Synthesis method and reaction system of arylamine compound

Abstract

The application discloses a synthesis method and a reaction system of an aromatic amine compound. The synthesis method of the aromatic amine ionic compound comprises the following steps: in a continuous flow reactor, carrying out a nucleophilic substitution reaction on water, an ionic compound A and a nitrogen source Y to obtain the aromatic amine ionic compound. The preparation method has the characteristics of short reaction time, simple and safe operation and no amplification effect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of synthesis of arylamine compounds, and particularly relates to a synthesis method and a reaction system of arylamine compounds, in particular, a synthesis method for continuously preparing arylamine compounds under catalyst-free conditions by using fluid chemistry technology. BACKGROUND

[0002] Arylamine compounds are important raw materials and intermediates in the field of chemical industry, and are widely used in the fields of medicine, pesticide, dye and polymer material due to their unique chemical properties. Common synthesis methods of arylamine compounds include reductive amination reaction, Buchwald-Hartwig reaction and Ullmann reaction. Although these reactions can realize the synthesis of arylamine compounds under mild conditions, transition state metals need to be introduced as catalysts to catalyze the directional and controllable synthesis of target compounds. Dawei Ma et al. (Organic Letters, 2003, 5(14): 2453-2455) developed a CuI / amino acid catalytic system applied to Ullmann type amination reaction and obtained N-arylamine and N,N-diarylamine with high yield. However, these methods have high cost and poor atom economy due to the use of catalysts.

[0003] Classic reactions such as nucleophilic substitution provide a simpler and cheaper synthesis route for the synthesis of a large number of high-value-added arylamine compounds, and thus are still applied in actual industrial production. However, when volatile amines such as methylamine are used in traditional tank reactors, more mild reaction conditions need to be adopted due to safety factors, and such safety considerations will become particularly important in scale-up production. In recent years, the production efficiency has been improved by using multi-tank series reaction process, using fixed bed reactors filled with supported catalysts and introducing phase transfer catalysts, but there are some obvious defects. For example, the sealing and pressure resistance of the stirred tank reactor are weak, the reaction microenvironment and residence time are difficult to control, and the total volume and residence time can only be reduced in principle but cannot be changed; the fixed bed reactor lacks catalysts with obvious activity and good stability, and the filling and loss of catalysts have great influence on production cost and stability; the phase transfer catalyst has no obvious effect on the reaction system, and increases the production cost and the difficulty of post-treatment. SUMMARY

[0004] The present application provides a synthesis method and a reaction system of arylamine compounds, which has the advantages of simple operation and easy scale-up.

[0005] The present application provides a synthesis method of an aromatic amine ionic compound, comprising the following steps: carrying out a nucleophilic substitution reaction of water, ionic compound A and a nitrogen source Y in a continuous flow reactor to obtain an aromatic amine ionic compound; the nucleophilic substitution reaction is carried out at a reaction temperature of 100-300 ℃.

[0006] The anion of the ionic compound A is shown in formula I

[0007] The anion of the aromatic amine ionic compound is shown in formula II

[0008] X is hydroxyl or halogen;

[0009] m is 0, 1, 2, 3 or 4;

[0010] R is independently C1-C 10 alkyl, hydroxyl, cyano, halogen, nitro, acetyl or carboxyl;

[0011] R 1 and R 2 are independently hydrogen, methyl or ethyl;

[0012] The cation of the ionic compound A is an inorganic cation;

[0013] When R 1 and R 2 are hydrogen, the nitrogen source Y is an ammonium source and / or NH3; when R 1 and R 2 are not hydrogen, the nitrogen source Y is

[0014] In a certain aspect, the ammonium source is a conventional ammonium source in the art; the ammonium source can be selected from one or more of aqueous ammonia, NH4Cl, NH4Ac and (NH4)2SO4, for example aqueous ammonia and / or NH4Cl, and further for example aqueous ammonia and NH4Cl.

[0015] In a certain aspect, the may be dimethylamine, diethylamine, N-methylethylamine or NH3, for example NH3.

[0016] In a certain aspect, when the ammonium source is aqueous ammonia and NH4Cl, the molar ratio of the aqueous ammonia and NH4Cl is 2.68:4.

[0017] In a certain aspect, when the ammonium source is aqueous ammonia, the molar ratio of the aqueous ammonia and the ionic compound A is 16.3:1.

[0018] In a certain aspect, when the ammonium source comprises aqueous ammonia, the aqueous ammonia is aqueous ammonia with a concentration of 25%.

[0019] In an embodiment, the nucleophilic substitution reaction has a reaction pressure of 900 to 1200 psi, for example 950 to 1050 psi or 900 to 1000 psi.

[0020] In an embodiment, the ionic compound A has a mass to volume ratio of 1 : (1 to 30) g / mL, for example 1 : (1 to 15) g / mL, further for example 1 : (5 to 10) g / mL with water.

[0021] In an embodiment, the ionic compound A has a molar ratio of 1 : (3 to 33), for example 1 : (3 to 18), further for example 1 : 6.68 or 1 : 16.3, with the nitrogen source Y.

[0022] In an embodiment, the nucleophilic substitution reaction has a reaction temperature of 200 to 300 °C, for example 220 to 285 °C, further for example 220 to 230 °C or 275 to 285 °C.

[0023] In an embodiment, the nucleophilic substitution reaction has a reaction time of 50 to 90 min, for example 60 min or 61 min, in a continuous flow reactor.

[0024] In an embodiment, the nucleophilic substitution reaction has a flow rate of 0.3 to 1.0 mL / min, further for example 0.5 to 0.8 mL / min, further for example 0.70 mL / min or 0.65 mL / min, in a continuous flow reactor.

[0025] In an embodiment, the cation in the ionic compound A is a conventional cation in the art, for example NH4 + , an alkali metal cation or an alkaline earth metal cation; further for example NH4 + or an alkali metal cation.

[0026] In an embodiment, when the cation in the ionic compound A is an alkali metal cation, the alkali metal cation is Na + , K + or Li + .

[0027] In an embodiment, when the cation in the ionic compound A is an alkaline earth metal cation, the alkaline earth metal cation is Mg 2+ or Ca 2+ .

[0028] In an embodiment, the cation in the ionic compound A is NH4 + or Na + .

[0029] In one embodiment, the cation of the aromatic amine ionized compound is the same as the cation of the ionized compound A.

[0030] In one embodiment, R is independently hydroxyl or halogen.

[0031] In one embodiment, when R is C1-C4 alkyl, the C1-C4 alkyl is C1-C4 alkyl, for example methyl, ethyl, n-propyl, isobutyl, n-butyl, isobutyl, or t-butyl, and / or the like. 10 10 In one embodiment, when R is C1-C4 alkyl, the C1-C4 alkyl is C1-C4 alkyl, for example methyl, ethyl, n-propyl, isobutyl, n-butyl, isobutyl, or t-butyl, and / or the like.

[0032] In one embodiment, when R is halogen, the halogen is fluorine, chlorine, bromine, or iodine, for example bromine and / or fluorine.

[0033] In one embodiment, when X is halogen, the halogen is fluorine, chlorine, bromine, or iodine, for example fluorine.

[0034] In one embodiment, X is hydroxyl or fluorine.

[0035] In one embodiment, m is 1 or 2.

[0036] In one embodiment, X is located at the ortho or meta position of the carboxylate.

[0037] In one embodiment, each R is independently located at the meta and para position of the carboxylate.

[0038] In one embodiment, when X is hydroxyl, X is located at the meta position of the carboxylate, or when X is halogen, X is located at the ortho position of the carboxylate.

[0039] In one embodiment, when R is hydroxyl, R is located at the meta position of the carboxylate, or when R is halogen, R is located at the meta or para position of the carboxylate.

[0040] In one embodiment, X is fluorine or hydroxyl; m is 1 or 2; and R is independently C1-C4 alkyl, hydroxyl, cyano, halogen, nitro, acetyl, or carboxyl.

[0041] In one embodiment, R 1 and R 2 are hydrogen.

[0042] In one embodiment, the anion of the ionized compound A of Formula I is any one of the following structures:

[0043]

[0044] In one embodiment, the ionized compound A is any one of the following structures:

[0045] ​

[0046] In one aspect, the continuous flow reactor has a pipe inner diameter of 1 / 8 inch.

[0047] In one aspect, the continuous flow reactor has a pipe wall thickness of 0.028 mm.

[0048] In one aspect, the continuous flow reactor has a pipe length of 16.4 meters.

[0049] In one aspect, the continuous flow reactor has a pipe material of Hastelloy.

[0050] In one aspect, the continuous flow reactor has a Hastelloy pipe connected by a HC276 fitting.

[0051] In one aspect, the synthesis method uses a reaction system comprising, in sequence, a raw material tank 2, a metering pump 3, a reaction section temperature control zone 4, a reaction inhibition section temperature control zone 6, a sampling valve 9, and a product collection tank 10; the reaction section temperature control zone 4 is provided with a continuous flow reactor 5; the reaction inhibition section temperature control zone 6 is provided with a reaction inhibition section pipe 7; a back pressure regulating valve 8 is provided between the reaction inhibition section temperature control zone 6 and the sampling valve 9.

[0052] In one aspect, the reaction system further comprises a nitrogen source Y solution tank 13.

[0053] In one aspect, the work-up of the nucleophilic substitution reaction can be conventional work-up for such reactions in the art, for example, it comprises the following steps:

[0054] (a) mixing the reaction liquid with water and an aqueous sodium hydroxide solution, heating, and concentrating to obtain a treated liquid;

[0055] (b) mixing the treated liquid of step (a) with an acid, crystallizing, and filtering to obtain a filter cake;

[0056] (c) slurrying the filter cake with water and filtering.

[0057] In one aspect, in step (a), the volume ratio of water to the reaction liquid is 6:1.

[0058] In one aspect, in step (a), the aqueous sodium hydroxide solution is a 30 wt% aqueous sodium hydroxide solution.

[0059] In one aspect, in step (a), the volume ratio of the aqueous sodium hydroxide solution to the reaction liquid is 4.5:1.

[0060] In one aspect, in step (a), the heating temperature is 85-95°C.

[0061] In one embodiment, in step (a), the heating is performed for 12-13 hours.

[0062] In one embodiment, in step (a), the heating is performed with stirring.

[0063] In one embodiment, in step (a), the concentration is performed at a temperature of 45-65°C.

[0064] In one embodiment, in step (a), the volume ratio of the concentrated treatment solution to the reaction solution is (4.0-4.5):1.

[0065] In one embodiment, in step (b), the acid is a conventional acid in the art, and the acid is hydrochloric acid or sulfuric acid.

[0066] In one embodiment, in step (b), the volume ratio of the hydrochloric acid to the reaction solution is 7.5:1.

[0067] In one embodiment, in step (b), the hydrochloric acid is a 35% hydrochloric acid aqueous solution.

[0068] In one embodiment, in step (b), the sulfuric acid is a 50% sulfuric acid aqueous solution.

[0069] In one embodiment, in step (b), when the acid is sulfuric acid, the pH of the treatment solution after the addition of the acid in step (a) is 4.5-5.5.

[0070] In one embodiment, in step (b), when the acid is hydrochloric acid, step (b) further comprises heating.

[0071] In one embodiment, in step (b), the heating is performed at a temperature of 95-105°C.

[0072] In one embodiment, in step (b), the heating is performed for 15-18 hours.

[0073] In one embodiment, in step (b), the heating is performed with stirring.

[0074] In one embodiment, in step (b), the crystallization is performed at a temperature of 0-10°C or 10-25°C.

[0075] In one embodiment, in step (b), the crystallization is performed for 1-3 hours.

[0076] In one embodiment, in step (c), the volume ratio of the water to the reaction solution is 7.5:1.

[0077] In one embodiment, in step (c), the temperature of the beating is 10-20°C.

[0078] In one embodiment, in step (c), the time of the beating is 1-2h.

[0079] In one embodiment, in step (c), the pH of the beating is 3.5±0.1.

[0080] In one embodiment, the work-up of the nucleophilic substitution reaction is as follows: the reaction solution is added to a reactor, water (6X), 30% NaOH (4.5X) is added, the temperature is adjusted to 85-95°C, and the mixture is stirred for 12-13h. The temperature is adjusted to 45-65°C, and the mixture is concentrated to 4.0-4.5V. 35% H2SO4 (7.5X) is added, the temperature is adjusted to 95-105°C, and the mixture is stirred for 15-18h. The temperature is slowly adjusted to 0-10°C, and the mixture is stirred for 1-3h. The mixture is filtered, the filter cake is added to a reactor, water (7.5X) is added, the temperature is adjusted to 10-20°C, and the mixture is stirred for 1-2h. 10% NaOH aqueous solution is added to adjust the pH to 3.5±0.1, the mixture is stirred for 2-8h, and the product is obtained by filtration.

[0081] In one embodiment, when the ionic compound A is the work-up of the nucleophilic substitution reaction is as follows: the reaction solution is added to a reactor, water (6X), 30% NaOH (4.5X) is added, the temperature is adjusted to 85-95°C, and the mixture is stirred for 12-13h. The temperature is adjusted to 45-65°C, and the mixture is concentrated to 4.0-4.5V. 35% H2SO4 (7.5X) is added, the temperature is adjusted to 95-105°C, and the mixture is stirred for 15-18h. The temperature is slowly adjusted to 0-10°C, and the mixture is stirred for 1-3h. The mixture is filtered, the filter cake is added to a reactor, water (7.5X) is added, the temperature is adjusted to 10-20°C, and the mixture is stirred for 1-2h. 10% NaOH aqueous solution is added to adjust the pH to 3.5±0.1, the mixture is stirred for 2-8h, and the product is obtained by filtration.

[0082] In one embodiment, the work-up of the nucleophilic substitution reaction is as follows: the reaction solution is added to a reactor, 35% NaOH aqueous solution (1X) is added, the temperature is adjusted to 10-30°C, and the mixture is stirred for 0.5-2h. The temperature is adjusted to 60-70°C, and the mixture is stirred for 12-13h. The temperature is adjusted to 0-20°C, 50% H2SO4 is added to adjust the pH to 4.5-5.5, the mixture is stirred for 2-6h, and the product is obtained by filtration. The filter cake is washed with water (2.5X), the filter cake is added to a reactor, THF (5.5X) is added, the temperature is adjusted to 10-25°C, and the mixture is stirred for 1-2h. Water (23X) is added, the mixture is stirred for 12-24h, the product is obtained by filtration, and the filter cake is dried at 40-45°C for 12-24h.

[0083] In one embodiment, when the ionic compound A is In one aspect, the work-up of the nucleophilic substitution reaction is performed by the following steps: the reaction mixture is added to a tank, the temperature is adjusted to 10-30 °C, the mixture is stirred for 0.5-2 h, the temperature is adjusted to 60-70 °C, the mixture is stirred for 12-13 h, the temperature is adjusted to 0-20 °C, the pH is adjusted to 4.5-5.5 using 50% H2SO4, the mixture is stirred for 2-6 h, the mixture is filtered, the filter cake is washed with water (2.5X), the filter cake is added to a tank, the temperature is adjusted to 10-25 °C, the mixture is stirred for 1-2 h, water (23X) is added, the mixture is stirred for 12-24 h, the mixture is filtered, and the filter cake is washed with water (2X). The filter cake is dried at 40-45 °C for 12-24 h. The product is obtained by filtration.

[0084] The method for synthesizing the aromatic amine ionic compound can further comprise the following step: reacting an acid of Formula B with a base in water to obtain the ionic compound A.

[0085]

[0086] wherein X, R, and m are as defined above.

[0087] In one aspect, the base is a conventional base in the art, and the base can be selected from one or more of NaOH, NaHCO3, KOH, and KHCO3, such as NaOH and / or NaHCO3.

[0088] In one aspect, the molar ratio of the acid of Formula B to the base is 1:(1.02-1.2).

[0089] In one aspect, the mass-to-volume ratio of the acid of Formula B to water is 1:(1-30) g / mL, such as 1:(1-15) g / mL, and for example 1:(5-10) g / mL; and for example 1:5 (g / mL) or 1:10 (g / mL).

[0090] In one aspect, the method for synthesizing the aromatic amine ionic compound comprises the following steps:

[0091] The compound of Formula B, water, and a base are added to a feed tank 2, the mixture is stirred at 15-50 °C for 5-120 min, a nitrogen source Y is added to the feed tank 2, the mixture is stirred at 20-25 °C for 5-120 min, the reaction mixture is filtered, the filtrate is passed through a metering pump 3 at a flow rate of 0.3-1.0 mL / min into a continuous flow reactor 5 in a temperature control zone 4 of a reaction section, the pressure of the continuous flow reactor 5 is 900-1200 psi, the temperature of the continuous flow reactor 5 is 200-300 °C, the reaction mixture is reacted in the continuous flow reactor 5 for 50-90 min, and the reaction mixture is flowed into a reaction inhibition section line 7 in a temperature control zone 6 of a reaction inhibition section.

[0092] In an embodiment, the synthesis method of the arylamine ionic compound comprises the following steps:

[0093] The compound of formula B, water and base are added to the raw material tank 2, stirred at 15-50℃ for 5-120min, then the nitrogen source Y is added to the raw material tank 2, stirred at 20-25℃ for 5-120min, the reaction solution is filtered, the filtrate is fed into the continuous flow reactor 5 in the temperature control zone 4 of the reaction section at a flow rate of 0.3-1.0mL / min through the metering pump 3, the pressure of the continuous flow reactor 5 is 900-1200psi, the temperature is 200-300℃, the reaction solution is reacted in the continuous flow reactor 5 for 50-90min, then flows into the reaction inhibition section pipeline 7 in the temperature control zone 6 of the reaction inhibition section, the temperature of the reaction inhibition section pipeline 7 is 0-50℃, the sampling valve 9 is used for sampling analysis, and the product is collected in the collection tank 10.

[0094] In an embodiment, the nitrogen source Y can also be fed into the continuous flow reactor 5 from the nitrogen source Y solution tank 13 through the metering pump 14.

[0095] The present application also provides a synthesis method of an arylamine compound, which comprises the following steps:

[0096] (1) preparing an arylamine ionic compound according to the synthesis method of the arylamine ionic compound described above;

[0097] (2) subjecting the arylamine ionic compound obtained in step (1) to an acidification reaction to obtain an arylamine compound of formula C;

[0098]

[0099] X, R and m are as defined above.

[0100] In an embodiment, the reaction in step (2) is a conventional acidification reaction in the art.

[0101] The present application also provides a reaction system, which comprises, in sequence, a raw material tank 2, a metering pump 3, a reaction section temperature control zone 4, a reaction inhibition section temperature control zone 6, a sampling valve 9 and a product collection tank 10; the reaction section temperature control zone 4 is provided with a continuous flow reactor 5; the reaction inhibition section temperature control zone 6 is provided with a reaction inhibition section pipeline 7; a back pressure regulating valve 8 is arranged between the reaction inhibition section temperature control zone 6 and the sampling valve 9; and the reaction system is applied to the synthesis method of the arylamine ionic compound described above.

[0102] In an embodiment, the reaction system further comprises a nitrogen source Y solution tank 13.

[0103] In the present application, “eq” refers to “equivalent”, which is a chemical term indicating that the amount of the substance is equivalent to the number of moles of a specific substance.

[0104] The term "nitrogen source" is a nitrogen-containing compound having one or more nitrogen atoms, which is an ammonium source (e.g., aqueous ammonia, NH4Cl, NH4Ac, or (NH4)2SO4) or an organic amine (e.g., dimethylamine, methylamine, diethylamine, ethylamine, or methylethylamine).

[0105] The term "alkyl" is a branched or straight-chain saturated aliphatic hydrocarbon group having the specified number of carbon atoms; for example, "C1-C10alkyl" includes methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. 10 "alkyl" generally refers to groups including those having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms in a straight or branched chain. For example, "C1-C10alkyl" includes methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl. 10 "alkyl" specifically includes methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl.

[0106] As understood by those skilled in the art, the use of the following groups in the structural formulas of the groups described herein is in accordance with the conventions used in the art. "at the indicated position" means that the corresponding group is connected to other fragments, groups in the compound through the position.

[0107] The above-mentioned preferred conditions can be combined in any manner without departing from the common knowledge in the art, thereby obtaining various preferred embodiments of the present application.

[0108] The reagents and raw materials used in the present application are commercially available.

[0109] The positive progress effect of the present application is that the present application prepares the arylamine ion compound by reacting the ion compound A with the nitrogen source Y in a continuous flow reactor without a catalyst under the condition that water is used as the solvent. The preparation method of the present application has the characteristics of short reaction time, simple and safe operation, and no amplification effect. BRIEF DESCRIPTION OF DRAWINGS

[0110] Figure 1 Synthetic process flow chart of arylamine ion compound (the double line part is double feed, and the part without double line is single feed)

[0111] In the figure, 1 is a nitrogen inlet (for balancing the pressure of the reaction system), 2 is a raw material tank, 3 and 14 are metering pumps, 4 is a reaction section temperature control zone, 5 is a continuous flow reactor, 6 is a reaction inhibition section temperature control zone, 7 is a reaction inhibition section pipeline (for cooling the reaction liquid), 8 is a back pressure regulating valve, 9 is a sampling valve, 10 is a product collection tank, 11 is a nitrogen outlet (for balancing the pressure of the reaction system), 12 is a nitrogen inlet (for balancing the pressure of the reaction system), and 13 is a nitrogen source Y solution tank. DETAILED DESCRIPTION

[0112] The application will be further described in the following by way of examples without thereby limiting the application to the examples described. The experimental methods in the following examples, if not otherwise specified, are carried out according to the conventional methods and conditions, or according to the instructions of the commercial products.

[0113] The reaction system of the arylamine ionized compound used in the following examples is shown as follows Figure 1 The compound as shown in formula B, water, base and nitrogen source Y are filtered from the raw material tank 2 (the nitrogen source Y can also be introduced into the continuous flow reactor 5 from the solution tank 13 through the metering pump 14), and the filtrate is introduced into the continuous flow reactor 5 in the temperature control zone 4 of the reaction section through the metering pump 3. After the reaction is completed, the reaction solution flows into the reaction inhibition section pipeline 7 (cooling reaction) in the temperature control zone 6 of the reaction inhibition section, and after the reaction solution is cooled, it is sampled and analyzed through the sampling valve 9, and the product is collected in the product collection tank 10.

[0114] The pipe diameter of the continuous flow reactor used in the examples of the application is 1 / 8 inch; the pipe wall thickness is 0.028 mm; the pipe length is 16.4 meters; and the pipe material is Hastelloy, and the pipes are connected through HC276 joints.

[0115] Example 1. Preparation method of 3-aminophenyl-5-hydroxybenzoic acid

[0116]

[0117] 3,5-dihydroxybenzoic acid (20 g, 130 mmol, 1.0 eq.), sodium hydroxide (6.24 g, 156 mmol, 1.2 eq.) and water (100 g, 5X) were added to the raw material tank and stirred at 20-25°C for 5 min; ammonia water (48.73 g, 2.68 eq. ammonia water concentration is 25%) and ammonium chloride (27.77 g, 519 mmol, 4 eq.) were added to the raw material tank and stirred at 20-25°C for 5 min. After the raw material reaction solution was filtered, the filtrate was introduced into the continuous flow reactor at a flow rate of 0.7 mL / min, the reactor pressure was 950-1050 psi, and the temperature was 275-285°C (1 / 8 inch Hastelloy pipe), the reaction solution was kept in the reactor for 60 min, then introduced into the reaction inhibition section pipeline for cooling, the cooling temperature was room temperature, after cooling, sampling, analysis and product collection tank was used to collect the product, wherein, The content of 3-aminophenyl-5-hydroxybenzoic acid is 55.4%. The content of 3-aminophenyl-5-hydroxybenzoic acid is 21.2% The 3-aminophenyl-5-hydroxybenzoic acid can be converted into ) by high temperature reaction with sodium hydroxide solution.

[0118] Post-treatment steps:

[0119] The reaction mixture obtained was added to the reactor along with water (6X) and 30% NaOH (4.5X), and the temperature was adjusted to 85-95°C and stirred for 12-13h. The temperature was adjusted to 45-65°C and concentrated to 4.0-4.5V. 35% HCl (7.5X) was added, the temperature was adjusted to 95-105°C and stirred for 15-18h. The temperature was slowly adjusted to 0-10°C and stirred for 1-3h. The product was obtained by filtration. The isolated yield was 65% and the purity was 98%.

[0120] The process was scaled up in the plant to 144kg of 3,5-dihydroxybenzoic acid and the results showed that the isolated yield of was 66% and the purity was 98%.

[0121] Example 2.2 Preparation of 2-amino-4-bromo-3-fluorobenzoic acid

[0122]

[0123] 4-bromo-2,3-difluorobenzoic acid (15g, 63mmol, 1.0eq.), sodium bicarbonate (5.4g, 64mmol, 1.02eq.) and water (150g, 10X) were added to the feed tank and stirred for 5min at 20-25°C. Ammonia (143.4g, ammonia concentration 25%, 16.3eq.) was added to the feed tank and stirred for 5min at 20-25°C. The feed reaction mixture was filtered and the filtrate was fed into the continuous flow reactor at a flow rate of 0.65ml / min. The pressure in the tubular reactor was 900-1000psi and the temperature was 220-230°C (1 / 8 inch Hastelloy tubing). The residence time of the reaction mixture in the reactor was 61min and the cooling temperature was room temperature. The sample was analyzed after cooling and the product was collected in the product collection tank. The sample obtained was analyzed by HPLC and the results showed that the content of 4-bromo-2,3-difluorobenzoic acid in the sample was 0.8% and the content of was 88.2% and the purity was 92%.

[0124] Work-up procedure:

[0125] The reaction mixture was added to a reactor, stirred for 0.5-2 h at 10-30 °C, stirred for 12-13 h at 60-70 °C, stirred for 2-6 h at 0-20 °C, filtered, the filter cake was washed with water (2.5X), the filter cake and THF (5.5X) were added to a reactor, stirred for 1-2 h at 10-25 °C, stirred for 12-24 h at room temperature, filtered, and the filter cake was washed with water (2X). The filter cake was dried at 40-45 °C for 12-24 h. The product was filtered The isolated yield was 70% and the purity was 98%.

[0126] The process has been scaled up in the plant to a feed size of 280 kg of 4-bromo-2,3-difluorobenzoic acid, The isolated yield was 72% and the purity was 98%.

[0127] Comparative Example 1

[0128] 3,5-Dihydroxybenzoic acid (20 g, 130 mmol, 1.0 eq.) and water (100 g, 5X) were added to a reactor, stirred for 5 min at 20-25 °C; ammonia (48.73 g, 2.68 eq. ammonia concentration 25%) and ammonium chloride (27.77 g, 519 mmol, 4 eq.) were added to the reactor, stirred for 5 min at 20-25 °C, reacted for 40 h at 180 °C, and the product was isolated after work-up (same as work-up procedure of Example 1) with an isolated yield of 68%.

[0129] The above reaction has a large amount of raw material (3,5-dihydroxybenzoic acid) that is not soluble in water, so the above reaction conditions cannot be used in a continuous flow reactor.

[0130] Comparative Example 2

[0131] 4-Bromo-2,3-difluorobenzoic acid (0.183 g, 0.77 mmol, 1.0 eq.), ethanol (2.196 g, 12X), and water (2.013 g, 11X) were added to a raw material tank, stirred for 5 min at 20-25 °C; ammonia (0.496 g, 4.6 eq. ammonia concentration 25%) was added to the raw material tank, stirred for 5 min at 20-25 °C, the raw material solution was filtered, and the filtrate was reacted in a reactor at 210 °C and 230 °C for 30 min, respectively, after cooling, the cooling temperature was room temperature, after cooling, the product The content of the product was only 23% and 20%, respectively, and a large amount of esterified impurities were contained, and the esterified impurities would not be converted into the final product in the work-up.

[0132] Comparative Example 3

[0133] 4-bromo-2,3-difluorobenzoic acid (1 g, 4.219 mmol, 1.0 eq.) and 1,4-dioxane (10.3 g, 10X) were stirred at 20-25 °C for 5 min; ammonia water (16.38 g, 27.7 eq. ammonia water concentration was 25%) was added to the raw material tank, stirred at 20-25 °C for 5 min, and the raw material solution was filtered. The filtrate was cooled after reaction at a temperature of 200 °C for 30 min and 50 min in the reaction kettle, and the cooling temperature was room temperature. After cooling, sampling and analysis were performed, and the content of the product was only 54% and 72%, and 42% and 22% of 4-bromo-2,3-difluorobenzoic acid was not completely reacted.

[0134] Comparative Example 4

[0135] 4-bromo-2,3-difluorobenzoic acid (1 g, 4.219 mmol, 1.0 eq.) and isopropanol (7.86 g, 7.9X) were stirred at 20-25 °C for 5 min; ammonia water (16.38 g, 27.7 eq. ammonia water concentration was 25%) was added to the raw material tank, stirred at 20-25 °C for 5 min, and the raw material solution was filtered. The filtrate was cooled after reaction at a temperature of 200 °C for 30 min and 50 min in the reaction kettle, and the cooling temperature was room temperature. After cooling, sampling and analysis were performed, and the content of the product was only 46% and 62%, and 50% and 32% of 4-bromo-2,3-difluorobenzoic acid was not completely reacted.

[0136] Comparative Example 5

[0137] 4-bromo-2,3-difluorobenzoic acid (1 g, 4.219 mmol, 1.0 eq.) and 1,4-dioxane (10.3 g, 10X) were stirred at 20-25 °C for 5 min; ammonia water (16.38 g, 27.7 eq. ammonia water concentration was 25%) was added to the raw material tank, stirred at 20-25 °C for 5 min, and the raw material solution was filtered. The filtrate was cooled after reaction at a temperature of 210 °C for 30 min and 60 min in the reaction kettle, and the cooling temperature was room temperature. After cooling, sampling and analysis were performed, and the content of the product was only 77% and 66%, and 20% of 4-bromo-2,3-difluorobenzoic acid was not completely reacted, and solid appeared.

[0138] Comparative Example 6

[0139] 4-Bromo-2,3-difluorobenzoic acid (1 g, 4.219 mmol, 1.0 eq.), triethylamine (0.56 g, 1.3 eq) and water (5 g, 5X) were stirred for 5 min at 20-25 °C; ammonia (9.555 g, 16.5 eq. ammonia concentration 25%) was added to the stock tank and stirred for 5 min at 20-25 °C, dissolved clear, the stock solution was filtered, the filtrate was reacted in a reaction kettle at a temperature of 210 °C for 30 min and 60 min respectively, then cooled, the cooling temperature was room temperature, after cooling, sampling, analysis, the purity of the product was 73% and 87%, containing 29% and 4% of the unreacted raw material.

[0140] Comparative Example 7

[0141] 4-Bromo-2,3-difluorobenzoic acid (10 g, 42.19 mmol, 1.0 eq.), triethylamine (5.63 g, 1.3 eq) and water (50 g, 5X) were stirred for 5 min at 20-25 °C; ammonia (95.55 g, 16.5 eq. ammonia concentration 25%) was added to the stock tank and stirred for 5 min at 20-25 °C, dissolved clear, the stock solution was filtered, the filtrate was introduced into a continuous flow reactor at a flow rate of 0.7 mL / min, the reactor pressure was 950-1050 psi, the temperature was 210 °C (1 / 8 inch Hastelloy piping), the reaction solution was cooled in a cooling reaction tank after staying in the reactor for 49 min, the cooling temperature was room temperature, after cooling, sampling, analysis and product collection tank was used to collect the product, the content of the product was 3-8%.

[0142] Comparative Example 8

[0143] 4-Bromo-2,3-difluorobenzoic acid (1 g, 4.219 mmol, 1.0 eq.), sodium bicarbonate (0.362 g, 1.02 eq) and water (10 g, 10X) were stirred for 5 min at 20-25 °C; ammonia (9.555 g, 16.5 eq. ammonia concentration 25%) was added to the stock tank and stirred for 5 min at 20-25 °C, dissolved clear, the stock solution was filtered, the filtrate was reacted in a reaction kettle at a temperature of 210 °C for 60 min, then cooled, the cooling temperature was room temperature, after cooling, sampling, analysis, the content of the product was 83%, containing 11% of the unreacted 4-bromo-2,3-difluorobenzoic acid.

Claims

1. A method for synthesizing an aromatic amine ionic compound, characterized in that, It includes the following steps: in a continuous flow reactor, water, ionic compound A, and nitrogen source Y undergo a nucleophilic substitution reaction to obtain an aromatic amine ionic compound; the reaction temperature of the nucleophilic substitution reaction is 100~300°C. o C; The anion of the ionic compound A is ; The anion in the aromatic amine ionic compound is ; The cation in the ionic compound A is an alkali metal cation; The nitrogen source Y is an ammonium source; the ammonium source is ammonia water and / or NH4Cl.

2. The method for synthesizing aromatic amine ionic compounds according to claim 1, characterized in that, The nucleophilic substitution reaction is carried out at a pressure of 900-1200 psi. And / or, the mass-to-volume ratio of the ionic compound A to water is 1:(1~30) g / mL; And / or, the molar ratio of the ionic compound A to the nitrogen source Y is 1:(3~33). And / or, the reaction temperature of the nucleophilic substitution reaction is 200~300℃; And / or, the nucleophilic substitution reaction is carried out in a continuous flow reactor for 50 to 90 minutes. And / or, the flow rate of the reaction solution for the nucleophilic substitution reaction in the continuous flow reactor is 0.3~1.0 mL / min; And / or, the cation in the ionic compound A is Na. + K + Or Li + ; And / or, the cation in the aromatic amine ionic compound is the same as the cation in the ionic compound A; And / or, the inner diameter of the pipes in the continuous flow reactor is 1 / 8 inch; And / or, the pipe wall thickness of the continuous flow reactor is 0.028 mm; And / or, the pipeline of the continuous flow reactor is 16.4 meters long; And / or, the pipes of the continuous flow reactor are made of Hastelloy material; And / or, the continuous flow reactor is connected to Hastelloy piping using an HC276 connector.

3. The method for synthesizing aromatic amine ionic compounds according to claim 2, characterized in that, The nucleophilic substitution reaction is carried out at a pressure of 950-1050 psi or 900-1000 psi. And / or, the mass-to-volume ratio of the ionic compound A to water is 1:(1~15) g / mL; And / or, the molar ratio of the ionic compound A to the nitrogen source Y is 1:(3~18). And / or, the reaction temperature of the nucleophilic substitution reaction is 220~285℃. o C; And / or, the nucleophilic substitution reaction is carried out in a continuous flow reactor for 60 min or 61 min; And / or, the flow rate of the reaction solution for the nucleophilic substitution reaction in the continuous flow reactor is 0.5~0.8 mL / min.

4. The method for synthesizing aromatic amine ionic compounds according to claim 2, characterized in that, The mass-to-volume ratio of the ionic compound A to water is 1:(5~10) g / mL; And / or, the molar ratio of the ionic compound A to the nitrogen source Y is 1: 6.68 or 1:16.3; And / or, the reaction temperature of the nucleophilic substitution reaction is 220~230°C. o C or 275~285 o C; And / or, the flow rate of the reaction solution for the nucleophilic substitution reaction in the continuous flow reactor is 0.70 mL / min or 0.65 mL / min.

5. The method for synthesizing aromatic amine ionic compounds according to claim 2, characterized in that, When the ammonium source contains ammonia water, the concentration of the ammonia water is 25%; And / or, when the ammonium source is ammonia and NH4Cl, the molar ratio of ammonia to NH4Cl is 2.68:4; And / or, when the ammonium source is ammonia water, the molar ratio of the ammonia water to the ionic compound A is 16.3:1; And / or, the cation in the ionic compound A is Na. + .

6. The method for synthesizing aromatic amine ionic compounds according to claim 1, characterized in that, The ionic compound A is .

7. The method for synthesizing the aromatic amine ionic compound according to any one of claims 1 to 6, characterized in that, The synthesis method employs the following reaction system, which includes: a raw material tank, a metering pump, a reaction section temperature control zone, a reaction inhibition section temperature control zone, a sampling valve, and a product collection tank connected in sequence; a continuous flow reactor is provided in the reaction section temperature control zone; a reaction inhibition section pipeline is provided in the reaction inhibition section temperature control zone; and a back pressure regulating valve is provided between the reaction inhibition section temperature control zone and the sampling valve.

8. The method for synthesizing aromatic amine ionic compounds according to claim 7, characterized in that, It also includes: reacting an acid and a base, as shown in Formula B, in water to obtain the ionic compound A; The compound shown in formula B is .

9. The method for synthesizing aromatic amine ionic compounds according to claim 8, characterized in that, The alkali is selected from one or more of NaOH, NaHCO3, KOH, and KHCO3; And / or, the mass-to-volume ratio of the acid as shown in Formula B to water is 1:(1~30) g / mL; And / or, the molar ratio of acid to base as shown in Formula B is 1:(1.02~1.2).

10. The method for synthesizing the aromatic amine ionic compound according to claim 9, characterized in that, The alkali is NaOH and / or NaHCO3; And / or, the mass-to-volume ratio of the acid as shown in Formula B to water is 1:(1~15) g / mL.

11. The method for synthesizing aromatic amine ionic compounds according to claim 9, characterized in that, The mass-to-volume ratio of the acid to water as shown in Formula B is 1:(5~10)g / mL.

12. The method for synthesizing aromatic amine ionic compounds according to claim 9, characterized in that, The mass-to-volume ratio of the acid to water as shown in Formula B is 1:5 g / mL or 1:10 g / mL.

13. A method for synthesizing an aromatic amine compound, characterized in that, It includes the following steps: (1) The aromatic amine ion compound is prepared according to the synthetic method of any one of claims 1 to 12; (2) The aromatic amine ionic compound obtained in step (1) is subjected to an acidification reaction to obtain an aromatic amine compound as follows: .

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