Preparation method of 2-substituted alkane aniline compound

Abstract

The present invention relates to the technical field of aniline compound synthesis, particularly to a 2-substituted alkane aniline compound preparation method, which comprises: carrying out a substitution reaction on a compound represented by a formula (I) to obtain a compound represented by a formula (II), carrying out a hydrolysis decarboxylation reaction on the product, optionally carrying out an amination reaction, and optionally carrying out a Hofmann degradation reaction to obtain the 2-substituted alkane aniline compound. A compound shown in the formula (III) is obtained; and carrying out catalytic hydrogenation on the product to obtain the 2-alkyl substituted aniline compound as shown in a formula (IV). The 2-alkyl substituted aniline compound prepared by the method disclosed by the invention has the advantages of low conversion rate, high selectivity, simple steps, mild reaction conditions and low cost.

Description

Technical Field

[0001] The invention relates to the technical field of synthesizing aniline compounds, and in particular to a method for preparing 2-substituted alkane aniline compounds. Background Art

[0002] 2-Substituted alkane aniline compounds are an important class of organic chemical intermediates and play an important role in pesticide chemistry. 2-(1,3-dimethylbutyl)aniline is one of the important intermediates for the synthesis of the fungicide penflufen.

[0003] CN106674021A discloses a method for preparing substituted aniline compounds by reacting aniline or 4-trifluoromethylaniline with aldehydes and ketones through Friedel-Crafts reaction in the presence of Lewis acid.

[0004] CN1255384C discloses a method for synthesizing N-pyrazolylcarboxanilide compounds by using aniline derivatives as raw materials and carboxylic acid derivatives in the presence of an acid binder and a diluent.

[0005] However, the existing aniline synthesis reaction by Friedel-Crafts reaction faces the problems of catalyst non-recyclability, large amount of wastewater generated by the reaction, which is difficult to handle, and reaction selectivity. Or the aniline synthesis reaction by reacting aniline derivatives with carboxylic acid derivatives has low conversion rate and poor selectivity, cumbersome steps, harsh reaction conditions, and high cost.

[0006] Therefore, a more suitable method for synthesizing 2-substituted alkane aniline is urgently needed. Summary of the invention

[0007] The purpose of the present invention is to overcome the problems of low conversion rate and poor selectivity, complicated steps, harsh reaction conditions and high cost in the prior art for preparing 2-alkyl substituted aniline compounds.

[0008] In order to achieve the above object, the present invention provides a method for preparing 2-alkyl substituted aniline compounds, wherein the method comprises:

[0009] Step 1, when R1 is a C1-C4 alkyl group, in the presence of a base and a co-solvent, the compound represented by formula (I-1), the compound represented by formula (I-2), the compound represented by formula (I-3), the compound represented by formula (I-4), and the compound represented by formula (I-5) are respectively subjected to a first substitution reaction with a 3-halogenated propylene compound to obtain corresponding compounds represented by formula (II-1), formula (II-2), formula (II-3), formula (II-4), and formula (II-5);

[0010] Or, when R1 is H, in the presence of a base and a co-solvent, the compound represented by formula (I-1), the compound represented by formula (I-2), the compound represented by formula (I-3), the compound represented by formula (I-4), and the compound represented by formula (I-5) are respectively subjected to a second substitution reaction with a 3-halogenated propylene compound, and then subjected to a third substitution reaction with a sulfate ester or a halogenated hydrocarbon to obtain corresponding compounds represented by formula (II-1), formula (II-2), formula (II-3), formula (II-4), and formula (II-5);

[0011] Step 2, subjecting the compound represented by formula (II-1) to a hydrolysis and decarboxylation reaction to obtain a compound represented by formula (III-1);

[0012] The compound represented by formula (II-2) is subjected to a hydrolysis and decarboxylation reaction to obtain a compound represented by formula (III-2);

[0013] The compound represented by formula (II-3) is subjected to a hydrolysis reaction, a hydrolysis decarboxylation reaction, and a Hofmann degradation reaction to obtain a compound represented by formula (III-2);

[0014] The compound represented by formula (II-4) is subjected to hydrolysis reaction, hydrolysis decarboxylation reaction, amination reaction, and Hofmann degradation reaction to obtain a compound represented by formula (III-2);

[0015] The compound represented by formula (II-5) is subjected to a hydrolysis decarboxylation reaction and a Hofmann degradation reaction to obtain a compound represented by formula (III-2);

[0016] Step 3, subjecting the compound represented by formula (III-1) or the compound represented by formula (III-2) to a catalytic hydrogenation reaction to obtain a 2-alkyl substituted aniline compound represented by formula (IV);

[0017]

[0018]

[0019] Wherein, X2 is selected from -(CH2) m COOR4, -(CH2) m CN, -(CH2) m CONH2 or -(CH2) m CONR5R6, m is a natural number from 0 to 5;

[0020] R1, R2, R3, R4, R5 and R6 are each independently H or C1-C4 alkyl; R7 is C1-C4 alkyl.

[0021] The above technical scheme solves the problems of low conversion rate and poor selectivity in the prior art for preparing 2-alkyl substituted aniline compounds, reduces costs, improves efficiency, reduces pollution, is simple to operate and can be industrialized. DETAILED DESCRIPTION

[0022] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0023] The present invention provides a method for preparing a 2-alkyl substituted aniline compound, wherein the method comprises:

[0024] Step 1, when R1 is a C1-C4 alkyl group, in the presence of a base and a co-solvent, the compound represented by formula (I-1), the compound represented by formula (I-2), the compound represented by formula (I-3), the compound represented by formula (I-4), and the compound represented by formula (I-5) are respectively subjected to a first substitution reaction with a 3-halogenated propylene compound to obtain corresponding compounds represented by formula (II-1), formula (II-2), formula (II-3), formula (II-4), and formula (II-5);

[0025] Or, when R1 is H, in the presence of a base and a co-solvent, the compound represented by formula (I-1), the compound represented by formula (I-2), the compound represented by formula (I-3), the compound represented by formula (I-4), and the compound represented by formula (I-5) are respectively subjected to a second substitution reaction with a 3-halogenated propylene compound, and then subjected to a third substitution reaction with a sulfate ester or a halogenated hydrocarbon to obtain corresponding compounds represented by formula (II-1), formula (II-2), formula (II-3), formula (II-4), and formula (II-5);

[0026] Step 2, subjecting the compound represented by formula (II-1) to a hydrolysis and decarboxylation reaction to obtain a compound represented by formula (III-1);

[0027] The compound represented by formula (II-2) is subjected to a hydrolysis and decarboxylation reaction to obtain a compound represented by formula (III-2);

[0028] The compound represented by formula (II-3) is subjected to a hydrolysis reaction, a hydrolysis decarboxylation reaction, and a Hofmann degradation reaction to obtain a compound represented by formula (III-2);

[0029] The compound represented by formula (II-4) is subjected to hydrolysis reaction, hydrolysis decarboxylation reaction, amination reaction, and Hofmann degradation reaction to obtain a compound represented by formula (III-2);

[0030] The compound represented by formula (II-5) is subjected to a hydrolysis decarboxylation reaction and a Hofmann degradation reaction to obtain a compound represented by formula (III-2);

[0031] Step 3, subjecting the compound represented by formula (III-1) or the compound represented by formula (III-2) to a catalytic hydrogenation reaction to obtain a 2-alkyl substituted aniline compound represented by formula (IV);

[0032]

[0033] Wherein, X2 is selected from -(CH2) m COOR4, -(CH2) m CN, -(CH2) m CONH2 or -(CH2) m CONR5R6, m is a natural number from 0 to 5;

[0034] R1, R2, R3, R4, R5 and R6 are each independently H or C1-C4 alkyl; R7 is C1-C4 alkyl.

[0035] The invention provides a new process route to provide a preparation method with better conversion rate and selectivity.

[0036] In the present invention, the first substitution reaction and the second substitution reaction have low process requirements, are easier to operate, and have a high yield of the product.

[0037] In the present invention, the first substitution reaction, the second substitution reaction and the third substitution reaction are all exothermic reactions. In order to prevent boiling over, the reactants are added in a slow addition method commonly used in the art. A most preferred implementation method is to slowly dropwise add the reactants within 1 hour.

[0038] In step 1, a first catalyst is added to promote the reaction. The first catalyst is a conventional catalyst in the art. A particularly preferred embodiment is to add polyethylene glycol, and the weight ratio of the compound represented by formula (I) to the first catalyst is 100:1.

[0039] In step 2, in order to remove water in the system, the temperature is raised after the reaction is completed, and the temperature should be higher than the boiling point of water. A particularly preferred embodiment is to raise the temperature to 110°C.

[0040] In step 2, a second catalyst is also added to the amination reaction. The second catalyst is a conventional catalyst in the art. A particularly preferred embodiment is to add triethylamine and / or trichloromethyl chloroformate.

[0041] In some preferred embodiments of the present invention, m is 0 or 1; R1, R2, R3, R4, R5 and R6 are each independently H or a C1-C2 alkyl group; and R7 is a C1-C2 alkyl group.

[0042] In some preferred embodiments of the present invention, in step 1, the first substitution reaction is carried out at a pH of 10-14, preferably 12-14. Specifically, the pH of the mixture of the materials participating in the first substitution reaction in step 1 is 10-14, preferably 12-14, and the mixture may include a base, a cosolvent, one of the compounds represented by formula (I-1) to (I-5), and a 3-halopropylene compound.

[0043] In the present invention, the pH range mentioned above can allow the base to remove active α hydrogen to form a carbon anion.

[0044] In some preferred embodiments of the present invention, the base is selected from inorganic bases and / or organic bases.

[0045] In some preferred embodiments of the present invention, the inorganic base is selected from at least one of sodium carbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide, preferably sodium hydroxide and / or sodium carbonate.

[0046] In some preferred embodiments of the present invention, the organic base is selected from at least one of sodium methoxide, sodium ethoxide, sodium methoxide, triethylamine, sodium tert-butoxide, potassium tert-butoxide and lithium diisopropylamide.

[0047] In some preferred embodiments of the present invention, the co-solvent is a conventional organic solvent in the art, selected from nitrile compounds or aromatic hydrocarbon compounds, preferably at least one of acetonitrile, butyronitrile, benzene, toluene and xylene.

[0048] In some preferred embodiments of the present invention, the mass ratio of the compound represented by formula (I) to the co-solvent is 1:1-5, preferably 1:2-4.5.

[0049] In some preferred embodiments of the present invention, the 3-halopropene compound is selected from 2-alkyl-3-halopropene, preferably 2-methyl-3-chloropropene.

[0050] Preferably, the molar ratio of the compound of formula (I) to the 3-halogenated propene compound is 1:1-3, preferably 1:1.1-2.

[0051] In the present invention, slowly adding a specific type and amount of 3-halogenated propene compounds can make the reaction more complete and sufficient.

[0052] In some preferred embodiments of the present invention, the sulfate is selected from dialkyl sulfates having an alkyl group of C1-C5, preferably dimethyl sulfate.

[0053] Preferably, the molar ratio of the compound represented by formula (I) to the sulfate is 1:1-2, preferably 1:1.1-1.7.

[0054] Preferably, the halogenated hydrocarbon is selected from at least one of methyl iodide, ethyl iodide and ethyl bromide, preferably ethyl iodide.

[0055] Preferably, the molar ratio of the compound represented by formula (I) to the halogenated hydrocarbon is 1:1-1.5, preferably 1:1-1.2.

[0056] In some preferred embodiments of the present invention, in step 2, the hydrolysis decarboxylation reaction further comprises adding acid to adjust the pH of the hydrolysis decarboxylation reaction to 1-6, preferably 2-4. Specifically, the pH of the mixture of various materials participating in the hydrolysis decarboxylation reaction may be 1-6, preferably 2-4.

[0057] In some preferred embodiments of the present invention, the acid is selected from at least one of hydrochloric acid, sulfuric acid and acetic acid, preferably hydrochloric acid.

[0058] In some preferred embodiments of the present invention, the amination reaction further comprises adding an aminating agent.

[0059] In some preferred embodiments of the present invention, the aminating agent is selected from aqueous ammonia and / or dimethylamine, preferably aqueous ammonia.

[0060] In some preferred embodiments of the present invention, the molar ratio of the compound represented by formula (II-4) to the aminating agent is 1:1-5, preferably 1:1-3.

[0061] In some preferred embodiments of the present invention, the Hofmann degradation reaction comprises adding a second base to adjust the pH of the Hofmann degradation reaction to 10-14, preferably 12-14.

[0062] In some preferred embodiments of the present invention, the second base is selected from sodium hydroxide and / or potassium hydroxide, preferably sodium hydroxide.

[0063] In some preferred embodiments of the present invention, the Hofmann degradation reaction further comprises adding NaXO, wherein X is selected from Cl or Br, preferably Cl.

[0064] In some preferred embodiments of the present invention, the molar ratio of the compound represented by formula (II-3), the compound represented by formula (II-4) or the compound represented by formula (II-5) to the NaXO is 1:1-5, preferably 1:1-4.

[0065] In some preferred embodiments of the present invention, the catalytic hydrogenation reaction is carried out in the presence of a hydrogenation catalyst, and the hydrogenation catalyst is a common metal catalyst in the art that can achieve a catalytic effect, and is at least one of a single metal catalyst, a multi-metal catalyst, a supported and unsupported metal catalyst. Preferably, the catalyst comprises a carrier and a supported active component, the carrier is selected from carbon, and the active component is selected from metal palladium and / or nickel.

[0066] In some preferred embodiments of the present invention, the hydrogenation catalyst is a carbon-supported palladium catalyst.

[0067] In some preferred embodiments of the present invention, in the hydrogenation catalyst, based on the total mass of the hydrogenation catalyst, the content of the active component is 1-10 wt%, and the content of the carrier is 90-99 wt%.

[0068] Preferably, in the hydrogenation catalyst, based on the total mass of the catalyst, the content of the active component is 1-5wt%, and the content of the carrier is 95-99wt%.

[0069] In some preferred embodiments of the present invention, the weight ratio of the compound represented by formula (III-1) or the compound represented by formula (III-2) to the catalyst is 1:0.005-0.016, preferably 1:0.01-0.012.

[0070] In some preferred embodiments of the present invention, in step 1, the temperature of the first substitution reaction is 10-40°C, preferably 10-30°C; the time of the first substitution reaction is 0.5-5h, preferably 0.5-3h.

[0071] In some preferred embodiments of the present invention, the temperature of the second substitution reaction is 20-50°C, preferably 30-40°C; the time of the second substitution reaction is 5-8h, preferably 5-7h.

[0072] In some preferred embodiments of the present invention, the temperature of the third substitution reaction is 20-50°C, preferably 30-40°C; the time of the third substitution reaction is 6-10h, preferably 6-8h.

[0073] In some preferred embodiments of the present invention, in step 2, the temperature of the hydrolysis decarboxylation reaction is 60-130° C., preferably 80-110° C.; the time of the hydrolysis decarboxylation reaction is 1-10 h, preferably 2-8 h.

[0074] In the present invention, the specific temperature and time of the hydrolysis and decarboxylation reaction can complete the reaction.

[0075] In some preferred embodiments of the present invention, the reaction temperature of the amination reaction is 0-50° C., preferably 10-30° C.; the reaction time of the amination reaction is 0.1-10 h, preferably 0.1-8 h.

[0076] In some preferred embodiments of the present invention, the temperature of the hydrolysis reaction is 60-130° C., preferably 80-110° C.; the time of the hydrolysis reaction is 1-10 h, preferably 2-8 h.

[0077] In the present invention, the conditions of the hydrolysis reaction and the hydrolysis decarboxylation reaction are consistent, and they are written separately because some functional groups in the compound only undergo hydrolysis reaction, such as -CN is hydrolyzed to -CONH2, and there is no removal of the carboxylic acid group; some undergo hydrolysis reaction and then decarboxylation, such as COOCH3 is hydrolyzed to -COOH and then -COOH is removed.

[0078] In the present invention, in order to protect the smooth progress of the Hofmann degradation reaction, stirring is performed at room temperature after the previous step of reaction is completed, so that the heat of the previous step of reaction can be completely dissipated and the Hofmann degradation will not be affected.

[0079] In some preferred embodiments of the present invention, the temperature of the Hofmann degradation reaction is 0-100° C., preferably 70-90° C.; the time of the Hofmann degradation reaction is 0.1-10 h, preferably 0.1-8 h.

[0080] In some preferred embodiments of the present invention, in step 3, the catalytic hydrogenation reaction is a conventional operation in the art, and the conditions of the catalytic hydrogenation reaction include: a hydrogen partial pressure of 0.1-1.2 MPa, preferably 0.9-1.2 MPa.

[0081] In some preferred embodiments of the present invention, the temperature of the catalytic hydrogenation reaction is 20-100°C, preferably 20-30°C.

[0082] In some preferred embodiments of the present invention, the catalytic hydrogenation reaction time is 1-20 h, preferably 6-10 h.

[0083] In some particularly preferred embodiments of the present invention, the compound represented by formula (I-1) is selected as methyl 2-nitrophenylacetate, and the 3-halogenated propene compound is selected as 2-methyl-3-chloropropene to prepare the 2-alkyl substituted aniline compound represented by formula (IV), and the process flow is as follows:

[0084]

[0085] In some particularly preferred embodiments of the present invention, the compound shown in formula (I-1) is selected as 2-(2-cyanophenyl)acetic acid methyl ester, and the 3-halogenated propene compound is selected as 2-methyl-3-chloropropene to prepare the 2-alkyl substituted aniline compound shown in formula (IV), and the process flow is as follows:

[0086]

[0087] The compound represented by formula (II-3) to the compound represented by formula (III-3) has the following changes:

[0088] -CN undergoes hydrolysis to generate -CONH2, and -COOCH3 undergoes hydrolysis to generate -COOH, as shown below: -CONH2 maintains, -COOH undergoes decarboxylation reaction to obtain the following compound -CONH2 undergoes Hofmann degradation reaction to generate -NH2 to obtain the compound represented by formula (III-1)

[0089] The present invention is further illustrated below by way of examples.

[0090] The present invention will be described in detail below through examples.

[0091] The amounts of reactants and products in the following examples were measured by gas chromatography (Agilent HPLC 1260).

[0092] Test conditions: room temperature, detection wavelength: 220 nm, flow rate: 1.0 ml / min, column temperature: 40 °C, running time: 25 min, equilibrium time: 5 min.

[0093] In the following examples, the conversion rate and selectivity of the reaction were calculated by the following formula:

[0094] Conversion rate % = (molar amount of raw material input - molar amount of raw material remaining in the product) / molar amount of raw material input × 100%

[0095] Selectivity % = actual molar amount of target product / theoretical molar amount of target product × 100%

[0096] Example 1

[0097] Preparation method of 2-(1,3-dimethylbutyl)aniline

[0098] Step 1: In a four-necked bottle equipped with a mechanical stirrer and a thermometer, 4.2 g (0.105 mol) of sodium hydroxide was added to adjust the pH to 14, and then 19.9 g (0.1 mol) of methyl 2-nitrophenylacetate, 0.2 g of polyethylene glycol-400, and 79.6 g of toluene were added. The mixture was stirred and cooled to 10° C., and 10.2 g (0.11 mol) of 2-methyl-3-chloropropylene was slowly added dropwise within 1 hour to carry out a second substitution reaction. The reaction temperature was controlled to be 20° C., and the reaction time was 3 hours. The gas phase detected that the methyl 2-nitrophenylacetate was completely reacted, and 20 g of water was added for extraction to obtain an organic phase. The conversion rate of the reaction was measured to be 99%, and the selectivity was 98%. Through quantitative analysis of the organic phase, the product was methyl 4-methyl-2-(2-nitrophenyl)pent-4-enoate, and the yield was 95% (based on methyl 2-nitrophenylacetate);

[0099] The organic phase obtained in the previous step was added to another four-necked bottle, refluxed to separate water, and after the water content was measured to be less than 0.1wt%, 4.2g (0.105mol) of sodium hydroxide was added to adjust the pH to 14, and the temperature was raised to 30°C with stirring, and 14.1g (0.11mol) of dimethyl sulfate was slowly added dropwise within 1h to carry out the third substitution reaction, and the reaction temperature was controlled to be 30°C, and the reaction time was 6h. The gas phase detected that 4-methyl-2-(2-nitrophenyl)pent-4-enoic acid methyl ester was completely reacted, and 20g of water was added for extraction to obtain an organic phase. The conversion rate of the reaction was measured to be 99%, and the selectivity was 98%. Through the quantitative analysis of the organic phase, the product was 2,4-dimethyl-2-(2-nitrophenyl)pent-4-enoic acid methyl ester, and the yield was 96% (based on 4-methyl-2-(2-nitrophenyl)pent-4-enoic acid methyl ester);

[0100] Step 2:

[0101] Hydrolysis decarboxylation reaction:

[0102] 20 g (0.2 mol) of hydrochloric acid was added dropwise to the organic phase to adjust the pH to 2, and the mixture was heated to 100° C. and stirred for 2 h. After the reaction was completed, the mixture was heated to 110° C. and refluxed to separate water to obtain 1-(4-methylpent-4-en-2-yl)-2-nitrobenzene with a conversion rate of 99%, a selectivity of 98.5%, and a yield of 98% (product purity of 95%).

[0103] Step 3: The remaining solution after the water separation is transferred to an autoclave, 0.2 g of palladium carbon is added, first replaced with nitrogen, then replaced with hydrogen, the autoclave is filled with a pressure of 1 MPa, stirred at room temperature for 8 h, and the reaction is controlled by gas phase until the raw material disappears to stop the reaction, the liquid in the autoclave is filtered with diatomaceous earth to remove the palladium carbon catalyst in the reaction solution, the filtrate toluene is removed by rotation, the obtained residue is dissolved in ethyl acetate, washed with saturated sodium bicarbonate aqueous solution and saturated brine in turn, and then dried with anhydrous magnesium sulfate, and finally spin-dried to remove ethyl acetate to obtain 15.2 g of brown oily product, which is subjected to chromatographic analysis. The product is 2-(1,3-dimethylbutyl)aniline, and its conversion rate is 97%, the selectivity is 90%, and the yield is 86.6% (product purity is 98%);

[0104] The spectral data of the obtained 2-(1,3-dimethylbutyl)aniline are as follows:

[0105] 1 H NMR (400MHz, CDCl3): δ=0.88-0.93(6H,m),1.21(3H,d,J=6.6Hz),1.36-1.44(1H,m),1.51-1.66(2H,m)2.85(l H,sext,J=6.6Hz),3.64(2H,brs),6.66-6.80(2H,m),6.98-7.10(2H,m).

[0106] Example 2

[0107] Preparation method of 2-(1,3-dimethylbutyl)aniline

[0108] Step 1: In a four-necked bottle equipped with a mechanical stirrer and a thermometer, 4.2 g (0.105 mol) of sodium hydroxide was added to adjust the pH to 14, and then 17.9 g (0.1 mol) of methyl 2-(2-cyanophenyl) acetate, 0.2 g of polyethylene glycol-600, and 79.6 g of toluene were added. The temperature was cooled to 10° C. with stirring, and 10.2 g (0.11 mol) of 2-methyl-3-chloropropene was slowly added dropwise within 1 hour to carry out a second substitution reaction. The reaction temperature was controlled to be 30° C. The reaction time was 3 hours. The gas phase detected that the methyl 2-cyanophenyl acetate was completely reacted. 20 g of water was added for extraction to obtain an organic phase. The conversion rate of the reaction was measured to be 99%, and the selectivity was 97%. Through the quantitative analysis of the organic phase, the product was methyl 4-methyl-2-(2-cyanophenyl) pent-4-enoate, and the yield was 95% (based on methyl 2-(2-cyanophenyl) acetate);

[0109] The organic phase obtained in the previous step was added to another four-necked flask, refluxed to separate water, and after the water content was measured to be less than 0.1wt%, 4.2g (0.105mol) of sodium hydroxide was added to adjust the pH to 12, and the temperature was raised to 30°C with stirring. 14.1g (0.11mol) of dimethyl sulfate was slowly added dropwise within 1h to carry out the third substitution reaction. The reaction temperature was controlled to be 30°C, and the reaction time was 6h. The gas phase detected that 4-methyl-2-(2-cyanophenyl)pent-4-enoic acid methyl ester had reacted completely, and 20g of water was added for extraction to obtain an organic phase. The conversion rate of the reaction was measured to be 99%, and the selectivity was 97%. Through the quantitative analysis of the organic phase, the product was 2,4-dimethyl-2-(2-cyanophenyl)pent-4-enoic acid methyl ester, and the yield was 96% (based on 4-methyl-2-(2-cyanophenyl)pent-4-enoic acid methyl ester);

[0110] Step 2:

[0111] Hydrolysis reaction and hydrolytic decarboxylation reaction:

[0112] 20 g (0.2 mol) of hydrochloric acid was added dropwise to the organic phase to adjust the pH to 2, and the mixture was heated to 100° C. and stirred for 2 h. After the reaction was completed, the mixture was heated to 110° C. for 1 h, refluxed and separated to obtain 2-(4-methylpent-4-en-2-yl)benzamide with a conversion rate of 99%, a selectivity of 98%, and a yield of 97.5% (product purity of 97%).

[0113] Hofmann degradation reaction:

[0114] Add 89.4 g (0.12 mol) of 10% sodium hypochlorite solution and 80 g (0.5 mol) of 25% sodium hydroxide solution into a four-necked bottle, adjust the pH to 12, cool to below 0°C, slowly drop the residue obtained in the first step within 1 hour, slowly warm to room temperature, stir for 0.5 hour to allow sufficient heat dissipation, then heat to 70°C, stir for 0.5 hour, slowly cool to room temperature, add 100 g of toluene for extraction to obtain an organic phase, and dry the organic phase over anhydrous magnesium sulfate; the conversion rate of the reaction is measured to be 98%, the selectivity is 95%, and the product is 2-(4-methylpent-4-ene-2-yl)aniline through quantitative analysis of the organic phase, and the yield is 90% (based on 2-(4-methylpent-4-ene-2-yl)benzamide);

[0115] Step 3: The organic phase obtained above was transferred to an autoclave, 0.2 g of palladium carbon was added, and the gas was replaced with nitrogen first and then with hydrogen. The autoclave was filled with a pressure of 1 MPa. The reaction was stirred at room temperature for 8 h, and the reaction was stopped. The reaction was controlled in the gas phase until the raw material disappeared and the reaction was stopped. The liquid in the autoclave was filtered with diatomaceous earth to remove the palladium carbon catalyst in the reaction solution. The filtrate toluene was removed by rotation, and the obtained residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate aqueous solution and saturated brine in turn, and then dried with anhydrous magnesium sulfate. Finally, the ethyl acetate was removed by rotation to obtain 14.6 g of a brown oily product. Chromatographic analysis showed that the product was 2-(1,3-dimethylbutyl)aniline, with a conversion rate of 96.5%, a selectivity of 90%, and a yield of 83.5% (product purity of 98%).

[0116] Example 3

[0117] Preparation method of 2-(1,3-dimethylbutyl)aniline

[0118] Step 1: In a four-necked bottle equipped with a mechanical stirrer and a thermometer, add 4.2 g (0.105 mol) of sodium hydroxide to adjust the pH to 14, then add 21.2 g (0.1 mol) of methyl 2-(2-methoxy-2-oxyethyl) benzoate, 0.2 g of polyethylene glycol-600, and 79.6 g of toluene, stir and cool to 10°C, slowly add 10.2 g (0.11 mol) of the second substitution reaction within 1 hour, and control the reaction temperature. The temperature was 30° C., the reaction time was 3 h. The gas phase detected that methyl 2-(2-methoxy-2-oxyethyl)benzoate was completely reacted. 20 g of water was added for extraction to obtain an organic phase. The conversion rate of the reaction was 99% and the selectivity was 97%. The product was methyl 2-(1-methoxy-4-methyl-1-oxopenten-4-ene-2-yl)benzoate by quantitative analysis of the organic phase. The yield was 95% (based on methyl (2-methoxy-2-oxyethyl)benzoate).

[0119] The organic phase obtained in the previous step was added to another four-necked bottle, refluxed to separate water, and after the water content was measured to be less than 0.1wt%, 4.9g (0.12mol) of sodium hydroxide was added to adjust the pH to 14, and the temperature was raised to 30°C with stirring. 14.1g (0.11mol) of dimethyl sulfate was slowly added dropwise within 1h to carry out the third substitution reaction. The reaction temperature was controlled to 30°C and the reaction time was 6h. The gas phase detected 2-(1-methoxy-4-methyl-1-oxo- The reaction mixture was concentrated to 20 g of water to obtain methyl 2-(1-methoxy-2,4-dimethyl-1-oxopenten-4-ene-2-yl)benzoate, and the yield was 96% (based on methyl 2-(1-methoxy-4-methyl-1-oxopenten-4-ene-2-yl)benzoate).

[0120] Step 2:

[0121] Hydrolysis reaction and hydrolytic decarboxylation reaction:

[0122] 22 g (0.22 mol) of hydrochloric acid was added dropwise to the organic phase to adjust the pH to 2, and the mixture was heated to 100° C. and stirred for 2 h. After the reaction was completed, the mixture was heated to 110° C. and refluxed to separate water to obtain 2-(4-methylpent-4-en-2-yl)benzoic acid with a conversion rate of 99%, a selectivity of 98%, and a yield of 98% (product purity of 97%).

[0123] Amination reaction:

[0124] The remaining solution after the water separation was added to 6.8 g (0.1 mol) of 25% ammonia solution, 0.2 g of triethylamine and 0.2 g of trichloromethyl chloroformate were added, and the mixture was stirred for 5 h at room temperature. Liquid phase detection showed that the reaction of 2-(4-methylpent-4-ene-2-yl)benzoic acid was complete, 100 g of toluene was added for extraction to obtain an organic phase, and the organic phase was spin-dried to obtain 15.6 g of 2-(4-methylpent-4-ene-2-yl)benzamide, with a conversion rate of 98%, a selectivity of 95%, and a yield of 90%;

[0125] Hofmann degradation reaction:

[0126] Add 89.4 g (0.12 mol) of 10% sodium hypochlorite solution and 80 g (0.5 mol) of 25% sodium hydroxide solution into a four-necked bottle, adjust the pH to 12, cool to below 0°C, slowly obtain 2-(4-methylpent-4-ene-2-yl)benzamide within 1 hour, slowly heat to room temperature, stir for 0.5 hour, then heat to 70°C, stir for 0.5 hour, slowly cool to room temperature, add 100 g of toluene for extraction to obtain an organic phase, and dry the organic phase with anhydrous magnesium sulfate; the conversion rate of the reaction is measured to be 96%, the selectivity is 92%, and the product is 2-(4-methylpent-4-ene-2-yl)aniline by quantitative analysis of the organic phase, and the yield is 89% (based on 2-(4-methylpent-4-ene-2-yl)benzamide);

[0127] Step 3: The above solution is transferred to an autoclave, 0.2 g of palladium carbon is added, and the gas is replaced with nitrogen first and then with hydrogen. The autoclave is filled with a pressure of 1 MPa, stirred at room temperature for 8 hours, and the reaction is controlled by gas phase until the raw material disappears to stop the reaction. The liquid in the autoclave is filtered with diatomaceous earth to remove the palladium carbon catalyst in the reaction solution, and the toluene in the filtrate is removed by rotation. The obtained residue is dissolved in ethyl acetate, washed with saturated sodium bicarbonate aqueous solution and saturated brine in turn, and then dried with anhydrous magnesium sulfate. Finally, the ethyl acetate is removed by rotation to obtain 2-(1,3-dimethylbutyl)aniline with a conversion rate of 97%, a selectivity of 90%, and a yield of 85.2% (product purity is 98%).

[0128] Example 4

[0129] Preparation method of 2-(1,3-dimethylbutyl)aniline

[0130] Step 1: In a four-necked bottle equipped with a mechanical stirrer and a thermometer, 4.2 g (0.105 mol) of sodium hydroxide was added to adjust the pH to 14, and then 18.4 g (0.1 mol) of 2-(2-nitrophenyl)acetamide, 0.2 g of polyethylene glycol-600, and 79.6 g of toluene were added. The temperature was cooled to 10° C. with stirring, and 10.2 g (0.11 mol) of 2-methyl-3-chloropropene was slowly added dropwise within 1 hour to carry out a second substitution reaction. The reaction temperature was controlled to be 30° C. The reaction time was 3 hours. The gas phase detected that the reaction of 2-(2-nitrophenyl)acetamide was complete. 20 g of water was added for extraction to obtain an organic phase. The conversion rate of the reaction was measured to be 99%, and the selectivity was 98%. Through quantitative analysis of the organic phase, the product was 4-methyl-2-(2-nitrophenyl)pent-4-eneamide, and the yield was 95% (based on 2-(2-nitrophenyl)acetamide);

[0131] The organic phase obtained in the previous step was added to another four-necked bottle, refluxed to separate water, and after the water content was measured to be less than 0.1wt%, 4.2g (0.105mol) of sodium hydroxide was added to adjust the pH to 14, and the temperature was raised to 30°C with stirring. 14.1g (0.11mol) of dimethyl sulfate was slowly added dropwise within 1h to carry out the third substitution reaction. The reaction temperature was controlled to be 30°C and the reaction time was 6h. The gas phase detected that 4-methyl-2-(2-nitrophenyl)pent-4-enamide was completely reacted. 20g of water was added for extraction to obtain an organic phase. The conversion rate of the reaction was measured to be 99% and the selectivity was 98%. Through the quantitative analysis of the organic phase, the product was 2,4-dimethyl-2-(2-nitrophenyl)pent-4-enamide with a yield of 96% (based on 4-methyl-2-(2-nitrophenyl)pent-4-enamide);

[0132] Step 2:

[0133] Hydrolysis decarboxylation reaction:

[0134] 20 g (0.2 mol) of hydrochloric acid was added dropwise to the organic phase to adjust the pH to 2, and the mixture was heated to 100° C. and stirred for 5 h. After the reaction was completed, the mixture was heated to 110° C. and refluxed to separate the water, thereby obtaining 1-(4-methylpent-4-en-2-yl)-2-nitrobenzene with a conversion rate of 98%, a selectivity of 97%, and a yield of 96% (product purity of 96%).

[0135] Step 3: The remaining solution after the above water separation is transferred to an autoclave, 0.2 g of palladium carbon is added, and the gas is replaced with nitrogen first and then with hydrogen. The autoclave is filled with a pressure of 1 MPa, stirred at room temperature for 8 h, and the reaction is controlled by gas phase until the raw material disappears to stop the reaction. The liquid in the autoclave is filtered with diatomaceous earth to remove the palladium carbon catalyst in the reaction solution, and the filtrate toluene is removed by rotation. The obtained residue is dissolved in ethyl acetate, washed with saturated sodium bicarbonate aqueous solution and saturated brine in turn, and then dried with anhydrous magnesium sulfate. Finally, the ethyl acetate is removed by rotation to obtain 15.1 g of a brown oily product. Chromatographic analysis shows that the product is 2-(1,3-dimethylbutyl)aniline, with a conversion rate of 97%, a selectivity of 93%, and a yield of 86.3% (product purity of 98%).

[0136] Example 5

[0137] Preparation method of 2-(1,3-dimethylbutyl)aniline

[0138] Step 1: In a four-necked bottle equipped with a mechanical stirrer and a thermometer, add 4.2 g (0.105 mol) of sodium hydroxide to adjust the pH to 14, then add 19.8 g (0.1 mol) of N-methyl-2-(2-nitrophenyl)acetamide, 0.2 g of polyethylene glycol-600, and 79.6 g of toluene, stir and cool to 10°C, and slowly add 10.2 g (0.11 mol) of 2-methyl-3-chloropropene in drops within 1 hour for the second substitution. reacting, controlling the reaction temperature to be 30° C., the reaction time to be 3 h, gas phase detection showing that N-methyl-2-(2-nitrophenyl)acetamide has reacted completely, adding 20 g of water for extraction to obtain an organic phase, and measuring the reaction conversion rate to be 99%, the selectivity to be 97%, and the product to be N-methyl-2-methyl-(2-nitrophenyl)pent-4-enamide by quantitative analysis of the organic phase, with a yield of 95% (based on N-methyl-2-(2-nitrophenyl)acetamide);

[0139] The organic phase obtained in the previous step was added to another four-necked bottle, refluxed to separate water, and after the water content was measured to be less than 0.1wt%, 4.2g (0.105mol) of sodium hydroxide was added to adjust the pH to 14, and the temperature was raised to 30°C with stirring, and 14.1g (0.11mol) of dimethyl sulfate was slowly added dropwise within 1h to carry out the third substitution reaction, and the reaction temperature was controlled to be 40°C, and the reaction time was 6h. The gas phase detected that the reaction of N-4-dimethyl-2-(2-nitrophenyl)pent-4-enamide was complete, and 20g of water was added for extraction to obtain an organic phase. The conversion rate of the reaction was measured to be 99%, and the selectivity was 97%. Through the quantitative analysis of the organic phase, the product was N-methyl-2,4-dimethyl-2-(2-nitrophenyl)pent-4-enamide, and the yield was 96% (based on N-methyl-2-methyl-(2-nitrophenyl)pent-4-enamide);

[0140] Step 2:

[0141] Hydrolysis decarboxylation reaction:

[0142] 20 g (0.2 mol) of hydrochloric acid was added dropwise to the organic phase to adjust the pH to 2, and the mixture was heated to 100° C. and stirred for 5 h. After the reaction was completed, the mixture was heated to 110° C. and refluxed to separate the water to obtain 1-(4-methylpent-4-en-2-yl)-2-nitrobenzene with a conversion rate of 99%, a selectivity of 98%, and a yield of 97% (product purity of 97%).

[0143] Step 3: The remaining solution after the above water separation is transferred to an autoclave, 0.2 g of palladium carbon is added, nitrogen is replaced, and then hydrogen is replaced. The autoclave is filled with a pressure of 1 MPa, stirred at room temperature for 8 hours, and the reaction is controlled by gas phase until the raw material disappears to stop the reaction. The liquid in the autoclave is filtered with diatomaceous earth to remove the palladium carbon catalyst in the reaction solution, and the filtrate toluene is removed by rotation. The obtained residue is dissolved in ethyl acetate, washed with saturated sodium bicarbonate aqueous solution and saturated brine in turn, and then dried with anhydrous magnesium sulfate. Finally, ethyl acetate is removed by rotation to obtain 15.1 g of a brown oily product. Chromatographic analysis shows that the product is 2-(1,3-dimethylbutyl)aniline, with a conversion rate of 97%, a selectivity of 90%, and a yield of 86.3% (product purity is 98%).

[0144] Example 6

[0145] Preparation method of 2-(1-ethyl-3-methylbutyl)aniline

[0146] Step 1: In a four-necked bottle equipped with a mechanical stirrer and a thermometer, 4.2 g (0.105 mol) of sodium hydroxide was added to adjust the pH to 14, and then 19.9 g (0.1 mol) of methyl 2-nitrophenylacetate, 0.2 g of polyethylene glycol-400, and 79.6 g of toluene were added. The mixture was stirred and cooled to 10° C., and 10.2 g (0.11 mol) of 2-methyl-3-chloropropylene was slowly added dropwise within 1 hour to carry out a second substitution reaction. The reaction temperature was controlled to be 30° C., and the reaction time was 3 hours. The gas phase detected that the methyl 2-nitrophenylacetate was completely reacted, and 20 g of water was added for extraction to obtain an organic phase. The conversion rate of the reaction was measured to be 99%, and the selectivity was 97%. Through quantitative analysis of the organic phase, the product was methyl 4-methyl-2-(2-nitrophenyl)pent-4-enoate, and the yield was 95% (based on methyl 2-nitrophenylacetate);

[0147] The organic phase obtained in the previous step was added to another four-necked flask, refluxed to separate water, and after the water content was measured to be less than 0.1wt%, 4.2g (0.105mol) of sodium hydroxide was added to adjust the pH to 14, and the temperature was raised to 30°C with stirring. 17.16g (0.11mol) of iodoethane was slowly added dropwise within 1h to carry out the third substitution reaction. The reaction temperature was controlled to be 40°C, and the reaction time was 6h. The gas phase detected that 4-methyl-2-(2-nitrophenyl)pent-4-enoic acid methyl ester was completely reacted. 20g of water was added for extraction to obtain an organic phase. The conversion rate of the reaction was measured to be 99%, and the selectivity was 97%. Through the quantitative analysis of the organic phase, the product was 2-ethyl-4-methyl-2-(2-nitrophenyl)pent-4-enoic acid methyl ester, and the yield was 95% (based on 4-methyl-2-(2-nitrophenyl)pent-4-enoic acid methyl ester);

[0148] Step 2: Add 20 g (0.2 mol) of hydrochloric acid dropwise to the organic phase to adjust the pH to 2, heat to 100° C., stir for 2 h, and after the reaction is completed, heat to 110° C. h, reflux and separate the water to obtain 1-(4-ethylpent-4-en-2-yl)-2-nitrobenzene with a conversion rate of 97%, a selectivity of 96%, and a yield of 95% (product purity of 95%);

[0149] Step 3: The remaining solution after the above water separation is transferred to an autoclave, 0.2g of palladium carbon is added, nitrogen is replaced, and then hydrogen is replaced. The autoclave is filled with a pressure of 1MPa, and at room temperature, stirred for 8h. The reaction is controlled by the gas phase until the raw material disappears and stops the reaction. The liquid in the autoclave is filtered with diatomaceous earth to remove the palladium carbon catalyst in the reaction solution, and the filtrate toluene is spun off. The obtained residue is dissolved in ethyl acetate, washed with saturated sodium bicarbonate aqueous solution and saturated brine in sequence, and then dried over anhydrous magnesium sulfate. Finally, ethyl acetate is spun off to obtain 16.2g of a brown oily product. Chromatographic analysis shows that the product is 2-(1-ethyl-3-methylbutyl)aniline, and its conversion rate is 97%, the selectivity is 90%, and the yield is 85% (product purity is 98%);

[0150] The spectral data of the obtained 2-(1-ethyl-3-methylbutyl)aniline are as follows:

[0151] 1 H NMR (400MHz, CDCl3): δ = 0.75 (3H, t), δ = 0.88-0.93 (6H, m), 1.21 (3H, d, J = 6.6Hz), 1.51 (2H, d), 1.36-1.44 (1H,m),1.51-1.66(2H,m)2.85(lH,sext,J=6.6Hz),3.64(2H,brs),6.66-6.80(2H,m),6.98-7.10(2H,m).

[0152] Comparative Example 1

[0153] Examples 1-4 disclosed in CN106674021A disclose a method for preparing substituted aniline compounds by Friedel-Crafts reaction. Compared with the product obtained by the preparation method of the present application, the yield is low and unstable at 65%, 75%, 78% and 91% respectively, and the purity is 98%.

[0154] Comparative Example 2

[0155] From the examples disclosed in CN1255384C, it can be seen that the method for synthesizing N-pyrazolylcarboxanilide compounds using aniline derivatives as raw materials and carboxylic acid derivatives in the presence of an acid binder and a diluent has a yield that is 10-42% lower than the product obtained by the preparation method of the present application, and no purity test is performed.

[0156] It can be seen from the results of the above examples and comparative examples that the method for preparing 2-alkyl substituted aniline compounds according to the present invention can achieve higher reaction conversion rate and selectivity, and the cost is greatly reduced.

[0157] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A method for preparing 2-alkyl substituted aniline compounds, characterized in that: The method includes: Step 1, when R1 is a C1-C4 alkyl group, in the presence of a base and a co-solvent, the compound represented by formula (I-1), the compound represented by formula (I-2), the compound represented by formula (I-3), the compound represented by formula (I-4), and the compound represented by formula (I-5) are respectively subjected to a first substitution reaction with a 3-halogenated propylene compound to obtain corresponding compounds represented by formula (II-1), formula (II-2), formula (II-3), formula (II-4), and formula (II-5); Or, when R1 is H, in the presence of a base and a co-solvent, the compound represented by formula (I-1), the compound represented by formula (I-2), the compound represented by formula (I-3), the compound represented by formula (I-4), and the compound represented by formula (I-5) are respectively subjected to a second substitution reaction with a 3-halogenated propylene compound, and then subjected to a third substitution reaction with a sulfate ester or a halogenated hydrocarbon to obtain corresponding compounds represented by formula (II-1), formula (II-2), formula (II-3), formula (II-4), and formula (II-5); Step 2, subjecting the compound represented by formula (II-1) to a hydrolysis and decarboxylation reaction to obtain a compound represented by formula (III-1); Or, subjecting the compound represented by formula (II-2) to a hydrolysis and decarboxylation reaction to obtain a compound represented by formula (III-2); Or, subjecting the compound represented by formula (II-3) to a hydrolysis reaction, a hydrolysis decarboxylation reaction, and a Hofmann degradation reaction to obtain a compound represented by formula (III-2); Or, subjecting the compound represented by formula (II-4) to hydrolysis reaction, hydrolysis decarboxylation reaction, amination reaction, and Hofmann degradation reaction to obtain the compound represented by formula (III-2); The compound represented by formula (II-5) is subjected to hydrolysis decarboxylation reaction and Hofmann degradation reaction to obtain a compound represented by formula (III-2); Step 3, subjecting the compound represented by formula (III-1) or the compound represented by formula (III-2) to a catalytic hydrogenation reaction to obtain a 2-alkyl substituted aniline compound represented by formula (IV); Wherein, X2 is selected from -(CH2) m COOR4, -(CH2) m CN, -(CH2) m CONH2 or -(CH2) m CONR5R6, m is a natural number from 0 to 5; R1, R2, R3, R4, R5 and R6 are each independently H or C1-C4 alkyl; R7 is C1-C4 alkyl.

2. The preparation method according to claim 1, wherein m is 0 or 1; R1, R2, R3, R4, R5 and R6 are each independently H or C1-C2 alkyl; R7 is C1-C2 alkyl.

3. The preparation method according to claim 1 or 2, wherein In step 1, the first substitution reaction is carried out at a pH of 10-14, preferably 12-14; Preferably, the base is selected from inorganic bases and / or organic bases; Preferably, the inorganic base is selected from at least one of sodium carbonate, sodium bicarbonate, sodium hydroxide and potassium hydroxide, preferably sodium hydroxide and / or sodium carbonate; Preferably, the organic base is selected from at least one of sodium methoxide, sodium ethoxide, sodium methoxide, triethylamine, sodium tert-butoxide, potassium tert-butoxide and lithium diisopropylamide; Preferably, the co-solvent is selected from nitrile compounds or aromatic hydrocarbon compounds; preferably at least one of acetonitrile, butyronitrile, benzene, toluene and xylene; Preferably, the mass ratio of the compound represented by formula (I) to the co-solvent is 1:1-5, preferably 1:2-4.

5.

4. The preparation method according to any one of claims 1 to 3, wherein The 3-halopropylene compound is selected from 2-alkyl-3-halopropylene, preferably 2-methyl-3-chloropropylene; Preferably, the molar ratio of the compound represented by formula (I) to the 3-halogenated propylene compound is 1:1-3, preferably 1:1.1-2.

5. The preparation method according to any one of claims 1 to 4, wherein: The sulfate is selected from dialkyl sulfates with an alkyl group of C1-C5, preferably dimethyl sulfate; Preferably, the molar ratio of the compound represented by formula (I) to the sulfate is 1:1-2, preferably 1:1.1-1.7; Preferably, the halogenated hydrocarbon is selected from at least one of methyl iodide, ethyl iodide and ethyl bromide, preferably ethyl iodide; Preferably, the molar ratio of the compound represented by formula (I) to the halogenated hydrocarbon is 1:1-1.5, preferably 1:1-1.

2.

6. The preparation method according to any one of claims 1 to 5, wherein: In step 2, the hydrolysis decarboxylation reaction further comprises adding an acid to adjust the pH of the hydrolysis decarboxylation reaction to 1-6, preferably 2-4; Preferably, the acid is selected from at least one of hydrochloric acid, sulfuric acid and acetic acid, preferably hydrochloric acid; Preferably, the amination reaction further comprises adding an aminating agent; Preferably, the aminating agent is selected from aqueous ammonia and / or dimethylamine, preferably aqueous ammonia; Preferably, the molar ratio of the compound represented by formula (II-4) to the aminating agent is 1:1-5, preferably 1:1-3; Preferably, the Hofmann degradation reaction comprises adding a second base to adjust the pH of the Hofmann degradation reaction to 10-14, preferably 12-14; Preferably, the second base is selected from sodium hydroxide and / or potassium hydroxide, preferably sodium hydroxide; Preferably, the Hofmann degradation reaction further comprises adding NaXO, wherein X is selected from Cl or Br, preferably Cl; Preferably, the molar ratio of the compound represented by formula (II-3), the compound represented by formula (II-4) or the compound represented by formula (II-5) to the NaXO is 1:1-5, preferably 1:1-4.

7. The preparation method according to any one of claims 1 to 6, wherein: The catalytic hydrogenation reaction is carried out in the presence of a hydrogenation catalyst, wherein the hydrogenation catalyst comprises a carrier and a supported active component, wherein the carrier is selected from carbon, and the active component is selected from metal palladium and / or nickel; Preferably, the hydrogenation catalyst is a carbon-supported palladium catalyst; Preferably, in the hydrogenation catalyst, based on the total mass of the hydrogenation catalyst, the content of the active component is 1-10wt%, and the content of the carrier is 90-99wt%; preferably, the content of the active component is 1-5wt%, and the content of the carrier is 95-99wt%; Preferably, the weight ratio of the compound represented by formula (III-1) or the compound represented by formula (III-2) to the hydrogenation catalyst is 1:0.005-0.016, preferably 1:0.01-0.

012.

8. The preparation method according to any one of claims 1 to 4, wherein: In step 1, the temperature of the first substitution reaction is 10-40°C, preferably 10-30°C; the time of the first substitution reaction is 0.5-5h, preferably 0.5-3h; Preferably, the temperature of the second substitution reaction is 20-50°C, preferably 30-40°C; the time of the second substitution reaction is 5-8h, preferably 5-7h; Preferably, the temperature of the third substitution reaction is 20-50°C, preferably 30-40°C; the time of the third substitution reaction is 6-10h, preferably 6-8h.

9. The preparation method according to any one of claims 1 to 8, wherein: In step 2, the temperature of the hydrolysis decarboxylation reaction is 60-130° C., preferably 80-110° C.; the time of the hydrolysis decarboxylation reaction is 1-10 h, preferably 2-8 h; Preferably, the reaction temperature of the amination reaction is 0-50°C, preferably 10-30°C; the reaction time of the amination reaction is 0.1-10h, preferably 0.1-8h; Preferably, the temperature of the hydrolysis reaction is 60-130°C, preferably 80-110°C; the time of the hydrolysis reaction is 1-10h, preferably 2-8h; Preferably, the temperature of the Hofmann degradation reaction is 0-100° C., preferably 70-90° C.; the time of the Hofmann degradation reaction is 0.1-10 h, preferably 0.1-8 h.

10. The preparation method according to any one of claims 1 to 9, wherein: In step 3, the conditions of the catalytic hydrogenation reaction include: a hydrogen partial pressure of 0.1-1.2 MPa, preferably 0.9-1.2 MPa; Preferably, the temperature of the catalytic hydrogenation reaction is 20-100°C, preferably 20-30°C; Preferably, the catalytic hydrogenation reaction time is 1-20 h, preferably 6-10 h.

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