Method for preparing an N-cyclopropylmethylaniline compound

Abstract

Method for preparing an N-cyclopropylmethylaniline compound, comprising: Hydrogenation of a compound represented by Formula II and of cyclopropylformaldehyde as raw materials in the presence of an acid and a catalyst to generate an N-cyclopropylmethylaniline compound represented by Formula I according to the following scheme: wherein R is selected from alkoxy, alkylamino, or a substituted anilino group represented by the following Formula III: wherein R1 is selected from methoxy or fluorine, R2 from fluorine or trifluoromethyl, R3 from H, fluorine, chlorine, bromine, iodine, nitro, or trifluoromethyl, R4 from trifluoromethyl, trifluoromethoxy, or difluoromethoxy, and represents the position to which the group is attached; The pressure of the hydrogenation reaction is controlled to 0.2-5.0 MPa after the introduction of the hydrogen gas; The hydrogenation reaction is carried out at a temperature of 30-150°C; the hydrogenation is carried out in a solvent which is one or a combination of at least two of an alcohol solvent, an ester solvent, an ether solvent, a halogenated hydrocarbon solvent or a benzene solvent; the molar ratio of the compound represented by formula II to cyclopropylformaldehyde is 1:(0.5-3); the acid is one or a combination of at least two acids selected from the group consisting of formic acid, acetic acid, propionic acid, hydrochloric acid and sulfuric acid.

Description

TECHNICAL AREA

[0001] The present invention relates to the field of the synthesis of pesticide and insecticide compounds, and in particular to a method for preparing an N-cyclopropylmethylaniline compound. The present invention relates to a "one-pot method" for preparing an N-cyclopropylmethylaniline compound, and in particular to a preparation method that offers the advantages of low cost, clean production, high yield, simple operation, etc. BACKGROUND

[0002] N-Cyclopropylmethylaniline is an important intermediate for the preparation of an M-diamide compound. As recently reported, the synthesis of the metadiamide insecticide cyproflanilide (CAS: 2375110-88-4) requires this type of intermediate, and in particular a compound with the following general formula: where R is an alkoxy, alkylamino, or substituted anilino group (i.e.,

[0003] Prior art documents describe the preparation of N-cyclopropylmethylaniline compounds. For example, CN109497062A describes a process in which bromomethylcyclopropane is reacted with substituted aniline to obtain an N-cyclopropylmethylaniline compound A according to the following scheme:

[0004] This process requires a long reaction time (16 h), has a low yield (49%), and necessitates complicated post-processing. Furthermore, the bromomethylcyclopropane used is expensive.

[0005] CN110028423A specifies a process in which a boron reagent and a cyclopropylformaldehyde are reacted with substituted aniline in a system of trifluoroacetic acid to obtain an N-cyclopropylmethylaniline compound B according to the following scheme:

[0006] The boron reagent (sodium triacetoxyborohydride) and trifluoroacetic acid are expensive. Furthermore, a large number of disubstituted compounds are generated during the reaction, and the yield is low.

[0007] US patent (US 10,844,005 B1) describes the reaction of cyclopropylformaldehyde with substituted aniline in a zinc powder-acetic acid system for the preparation of an N-cyclopropylmethylaniline compound C. The scheme is as follows:

[0008] This process has a high yield. However, it uses zinc metal powder in the reaction process, which produces a large amount of solid slag, making post-treatment difficult.

[0009] Zhou, Y. et al., Tetrahedron 2017, 73, 3898-3904 discloses a palladium-catalyzed chemoselective reduction and reductive amination of nitroarenes with water as a hydrogen source, mediated by diboronic acid, and a series of arylamines containing various reducible functional groups were obtained.

[0010] Therefore, according to the state of the art, there is a need for the development of a process for preparing an N-cyclopropylmethylaniline compound with low cost, clean production, high yield and simple operation. SUMMARY

[0011] To overcome the disadvantages of the prior art, the present invention aims to provide a method for preparing an N-cyclopropylmethylaniline compound. In particular, a method for preparing an N-cyclopropylmethylaniline compound is provided by applying a "one-pot method". Specifically, a preparation method for N-cyclopropylmethylaniline compounds is provided that offers low costs, clean production, high yield, and simple operation.

[0012] To accomplish this task, the present invention uses the technical solutions described below.

[0013] The present invention provides a method for preparing an N-cyclopropylmethylaniline compound, comprising the following steps:

[0014] The compound represented by Formula II and cyclopropylformaldehyde are used as raw materials, and the hydrogenation reaction is carried out under the influence of an acid and a catalyst to obtain the N-cyclopropylmethylaniline compound represented by Formula I. The scheme is as follows: where R is selected from an alkoxy, alkylamino, or a substituted anilino group represented by the following Formula III: where R1 is selected from methoxy or fluorine, R2 from fluorine or trifluoromethyl, R3 from H, fluorine, chlorine, bromine, iodine, nitro, or trifluoromethyl, R4 from trifluoromethyl, trifluoromethoxy, or difluoromethoxy, and represents the position to which the group is attached.

[0015] The preparation method of the present invention uses the compound of formula II and cyclopropylformaldehyde as raw materials and employs a "one-pot method" to carry out the two-step reaction involving nitro reduction and aminoalkylation via catalytic hydrogenation, thereby reducing post-treatment operations. This method also offers the advantages of simplified operation, low cost, and clean manufacturing. The reaction yield is improved, and the method is suitable for industrial production. The preparation method of the present invention generates fewer impurities, resulting in a high product yield. A high-purity product can be obtained through simple post-processing, i.e., without complicated and time-consuming post-processing.

[0016] According to the present invention, the pressure of the hydrogenation reaction is controlled to 0.2-5.0 MPa after the introduction of the hydrogen gas; the hydrogenation reaction is carried out at a temperature of 30-150°C; the hydrogenation is carried out in a solvent that is one or a combination of at least two alcoholic solvents, ester solvents, ether solvents, halogenated hydrocarbon solvents, or benzene solvents; the molar ratio of the compound represented by formula II to cyclopropylformaldehyde is 1:(0.5-3); and the acid is one or a combination of at least two acids selected from the group consisting of formic acid, acetic acid, propionic acid, hydrochloric acid, and sulfuric acid.

[0017] The combination of at least two solvents is, for example, a combination of an alcohol solvent and an ester solvent, a combination of an ester solvent and an ether solvent, etc. However, other combinations not mentioned here can also be chosen.

[0018] According to the present invention, in a preferred technical solution, R is selected from a C1-C6 alkoxy (for example, C1, C2, C3, C4, C5 or C6 alkoxy) and preferably methoxy, ethoxy, propoxy or isopropoxy.

[0019] According to the present invention, in a preferred technical solution R is selected from a C1-C6 alkylamino (for example C1, C2, C3, C4, C5 or C6 alkylamino) and preferably methylamino.

[0020] According to the present invention, in a preferred technical solution, R is selected from a substituted anilino group represented by formula III: wherein R1 is fluorine, R2 is fluorine, R3 is selected from H, bromine or iodine, and R4 is selected from trifluoromethyl, trifluoromethoxy or difluoromethoxy and represents the position to which the group is attached.

[0021] Preferably, the alcohol solvent contains one or a combination of at least two of methanol, ethanol, or isopropanol. The combination of at least two is, for example, a combination of methanol and ethanol, a combination of ethanol and isopropanol, a combination of methanol and isopropanol, etc. Any other combination not mentioned here may also be selected.

[0022] Preferably, the ester solvent contains one or a combination of at least two of methyl acetate, ethyl acetate, propyl acetate, or butyl acetate. The combination of at least two is, for example, a combination of methyl acetate and ethyl acetate, a combination of ethyl acetate and propyl acetate, etc. Any other combination not mentioned here may also be selected.

[0023] Preferably, the ether solvent contains one or a combination of at least two of diethyl ether, methyl tert-butyl ether, or tetrahydrofuran. The combination of at least two is, for example, a combination of diethyl ether and methyl tert-butyl ether, a combination of methyl tert-butyl ether and tetrahydrofuran, etc. Any other combination not mentioned here may also be selected.

[0024] Preferably, the halogenated hydrocarbon solvent contains dichloromethane and / or dichloroethane.

[0025] Preferably, the benzene solvent contains toluene and / or xylene.

[0026] Preferably, the solvent is one or a combination of at least two of methanol, ethanol, ethyl acetate, or toluene. The combination of at least two is, for example, a combination of methanol and ethanol, a combination of ethyl acetate and toluene, a combination of ethanol and ethyl acetate, etc. Any other combination not mentioned here may also be selected.

[0027] The reaction solvent used according to the present invention is preferably one or a combination of at least two of methanol, ethanol, ethyl acetate or toluene, because the reaction conditions in these solvents are good and the solvents can be easily recovered and processed.

[0028] The acid is a combination of at least two of formic acid, acetic acid, propionic acid, hydrochloric acid, or sulfuric acid. For example, a combination of formic acid and acetic acid, a combination of hydrochloric acid and sulfuric acid, etc. Any other combination not mentioned here can also be chosen.

[0029] Preferably, the acid is acetic acid and / or propionic acid.

[0030] The acid used according to the present invention is preferably acetic acid and / or propionic acid, because the reaction effect of acetic acid and / or propionic acid is best.

[0031] According to the present invention, the catalyst contains palladium carbon, platinum carbon or Raney nickel and preferably platinum carbon.

[0032] The reaction catalyst used according to the present invention is preferably platinum carbon because of its best reaction effect.

[0033] The molar ratio of the compound represented by formula II to the cyclopropylformaldehyde is 1:(0.5-3), i.e., for example, 1:0.5, 1:1, 1:1.2, 1:1.5, 1:1.6, 1:2, 1:2.5, 1:3, and preferably 1:(1.2-1.6), although other specific values ​​not mentioned here may also be selected within the numerical range given above.

[0034] Preferably, the mass ratio of the compound represented by formula II to the acid is 1:(0.01-0.6), i.e., for example, 1:0.01, 1:0.05, 1:0.1, 1:0.2, 1:0.3, 1:0.4 or 1:0.6, and preferably 1:(0.05-0.4), although other specific values ​​not mentioned here may also be selected within the numerical range specified above.

[0035] The mass ratio of the compound represented by Formula II to the acid is specifically selected within the numerical range of 1:(0.1–0.6), because increasing the amount of acid added further wastes resources and increases costs. Conversely, decreasing the amount of acid added further results in incomplete reaction of the raw materials.

[0036] Preferably, the mass ratio of the compound represented by Formula II to the catalyst is 1:(0.001-0.05), i.e., for example, 1:0.001, 1:0.002, 1:0.005, 1:0.01, 1:0.02, 1:0.03, 1:0.04 or 1:0.05, and preferably 1:(0.005-0.02), although other specific values ​​not mentioned here may also be selected within the numerical range specified above.

[0037] The mass ratio of the compound represented by Formula II to the acid is specifically selected within the numerical range of 1:(0.001–0.05), because increasing the amount of catalyst added further wastes resources and increases costs. Conversely, decreasing the amount of catalyst added further results in incomplete reaction of the raw materials.

[0038] Preferably, the mass ratio of the compound represented by formula II to the solvent is 1:(2-10), i.e., for example, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 or 1:10, and preferably 1:(3-8), although other specific values ​​not mentioned here may also be selected within the numerical range specified above.

[0039] According to the present invention, the hydrogenation reaction is carried out at a temperature of 30-150°C, such as 30°C, 40°C, 50°C, 60°C, 80°C, 100°C, 120°C or 150°C, and preferably 40-100°C, and the hydrogenation reaction is carried out for 8-20 h, and preferably for 12-16 h, such as 8 h, 10 h, 12 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h or 20 h, etc., although other specific values ​​not mentioned here within the numerical range specified above may also be selected.

[0040] In the hydrogenation reaction, the pressure after the introduction of hydrogen is controlled to 0.2–5.0 MPa, for example 0.2 MPa, 0.5 MPa, 1.0 MPa, 2.0 MPa, 3.0 MPa, 4.0 MPa, or 5.0 MPa, and preferably 1.0–3.0 MPa. Other specific values ​​within the above-mentioned numerical range can also be selected.

[0041] As a preferred technical solution of the present invention, the preparation method for the N-cyclopropylmethylaniline compound particularly includes the following steps:

[0042] Taking the compound represented by formula II and cyclopropylformaldehyde as raw materials under the action of an acid and a catalyst, wherein the hydrogenation reaction is carried out at 30-150°C for 8-20 h and the pressure is controlled to 0.2-5.0 MPa to obtain the N-cyclopropylmethylaniline compound represented by formula I.

[0043] The scheme is as follows: wherein the limited area of ​​R corresponds to claim 1, the molar ratio of the compound represented by formula II to cyclopropylformaldehyde is 1:(0.5-3), the mass ratio of the compound represented by formula II to the acid is 1:(0.01-0.6), the mass ratio of the compound represented by formula II to the catalyst is 1:(0.001-0.05), and the mass ratio of the compound represented by formula II to the solvent is 1:(2-10).

[0044] In comparison to the prior art, the present invention has the following advantageous effects: The preparation process according to the present invention uses the compound of formula II and cyclopropylformaldehyde as raw materials. The reaction, involving a catalytic hydrogenation and a two-step nitroreduction and aminoalkylation, is carried out in a "one-pot" method, thereby reducing post-processing operations. The process is simple, the operation is straightforward, the costs are low, the production is clean, and the reaction yield is simultaneously improved, making the process suitable for industrial production. The preparation process generates few impurities, resulting in a high product yield and the ability to obtain a product of relatively high purity after simple post-treatment, i.e., without complicated and costly post-treatment. DETAILED DESCRIPTION

[0045] In order to describe the technical means of the present invention and its effects in more detail, the technical solutions of the present invention are described below with reference to preferred embodiments of the present invention, although the present invention is not limited to the embodiments described here. Example 1

[0046] In this example, methyl 3-[(cyclopropylmethyl)amino]-2-fluorobenzoate was prepared according to the following scheme:

[0047] In a 500 ml autoclave, 40.2 g (0.2 mol, 99% purity) of methyl 2-fluoro-3-nitrobenzoate, 0.2 g of 5% platinum carbon catalyst, 7.96 g (0.13 mol, 99% purity) of acetic acid, 16.8 g of cyclopropyl formaldehyde (0.24 mol, 99% purity), and 119.4 g of methanol were successively added. Hydrogen was introduced at a pressure of 1.0 MPa, and the reaction was carried out at 40°C for 12 h.

[0048] After the reaction, the solution was filtered and the residue was washed with 20 g of methanol. The filtrate was combined, and the solvent was removed under reduced pressure. The mixture was dried to give 43.2 g of methyl 3-[(cyclopropylmethyl)amino]-2-fluorobenzoate with a purity of 98.5% (external standard method; this also applies to the following examples) and a yield of 95.4% (mass yield; this also applies to the following examples). Characteristic data: LC / MS [M+1]: m / z=224

[0049] 1 H NMR (400 MHz, CDCl3) data (δ[ppm]): 7.18-7.15 (m, 1H), 7.05-7.01 (m, 1H), 6.85-6.82 (m, 1H), 4.21 (br s, 1H), 3.93 (s, 3H), 3.01 (d, J = 5.6 Hz, 2H), 1.15-1.12 (m, 1H), 0.62-0.58 (m, 2H), 0.30-0.25 (m, 2H). Example 2

[0050] In this example, ethyl 3-[(cyclopropylmethyl)amino]-2-fluorobenzoate was prepared according to the following scheme:

[0051] In a 500 ml autoclave, 43.0 g (0.2 mol, 99% purity) of ethyl 2-fluoro-3-nitrobenzoate, 0.42 g of 5% platinum carbon catalyst, 8.52 g (0.14 mol, 99% purity) of acetic acid, 19.6 g of cyclopropylformaldehyde (0.28 mol, 99% purity), and 213 g of ethanol were successively added. Hydrogen was introduced at a pressure of 2.0 MPa, and the reaction was carried out at 60°C for 14 h.

[0052] After the reaction, the solution was filtered and the residue was washed with 20 g of ethanol. The filtrate was combined, and the solvent was removed under reduced pressure. The mixture was dried to yield 45.1 g of ethyl 3-[(cyclopropylmethyl)amino]-2-fluorobenzoate with a purity of 98.0% and a yield of 95.4%.

[0053] Characteristic data: LC / MS [M+1]: m / z=238. Example 3

[0054] In this example, propyl 3-[(cyclopropylmethyl(amino)]-2-fluorobenzoate was prepared according to the following scheme:

[0055] In a 500 mL autoclave, 45.9 g (0.2 mol, 99% purity) of propyl 2-fluoro-3-nitrobenzoate, 0.91 g of 5% platinum carbon catalyst, 18.6 g (0.30 mol, 99% purity) of acetic acid, 22.4 g of cyclopropyl formaldehyde (0.32 mol, 99% purity), and 136.2 g of ethyl acetate were successively added. Hydrogen was introduced at a pressure of 3.0 MPa, and the reaction was carried out at 100°C for 16 h. After the reaction, the solution was filtered, and the residue was washed with 20 g of ethyl acetate. The filtrate was combined, and the solvent was removed under reduced pressure. The mixture was dried to obtain 48.5 g of propyl-3-[(cyclopropylmethyl)amino]-2-fluorobenzoate with a content of 97.5% and a yield of 94.2%.

[0056] Characteristic data: LC / MS [M+1]: m / z=252. Example 4

[0057] In this example, isopropyl 3-[(cyclopropylmethyl)amino]-2-fluorobenzoate was prepared according to the following scheme:

[0058] In a 500 mL autoclave, 45.9 g (0.2 mol, 99% purity) of isopropyl 2-fluoro-3-nitrobenzoate, 0.91 g of 5% platinum carbon catalyst, 9.08 g (0.15 mol, 99% purity) of acetic acid, 16.8 g of cyclopropyl formaldehyde (0.24 mol, 99% purity), and 227 g of ethyl acetate were successively added. Hydrogen was introduced at a pressure of 2.0 MPa, and the reaction was carried out at 60°C for 12 h. After the reaction, the solution was filtered, and the residue was washed with 20 g of ethyl acetate. The filtrate was combined, and the solvent was removed under reduced pressure. The mixture was dried to yield 48.0 g of isopropyl 3-[(cyclopropylmethyl)amino]-2-fluorobenzoate with a purity of 97.8% and a yield of to obtain 93.5%. Example 5-1

[0059] In this example, an N-cyclopropylmethylaniline compound was prepared according to the following scheme:

[0060] In a 500 mL autoclave, 50.1 g (0.1 mol, 99% purity) of 2-fluoro-3-nitro-N-(4-(perfluoropropan-2-yl)-2-(trifluoromethyl)phenyl)benzamide, 0.49 g of 5% platinum carbon catalyst, 2.48 g (0.03 mol, 99% purity) of propionic acid, 9.8 g of cyclopropylformaldehyde (0.14 mol, 99% purity), and 248 g of methanol were successively added. Hydrogen was introduced at a pressure of 3.0 MPa, and the reaction was carried out at 40°C for 16 h. After the reaction, the solution was filtered, and the filter residue was washed with 20 g of methanol. The filtrate was combined, and the solvent was removed under reduced pressure. After drying, a solid weighing 50.4 g was obtained with a content of 98.4 g and a yield of 95.4%.

[0061] Characteristic data: LC / MS [M+1]: m / z=521.

[0062] 1H NMR (400 MHz, DMSO-d6) data (δ[ppm]): 10.18 (s, 1H), 8.12-8.07 (m, 1H), 8.04 (d, J = 8.7 Hz, 1H), 7.92 (s, 1H), 7.10 (t, J = 7.9 Hz, 1H), 6.94 (t, J = 8.2 Hz, 1H), 6.90-6.82 (m, 1H), 5.82-5.72 (m, 1H), 3.03 (t, J = 6.2 Hz, 2H), 1.12-1.08 (m, 1H), 0.50-0.42 (m, 2H), 0.24 (q, J = 4.4Hz, 2H). Example 5-2

[0063] In this example, an N-cyclopropylmethylaniline compound was prepared according to the following scheme:

[0064] The preparation procedure differs from that of Example 5-1 only in that the 0.49 g of the 5% platinum carbon catalyst were replaced by a 5% palladium carbon catalyst of the same mass, while the other conditions remained unchanged. The yield was 81.2%. Example 5-3

[0065] In this example, an N-cyclopropylmethylaniline compound was prepared according to the following scheme:

[0066] The preparation procedure differs from that of Example 5-1 only in that the 0.49 g of the 5% platinum carbon catalyst were replaced by a 5% Raney nickel catalyst of the same mass, while the other conditions remained unchanged. The yield was 73.5%. Example 5-4

[0067] In this example, an N-cyclopropylmethylaniline compound was prepared according to the following scheme:

[0068] The preparation procedure differs from that of Example 5-1 only in that the 2.48 g of propionic acid were replaced by formic acid of the same mass, while the other conditions remained unchanged. The yield was 83.6%. Example 5-5

[0069] In this example, an N-cyclopropylmethylaniline compound was prepared according to the following scheme:

[0070] The preparation procedure differs from that of Example 5-1 only in that the 2.48 g of propionic acid were replaced by 36% hydrochloric acid of the same mass, while the other conditions remained unchanged. The yield was 56.2%. Example 6

[0071] In this example, an N-cyclopropylmethylaniline compound was prepared according to the following scheme:

[0072] In a 500 mL autoclave, 62.8 g (0.1 mol, 99% purity) of 2-fluoro-N-(2-iodo-4-perfluoropropan-2-yl)-6-(trifluoromethyl)phenyl)-3-nitrobenzamide, 0.62 g of 5% platinum carbon catalyst, 12.44 g (0.21 mol, 99% purity) of acetic acid, 11.2 g of cyclopropylformaldehyde (0.16 mol, 99% purity), and 311 g of toluene were successively added. Hydrogen was introduced at a pressure of 1.0 MPa, and the reaction was carried out at 60°C for 14 h. After the reaction, the solution was filtered, and the residue was washed with 20 g of toluene. The filtrate was combined, and the solvent was removed under reduced pressure. After drying, a solid weighing 62.6 g was obtained with a content of 97.6% and a yield of 94.6%.

[0073] Characteristic data: LC / MS [M+1]: m / z=647.

[0074] 1H NMR (400 MHz, DMSO-d6) data (δ[ppm]): 10.53 (s, 1H), 8.41 (s, 1H), 7.97 (s, 1H), 7.11 (m, 1H), 6.96-6.91 (m, 1H), 6.84-6.81 (m, 1H), 5.79-5.75 (m, 1H), 3.04 (t, J = 6.2 Hz, 2H), 1.15-1.07 (m, 1H), 0.49-0.44 (m, 2H), 0.28-0.24 (m, 2H). Example 7

[0075] In this example, an N-cyclopropylmethylaniline compound was prepared according to the following scheme:

[0076] In a 500 mL autoclave, 57.9 g (0.1 mol, 99% purity) of N-(2-bromo-6-(difluoromethoxy)-4-(perfluoropropan)-2-yl)-phenyl)-2-fluoro-3-nitrobenzamide, 0.29 g of 5% platinum carbon catalyst, 2.86 g (0.038 mol, 99% purity) of propionic acid, 9.8 g of cyclopropylformaldehyde (0.14 mol, 99% purity), and 171.6 g of ethyl acetate were successively added. Hydrogen was introduced at a pressure of 2.0 MPa, and the reaction was carried out at 100°C for 16 h. After the reaction, the solution was filtered, and the filter residue was washed with 20 g of ethyl acetate. The filtrate was combined, and the solvent was removed under reduced pressure. After drying, a solid weighing 57.8 g was obtained with a content of 98.0% and a yield of 94.9%.

[0077] Characteristic data: LC / MS [M+1]: m / z=598.

[0078] 1 H NMR (400 MHz, DMSO-d6) data (δ[ppm]): 1H NMR (400 MHz, DMSO-d6), 10.01 (s, 1H), 7.66 (s, 1H), 7.30 (s, 1H), 7.09 (t, J = 72.0 Hz, 1H), 6.85 (t, J = 7.8 Hz, 1H), 6.69 (t, J = 7.7 Hz, 1H) 6.56 (t, J = 6.2 Hz, 1H), 5.47 (s, 1H), 2.79 (t, J = 5.7 Hz, 2H), 0.90-0.80 (m, 1H), 0.24-0.18 (m, 2H), 0.01 (q, J = 4.9 Hz, 2H). Example 8

[0079] In this example, an N-cyclopropylmethylaniline compound was prepared according to the following scheme:

[0080] In a 1000 ml autoclave, 59.7 g (0.1 mol, 99% purity) of N-(2-bromo-4-(perfluoropropan-2-yl)-6-(trifluoromethoxy)phenyl)-2-fluoro-3-nitrobenzamide, 1.18 g of 5% platinum carbon catalyst, 23.6 g (0.39 mol, 99% purity) of acetic acid, 9.8 g of cyclopropylformaldehyde (0.14 mol, 99% purity), and 472 g of methanol were successively added. Hydrogen was introduced at a pressure of 3.0 MPa, and the reaction was carried out at 60°C for 12 h. After the reaction, the solution was filtered, and the residue was washed with 20 g of methanol. The filtrate was combined, and the solvent was removed under reduced pressure. After drying, a 59.7 g solid containing a proportion of 98.2% and a yield of 95.3% were obtained.

[0081] Labelling data: LC / MS [M+1]: m / z=616.

[0082] 1H NMR (400 MHz, DMSO-d6) data (δ[ppm]): 10.53 (s, 1H), 8.10 (s, 1H), 7.78 (s, 1H), 7.13-7.07 (m, 1H), 6.96-6.91 (m, 1H), 6.78-6.75 (m, 1H), 5.78-5.74 (m, 1H), 3.03 (t, J = 6.2 Hz, 2H), 0.98-0.90 (m, 1H), 0.26-0.22 (m, 2H), 0.16-0.12 (m, 2H). Example 9

[0083] In this example, an N-cyclopropylmethylaniline compound was prepared according to the following scheme:

[0084] In a 500 mL autoclave, 40.0 g (0.2 mol, 99% purity) of 2-fluoro-N-methyl-3-nitrobenzamide, 0.2 g of 5% platinum carbon catalyst, 7.96 g (0.13 mol, 99% purity) of acetic acid, 16.8 g of cyclopropylformaldehyde (0.24 mol, 99% purity), and 119.4 g of methanol were successively added. Hydrogen was introduced at a pressure of 1.0 MPa, and the reaction was carried out at 40°C for 12 h. After the reaction, the solution was filtered, and the residue was washed with 20 g of methanol. The filtrate was combined, and the solvent was removed under reduced pressure. After drying, a 42.8 g solid was obtained with a purity of 98.5% and a yield of 94.9%.

[0085] The preparation method for an N-cyclopropylmethylaniline compound of the present invention has been described above with reference to various embodiments. However, the present invention is not limited to the embodiments described here. The present invention can therefore also be implemented differently than described above. It should be clear to those skilled in the art that various improvements can be made to the embodiments described here, such as replacing the raw materials with equivalent materials, adding excipients, etc., without thereby departing from the scope of the invention.

[0086] The preferred embodiments of the present invention have been described in detail. However, the present invention is not limited to the specific details described herein. Within the technical concept of the present invention, various modifications to the technical solution can be made without thereby departing from the scope of the invention.

[0087] Furthermore, features of one specific embodiment can be combined with features of other specific embodiments. To simplify the description, not all possible combinations are described here.

Claims

[1] Method for preparing an N-cyclopropylmethylaniline compound, comprising: Hydrogenation of a compound represented by Formula II and of cyclopropylformaldehyde as raw materials in the presence of an acid and a catalyst to generate an N-cyclopropylmethylaniline compound represented by Formula I according to the following scheme: wherein R is selected from alkoxy, alkylamino, or a substituted anilino group represented by the following Formula III: wherein R1 is selected from methoxy or fluorine, R2 from fluorine or trifluoromethyl, R3 from H, fluorine, chlorine, bromine, iodine, nitro, or trifluoromethyl, R4 from trifluoromethyl, trifluoromethoxy, or difluoromethoxy, and represents the position to which the group is attached; The pressure of the hydrogenation reaction is controlled to 0.2-5.0 MPa after the introduction of the hydrogen gas; The hydrogenation reaction is carried out at a temperature of 30-150°C; the hydrogenation is carried out in a solvent which is one or a combination of at least two of an alcohol solvent, an ester solvent, an ether solvent, a halogenated hydrocarbon solvent or a benzene solvent; the molar ratio of the compound represented by formula II to cyclopropylformaldehyde is 1:(0.5-3); the acid is one or a combination of at least two acids selected from the group consisting of formic acid, acetic acid, propionic acid, hydrochloric acid and sulfuric acid. [2] Method according to claim 1, wherein R is selected from C1-C6 alkoxy. [3] Method according to claim 2, wherein R is selected from methoxy, ethoxy, propoxy or isopropoxy. [4] Method according to claim 1, wherein R is selected from one of C1-C6 alkylamino groups. [5] Method according to claim 4, wherein R is selected from a methylamino group. [6] The method of claim 1, wherein R is selected from a substituted anilino group represented by formula III: wherein R1 is fluorine, R2 is fluorine, R3 is selected from H, bromine or iodine and R4 is selected from trifluoromethyl, trifluoromethoxy or difluoromethoxy and represents the position at which the group is attached [7] The method of claim 1, wherein the alcohol solvent contains one or a combination of at least two of methanol, ethanol or isopropanol, the ester solvent contains one or a combination of at least two of methyl acetate, ethyl acetate, propyl acetate or butyl acetate, the ether solvent contains one or a combination of at least two diethyl ether, methyl tert-butyl ether or tetrahydrofuran the halogenated hydrocarbon solvent dichloromethane and / or dichloroethane, The benzene solvent contains toluene and / or xylene. [8] Method according to claim 1, wherein the solvent contains one or a combination of at least two of methanol, ethanol, ethyl acetate or toluene. [9] The method of claim 1, wherein the acid is acetic acid and / or propionic acid. [10] Method according to any one of claims 1 to 9, wherein the catalyst contains palladium carbon, platinum carbon or Raney nickel. [11] Method according to claim 10, wherein the catalyst is platinum carbon. [12] Method according to any one of claims 1 to 11, wherein the molar ratio of the compound represented by formula II to cyclopropylformaldehyde is 1:(1,2-1,6), the mass ratio of the compound represented by formula II to the acid is preferably 1:(0.01-0.6), the mass ratio of the compound represented by formula II to the catalyst is preferably 1:(0.001-0.05), and the mass ratio of the compound represented by formula II to the solvent is preferably 1:(2-10). [13] Method according to any one of claims 1 to 12, wherein the hydrogenation reaction is carried out at a temperature of 40-100°C for 8-20 h. [14] Method according to any one of claims 1 to 13, wherein the pressure of the hydrogenation reaction is controlled to 1.0-3.0 MPa after the introduction of the hydrogen gas. [15] A process according to any one of claims 1 to 14, comprising hydrogenating a compound represented by formula II and cyclopropylformaldehyde as raw materials in the presence of an acid and a catalyst under a pressure of 0.2-5.0 MPa at 30°C to 150°C for 8 to 20 hours to obtain an N-cyclopropylmethylaniline compound represented by formula I according to the following scheme, wherein the limited range of R corresponds to claim 1, the molar ratio of the compound represented by formula II to cyclopropylformaldehyde is 1:(0.5-3), the mass ratio of the compound represented by formula II to the acid is 1:(0.01-0.6), the mass ratio of the compound represented by formula II to the catalyst is 1:(0.001-0.05), and the mass ratio of the compound represented by formula II to the solvent is 1:(2-10). is.