A method for producing anthranilamide derivatives

Abstract

The present invention provides a method for producing anthranilamide derivatives, comprising the following steps: S1) transporting a mixed solution A of anthranilic acid derivatives, a solvent and an organic base and a mixed solution B of triphosgene and a solvent to a first continuous reactor respectively, and performing a cyclization reaction at 55-90° C. to obtain a cyclization reaction liquid; S2) treating the cyclization reaction liquid with an alkali solution to obtain a treated cyclization reaction liquid; S3) transporting the treated cyclization reaction liquid and an organic amine or an aqueous solution of an organic amine to a second continuous reactor respectively, and performing an aminolysis reaction at 55-85° C. to obtain an aminolysis reaction liquid containing anthranilamide derivatives. The present invention adopts a continuous reactor to perform a cyclization reaction at a relatively high temperature, and the obtained cyclization reaction liquid is treated with an alkali solution and directly used for the continuous aminolysis reaction in the next step, thereby simplifying the operation, improving the production efficiency, and omitting the use of a catalyst.

Description

Technical Field

[0001] The present invention relates to the technical field of pesticide production, in particular to a method for producing an anthranilamide derivative. Background Art

[0002] o-Aminobenzamide is an important intermediate in the field of pharmaceutical pesticides. For example, 2-amino-N,3-dimethylbenzamide and 2-amino-5-chloro-N,3-dimethylbenzamide are both key intermediates for the synthesis of the pesticide chlorantraniliprole. This type of compound has a variety of preparation methods. For example, using o-aminobenzoic acid as a raw material, first reacting with a halogenating agent (sulfoxide chloride, phosphorus trichloride, etc.) to generate an acyl halide, and then reacting with an organic amine to generate a target product through a nucleophilic substitution reaction, such as Bu Minglei's "Synthesis of o-aminobenzamide compounds"; or first reacting with an alcohol to generate an ester, and then reacting with an organic amine to generate a target product through a nucleophilic substitution reaction, such as patent CN111517975A; or first reacting with an acylating agent to generate a ring-forming reaction, and then aminolysis in the presence of an organic amine to obtain the target product, such as patent CN112457209A. Among them, the acyl halide and amination routes have a large amount of three wastes, and the generated sulfur- or phosphorus-containing wastewater is difficult to treat and has a high treatment cost; the esterification and amination routes are difficult to achieve continuous production because the esterification reaction is a reversible reaction with a long reaction time; in the cyclization and amination routes, the acylating agent is mostly selected as highly toxic phosgene. In order to ensure the conversion rate of the raw materials, excessive phosgene or triphosgene is often used, and after the cyclization reaction is completed, the excess phosgene in the reaction solution is driven out by heating and reflux, and then the reaction solution is cooled and used for the next amination reaction. In industrial production, not only is the operation cumbersome, time-consuming, energy-intensive, and low in production efficiency, but it is also difficult to completely drive out the phosgene. In the amination reaction stage, more organic amines still need to be added, and acetic acid needs to be additionally added to catalyze the amination reaction. If the amination reaction is directly carried out after the cyclization reaction, the amount of organic amine used will increase and the nitrogen content of the wastewater will increase, increasing the burden of wastewater treatment. Summary of the invention

[0003] In view of this, the technical problem to be solved by the present invention is to provide a method for producing anthranilamide derivatives, which simplifies the production process while reducing the amount of organic amine used and has a higher yield and purity.

[0004] To achieve the above object, the present invention provides a method for producing an anthranilamide derivative, comprising the following steps:

[0005] S1) conveying a mixed solution A of an anthranilic acid derivative, a solvent and an organic base and a mixed solution B of triphosgene and a solvent to a first continuous reactor respectively to carry out a cyclization reaction at 55-90° C. to obtain a cyclization reaction solution;

[0006] S2) treating the cyclization reaction liquid with alkali solution to obtain a treated cyclization reaction liquid;

[0007] S3) The treated cyclization reaction liquid and the organic amine or the aqueous solution of the organic amine are respectively transported to a second continuous reactor to carry out an aminolysis reaction at 55-85° C. to obtain an aminolysis reaction liquid containing an o-aminobenzamide derivative.

[0008] Preferably, the molar ratio of the anthranilic acid derivative to triphosgene is 1:0.34-0.45.

[0009] Preferably, the anthranilic acid derivative is one of 2-amino-benzoic acid, 2-amino-3-methylbenzoic acid, and 2-amino-3-methyl-5-chlorobenzoic acid;

[0010] The organic amine is R-NH2, wherein R is a C1-C4 alkyl group.

[0011] Preferably, in step S1), the organic base is selected from one or more of 3-methylpyridine, pyridine, 2-methylpyridine, and triethylamine;

[0012] The solvent is selected from one or more of dichloromethane, dichloropropane, dichloroethane, acetonitrile, propionitrile, toluene, acetone and tetrahydrofuran.

[0013] Preferably, the first continuous reactor and the second continuous reactor are both dynamic tubular reactors or a dynamic tubular reactor and a reaction kettle connected in series.

[0014] Preferably, gas is generated during the cyclization reaction of step S1);

[0015] The gas is introduced into the tail gas treatment unit;

[0016] The tail gas treatment unit is an absorption tank and a neutralization tank connected in sequence;

[0017] The absorption tank is filled with an organic solvent for dissolving and absorbing phosgene, and the neutralization tank is filled with alkali solution for neutralizing the gas that is not dissolved and absorbed.

[0018] Preferably, the alkali solution in step S2) is an aqueous solution of sodium hydroxide, sodium carbonate or sodium bicarbonate.

[0019] Preferably, the reaction of treating the cyclization reaction liquid with alkaline solution in step S2) is carried out in the second continuous reactor, or in a separate third continuous reactor;

[0020] The third continuous reactor is a dynamic tubular reactor or a static mixing tubular reactor.

[0021] Preferably, the molar ratio of the anthranilic acid derivative to the organic amine in step S3) is 1:1.05-1.5.

[0022] Preferably, after obtaining the aminolysis reaction solution, the step S3) further comprises:

[0023] Post-processing includes distillation concentration, washing, filtration and drying.

[0024] Compared with the prior art, the present invention provides a method for producing anthranilamide derivatives, comprising the following steps: S1) respectively conveying a mixed solution A of anthranilic acid derivatives, a solvent and an organic base and a mixed solution B of triphosgene and a solvent to a first continuous reactor for cyclization reaction at 55-90°C to obtain a cyclization reaction solution; S2) treating the cyclization reaction solution with an alkali solution to obtain a treated cyclization reaction solution; S3) respectively conveying the treated cyclization reaction solution and an organic amine or an aqueous solution of an organic amine to a second continuous reactor for aminolysis reaction at 55-85°C to obtain an aminolysis reaction solution containing the product anthranilamide derivatives.

[0025] The production method of anthranilamide derivatives provided by the present invention adopts a continuous reactor to carry out a cyclization reaction at a relatively high temperature, hydrogen chloride gas generated by the reaction and a small amount of phosgene entrained are introduced into a tail gas treatment system, the obtained cyclization reaction liquid is treated with an alkali solution, and the residual phosgene and hydrogen chloride in the cyclization reaction liquid are neutralized into salts by the alkali solution and then directly used for the continuous aminolysis reaction in the next step, thereby avoiding the high energy consumption operation of long-term reflux and light removal, simplifying the cumbersome operation of first heating up the reflux and light removal, then cooling down for aminolysis reaction and dropping materials after the cyclization reaction is completed in intermittent production, improving the production efficiency, avoiding the influence of the residual phosgene and hydrogen chloride in the cyclization reaction liquid on the aminolysis reaction, omitting the use of a catalyst, simplifying the production process and reducing the amount of organic amine used. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 This is a schematic diagram of the structure of the production device used in Example 2;

[0027] Among them, 1-the first continuous reactor; 2-the second continuous reactor; 3-the absorption tank; 4-the neutralization tank; 5-the concentration and washing unit; 6-the solid-liquid separation unit; 7-the drying unit. DETAILED DESCRIPTION

[0028] The present invention provides a method for producing an anthranilamide derivative, comprising the following steps:

[0029] S1) conveying a mixed solution A of an anthranilic acid derivative, a solvent and an organic base and a mixed solution B of triphosgene and a solvent to a first continuous reactor respectively to carry out a cyclization reaction at 55-90° C. to obtain a cyclization reaction solution;

[0030] S2) treating the cyclization reaction liquid with alkali solution to obtain a treated cyclization reaction liquid;

[0031] S3) The treated cyclization reaction liquid and the organic amine or the aqueous solution of the organic amine are respectively transported to a second continuous reactor to carry out an aminolysis reaction at 55-85° C. to obtain an aminolysis reaction liquid containing an o-aminobenzamide derivative.

[0032] Among them, the anthranilic acid derivative is preferably one of 2-amino-benzoic acid, 2-amino-3-methylbenzoic acid, and 2-amino-3-methyl-5-chlorobenzoic acid.

[0033] The invention adopts a continuous reactor, performs a cyclization reaction at a relatively high temperature, and then treats the obtained cyclization reaction liquid with an alkali solution, neutralizes the residual phosgene in the cyclization reaction liquid with hydrogen chloride to form a salt, and then directly uses it for the continuous aminolysis reaction in the next step. It is found through research that the direct aminolysis of the cyclization reaction liquid treated with the alkali solution has no adverse effect on the aminolysis reaction, simplifies the cumbersome operations of heating and refluxing to drive out the phosgene, cooling for aminolysis and dropping materials in intermittent production, reduces energy consumption and improves production efficiency, avoids the influence of the residual phosgene and hydrogen chloride in the cyclization reaction liquid on the aminolysis reaction, omits the use of catalyst acetic acid, reduces the use amount of organic amines, reduces the generation of alkylamine hydrochloride, thereby reducing the nitrogen content in wastewater and simplifying the treatment of wastewater.

[0034] In the first step of the cyclization reaction, the prior art usually uses a lower temperature, because phosgene will escape at high temperature and cause waste. The present invention has been found through research that step S1 uses a first continuous reactor, and the mixed solution A of anthranilic acid derivatives, solvents, and organic bases and the mixed solution B of triphosgene and solvents are respectively transported to the continuous reactor, and the reaction temperature is controlled to be 55-90°C, preferably 60-85°C. In the presence of an organic base, the phosgene generated by the rapid decomposition of triphosgene rapidly undergoes condensation cyclization with the anthranilic acid derivative, and the cyclization reaction liquid containing substituted benzoxazinedione is continuously obtained, which reduces the waste of phosgene, and then the treated cyclization reaction liquid, organic amine or aqueous solution of organic amine are introduced into the second continuous reactor, and the reaction temperature is controlled to be 55-85°C, preferably 60-80°C. The cyclization reaction liquid without phosgene and hydrogen chloride directly reacts rapidly with the organic amine to continuously obtain anthranilamide derivatives. The two-step reaction is carried out continuously, and the feeding and discharging of materials in industrial production can be automated, thereby improving production efficiency.

[0035] Preferably, the first continuous reactor described in step S1 and the second continuous reactor described in step S3 are both dynamic tubular reactors or dynamic tubular reactors and reactors connected in series. When the first continuous reactor and the second continuous reactor are dynamic tubular reactors and reactors connected in series, the material first enters the dynamic tubular reactor and then enters the reactor. The dynamic tubular reactor is a plug flow reactor having a reaction chamber and a heat exchange chamber. The reaction chamber is used to provide a place for the material to react. The reaction chamber is provided with a stirring shaft having a stirring paddle or stirring fins, which play a role of stirring and mixing by rotation. The heat exchange chamber is used to exchange heat in the reaction chamber by circulating a heat exchange medium. The reactor is a conventional kettle reactor with stirring and heat exchange functions.

[0036] In step S1, an organic base is added to promote the decomposition of triphosgene to produce phosgene to participate in the cyclization reaction. The organic base is preferably one or more of 3-methylpyridine, pyridine, 2-methylpyridine, and triethylamine. The amount of the organic base added is preferably 3% to 15% of the mass of the raw material anthranilic acid derivative.

[0037] In the present invention, in order to realize continuous feeding, continuous reaction and continuous discharging of raw materials, the anthranilic acid derivative is pre-mixed with the solvent and the organic base before feeding to obtain a mixed solution A, and triphosgene is mixed with the solvent to obtain a mixed solution B, wherein the solvent used is preferably one or more of dichloromethane, dichloropropane, dichloroethane, acetonitrile, propionitrile, toluene, acetone and tetrahydrofuran. In the preparation stage of the mixed solution A, the amount of the solvent used is preferably 2-10 times the mass of the anthranilic acid derivative, and in the preparation stage of the mixed solution B, the amount of the solvent used is preferably 2-8 times the mass of triphosgene. Too much solvent will reduce the production capacity of the production equipment and increase the energy consumption of subsequent solvent recovery. Too little solvent is not enough to transport the raw materials to the continuous reactor in the form of a fluid. When the boiling point of the solvent is lower than the reaction temperature, a back pressure valve can be used to back pressure the reaction system to avoid serious solvent vaporization due to excessively high reaction temperature, which affects the processing capacity of the reactor and the stability of the reaction process. The pressure of the back pressure can be calculated in advance according to the saturated vapor pressure of the solvent at different temperatures.

[0038] Preferably, the mixed solution A and the mixed solution B are respectively transported to the first continuous reactor by a feed pump. The mixed solution A and the mixed solution B may also be transported to the first continuous reactor by other methods well known to those skilled in the art, and the present invention is not limited thereto.

[0039] In step S1, mixed solution A and mixed solution B are fed according to the ratio of anthranilic acid derivatives to triphosgene, wherein the molar ratio of anthranilic acid derivatives to triphosgene is preferably 1:0.34-0.45, more preferably 1:0.35-0.42, and further preferably 1:0.37-0.4. Although excessive use of triphosgene helps promote the cyclization reaction, it will also increase the burden of subsequent phosgene recovery. Too little use of triphosgene will reduce the conversion rate of anthranilic acid derivatives.

[0040] Preferably, in the step S1) of the present invention, the generated gas is introduced into a tail gas treatment unit.

[0041] In the present invention, the rear end of the first continuous reactor is connected to a tail gas treatment unit for treating the hydrogen chloride gas generated in step S1 and the entrained phosgene that does not participate in the reaction. The tail gas treatment unit is preferably an absorption tank and a neutralization tank connected in sequence. The absorption tank contains an organic solvent, preferably a halogenated alkane solvent, for dissolving and absorbing the phosgene. The neutralization tank contains an alkali solution, preferably a sodium hydroxide solution, for neutralizing the gas that is not dissolved and absorbed. The gas derived from the first continuous reactor first enters the absorption tank. At low temperature, the phosgene that does not participate in the reaction is absorbed by the organic solvent, and the unabsorbed gas enters the neutralization tank and is directly neutralized into salt by the alkali solution in the neutralization tank.

[0042] The present invention introduces the gas generated by the reaction into a tail gas treatment unit for treatment, which can recover excess phosgene on the one hand and avoid the treatment burden caused by more salt generated in the alkali solution treatment stage on the other hand.

[0043] In step S1 of the present invention, after the hydrogen chloride gas generated by the reaction and the phosgene that does not participate in the reaction are extracted, the obtained cyclization reaction liquid contains a small amount of phosgene and hydrogen chloride. In order to avoid affecting the next aminolysis reaction and reduce by-products, in step S2, the cyclization reaction liquid obtained in step S1 is treated with alkali solution, and the alkali solution is preferably an aqueous solution of sodium hydroxide, sodium carbonate or sodium bicarbonate. The amount of the alkali solution used is adjusted according to the acidity and alkalinity of the cyclization reaction liquid in the actual production process, and preferably the pH of the cyclization reaction liquid is adjusted to 7-9.

[0044] Optionally, the cyclization reaction liquid treated with alkali solution in step S2 can be carried out in a second continuous reactor, the cyclization reaction liquid obtained in step S1 and the alkali solution respectively enter the second continuous reactor to react, and then the organic amine or the aqueous solution of the organic amine is added to react with the cyclization reaction liquid treated with alkali solution. In actual operation, the cyclization reaction liquid obtained in step S1 and the alkali solution enter the reactor from the front feed port of the dynamic tubular reactor of the second continuous reactor to react, and the organic amine or the aqueous solution of the organic amine flows from the front feed port of the dynamic tubular reactor to the rear feed port to enter the reactor and react with the cyclization reaction liquid treated with alkali solution, wherein the material flow direction is from the front feed port of the dynamic tubular reactor to the discharge port.

[0045] Optionally, the cyclization reaction liquid treated with alkali solution in step S2 can also be carried out in a separate third continuous reactor, and the third continuous reactor is preferably a dynamic tubular reactor or a static mixing tubular reactor. In one embodiment of the present invention, the cyclization reaction liquid obtained in step S1 and the alkali solution enter the third continuous reactor for reaction, and the cyclization reaction liquid treated with alkali solution flows out from the discharge port of the third continuous reactor and enters the second continuous reactor for aminolysis reaction with the organic amine or the aqueous solution of the organic amine.

[0046] In step S3, the organic amine or the organic amine aqueous solution is fed in a ratio of anthranilic acid derivative to the organic amine, wherein the molar ratio of anthranilic acid derivative to organic amine is preferably 1:1.05-1.5, more preferably 1:1.05-1.3, and further preferably 1:1.05:1.2.

[0047] The organic amine is preferably R-NH2, wherein R is preferably a C1-C4 alkyl group. Preferably, the organic amine includes but is not limited to methylamine, dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine, butylamine, etc.

[0048] In the present invention, the reaction time of the reaction liquid in the continuous reactor is mainly related to the reaction temperature. In the cyclization reaction stage of step S1, when the reaction temperature is 55-90°C, the residence time of the material of the cyclization reaction in the dynamic tubular reactor is 2-30min, and the residence time in the reactor is 0-40min. In the aminolysis reaction stage of step S3, when the reaction temperature is 55-85°C, the residence time of the material of the aminolysis reaction in the dynamic tubular reactor is 3-30min, and the residence time in the reactor is 0-40min. In step S2, the reaction temperature is controlled to be the same as that in the aminolysis reaction stage, and the residence time is 1-5min.

[0049] In order to obtain anthranilamide derivatives in the present invention, the aminolysis reaction liquid containing anthranilamide derivatives needs to be post-treated. Preferably, the aminolysis reaction liquid obtained in step S3) further includes: distillation concentration, washing, filtering, and drying. Specifically, the aminolysis reaction liquid flowing out of the second continuous reactor is first concentrated to recover the solvent, and a washing agent such as water, a mixture of acetonitrile and water, a mixture of methanol and water, or a mixture of ethanol and water is added to the concentrated reaction liquid, stirred and mixed, and then cooled and crystallized, and then filtered and dried to obtain the product anthranilamide derivatives.

[0050] In order to further illustrate the present invention, the production method of the anthranilamide derivatives provided by the present invention is described in detail below in conjunction with examples.

[0051] Example 1

[0052] 2-aminobenzoic acid, dichloromethane and 3-methylpyridine were prepared into a mixed solution A in a mass ratio of 1:4:0.03, and triphosgene and dichloromethane were prepared into a mixed solution B in a mass ratio of 1:4.

[0053] The molar ratio of 2-aminobenzoic acid to triphosgene was controlled to be 1:0.34. According to the ratio, the mixed solution A and the mixed solution B were respectively transported to the dynamic tubular reactor of the first continuous reactor through a feed pump at flow rates of 1.38 kg / h and 1.01 kg / h, reacted at a temperature of 55° C. for 15 min, and then entered the reactor of the first continuous reactor to be aged for 25 min to obtain a cyclization reaction liquid. The tail gas generated by the first continuous reactor entered the absorption tank filled with ethylene dichloride and the neutralization tank filled with sodium hydroxide solution in sequence for recovery and neutralization treatment. The cyclization reaction liquid was pumped out of the reactor and then pumped into the dynamic tubular reactor of the third continuous reactor to mix with the 5 % sodium hydroxide solution was reacted at 55° C. for 5 min to obtain a cyclization reaction liquid with a pH of 8. The treated cyclization reaction liquid flowing out of the third continuous reactor entered the static tubular mixer of the second continuous reactor, and reacted with diethylamine simultaneously input at a flow rate of 0.154 kg / h at a temperature of 55° C. for 5 min. Then, it entered the reactor of the second continuous reactor and aged for 40 min to obtain an aminolysis reaction liquid. After stable operation, the aminolysis reaction liquid with continuous discharge for 10 min was collected, and after distillation, concentration, washing, filtering and drying, 62.5 g of product 2-amino-N,N-diethylbenzamide was obtained with a yield of 97.5% and a purity of 98.4%.

[0054] Example 2

[0055] 2-Amino-3-methylbenzoic acid, dichloroethane and 2-methylpyridine were prepared into a mixed solution A in a mass ratio of 1:2:0.05, and triphosgene and dichloroethane were prepared into a mixed solution B in a mass ratio of 1:2.

[0056] The molar ratio of 2-amino-3-methylbenzoic acid to triphosgene was controlled to be 1:0.35. According to the ratio, the mixed solution A and the mixed solution B were respectively transported to the dynamic tubular reactor of the first continuous reactor through a feed pump at flow rates of 0.92 kg / h and 0.62 kg / h, and reacted at a temperature of 70° C. for 18 min to obtain a cyclization reaction liquid. The tail gas generated in the first continuous reactor was sequentially fed into an absorption tank containing ethylene dichloride and a neutralization tank containing sodium hydroxide solution for recovery and neutralization treatment. After the cyclization reaction liquid flowed out of the reactor, it was pumped into the front feed port of the dynamic tubular reactor in the second continuous reactor. The reactor was reacted with 10% sodium bicarbonate solution pumped in from the front feed port at 70°C for 2.5 minutes to obtain a cyclization reaction liquid with a pH of 8, and then reacted with 40% methylamine simultaneously input at a rate of 0.171 kg / h from the front feed port of the reactor to the rear feed port at 70°C for 20 minutes to obtain an aminolysis reaction liquid. After stable operation, the aminolysis reaction liquid with continuous discharge for 10 minutes was collected, and after distillation, concentration, washing, filtering and drying, 54.2 g of the product 2-amino-N,3-dimethylbenzamide was obtained with a yield of 99.1% and a purity of 99%.

[0057] Example 3

[0058] 2-Amino-3-methyl-5-chlorobenzoic acid, acetonitrile and pyridine were prepared into a mixed solution A in a mass ratio of 1:5:0.08, and triphosgene and acetonitrile were prepared into a mixed solution B in a mass ratio of 1:5.

[0059] The molar ratio of 2-amino-3-methyl-5-chlorobenzoic acid to triphosgene was controlled to be 1:0.38. According to the ratio, the mixed solution A and the mixed solution B were respectively transported to the dynamic tubular reactor of the first continuous reactor through a feed pump at flow rates of 2.26 kg / h and 1.35 kg / h, and reacted at a temperature of 85° C. for 10 min to obtain a cyclization reaction liquid. The tail gas generated in the first continuous reactor was sequentially fed into an absorption tank containing acetonitrile and a neutralization tank containing sodium hydroxide solution for recovery and neutralization treatment. After the cyclization reaction liquid flowed out of the reactor, it was pumped into the dynamic tubular reactor of the third continuous reactor and mixed with 1 0% sodium carbonate solution was reacted at 80°C for 1.5min to obtain a cyclization reaction liquid with a pH of 7. The treated cyclization reaction liquid flowing out of the third continuous reactor entered the dynamic tubular reactor of the second continuous reactor and reacted with 40% methylamine simultaneously input at a rate of 0.179kg / h at a temperature of 80°C for 10min to obtain an aminolysis reaction liquid. After stable operation, the aminolysis reaction liquid continuously discharged for 10min was collected and concentrated by distillation, and then washed, filtered and dried to obtain 65.3g of the product 2-amino-5-chloro-N,3-dimethylbenzamide with a yield of 98.6% and a purity of 98.5%.

[0060] Example 4

[0061] 2-aminobenzoic acid, propionitrile and triethylamine were prepared into a mixed solution A in a mass ratio of 1:6:0.03, and triphosgene and propionitrile were prepared into a mixed solution B in a mass ratio of 1:6.

[0062] The molar ratio of 2-aminobenzoic acid to triphosgene was controlled to be 1:0.4. According to the ratio, the mixed solution A and the mixed solution B were respectively transported to the dynamic tubular reactor of the first continuous reactor at flow rates of 1.95 kg / h and 1.66 kg / h through a feed pump, reacted at a temperature of 75° C. for 2 min, and then entered the reactor of the first continuous reactor to be aged for 40 min to obtain a cyclization reaction liquid. After the cyclization reaction liquid flowed out of the reactor, it was pumped into the dynamic tubular reactor of the third continuous reactor and reacted with a 5% sodium hydroxide solution pumped in at the same time at 75° C. for 2 min to obtain a cyclization reaction liquid with a pH of 9. The treated cyclization reaction liquid flowing out of the third continuous reactor enters the dynamic tubular reactor of the second continuous reactor, reacts with 40% dimethylamine simultaneously input at a flow rate of 0.271 kg / h at a temperature of 75°C for 15 min, and then enters the reactor of the second continuous reactor for aging for 10 min to obtain an aminolysis reaction liquid. After stable operation, the aminolysis reaction liquid with continuous discharge for 10 min is collected, and the product 2-amino-N,N-dimethylbenzamide 54 g is obtained after distillation, concentration, washing, filtering and drying, with a yield of 98.7% and a purity of 99.2%.

[0063] Example 5

[0064] 2-Amino-3-methylbenzoic acid, toluene and pyridine were prepared into a mixed solution A in a mass ratio of 1:3:0.12, and triphosgene and toluene were prepared into a mixed solution B in a mass ratio of 1:6.

[0065] The molar ratio of 2-amino-3-methylbenzoic acid to triphosgene was controlled to be 1:0.42. According to the ratio, the mixed solution A and the mixed solution B were respectively transported to the dynamic tubular reactor of the first continuous reactor through a feed pump at flow rates of 1.25 kg / h and 0.75 kg / h, and reacted at a temperature of 90° C. for 5 min to obtain a cyclization reaction liquid. The tail gas generated in the first continuous reactor was sequentially fed into an absorption tank containing toluene and a neutralization tank containing sodium hydroxide solution for recovery and neutralization treatment. After the cyclization reaction liquid flowed out of the reactor, it was pumped into the dynamic tubular reactor of the third continuous reactor and simultaneously pumped into The 10% sodium carbonate solution was reacted at 85°C for 1 min to obtain a cyclization reaction liquid with a pH of 8. The treated cyclization reaction liquid flowing out of the third continuous reactor entered the dynamic tubular reactor of the second continuous reactor and reacted with 0.154 kg / h of propylamine at 85°C for 5 min to obtain an aminolysis reaction liquid. After stable operation, the aminolysis reaction liquid with continuous discharge for 10 min was collected and concentrated by distillation. After washing, filtering and drying, 63.1 g of the product 2-amino-3-methyl-N-propylbenzamide was obtained with a yield of 98.4% and a purity of 98.3%.

[0066] Example 6

[0067] 2-Amino-3-methyl-5-chlorobenzoic acid, acetone and triethylamine were prepared into a mixed solution A in a mass ratio of 1:8:0.15, and triphosgene and acetone were prepared into a mixed solution B in a mass ratio of 1:8.

[0068] The molar ratio of 2-amino-3-methyl-5-chlorobenzoic acid to triphosgene was controlled to be 1:0.45. According to the ratio, the mixed solution A and the mixed solution B were respectively transported to the dynamic tubular reactor of the first continuous reactor through a feed pump at flow rates of 3.34 kg / h and 2.4 kg / h, and reacted at a temperature of 60° C. for 30 min to obtain a cyclization reaction liquid. After the cyclization reaction liquid flowed out of the reactor, it was pumped into the dynamic tubular reactor of the third continuous reactor and reacted with a 10% sodium carbonate solution pumped in at the same time at 60° C. for 4 min to obtain p The cyclization reaction liquid with H being 7, the treated cyclization reaction liquid flowing out from the third continuous reactor enters the dynamic tubular reactor of the second continuous reactor, and reacts with isopropylamine simultaneously input at a rate of 0.166 kg / h at a temperature of 60°C for 30 min to obtain an aminolysis reaction liquid, and after stable operation, the aminolysis reaction liquid continuously discharged for 10 min is collected, and after distillation, concentration, washing, filtering and drying, 70.2 g of the product 2-amino-3-methyl-5-chloro-N-isopropylbenzamide is obtained, with a yield of 99% and a purity of 98.7%.

[0069] Example 7

[0070] 2-Aminobenzoic acid, tetrahydrofuran and pyridine were prepared into a mixed solution A in a mass ratio of 1:10:0.08, and triphosgene and tetrahydrofuran were prepared into a mixed solution B in a mass ratio of 1:5.

[0071] The molar ratio of 2-aminobenzoic acid to triphosgene was controlled to be 1:0.37. According to the ratio, the mixed solution A and the mixed solution B were respectively transported to the dynamic tubular reactor of the first continuous reactor at flow rates of 3.04 kg / h and 1.32 kg / h through a feed pump, reacted at a temperature of 80° C. for 10 min, and then entered the reactor of the first continuous reactor for aging for 100 min to obtain a cyclization reaction liquid. After the cyclization reaction liquid flowed out of the reactor, it was pumped into the dynamic tubular reactor of the third continuous reactor and reacted with a 5% sodium bicarbonate solution pumped in at the same time at 65° C. for 3 min to obtain a pH of The treated cyclization reaction liquid flowing out of the third continuous reactor enters the dynamic tubular reactor of the second continuous reactor, and reacts with butylamine simultaneously input at a flow rate of 0.219 kg / h at a temperature of 65°C for 10 min, and then enters the reactor of the second continuous reactor to age for 20 min to obtain an aminolysis reaction liquid, and after stable operation, the aminolysis reaction liquid with continuous discharge of 10 min is collected, and the product 2-amino-N-butylbenzamide 63.1 g is obtained after distillation, concentration, washing, filtering and drying, with a yield of 98.5% and a purity of 98.6%.

[0072] Comparative Example 1

[0073] 2-Amino-3-methylbenzoic acid, dichloroethane and 2-methylpyridine were prepared into a mixed solution A in a mass ratio of 1:2:0.05, and triphosgene and dichloroethane were prepared into a mixed solution B in a mass ratio of 1:2.

[0074] The molar ratio of 2-amino-3-methylbenzoic acid to triphosgene was controlled to be 1:0.35. According to the ratio, the mixed solution A and the mixed solution B were respectively transported to the dynamic tubular reactor of the first continuous reactor through a feed pump at flow rates of 0.92 kg / h and 0.62 kg / h, and reacted at a temperature of 70°C for 18 min to obtain a cyclization reaction liquid. After the cyclization reaction liquid flowed out of the reactor, it was pumped into the reactor from the front feed port of the dynamic tubular reactor in the second continuous reactor and reacted with 40% methylamine simultaneously input from the front feed port at a flow rate of 0.171 kg / h at a temperature of 70°C for 20 min to obtain an aminolysis reaction liquid. After stable operation, the aminolysis reaction liquid with continuous discharge for 10 min was collected, and after distillation, concentration, washing, filtering and drying, 30.9 g of a crude product of 2-amino-N,3-dimethylbenzamide was obtained with a yield of 56.5% and a purity of 45.2% (54% of the product was a cyclization intermediate).

[0075] Compared with Example 2, this comparative example is directly contacted with methylamine for reaction after the cyclization reaction is completed without alkali solution treatment. Under the condition of the same amount of methylamine used as in Example 2, the yield and purity of the product are significantly reduced, and a large amount of cyclization intermediates that do not participate in the reaction are contained in the product. The reason is that the hydrogen chloride in the cyclization reaction liquid and the triphosgene that does not participate in the reaction consume a large amount of methylamine, resulting in a large amount of residual cyclization intermediates.

[0076] Comparative Example 2

[0077] The flow rate of 40% methylamine in Comparative Example 1 was increased to 0.62 kg / h. Other conditions were the same as those in Comparative Example 1. After stable operation, the aminolysis reaction liquid with continuous discharge for 10 min was collected. After the same post-treatment as in Comparative Example 1, 52.1 g of the product 2-amino-N,3-dimethylbenzamide was obtained with a yield of 95.2% and a purity of 98.4%.

[0078] Compared with Example 2, this comparative example is directly contacted with methylamine for reaction without alkaline solution treatment after the cyclization reaction is completed. Under the condition of significantly increasing the amount of methylamine used, the cyclization intermediate is fully reacted, and the yield and purity of the product are not much different from those in Example 2. However, since the hydrogen chloride in the cyclization reaction liquid and the triphosgene that does not participate in the reaction consume a large amount of methylamine, compared with Example 2, the aminolysis mother liquor after separating the product in this comparative example contains a large amount of methylamine hydrochloride, resulting in a high nitrogen content in the aminolysis mother liquor. Not only is it difficult to recover the excess methylamine and the solvent, but the generated wastewater is also difficult to treat, which does not conform to the concept of economy and environmental protection.

[0079] Comparative Example 3

[0080] 151 g of 2-amino-3-methylbenzoic acid, 10 g of pyridine, and 1 L of acetonitrile were added to a reaction kettle, and the temperature was raised to 50-60° C. with stirring. Then, a mixed solution of 122 g of triphosgene and 300 mL of acetonitrile was added dropwise. After the addition was completed, the reaction was continued for 4 h, and then refluxed for 2 h to drive out the phosgene. The escaped phosgene was directly introduced into a sodium hydroxide solution. The reaction solution was then cooled to room temperature, 15 g of acetic acid was added, and then 116 g of a 40% methylamine aqueous solution was added dropwise. After the addition was completed, the temperature was raised and refluxed for 1 h to obtain an aminolysis reaction solution. After the reaction was completed, the aminolysis reaction solution was distilled and concentrated, and after washing, filtering and drying, 157.8 g of a crude product of 2-amino-N,3-dimethylbenzamide was obtained with a yield of 96.1% and a purity of 97.8%.

[0081] The comparative example cyclization reaction needs to be heated up and refluxed to drive out the catalysis after completion, which is time-consuming and energy-consuming, has low production efficiency, and requires the use of catalyst acetic acid during the reaction process.

[0082] The above embodiments are only used to help understand the method and core idea of ​​the present invention. It should be noted that, for those skilled in the art, several improvements and modifications can be made to the present invention without departing from the principles of the present invention, and these improvements and modifications also fall within the scope of protection of the claims of the present invention.

Claims

1. A method for producing an anthranilamide derivative, comprising the following steps: S1) conveying a mixed solution A of an anthranilic acid derivative, a solvent and an organic base and a mixed solution B of triphosgene and a solvent to a first continuous reactor respectively to carry out a cyclization reaction at 55-90° C. to obtain a cyclization reaction solution; S2) treating the cyclization reaction liquid with alkali solution to obtain a treated cyclization reaction liquid; S3) transporting the treated cyclization reaction liquid and the organic amine or the aqueous solution of the organic amine to a second continuous reactor respectively to carry out an aminolysis reaction at 55-85° C. to obtain an aminolysis reaction liquid containing an o-aminobenzamide derivative; The molar ratio of the anthranilic acid derivative to the organic amine in step S3) is 1:1.05-1.2; The anthranilic acid derivative is one of 2-amino-benzoic acid, 2-amino-3-methylbenzoic acid, and 2-amino-3-methyl-5-chlorobenzoic acid; The organic amine is R-NH2, wherein R is a C1-C4 alkyl group.

2. The production method according to claim 1, characterized in that The molar ratio of the anthranilic acid derivative to triphosgene is 1:0.34-0.

45.

3. The production method according to claim 1, characterized in that In the step S1), the organic base is selected from one or more of 3-methylpyridine, pyridine, 2-methylpyridine, and triethylamine; The solvent is selected from one or more of dichloromethane, dichloropropane, dichloroethane, acetonitrile, propionitrile, toluene, acetone and tetrahydrofuran.

4. The production method according to claim 1, characterized in that The first continuous reactor and the second continuous reactor are both dynamic tubular reactors or a dynamic tubular reactor and a reaction kettle connected in series.

5. The production method according to claim 1, characterized in that: Gas is generated during the cyclization reaction of step S1); The gas is introduced into the tail gas treatment unit; The tail gas treatment unit is an absorption tank and a neutralization tank connected in sequence; The absorption tank is filled with an organic solvent for dissolving and absorbing phosgene, and the neutralization tank is filled with alkali solution for neutralizing the gas that is not dissolved and absorbed.

6. The production method according to claim 1, characterized in that: The alkali solution in step S2) is an aqueous solution of sodium hydroxide, sodium carbonate or sodium bicarbonate.

7. The production method according to claim 1, characterized in that: The reaction of treating the cyclization reaction liquid with alkali solution in step S2) is carried out in the second continuous reactor, or in a separate third continuous reactor; The third continuous reactor is a dynamic tubular reactor or a static mixing tubular reactor.

8. The production method according to claim 1, characterized in that: After obtaining the aminolysis reaction solution, the step S3) further comprises: Post-processing includes distillation concentration, washing, filtration and drying.

9. The production method according to claim 1, characterized in that: The following steps are involved: 2-amino-3-methylbenzoic acid, dichloroethane and 2-methylpyridine are prepared into a mixed solution A in a mass ratio of 1:2:0.05, and triphosgene and dichloroethane are prepared into a mixed solution B in a mass ratio of 1:2; The molar ratio of 2-amino-3-methylbenzoic acid to triphosgene was controlled to be 1:0.

35. According to the ratio, the mixed solution A and the mixed solution B were respectively transported to the dynamic tubular reactor of the first continuous reactor through a feed pump at flow rates of 0.92 kg / h and 0.62 kg / h, and reacted at a temperature of 70° C. for 18 min to obtain a cyclization reaction liquid. The tail gas generated in the first continuous reactor was sequentially fed into an absorption tank containing ethylene dichloride and a neutralization tank containing sodium hydroxide solution for recovery and neutralization treatment. After the cyclization reaction liquid flowed out of the reactor, it was pumped into the front feed port of the dynamic tubular reactor in the second continuous reactor. The reactor was reacted with 10% sodium bicarbonate solution pumped in from the front feed port at 70°C for 2.5 minutes to obtain a cyclization reaction liquid with a pH of 8, and then reacted with 40% methylamine simultaneously input at a rate of 0.171 kg / h from the front feed port of the reactor to the rear feed port at 70°C for 20 minutes to obtain an aminolysis reaction liquid. After stable operation, the aminolysis reaction liquid with continuous discharge for 10 minutes was collected, and after distillation, concentration, washing, filtering and drying, 54.2 g of the product 2-amino-N,3-dimethylbenzamide was obtained with a yield of 99.1% and a purity of 99%.

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