obtain MTA,

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