Preparation method of 3, 5-dichloroaniline

Abstract

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

Description

Technical Field

[0001] The invention belongs to the technical field of synthesis of medicines and pharmaceutical intermediates, and specifically relates to a method for preparing 3,5-dichloroaniline. Background Art

[0002] 3,5-Dichloroaniline is an important intermediate of cyclic imide fungicides and is widely used in medicine, pesticides, dyes, pigments, and plant growth promoters. Using 3,5-dichloroaniline as a raw material, agricultural fungicides such as procymidone, sclerotinol, vinclozolin, isoprodinil, dimethomorph, chlorfenapyr, ethoxyclostrobin, chlorfenapyr, chlorfenapyr, and chlorfenapyr can be synthesized. With the increase in the production of cyclic imide fungicides, 3,5-dichloroaniline is very popular in the international market. Therefore, the synthesis of 3,5-dichloroaniline has received more and more attention.

[0003] At present, there are many process synthesis routes for 3,5-dichloroaniline, such as: 1) using p-nitroaniline as raw material, chlorination, diazotization-denitrogenation to produce 3,5-dichloronitrobenzene, and then reducing the nitro group to obtain 3,5-dichloroaniline. This process has problems such as low utilization of chlorine element, difficult treatment of byproduct sodium sulfate and large environmental pollution; 2) using mixed dichlorobenzene as raw material, bromination, isomerization and aminolysis to produce 3,5-dichloroaniline. This process route uses aluminum chloride, which will produce a large amount of corrosive waste, and it is difficult to recycle and treat; in addition, there are nitrobenzene meta-oil chlorination-reduction-dechlorination method (CN201210219294.8), 3,5-dichlorobenzamide decarbonylation method, 4-chloro-2-nitrotoluene chlorination-oxidation-decarboxylation method (CN200410014747.9), polychloronitrobenzene catalytic hydrogenation dechlorination method, etc. However, the above synthetic routes have a common problem, that is, the raw material cost is high and the wastewater generated 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 of the invention

[0006] Aiming at the problems of serious environmental pollution, high cost, low content, and difficulty in sewage treatment in the preparation process of 3,5-dichloroaniline in the prior art, the present invention provides a preparation method of 3,5-dichloroaniline, which has simple preparation process, low production cost, and is environmentally friendly.

[0007] The objective of the present invention is achieved through the following technical solutions:

[0008] The present invention provides a method for preparing 3,5-dichloroaniline, and the specific route is as follows:

[0009]

[0010] The following steps are involved:

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

[0012] Wherein, the ammonia source is selected from at least one of ammonia gas, ammonia solution and ammonium salt;

[0013] The ligand is selected from one or more of the compounds shown in the following structures:

[0014]

[0015] Among them, in the structure of formula III,

[0016] R a Selected from the following groups: 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 to 5 heteroatoms selected from the following: N, O or S; the cycloalkyl or heterocyclyl may be a monocyclic, polycyclic, spirocyclic or bridged ring structure;

[0017] R b Selected from the following groups: 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 the following: N, O or S; the cycloalkyl or heterocyclyl may be a monocyclic, polycyclic, spirocyclic or bridged ring structure;

[0018] In the structure of Formula IV, R aSelected from the following groups: 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 to 5 heteroatoms selected from the following: N, O or S; the cycloalkyl or heterocyclyl may be a monocyclic, polycyclic, spirocyclic or bridged ring structure;

[0019] In the structure of formula V, R c Selected from the following groups: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C20 cycloalkyl, or substituted or unsubstituted 3- to 20-membered heterocyclic group; wherein the heterocyclic group has 1-5 heteroatoms selected from the following: N, O or S; the cycloalkyl group may be a monocyclic, polycyclic, spirocyclic or bridged ring structure;

[0020] In the structure of Formula VI, R c Selected from the following groups: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C20 cycloalkyl, or substituted or unsubstituted 3- to 20-membered heterocyclic group; wherein the heterocyclic group has 1-5 heteroatoms selected from the following: N, O or S; the cycloalkyl group may be a monocyclic, polycyclic, spirocyclic or bridged ring structure;

[0021] In the structure of formula VII, R c Selected from the following groups: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C20 cycloalkyl, or substituted or unsubstituted 3- to 20-membered heterocyclic group; wherein the heterocyclic group has 1-5 heteroatoms selected from the following: N, O or S; the cycloalkyl group may be a monocyclic, polycyclic, spirocyclic or bridged ring structure;

[0022] In the structure of formula VIII, R c Selected from the following groups: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C20 cycloalkyl, or substituted or unsubstituted 3- to 20-membered heterocyclic group; wherein the heterocyclic group has 1-5 heteroatoms selected from the following: N, O or S; the cycloalkyl group may be a monocyclic, polycyclic, spirocyclic or bridged ring structure;

[0023] The substitution refers to that one or more hydrogen atoms on the group are replaced by substituents selected from the following: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 aryl-oxy, C2-C10 ester group (alkyl-COO-), C2-C10 acyl-alkoxy (alkyl-OOC-), C2-C10 acyl group (alkyl-CO-), C2-C10 amide group (alkyl / aryl NHC(O)-), -COOH, nitro, hydroxyl, amino, amino substituted by 1 or 2 C1-C6 alkyl groups.

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

[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 sodium alkoxide, C1-C5 potassium alkoxide, and sodium hydride.

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

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

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

[0030] Preferably, the inert solvent is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, acetonitrile, ether solvents, ketone solvents, and alcohol solvents;

[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, and ethylene glycol diethyl ether;

[0032] The ketone solvent is selected from one or more of acetone, 2-butanone, and 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 and tert-butanol.

[0035] Preferably, the copper catalyst is used in an amount of 1 to 15 mol% of the total molar amount of 1,3,5-trichlorobenzene;

[0036] The amount of the ligand used is 1 to 15 mol% of the total molar amount 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 the 1,3,5-trichlorobenzene to the 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 to 36 hours.

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

[0043] The present invention also provides an application of 3,5-dichloroaniline prepared according to the above method as an intermediate in the preparation of cyclic imide fungicides.

[0044] The existing method for preparing 3,5-dichloroaniline based on ammonia source is described in patent document CN106748801A, which uses 1,3,5-trichlorobenzene as a raw material, adds a base, ammonia solution or ammonium salt as an ammonia source in an organic solvent, and a coupling reaction occurs under the action of a transition metal catalyst and a ligand to obtain the product 3,5-dichloroaniline. The ammonia source specifically used is an ammonia solution or an ammonium salt, the organic solvent used is 1,4-dioxane, the base used is sodium tert-butyl alcoholate, potassium tert-butyl alcoholate, 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 this method is as follows: the palladium catalyst and the ligand are complexed to form a zero-valent palladium species PdL2 complexed with palladium and the ligand, which then undergoes oxidative addition with trichlorobenzene to generate a reaction intermediate A, which then combines with ammonia and undergoes ligand exchange and, under the action of an alkali, removes a molecule of hydrogen chloride to generate a reaction intermediate B, and finally reduction elimination is performed to obtain the target compound, and the catalyst can be recycled.

[0045]

[0046] Although this method achieves a yield of more than 80% and allows the palladium catalyst to be recycled, it still uses an expensive palladium catalyst and the ligand used is also relatively expensive. Therefore, the production cost of this method is still too high when it is used for industrial production.

[0047] Based on this, the present invention aims to develop an alternative method that can significantly reduce production costs while maintaining a high yield. The coupling reaction of aryl halides and ammonia sources under copper catalysis (Ullmann coupling reaction) has a long history. However, although copper catalysts are cheap, such reactions often require more drastic reaction conditions, such as high temperature (reaction temperature is higher than 200°C), poor substrate compatibility, etc., and when cheap aryl chlorides are used as reaction substrates, the yield is often extremely low, which is difficult to be actually applied in organic synthesis. With the development of metal organic chemistry, bidentate ligand-promoted copper-catalyzed Ullmann reaction was developed, which broke through the limitations of harsh reaction conditions and poor universality, and can be applied to the coupling reaction of inactive chloroaryl hydrocarbons with amines (JACS, 2015, 137, 11942; Org. Lett. 2015, 17, 5934; Org. Lett. 2017, 19, 2809).

[0048] In order to realize the application of Ullmann coupling reaction under copper catalysis, the present invention has carried out a large number of experimental studies, 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. The reaction mechanism is: the copper catalyst and the ligand are complexed to generate a monovalent copper species Cu I L2, and then coordinates with ammonia to generate a monovalent copper species C (Cu I L2(NH3)), and under the action of alkali, it removes protons to produce monovalent copper species D(Cu I L2(NH2)), followed by oxidative addition reaction with 1,3,5-trichlorobenzene to generate trivalent copper intermediate E, and finally reduction elimination to obtain the target compound, and realize the recycling of the copper catalyst.

[0049]

[0050] The method of the invention 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 invention has the following beneficial effects:

[0052] The present invention designs a new route for synthesizing 3,5-dichloroaniline, using 1,3,5-trichlorobenzene as a raw material, and obtaining the product 3,5-dichloroaniline by ammonolysis under the conditions of a copper catalyst, a ligand, a base and an inert solvent. The preparation method of the present invention is simple, easy to operate, low in cost and environmentally friendly; and adding a ligand during the ammoniation reaction can reduce the temperature of the ammoniation reaction, shorten the reaction time and improve the reaction yield. DETAILED DESCRIPTION

[0053] The present invention is described in detail below in conjunction with specific embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but are not intended to limit the present invention in any form. It should be noted that, for those of ordinary skill in the art, several variations and improvements may be made without departing from the concept of the present invention. These all belong to the protection scope of the present invention.

[0054] Example 1

[0055] This embodiment provides a method for preparing 3,5-dichloroaniline, and the specific steps are as follows:

[0056] 1.35g (7.5mmol) 1,3,5-trichlorobenzene, 50mg (0.5mmol) CuCl catalyst, 70mg (0.5mmol) 8-hydroxyquinoline ligand (L6), 636mg (3mmol) potassium phosphate and 10ml dimethyl sulfoxide solvent were added to a 250ml pressure reactor. After sealing, the ammonia gas was evacuated for 7-8 times, and then filled with 0.4-0.5MPa ammonia gas. The reactor was placed in a heating reactor, the external temperature was raised to 160°C, the temperature inside the reactor was 130°C, the pressure was raised to 1.2-1.4MPa, and the heating reactor was closed after 24 hours of heat preservation. When the reactor was cooled to room temperature, the gas valve was opened to slowly release the remaining ammonia gas, and the reaction liquid was taken for GCMS test, and the yield was 83%. The reaction solution was diluted with water, extracted with a large amount of methyl tert-butyl ether, and the extract was vortexed to 5-10 ml. 3 ml of hydrochloric acid tetrahydrofuran solvent was added, and a yellow solid was precipitated. The residue was filtered and dissolved with water. Sodium hydroxide solution was added to adjust the pH to > 11, and extracted with methyl tert-butyl ether for 3 times. The solvent was removed to obtain 0.97 g of 3,5-dichloroaniline with a yield of 80%. The filtrate was vortexed to dryness to recover 0.2 g of raw material, and the raw material recovery rate was 15%. The NMR results of the obtained product 3,5-dichloroaniline are as follows: 1 H NMR (400MHz, CDCl3) δ6.73-6.71(m,1H),6.54-6.53(m,2H),3.79(s,2H); 13 C NMR (100MHz, CDCl3) δ148.3, 135.5, 118.4, 113.3.

[0057] Example 2

[0058] 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 to a 250ml pressure reactor. After sealing, ammonia was evacuated for 7-8 times, and then 0.4-0.5MPa ammonia was filled. The reactor was placed in a heating reactor, the external temperature was raised to 160°C, the temperature inside the reactor was 130°C, the pressure was raised to 1.2-1.4MPa, and the heating reactor was closed after 24 hours of heat preservation. When the reactor was cooled to room temperature, the gas valve was opened to slowly release the remaining ammonia, and the reaction liquid was taken for GCMS test, and the yield was 88%. The reaction solution was diluted with water, extracted with a large amount of methyl tert-butyl ether, the extract was vortexed to 5-10 ml, 3 ml of hydrochloric acid tetrahydrofuran solvent was added, a yellow solid was precipitated, filtered, the filter residue was dissolved with water, sodium hydroxide solution was added to adjust the pH>11, extracted with methyl tert-butyl ether for 3 times, and the solvent was removed to obtain 1.03 g of 3,5-dichloroaniline, with a yield of 85%. The filtrate was vortexed to dryness to recover 0.14 g of raw material, with a raw material recovery rate of 10%.

[0059] Example 3

[0060] 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 to a 250ml pressure reactor. After sealing, ammonia was evacuated for 7-8 times, and then 0.4-0.5MPa ammonia was filled. The reactor was placed in a heating reactor, the external temperature was raised to 160°C, the temperature inside the reactor was 130°C, the pressure was raised to 1.2-1.4MPa, and the heating reactor was closed after 24 hours of heat preservation. When the reactor was cooled to room temperature, the gas valve was opened to slowly release the remaining ammonia, and the reaction liquid was taken for GCMS test, and the yield was 92%. The reaction solution was diluted with water, extracted with a large amount of methyl tert-butyl ether, the extract was vortexed to 5-10 ml, 3 ml of hydrochloric acid tetrahydrofuran solvent was added, a yellow solid was precipitated, filtered, the filter residue was dissolved with water, sodium hydroxide solution was added to adjust the pH>11, extracted with methyl tert-butyl ether for 3 times, and the solvent was removed to obtain 1.08 g of 3,5-dichloroaniline, with a yield of 89%. The filtrate was vortexed to dryness to recover 0.08 g of raw material, with a raw material recovery rate of 6%.

[0061] Example 4

[0062] 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 to a 250ml pressure reactor. After sealing, ammonia was evacuated for 7-8 times, and then 0.4-0.5MPa ammonia was filled. The reactor was placed in a heating reactor, the external temperature was raised to 160°C, the temperature inside the reactor was 130°C, the pressure was raised to 1.2-1.4MPa, and the heating reactor was closed after 24 hours of heat preservation. When the reactor was cooled to room temperature, the gas valve was opened to slowly release the remaining ammonia, and the reaction liquid was taken for GCMS test, and the yield was 88%. The reaction solution was diluted with water, extracted with a large amount of methyl tert-butyl ether, the extract was vortexed to 5-10 ml, 3 ml of hydrochloric acid tetrahydrofuran solvent was added, a yellow solid was precipitated, filtered, the filter residue was dissolved with water, sodium hydroxide solution was added to adjust the pH>11, extracted with methyl tert-butyl ether for 3 times, and the solvent was removed to obtain 2.07 g of 3,5-dichloroaniline, with a yield of 85%. The filtrate was vortexed to dryness to recover 0.27 g of raw material, with a raw material recovery rate of 10%.

[0063] Example 5

[0064] 2.7g (15mmol) 1,3,5-trichlorobenzene, 95mg (0.5mmol) CuI catalyst, 70mg (0.5mmol) 8-hydroxyquinoline ligand, 636mg (3.0mmol) potassium phosphate and 20ml dimethyl sulfoxide solvent were added to a 250ml pressure reactor. After sealing, ammonia was evacuated for 7-8 times, and then 0.4-0.5MPa ammonia was filled. The reactor was placed in a heating reactor, the external temperature was raised to 160°C, the temperature inside the reactor was 130°C, the pressure was raised to 1.2-1.4MPa, and the heating reactor was closed after 24 hours of heat preservation. When the reactor was cooled to room temperature, the gas valve was opened to slowly release the remaining ammonia, and the reaction liquid was taken for GCMS test, and the yield was 87%. The reaction solution was diluted with water, extracted with a large amount of methyl tert-butyl ether, the extract was vortexed to 5-10 ml, 3 ml of hydrochloric acid tetrahydrofuran solvent was added, a yellow solid was precipitated, filtered, the filter residue was dissolved with water, sodium hydroxide solution was added to adjust the pH>11, extracted with methyl tert-butyl ether for 3 times, and the solvent was removed to obtain 2.07 g of 3,5-dichloroaniline, with a yield of 85%. The filtrate was vortexed to dryness to recover 0.35 g of raw material, with a raw material recovery rate of 13%.

[0065] Example 6

[0066] 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 to a 250ml pressure reactor. After sealing, ammonia was evacuated for 7-8 times, and then 0.4-0.5MPa ammonia was filled. The reactor was placed in a heating reactor, the external temperature was raised to 130°C, the temperature inside the reactor was 100°C, the pressure was raised to 1.2-1.4MPa, and the heating reactor was closed after 24 hours of heat preservation. When the reactor was cooled to room temperature, the gas valve was opened to slowly release the remaining ammonia, and the reaction liquid was taken for GCMS test, and the yield was 53%. The reaction solution was diluted with water, extracted with a large amount of methyl tert-butyl ether, the extract was vortexed to 5-10 ml, 3 ml of hydrochloric acid tetrahydrofuran solvent was added, a yellow solid was precipitated, filtered, the filter residue was dissolved with water, sodium hydroxide solution was added to adjust the pH>11, extracted with methyl tert-butyl ether for 3 times, and the solvent was removed to obtain 0.61 g of 3,5-dichloroaniline, with a yield of 50%. The filtrate was vortexed to dryness to recover 0.6 g of raw material, with a raw material recovery rate of 45%.

[0067] Example 7

[0068] 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 to a 250ml pressure reactor. After sealing, ammonia was evacuated for 7-8 times, and then 0.4-0.5MPa ammonia was filled. The reactor was placed in a heating reactor, the external temperature was raised to 80°C, the temperature inside the reactor was 60°C, the pressure was raised to 1.2-1.4MPa, and the heating reactor was closed after 24 hours of heat preservation. When the reactor was cooled to room temperature, the gas valve was opened to slowly release the remaining ammonia, and the reaction liquid was taken for GCMS test, and the yield was 42%. The reaction solution was diluted with water, extracted with a large amount of methyl tert-butyl ether, the extract was vortexed to 5-10 ml, 3 ml of hydrochloric acid tetrahydrofuran solvent was added, a yellow solid was precipitated, filtered, the filter residue was dissolved with water, sodium hydroxide solution was added to adjust the pH>11, extracted with methyl tert-butyl ether for 3 times, and the solvent was removed to obtain 0.47 g of 3,5-dichloroaniline, with a yield of 39%. The filtrate was vortexed to dryness to recover 0.76 g of raw material, with a raw material recovery rate of 56%.

[0069] Example 8

[0070] 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 to a 250ml pressure reactor, sealed and ventilated with nitrogen for 3-4 times, and then ammonia solution (w / w 25%, 1.80mL, 22.5mmol) was added. The reactor was placed in a heating reactor, the external temperature was raised to 160°C, the temperature inside the reactor was 130°C, the pressure was raised to 1.2-1.4MPa, and the heating reactor was closed after 24 hours of heat preservation. When the reactor was cooled to room temperature, the gas valve was opened to slowly release the remaining ammonia, and the reaction liquid was taken for GCMS test, and the yield was 53%. The reaction solution was diluted with water, extracted with a large amount of methyl tert-butyl ether, the extract was vortexed to 5-10 ml, 3 ml of hydrochloric acid tetrahydrofuran solvent was added, a yellow solid was precipitated, filtered, the filter residue was dissolved with water, sodium hydroxide solution was added to adjust the pH>11, extracted with methyl tert-butyl ether for 3 times, and the solvent was removed to obtain 0.61 g of 3,5-dichloroaniline, with a yield of 50%. The filtrate was vortexed to dryness to recover 0.6 g of raw material, with a raw material recovery rate of 45%.

[0071] Example 9

[0072] 1.35g (7.5mmol) 1,3,5-trichlorobenzene, 95mg (0.5mmol) CuI catalyst, 70mg (0.5mmol) 8-hydroxyquinoline ligand, 415mg (3mmol) potassium carbonate, and 10ml dimethyl sulfoxide solvent were added to a 250ml pressure reactor. After sealing, ammonia was evacuated for 7-8 times, and then 0.4-0.5MPa ammonia was filled. The reactor was placed in a heating reactor, the external temperature was raised to 160°C, the temperature inside the reactor was 130°C, the pressure was raised to 1.2-1.4MPa, and the heating reactor was closed after 24 hours of heat preservation. When the reactor was cooled to room temperature, the gas valve was opened to slowly release the remaining ammonia, and the reaction liquid was taken for GCMS test, and the yield was 77%. The reaction solution was diluted with water, extracted with a large amount of methyl tert-butyl ether, the extract was vortexed to 5-10 ml, 3 ml of hydrochloric acid tetrahydrofuran solvent was added, a yellow solid was precipitated, filtered, the filter residue was dissolved with water, sodium hydroxide solution was added to adjust the pH>11, extracted with methyl tert-butyl ether for 3 times, and the solvent was removed to obtain 0.85 g of 3,5-dichloroaniline, with a yield of 70%. The filtrate was vortexed to dryness to recover 0.22 g of raw material, with a raw material recovery rate of 16%.

[0073] Example 10

[0074] 1.35g (7.5mmol) 1,3,5-trichlorobenzene, 95mg (0.5mmol) CuI catalyst, 31mg (0.5mmol) ethylene glycol ligand (L7), 636mg (3mmol) potassium phosphate, and 10ml dimethyl sulfoxide solvent were added to a 250ml pressure reactor. After sealing, the ammonia gas was evacuated for 7-8 times, and then filled with 0.4-0.5MPa ammonia gas. The reactor was placed in a heating reactor, the external temperature was raised to 160°C, the temperature inside the reactor was 130°C, the pressure was raised to 1.2-1.4MPa, and the heating reactor was closed after 24 hours of heat preservation. When the reactor was cooled to room temperature, the gas valve was opened to slowly release the remaining ammonia gas, and the reaction liquid was taken for GCMS test, and the yield was 52%. The reaction solution was diluted with water, extracted with a large amount of methyl tert-butyl ether, the extract was vortexed to 5-10 ml, 3 ml of hydrochloric acid tetrahydrofuran solvent was added, a yellow solid was precipitated, filtered, the filter residue was dissolved with water, sodium hydroxide solution was added to adjust the pH>11, extracted with methyl tert-butyl ether for 3 times, and the solvent was removed to obtain 0.60 g of 3,5-dichloroaniline, with a yield of 49%. The filtrate was vortexed to dryness to recover 0.60 g of raw material, with a raw material recovery rate of 44%.

[0075] Embodiment 11

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

[0077] Table 1

[0078] Ligand Conversion rate / % Yield / % Raw material recovery rate / % 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 formulas of the ligands in Table 1 are as follows:

[0081]

[0082] Example 12

[0083] This embodiment provides a method for preparing 3,5-dichloroaniline, and the specific steps are basically the same as those in Example 3, except that the inert solvents shown in Table 2 are used instead of dimethyl sulfoxide in Example 3, and other conditions remain unchanged. The yield, yield and raw material recovery rate of preparing 3,5-dichloroaniline using various inert solvents are shown in Table 2. In the results of Table 2, when DMF or (CH2OH)2 is used for preparation, by-products 5-chlorobenzene-1,3-diamine and / or 1,3,5-triaminobenzene are generated.

[0084] Table 2

[0085]

[0086] Embodiment 13

[0087] This example provides a method for preparing 3,5-dichloroaniline, and the specific steps are basically the same as those in Example 3, except that the bases shown in Table 2 are used instead of dimethyl sulfoxide in Example 3, and other conditions remain unchanged. The yield, yield and raw material recovery rate of preparing 3,5-dichloroaniline using the bases are shown in Table 3.

[0088] Table 3

[0089] Alkali Conversion rate / % Yield / % Raw material recovery rate / % <![CDATA[K2CO3]]> 77 60 23 <![CDATA[Cs2CO3]]> 89 67 11 <![CDATA[Na3PO4]]> 66 58 34 <![CDATA[Na2CO3]]> 72 57 28 <![CDATA[CH3ONa]]> 76 65 24 NaOH 12 10 88

[0090] It should be noted that the above examples have proved that the use of L1, L2, L9, L10 ligands can be used for copper-catalyzed preparation of 3,5-dichloroaniline, and it can be reasonably predicted that the compound shown in the structure of formula III As ligands, they can all be used in the copper-catalyzed preparation of 3,5-dichloroaniline, and the present invention will not list them one by one.

[0091] The above description of the embodiments is to facilitate the understanding and use of the invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the scope of protection of the present invention.

Claims

1. A method for preparing 3,5-dichloroaniline, characterized in that: The preparation method comprises the following steps: In an inert solvent, in the presence of a copper catalyst, a ligand and a base, 1,3,5-trichlorobenzene is reacted with a coupling reagent ammonia source to generate 3,5-dichloroaniline; Wherein, the ammonia source is selected from at least one of ammonia gas, ammonia solution and ammonium salt.

2. The method for preparing 3,5-dichloroaniline according to claim 1, characterized in that: The ligand is selected from one or more of the compounds shown in the following structures: Among them, in the structure of formula III, R a Selected from the following groups: 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 to 5 heteroatoms selected from the following: N, O or S; the cycloalkyl or heterocyclyl may be a monocyclic, polycyclic, spirocyclic or bridged ring structure; R b Selected from the following groups: 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 the following: N, O or S; the cycloalkyl or heterocyclyl may be a monocyclic, polycyclic, spirocyclic or bridged ring structure; In the structure of Formula IV, R a Selected from the following groups: 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 to 5 heteroatoms selected from the following: N, O or S; the cycloalkyl or heterocyclyl may be a monocyclic, polycyclic, spirocyclic or bridged ring structure; In the structure of formula V, R c Selected from the following groups: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C20 cycloalkyl, or substituted or unsubstituted 3- to 20-membered heterocyclic group; wherein the heterocyclic group has 1-5 heteroatoms selected from the following: N, O or S; the cycloalkyl group may be a monocyclic, polycyclic, spirocyclic or bridged ring structure; In the structure of Formula VI, R c Selected from the following groups: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C20 cycloalkyl, or substituted or unsubstituted 3- to 20-membered heterocyclic group; wherein the heterocyclic group has 1-5 heteroatoms selected from the following: N, O or S; the cycloalkyl group may be a monocyclic, polycyclic, spirocyclic or bridged ring structure; In the structure of formula VII, R c Selected from the following groups: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C20 cycloalkyl, or substituted or unsubstituted 3- to 20-membered heterocyclic group; wherein the heterocyclic group has 1-5 heteroatoms selected from the following: N, O or S; the cycloalkyl group may be a monocyclic, polycyclic, spirocyclic or bridged ring structure; In the structure of formula VIII, R c Selected from the following groups: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C20 cycloalkyl, or substituted or unsubstituted 3- to 20-membered heterocyclic group; wherein the heterocyclic group has 1-5 heteroatoms selected from the following: N, O or S; the cycloalkyl group may be a monocyclic, polycyclic, spirocyclic or bridged ring structure; The substitution refers to that one or more hydrogen atoms on the group are replaced by substituents selected from the following: halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryl, C6-C10 aryl-oxy, C2-C10 ester group (alkyl-COO-), C2-C10 acyl-alkoxy (alkyl-OOC-), C2-C10 acyl group (alkyl-CO-), C2-C10 amide group (alkyl / aryl NHC(O)-), -COOH, nitro, hydroxyl, amino, amino substituted by 1 or 2 C1-C6 alkyl groups.

3. The method for preparing 3,5-dichloroaniline according to claim 1, characterized in that: 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 sodium alkoxide, C1-C5 potassium alkoxide, and sodium hydride.

4. The method for preparing 3,5-dichloroaniline according to claim 1, characterized in that: The copper catalyst is a copper salt and / or copper oxide; Preferably, the copper catalyst is selected from at least one of cuprous oxide, cupric oxide, copper sulfate, cuprous thiophene-2-carboxylate, cupric acetate, copper nitrate, cupric ethylacetoacetate, cupric bromide, cupric chloride, cupric cyanide, cupric acetylacetonate, cuprous thiocyanate, cupric iodide, cuprous iodide, cuprous bromide, cuprous chloride, and cuprous cyanide; More preferably, the copper catalyst is selected from at least one of cuprous iodide, cuprous oxide, cuprous chloride and cuprous bromide.

5. The method for preparing 3,5-dichloroaniline according to claim 1, characterized in that: The inert solvent is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide, sulfolane, acetonitrile, ether solvents, ketone solvents, and alcohol solvents; 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, and ethylene glycol diethyl ether; The ketone solvent is selected from one or more of acetone, 2-butanone, and methyl isopropyl ketone; The alcohol solvent is selected from one or more of C1-C8 alcohols; more preferably, the alcohol solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, and tert-butanol.

6. The method for preparing 3,5-dichloroaniline according to claim 1, characterized in that: The copper catalyst is used in an amount of 1 to 15 mol% of the total molar amount of 1,3,5-trichlorobenzene; The amount of the ligand used is 1 to 15 mol% of the total molar amount of 1,3,5-trichlorobenzene.

7. The method for preparing 3,5-dichloroaniline according to claim 1, 2 or 4, characterized in that: The molar ratio of the ligand to the copper catalyst is 1:(0.5-2).

8. The method for preparing 3,5-dichloroaniline according to claim 1, 3 or 5, characterized in that: The molar ratio of the base to 1,3,5-trichlorobenzene is 1:(1-10); The molar volume ratio of the 1,3,5-trichlorobenzene to the inert solvent is 0.1-1.0 mmol / mL.

9. The method for preparing 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° C., the reaction pressure is 0.5-3.0 MPa, and the reaction time is 10 to 36 hours.

10. Use of 3,5-dichloroaniline prepared by the method according to any one of claims 1 to 9 as an intermediate in the preparation of cyclic imide fungicides.

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