A process for the preparation of 3,5-dichloroaniline

Abstract

The application provides a preparation method of 3,5-dichloroaniline, and the preparation method comprises the following steps: reacting 1,3,5-trichlorobenzene with a coupling reagent ammonia source in the presence of a copper catalyst, a ligand and a base in an inert solvent to generate 3,5-dichloroaniline. The copper catalyst is adopted, and a suitable ligand and a base are selected, so that the preparation of 3,5-dichloroaniline with low cost, low reaction temperature and high yield is realized.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine and synthesis of medicine intermediates, and particularly relates to a preparation method of 3,5-dichloroaniline. BACKGROUND

[0002] 3,5-dichloroaniline is an important intermediate of cyclic imide fungicides, and has a wide application in medicine, pesticide, dye, pigment and plant growth promoter. 3,5-dichloroaniline can be used as raw material to synthesize agricultural fungicides such as procymidone, dimethirimol, vinclozolin, iprodione, triforine, chlorfenazole, etridiazole, flusulfamide and so on. With the increase of the production of cyclic imide fungicides, 3,5-dichloroaniline is in great demand in the international market. Therefore, the synthesis of 3,5-dichloroaniline has attracted more and more attention.

[0003] At present, there are many process synthesis routes of 3,5-dichloroaniline, such as: 1) taking p-nitroaniline as raw material, 3,5-dichloronitrobenzene is prepared through chlorination, diazotization and denitrogenation, and then 3,5-dichloroaniline is obtained by reducing nitro group. This process has problems of low utilization rate of chlorine element, difficult treatment of by-product sodium sulfate and serious environmental pollution; 2) taking mixed dichlorobenzene as raw material, 3,5-dichloroaniline is prepared through bromination, isomerization and aminolysis. This process route produces a large amount of corrosive waste with aluminum chloride, which is difficult to recover and treat; in addition, there are methods such as meta-position oil chlorination-reduction-dechlorination of nitrochlorobenzene (CN201210219294.8), decarboxylation of 3,5-dichlorobenzamide, chlorination-oxidation-decarboxylation of 4-chloro-2-nitrotoluene (CN200410014747.9), and catalytic hydrogenation-dechlorination of polychloronitrobenzene. However, the above synthesis routes have a common problem that the cost of raw materials is high, and the generated wastewater is difficult to treat. With the improvement of environmental protection requirements, it is of great significance to develop a preparation method of 3,5-dichloroaniline with simple preparation process, low production cost and light environmental pollution.

[0004] 1)

[0005] 2) SUMMARY

[0006] In view of the problems of serious environmental pollution, high cost, low content and difficult wastewater treatment of 3,5-dichloroaniline in the preparation process in the prior art, the present application provides a preparation method of 3,5-dichloroaniline, which has simple preparation process, low production cost and is friendly to the environment.

[0007] The object of the present application is achieved by the following technical solutions.

[0008] The application provides a preparation method of 3,5-dichloroaniline, and the specific route is as follows:

[0009]

[0010] comprising the following steps:

[0011] reacting 1,3,5-trichlorobenzene with a coupling reagent ammonia source in the presence of a copper catalyst, a ligand and a base in an inert solvent to generate 3,5-dichloroaniline;

[0012] wherein the ammonia source is at least one selected from the group consisting of ammonia, aqueous ammonia solution and ammonium salt;

[0013] the ligand is selected from one or more of the following compounds:

[0014]

[0015] wherein in the structure of formula III,

[0016] R a is selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 3- to 20-membered heteroaryl, substituted or unsubstituted C7-C25 alkyl-aryl, substituted or unsubstituted C1-C5 alkyl-3- to 20-membered heteroaryl, substituted or unsubstituted C3-C20 cycloalkyl, or substituted or unsubstituted 3- to 20-membered heterocyclyl; wherein the heteroaryl or heterocyclyl has 1-5 heteroatoms selected from N, O and S; and the cycloalkyl or heterocyclyl can be monocyclic, polycyclic, spiro or bridged ring structure;

[0017] R b is selected from the group consisting of H, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted 3- to 20-membered heteroaryl, substituted or unsubstituted C7-C25 alkyl-aryl, substituted or unsubstituted C7-C25 aryl-alkyl, substituted or unsubstituted C1-C5 alkyl-3- to 20-membered heteroaryl, substituted or unsubstituted 3- to 20-membered heteroaryl-C1-C5 alkyl, substituted or unsubstituted C3-C20 cycloalkyl, or substituted or unsubstituted 3- to 20-membered heterocyclyl; wherein the heteroaryl or heterocyclyl has 1-5 heteroatoms selected from N, O and S; and the cycloalkyl or heterocyclyl can be monocyclic, polycyclic, spiro or bridged ring structure;

[0018] R aselected from the group consisting of substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C6-C20aryl, substituted or unsubstituted 3- to 20-membered heteroaryl, substituted or unsubstituted C7-C25alkyl-aryl, substituted or unsubstituted C1-C5alkyl-3- to 20-membered heteroaryl, substituted or unsubstituted C3-C20cycloalkyl, or substituted or unsubstituted 3- to 20-membered heterocyclyl; wherein the heteroaryl or heterocyclyl has 1 to 5 heteroatoms selected from N, O, or S; and the cycloalkyl or heterocyclyl can be monocyclic, polycyclic, spiro, or bridged;

[0019] R is selected from the group consisting of substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C20cycloalkyl, or substituted or unsubstituted 3- to 20-membered heterocyclyl; wherein the heterocyclyl has 1 to 5 heteroatoms selected from N, O, or S; and the cycloalkyl can be monocyclic, polycyclic, spiro, or bridged; c R is selected from the group consisting of substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C20cycloalkyl, or substituted or unsubstituted 3- to 20-membered heterocyclyl; wherein the heterocyclyl has 1 to 5 heteroatoms selected from N, O, or S; and the cycloalkyl can be monocyclic, polycyclic, spiro, or bridged;

[0020] R is selected from the group consisting of substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C20cycloalkyl, or substituted or unsubstituted 3- to 20-membered heterocyclyl; wherein the heterocyclyl has 1 to 5 heteroatoms selected from N, O, or S; and the cycloalkyl can be monocyclic, polycyclic, spiro, or bridged; c R is selected from the group consisting of substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C20cycloalkyl, or substituted or unsubstituted 3- to 20-membered heterocyclyl; wherein the heterocyclyl has 1 to 5 heteroatoms selected from N, O, or S; and the cycloalkyl can be monocyclic, polycyclic, spiro, or bridged;

[0021] R is selected from the group consisting of substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C20cycloalkyl, or substituted or unsubstituted 3- to 20-membered heterocyclyl; wherein the heterocyclyl has 1 to 5 heteroatoms selected from N, O, or S; and the cycloalkyl can be monocyclic, polycyclic, spiro, or bridged; c R is selected from the group consisting of substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C20cycloalkyl, or substituted or unsubstituted 3- to 20-membered heterocyclyl; wherein the heterocyclyl has 1 to 5 heteroatoms selected from N, O, or S; and the cycloalkyl can be monocyclic, polycyclic, spiro, or bridged;

[0022] R is selected from the group consisting of substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C20cycloalkyl, or substituted or unsubstituted 3- to 20-membered heterocyclyl; wherein the heterocyclyl has 1 to 5 heteroatoms selected from N, O, or S; and the cycloalkyl can be monocyclic, polycyclic, spiro, or bridged; c R is selected from the group consisting of substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C3-C20cycloalkyl, or substituted or unsubstituted 3- to 20-membered heterocyclyl; wherein the heterocyclyl has 1 to 5 heteroatoms selected from N, O, or S; and the cycloalkyl can be monocyclic, polycyclic, spiro, or bridged;

[0023] The substitution means that one or more hydrogen atoms of the group are replaced by a substituent selected from the group consisting of halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 aryl-oxy, C2-C10 ester (alkyl-COO-), C2-C10 acyl-alkoxy (alkyl-OOC-), C2-C10 acyl (alkyl-CO-), C2-C10 amido (alkyl / aryl NHC(O)-), -COOH, nitro, hydroxyl, amino, amino substituted with one or two C1-C6 alkyl groups.

[0024] Preferably, the ligand is selected from one or more of the following compounds:

[0025]

[0026] Preferably, the base is selected from at least one of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate, sodium phosphate, dipotassium hydrogen phosphate, C1-C5 alkoxide sodium, C1-C5 alkoxide potassium, sodium hydride.

[0027] Preferably, the copper catalyst is a copper salt and / or a copper oxide.

[0028] More preferably, the copper catalyst is selected from at least one of cuprous oxide, copper oxide, copper sulfate, cuprous thiophene-2-carboxylate, copper acetate, copper nitrate, copper ethylacetoacetate, copper bromide, copper chloride, copper cyanide, copper acetylacetonate, cuprous thiocyanate, copper iodide, cuprous iodide, cuprous bromide, cuprous chloride, cuprous cyanide.

[0029] Most preferably, the copper catalyst is selected from at least one of cuprous iodide, cuprous oxide, cuprous chloride, cuprous bromide.

[0030] Preferably, the inert solvent is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, sulfolane, acetonitrile, an ether solvent, a ketone solvent, an alcohol solvent;

[0031] More preferably, the ether solvent is selected from one or more of tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether;

[0032] The ketone solvent is selected from one or more of acetone, 2-butanone, methyl isopropyl ketone;

[0033] The alcohol solvent is selected from one or more of C1-C8 alcohols.

[0034] Most preferably, the alcohol solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, t-butanol.

[0035] Preferably, the amount of copper catalyst is 1-15 mol% of the total moles of 1,3,5-trichlorobenzene.

[0036] The amount of ligand is 1-15 mol% of the total moles of 1,3,5-trichlorobenzene.

[0037] Preferably, the molar ratio of the ligand to the copper catalyst is 1:(0.5-2).

[0038] Preferably, the molar ratio of the base to 1,3,5-trichlorobenzene is 1:(1-10).

[0039] Preferably, the molar volume ratio of 1,3,5-trichlorobenzene to inert solvent is 0.1-1.0 mmol / mL.

[0040] Preferably, the molar ratio of 1,3,5-trichlorobenzene to ammonia source is 1:(5-20).

[0041] The reaction temperature is 80-160°C, the reaction pressure is 0.5-3.0 MPa, and the reaction time is 10-36 hours.

[0042] More preferably, the reaction temperature is 100-160°C, and most preferably the reaction temperature is 130°C.

[0043] The application also provides the use of 3,5-dichloroaniline prepared according to the aforementioned method as an intermediate in the preparation of cyclic imide bactericides.

[0044] The existing method for preparing 3,5-dichloroaniline based on an ammonia source is described in patent document CN106748801A. The method uses 1,3,5-trichlorobenzene as a raw material, adds a base, an ammonia solution or an ammonium salt as an ammonia source in an organic solvent, and under the action of a transition metal catalyst and a ligand, a coupling reaction occurs to obtain the product 3,5-dichloroaniline. The ammonia source used is ammonia gas solution or ammonium salt, the organic solvent used is 1,4-dioxane, the base used is sodium tert-butoxide or potassium tert-butoxide, the transition metal catalyst used is a palladium catalyst, and the ligand used is 2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl. The reaction mechanism of the method is as follows: the palladium catalyst and the ligand are complexed to form a zero-valent palladium species PdL2, then an oxidative addition reaction occurs with trichlorobenzene to form a reaction intermediate A, then the ammonia gas is combined and ligand exchange occurs, and under the action of the base, a molecule of hydrogen chloride is removed to form a reaction intermediate B, and finally reductive elimination can obtain the target compound and realize the recycling of the catalyst.

[0045]

[0046] Although the method can obtain a yield of more than 80% and recycle the palladium catalyst, the palladium catalyst is expensive, and the ligand used is also expensive, so the production cost is still too high when the method is used for industrial production.

[0047] Therefore, the present application aims to develop an alternative method that can significantly reduce production costs while maintaining high yield. The coupling reaction of aryl halides and ammonia sources (Ullmann coupling reaction) under copper catalysis has a long history. However, although the copper catalyst is inexpensive, such reactions often require harsh reaction conditions, such as high temperature (reaction temperature higher than 200℃), poor substrate compatibility, etc., and the yield is extremely low when inexpensive aryl chlorides are used as reaction substrates, making it difficult to be practically applied in organic synthesis. With the development of metal organic chemistry, bidentate ligand-promoted copper-catalyzed Ullmann reaction has been developed, which breaks through the limitations of harsh reaction conditions and poor universality, and can be applied to the coupling reaction of unreactive chloroarenes and amines (JACS, 2015, 137, 11942; Org. Lett. 2015, 17, 5934; Org. Lett. 2017, 19, 2809).

[0048] To realize the application of Ullmann coupling reaction under copper catalysis, the present application has conducted a large number of experimental researches, and screened suitable ligands, bases, etc., and finally realized the method of preparing 3,5-dichloroaniline by ammonolysis of 1,3,5-trichlorobenzene under copper catalysis, and the reaction mechanism is as follows: the copper catalyst and the ligand are complexed to generate monovalent copper species Cu I L2, and then coordinated with ammonia to generate monovalent copper species C(Cu I L2(NH3)), and under the action of base, the proton is removed to generate monovalent copper species D(Cu I L2(NH2)), then oxidative addition occurs with 1,3,5-trichlorobenzene to generate trivalent copper intermediate E, and finally reductive elimination to obtain the target compound, and realize the recycling of the copper catalyst.

[0049]

[0050] The method of the present application has the advantages of high yield, low raw material cost and low reaction temperature, and is very suitable for large-scale industrial production.

[0051] Compared with the prior art, the present application has the following beneficial effects:

[0052] The application designs a new path for synthesizing 3,5-dichloroaniline, and the 3,5-dichloroaniline is obtained by ammonolysis under the conditions of a copper catalyst, a ligand, a base and an inert solvent, with 1,3,5-trichlorobenzene as raw material. The preparation method is simple, easy to operate, low in cost and friendly to the environment; and the addition of the ligand in the ammoniation reaction process can reduce the temperature of the ammoniation reaction, shorten the reaction time and improve the reaction yield. DETAILED DESCRIPTION

[0053] The application will be described in detail below in combination with specific examples. The following examples will help those skilled in the art to further understand the application, but do not limit the application in any form. It should be pointed out that, for those skilled in the art, without departing from the concept of the application, a number of modifications and improvements can be made. These all belong to the protection scope of the application.

[0054] Example 1

[0055] The application provides a preparation method of 3,5-dichloroaniline, and the specific steps are as follows:

[0056] 1.35 g (7.5 mmol) of 1,3,5-trichlorobenzene, 50 mg (0.5 mmol) of CuCl catalyst, 70 mg (0.5 mmol) of 8-hydroxyquinoline ligand (L6), 636 mg (3 mmol) of potassium phosphate and 10 ml of dimethyl sulfoxide solvent are added into a 250 ml pressure reaction kettle, and after sealing, the ammonia gas is replaced for 7-8 times, and then 0.4-0.5 MPa of ammonia gas is filled, the reaction kettle is put into a heating reactor, the outer temperature is warmed to 160℃, the temperature in the reaction kettle is 130℃, the pressure is raised to 1.2-1.4 MPa, and after 24 hours of insulation, the heating reactor is turned off. When the reaction kettle is cooled to room temperature, the remaining ammonia gas is slowly released by opening the gas valve, and the reaction liquid is taken for GCMS test, and the yield is 83%. The reaction liquid is diluted with water, and a large amount of methyl tert-butyl ether is extracted, the extract is concentrated to 5-10 ml, 3 ml of hydrochloric acid tetrahydrofuran solvent is added, yellow solid is precipitated, filtration is carried out, the filter residue is dissolved with water, sodium hydroxide solution is added to adjust the pH to >11, methyl tert-butyl ether is extracted for 3 times, and the solvent is removed to obtain 0.97 g of 3,5-dichloroaniline, and the yield is 80%. The filtrate is concentrated to recover 0.2 g of raw material, and the raw material recovery rate is 15%. The NMR result of the obtained product 3,5-dichloroaniline is as follows: 1 H NMR (400 MHz, CDCl3) δ 6.73-6.71 (m, 1H), 6.54-6.53 (m, 2H), 3.79 (s, 2H); 13 C NMR (100 MHz, CDCl3) δ 148.3, 135.5, 118.4, 113.3.

[0057] Example 2

[0058] Into a 250ml pressure reactor, 1.35g (7.5mmol) 1,3,5-trichlorobenzene, 72mg (0.5mmol) CuBr catalyst, 70mg (0.5mmol) 8-hydroxyquinoline ligand, 636mg (3mmol) potassium phosphate and 10ml dimethyl sulfoxide solvent were added. After sealing, the reactor was purged with ammonia gas for 7-8 times, and then filled with 0.4-0.5MPa ammonia gas. The reactor was placed in a heating reactor, and the external temperature was raised to 160°C. The internal temperature of the reactor was 130°C, and the pressure was raised to 1.2-1.4MPa. After 24 hours of incubation, the heating reactor was turned off. When the reactor cooled to room temperature, the remaining ammonia gas was slowly released by opening the valve. The reaction solution was tested by GCMS, and the yield was 88%. The reaction solution was diluted with water, and a large amount of methyl tert-butyl ether was extracted. The extract was concentrated to 5-10ml, 3ml hydrochloric acid tetrahydrofuran solution was added, and yellow solid was precipitated. The solid was filtered, dissolved in water, and adjusted to pH>11 with sodium hydroxide solution. The solution was extracted with methyl tert-butyl ether three times, and the solvent was removed to obtain 3,5-dichloroaniline 1.03g, with a yield of 85%. The filtrate was concentrated to recover 0.14g of raw material, with a recovery rate of 10%.

[0059] Example 3

[0060] Into a 250ml pressure reactor, 1.35g (7.5mmol) 1,3,5-trichlorobenzene, 72mg (0.5mmol) CuBr catalyst, 70mg (0.5mmol) 8-hydroxyquinoline ligand, 636mg (3mmol) potassium phosphate and 10ml dimethyl sulfoxide solvent were added. After sealing, the reactor was purged with ammonia gas for 7-8 times, and then filled with 0.4-0.5MPa ammonia gas. The reactor was placed in a heating reactor, and the external temperature was raised to 160°C. The internal temperature of the reactor was 130°C, and the pressure was raised to 1.2-1.4MPa. After 24 hours of incubation, the heating reactor was turned off. When the reactor cooled to room temperature, the remaining ammonia gas was slowly released by opening the valve. The reaction solution was tested by GCMS, and the yield was 88%. The reaction solution was diluted with water, and a large amount of methyl tert-butyl ether was extracted. The extract was concentrated to 5-10ml, 3ml hydrochloric acid tetrahydrofuran solution was added, and yellow solid was precipitated. The solid was filtered, dissolved in water, and adjusted to pH>11 with sodium hydroxide solution. The solution was extracted with methyl tert-butyl ether three times, and the solvent was removed to obtain 3,5-dichloroaniline 1.03g, with a yield of 85%. The filtrate was concentrated to recover 0.14g of raw material, with a recovery rate of 10%.

[0061] Example 4

[0062] Into a 250ml pressure reactor, 2.7g (15mmol) 1,3,5-trichlorobenzene, 190mg (1.0mmol) CuI catalyst, 140mg (1.0mmol) 8-hydroxyquinoline ligand, 1.2g (6mmol) potassium phosphate and 20ml dimethyl sulfoxide solvent were added, after sealing, the reactor was purged with ammonia gas for 7-8 times, then filled with 0.4-0.5MPa ammonia gas, the reactor was put into a heating reactor, the outside temperature was raised to 160°C, the temperature in the reactor was 130°C, the pressure was raised to 1.2-1.4MPa, after 24 hours of incubation, the heating reactor was turned off. When the reactor cooled to room temperature, the remaining ammonia gas was slowly released by opening the valve, the reaction solution was taken for GCMS test, the yield was 88%. The reaction solution was diluted with water, a large amount of methyl tert-butyl ether was extracted, the extract was concentrated to 5-10ml, 3ml hydrochloric acid tetrahydrofuran solution was added, yellow solid was precipitated, filtration, the filtrate was dissolved with water, sodium hydroxide solution was added to adjust pH>11, methyl tert-butyl ether was extracted 3 times, the solvent was removed to obtain 3,5-dichloroaniline 2.07g, the yield was 85%. The filtrate was concentrated to recover 0.27g of raw material, the raw material recovery rate was 10%.

[0063] Example 5

[0064] Into a 250ml pressure reactor, 2.7g (15mmol) 1,3,5-trichlorobenzene, 190mg (1.0mmol) CuI catalyst, 140mg (1.0mmol) 8-hydroxyquinoline ligand, 1.2g (6mmol) potassium phosphate and 20ml dimethyl sulfoxide solvent were added, after sealing, the reactor was purged with ammonia gas for 7-8 times, then filled with 0.4-0.5MPa ammonia gas, the reactor was put into a heating reactor, the outside temperature was raised to 160°C, the temperature in the reactor was 130°C, the pressure was raised to 1.2-1.4MPa, after 24 hours of incubation, the heating reactor was turned off. When the reactor cooled to room temperature, the remaining ammonia gas was slowly released by opening the valve, the reaction solution was taken for GCMS test, the yield was 88%. The reaction solution was diluted with water, a large amount of methyl tert-butyl ether was extracted, the extract was concentrated to 5-10ml, 3ml hydrochloric acid tetrahydrofuran solution was added, yellow solid was precipitated, filtration, the filtrate was dissolved with water, sodium hydroxide solution was added to adjust pH>11, methyl tert-butyl ether was extracted 3 times, the solvent was removed to obtain 3,5-dichloroaniline 2.07g, the yield was 85%. The filtrate was concentrated to recover 0.27g of raw material, the raw material recovery rate was 10%.

[0065] Example 6

[0066] Into a 250ml pressure reactor, 1.35g (7.5mmol) 1,3,5-trichlorobenzene, 95mg (0.5mmol) CuI catalyst, 70mg (0.5mmol) 8-hydroxyquinoline ligand, 636mg (3mmol) potassium phosphate and 10ml dimethyl sulfoxide solvent were added, after sealing, the reactor was purged with ammonia gas for 7-8 times, then filled with 0.4-0.5MPa ammonia gas, the reactor was put into a heating reactor, the outside temperature was raised to 130°C, the temperature in the reactor was 100°C, the pressure was raised to 1.2-1.4MPa, after 24 hours of incubation, the heating reactor was turned off. When the reactor cooled to room temperature, the remaining ammonia gas was slowly released by opening the valve, the reaction solution was taken for GCMS test, the yield was 53%. The reaction solution was diluted with water, a large amount of methyl tert-butyl ether was extracted, the extract was concentrated to 5-10ml, 3ml hydrochloric acid tetrahydrofuran solvent was added, yellow solid was precipitated, filtration, the filter residue was dissolved with water, sodium hydroxide solution was added to adjust pH>11, methyl tert-butyl ether was extracted 3 times, the solvent was removed to obtain 3,5-dichloroaniline 0.61g, the yield was 50%. The filtrate was concentrated to recover the raw material 0.6g, the raw material recovery rate was 45%.

[0067] Example 7

[0068] Into a 250ml pressure reactor, 1.35g (7.5mmol) 1,3,5-trichlorobenzene, 95mg (0.5mmol) CuI catalyst, 70mg (0.5mmol) 8-hydroxyquinoline ligand, 636mg (3mmol) potassium phosphate and 10ml dimethyl sulfoxide solvent were added, after sealing, the reactor was purged with ammonia gas for 7-8 times, then filled with 0.4-0.5MPa ammonia gas, the reactor was put into a heating reactor, the outside temperature was raised to 80°C, the temperature in the reactor was 60°C, the pressure was raised to 1.2-1.4MPa, after 24 hours of incubation, the heating reactor was turned off. When the reactor cooled to room temperature, the remaining ammonia gas was slowly released by opening the valve, the reaction solution was taken for GCMS test, the yield was 42%. The reaction solution was diluted with water, a large amount of methyl tert-butyl ether was extracted, the extract was concentrated to 5-10ml, 3ml hydrochloric acid tetrahydrofuran solvent was added, yellow solid was precipitated, filtration, the filter residue was dissolved with water, sodium hydroxide solution was added to adjust pH>11, methyl tert-butyl ether was extracted 3 times, the solvent was removed to obtain 3,5-dichloroaniline 0.47g, the yield was 39%. The filtrate was concentrated to recover the raw material 0.76g, the raw material recovery rate was 56%.

[0069] Example 8

[0070] Into a 250ml pressure reactor, 1.35g (7.5mmol) 1,3,5-trichlorobenzene, 95mg (0.5mmol) CuI catalyst, 70mg (0.5mmol) 8-hydroxyquinoline ligand, 636mg (3mmol) potassium phosphate, and 10ml dimethyl sulfoxide solvent were added, after sealing, the reactor was purged with ammonia for 3-4 times, then the reactor was put into a heating reactor, the temperature of the heating reactor was raised to 160°C, the temperature in the reactor was 130°C, the pressure was raised to 1.2-1.4MPa, after 24 hours, the heating reactor was turned off. When the reactor was cooled to room temperature, the remaining ammonia was slowly released, the reaction solution was taken for GCMS test, the yield was 53%. The reaction solution was diluted with water, a large amount of methyl tert-butyl ether was extracted, the extract was concentrated to 5-10ml, 3ml hydrochloric acid tetrahydrofuran solution was added, yellow solid was precipitated, filtration, the residue was dissolved with water, sodium hydroxide solution was added to adjust the pH>11, methyl tert-butyl ether was extracted 3 times, the solvent was removed to obtain 3,5-dichloroaniline 0.61g, the yield was 50%. The filtrate was concentrated to recover the raw material 0.6g, the raw material recovery rate was 45%.

[0071] Example 9

[0072] Into a 250ml pressure reactor, 1.35g (7.5mmol) 1,3,5-trichlorobenzene, 95mg (0.5mmol) CuI catalyst, 70mg (0.5mmol) 8-hydroxyquinoline ligand, 636mg (3mmol) potassium phosphate, and 10ml dimethyl sulfoxide solvent were added, after sealing, the reactor was purged with ammonia for 3-4 times, then the reactor was put into a heating reactor, the temperature of the heating reactor was raised to 160°C, the temperature in the reactor was 130°C, the pressure was raised to 1.2-1.4MPa, after 24 hours, the heating reactor was turned off. When the reactor was cooled to room temperature, the remaining ammonia was slowly released, the reaction solution was taken for GCMS test, the yield was 53%. The reaction solution was diluted with water, a large amount of methyl tert-butyl ether was extracted, the extract was concentrated to 5-10ml, 3ml hydrochloric acid tetrahydrofuran solution was added, yellow solid was precipitated, filtration, the residue was dissolved with water, sodium hydroxide solution was added to adjust the pH>11, methyl tert-butyl ether was extracted 3 times, the solvent was removed to obtain 3,5-dichloroaniline 0.61g, the yield was 50%. The filtrate was concentrated to recover the raw material 0.6g, the raw material recovery rate was 45%.

[0073] Example 10

[0074] Into a 250 ml pressure reactor, 1.35 g (7.5 mmol) of 1,3,5-trichlorobenzene, 95 mg (0.5 mmol) of CuI catalyst, 31 mg (0.5 mmol) of ethylene glycol ligand (L7), 636 mg (3 mmol) of potassium phosphate, and 10 ml of dimethyl sulfoxide solvent were added. After sealing, the reactor was subjected to 7-8 times of ammonia replacement, and then filled with 0.4-0.5 MPa of ammonia. The reactor was placed in a heating reactor, and the outer temperature was raised to 160°C. The temperature in the reactor was 130°C, and the pressure was raised to 1.2-1.4 MPa. After 24 hours of incubation, the heating reactor was turned off. When the reactor cooled to room temperature, the remaining ammonia was slowly released by opening the valve. The reaction solution was subjected to GCMS test, and the yield was 52%. The reaction solution was diluted with water, and a large amount of methyl tert-butyl ether was used for extraction. The extract was concentrated to 5-10 ml, 3 ml of hydrochloric acid tetrahydrofuran solution was added, and yellow solid was precipitated. Filtration was performed, and the filtrate was dissolved in water. Sodium hydroxide solution was added to adjust the pH to >11. Methyl tert-butyl ether was used for extraction 3 times, and the solvent was removed to obtain 3,5-dichloroaniline 0.60 g, with a yield of 49%. The filtrate was concentrated to recover the raw material 0.60 g, with a raw material recovery rate of 44%.

[0075] Example 11

[0076] This example provides a method for preparing 3,5-dichloroaniline. The specific steps are basically the same as those in Example 3, except that each ligand shown in Table 1 is used instead of L6 in Example 3, and other conditions remain unchanged. The yield, yield, and raw material recovery rate of 3,5-dichloroaniline prepared by using each ligand are shown in Table 1.

[0077] Table 1

[0078] ligand conversion / % yield / % raw material recovery / % L1 79 66 20 L2 56 51 42 L3 18 15 81 L4 27 24 72 L5 39 36 60 L8 42 39 57 L9 17 10 82 L10 15 13 82 L11 9 7 90 L12 10 5 89 L13 3 0 95

[0079] The structural formula of each ligand in Table 1 is as follows:

[0080]

[0081] Example 12

[0082] This example provides a method for preparing 3,5-dichloroaniline. The specific steps are basically the same as those in Example 3, except that each inert solvent shown in Table 2 is used instead of dimethyl sulfoxide in Example 3, and other conditions remain unchanged. The yield, yield, and raw material recovery rate of 3,5-dichloroaniline prepared by using each inert solvent are shown in Table 2. In the results of Table 2, when DMF or (CH2OH)2 is used, by-products 5-chlorobenzene-1,3-diamine and / or 1,3,5-triaminobenzene are generated.

[0083] Table 2

[0084]

[0085] Example 13

[0086] This example provides a method for preparing 3,5-dichloroaniline, the specific steps are basically the same as those of Example 3, the difference is only that each base shown in Table 2 is used instead of dimethyl sulfoxide in Example 3, and other conditions remain unchanged. The yield, yield and raw material recovery rate of 3,5-dichloroaniline prepared by using each base are shown in Table 3.

[0087] Table 3

[0088] base conversion / % yield / % raw material recovery / % K2CO3 77 60 23 Cs2CO3 89 67 11 Na3PO4 66 58 34 Na2CO3 72 57 28 CH3ONa 76 65 24 NaOH 12 10 88

[0089] It should be noted that the above examples have proved that the ligands L1, L2, L9 and L10 can be used for copper-catalyzed preparation of 3,5-dichloroaniline, and it can be reasonably predicted that the compounds shown in formula III As ligands can also be used for copper-catalyzed preparation of 3,5-dichloroaniline, the present application will not be enumerated one by one.

[0090] The above description of examples is for the convenience of ordinary skilled persons in the art to understand and use the application. Those skilled in the art can obviously make various modifications to these examples, and apply the general principles described herein to other examples without creative labor. Therefore, the present application is not limited to the above examples, and the improvements and modifications made by those skilled in the art according to the disclosure of the present application without departing from the scope of the present application should be within the scope of protection of the present application.

Claims

1. A process for the preparation of 3,5-dichloroaniline, characterized in that, The preparation method comprises the following steps: reacting 1,3,5-trichlorobenzene with a coupling reagent ammonia source in the presence of a copper catalyst, a ligand and a base in an inert solvent to generate 3,5-dichloroaniline; The ammonia source is selected from at least one of ammonia, aqueous ammonia solution and ammonium salt; The ligand is selected from one or more of the compounds shown in the following structures: ； The base is selected from at least one of sodium carbonate, potassium carbonate, cesium carbonate, sodium phosphate and sodium methoxide; The inert solvent is dimethyl sulfoxide; The copper catalyst is at least one of cuprous iodide, cuprous bromide and cuprous chloride.

2. The process for the preparation of 3,5-dichloroaniline according to claim 1, characterized in that, The amount of the copper catalyst is 1-15 mol% of the total moles of 1,3,5-trichlorobenzene; The amount of the ligand is 1-15 mol% of the total moles of 1,3,5-trichlorobenzene.

3. The process for the preparation of 3,5-dichloroaniline according to claim 1, characterized in that, The molar ratio of the ligand to the copper catalyst is 1:(0.5-2).

4. The process for the preparation of 3,5-dichloroaniline according to claim 1, characterized in that, The molar ratio of the base to 1,3,5-trichlorobenzene is 1:(1-10); The molar volume ratio of 1,3,5-trichlorobenzene to the inert solvent is 0.1-1.0 mmol / mL; 5. The process for the preparation of 3,5-dichloroaniline according to claim 1, characterized in that, The molar ratio of 1,3,5-trichlorobenzene to the ammonia source is 1:(5-20); The reaction temperature is 80-160 ℃, the reaction pressure is 0.5-3.0 Mpa, and the reaction time is 10-36 hours.

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