METHOD FOR PREPARING AN N-CYCLOPROPYLMETHYL ANILINE COMPOUND

Abstract

Provided is a method for preparing an N-cyclopropylmethyl aniline compound, which comprises hydrogenating a compound represented by Formula II and cyclopropyl formaldehyde as raw materials in the presence of an acid and catalyst to generate an N-cyclopropylmethyl aniline compound represented by Formula I, wherein R is alkoxy, alkylamino or a substituted anilino group represented by Formula III.

Claims

1. A method for preparing an N-cyclopropylmethyl aniline compound, comprising: hydrogenating a compound represented by Formula II and cyclopropyl formaldehyde as raw materials in the presence of an acid and a catalyst to generate an N-cyclopropylmethyl aniline compound represented by Formula I according to the scheme as follows: ##STR00023## wherein R is selected from alkoxy, alkylamino or a substituted anilino group represented by Formula III: ##STR00024## wherein R.sub.1 is selected from methoxy or fluorine, R.sub.2 is selected from fluorine or trifluoromethyl, R.sub.3 is selected from any one of H, fluorine, chlorine, bromine, iodine, nitro or trifluoromethyl, and R.sub.4 is selected from any one of trifluoromethyl, trifluoromethoxy or difluoromethoxy; and represents the position at which the group is attached.

2. The method according to claim 1, wherein R is selected from any one of C1-C6 alkoxy groups; or R is selected from any one of C1-C6 alkylamino groups; or R is selected from a substituted anilino group represented by Formula III ##STR00025## wherein R.sub.1 is fluorine, R.sub.2 is fluorine, R.sub.3 is selected from any one of H, bromine or iodine, and R.sub.4 is selected from any one of trifluoromethyl, trifluoromethoxy or difluoromethoxy; and represents the position at which the group is attached.

3. The method according to claim 1, wherein the hydrogenation is carried out in a solvent which is any one or a combination of at least two selected from the group consisting of an alcohol solvent, an ester solvent, an ether solvent, a halogenated hydrocarbon solvent or a benzene solvent.

4. The method according to claim 3, wherein the alcohol solvent includes any one or a combination of at least two selected from the group consisting of methanol, ethanol and isopropanol.

5. The method according to claim 1, wherein the acid includes inorganic acids or organic acids.

6. The method according to claim 1, wherein the catalyst includes any one of palladium carbon, platinum carbon or Raney nickel.

7. The method according to claim 1, wherein the molar ratio of the compound represented by Formula II to cyclopropyl formaldehyde is 1:(0.5-3).

8. The method according to claim 1, wherein the hydrogenation reaction is carried at a temperature of 30-150° C., for 8-20 h.

9. The method according to claim 1, wherein the pressure of the hydrogenation reaction after introducing hydrogen gas is controlled to be 0.2-5.0 MPa.

10. The method according to claim 1, comprising: hydrogenating a compound represented by Formula II and cyclopropyl formaldehyde as raw materials in the presence of an acid and a catalyst under the pressure of 0.2-5.0 MPa at 30° C. to 150° C. for 8 to 20 hours to generate an N-cyclopropylmethyl aniline compound represented by Formula I according to the scheme as follows: ##STR00026## wherein R is selected from alkoxy, alkylamino or a substituted anilino group represented by Formula III: ##STR00027## wherein R.sub.1 is selected from methoxy or fluorine, R.sub.2 is selected from fluorine or trifluoromethyl, R.sub.3 is selected from any one of H, fluorine, chlorine, bromine, iodine, nitro or trifluoromethyl, and R.sub.4 is selected from any one of trifluoromethyl, trifluoromethoxy or difluoromethoxy; and represents the position at which the group is attached; the molar ratio of the compound represented by Formula II to cyclopropyl formaldehyde 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).

11. The method of claim 2 wherein the alkoxy group is selected from methoxy, ethoxy, propoxy or isopropoxy.

12. The method of claim 2 wherein the alkylamino group is a methylamino group.

13. The method according to claim 4 wherein the ester solvent includes any one or a combination of at least two selected from the group consisting of methyl acetate, ethyl acetate, propyl acetate and butyl acetate.

14. The method according to claim 4 wherein the ether solvent includes any one or a combination of at least two selected from the group consisting of diethyl ether, methyl tert-butyl ether and tetrahydrofuran.

15. The method according to claim 4 wherein the halogenated hydrocarbon solvent includes at least one of dichloromethane and dichlorethane.

16. The method according to claim 4 wherein the benzene solvent includes at least one of toluene and xylene.

17. The method according to claim 4 wherein the solvent includes any one or a combination of at least two selected from the group consisting of methanol, ethanol, ethyl acetate and toluene.

18. The method according to claim 5 wherein the acid is any one or a combination of at least two selected from the group consisting of formic acid, acetic acid, propionic acid, hydrochloric acid and sulfuric acid.

19. The method according to claim 5 wherein the acid is at least one of acetic acid and propionic acid.

20. The method of claim 6 wherein the catalyst includes platinum carbon.

21. The method of claim 7 wherein the molar ratio of the compound represented by Formula II to cyclopropyl formaldehyde is 1:(1.2-1.6).

22. The method of claim 7 wherein the mass ratio of the compound represented by Formula II to the acid is 1:(0.01-0.6).

23. The method of claim 22 wherein the mass ratio is 1:(0.05-0.4).

24. The method of claim 7 wherein the mass ratio of the compound represented by Formula II to the catalyst is 1:(0.001-0.05).

25. The method of claim 24 wherein the mass ratio is 1:(0.005-0.02).

26. The method of claim 7 wherein the mass ratio of the compound represented by Formula II to the solvent is 1:(2-10).

27. The method of claim 26 wherein the mass ratio is 1:(3-8).

28. The method of claim 8 wherein the temperature is 40-100° C.

29. The method of claim 8 wherein the hydrogenation reaction is carried out for 12-16 h.

30. The method of claim 9 wherein the pressure of the hydrogenation reaction after introducing hydrogen gas is controlled to 1.0-3.0 MPa.

Description

DETAILED DESCRIPTION

[0050] In order to further illustrate the technical means adopted by the present disclosure and its effects, the technical solutions of the present disclosure will be further described below in conjunction with preferred embodiments of the present disclosure, but the present disclosure is not limited to the scope of the embodiments.

EXAMPLE 1

[0051] In this Example, methyl 3-[(cyclopropylmethyl)amino]-2-fluorobenzoate was prepared according to the following scheme:

##STR00010##

[0052] In a 500 mL autoclave, 40.2 g (0.2 mol, purity 99%) of methyl 2-fluoro-3-nitrobenzoate, 0.2 g of 5% platinum carbon catalyst, 7.96 g (0.13 mol, purity 99%) of acetic acid, 16.8 g of cyclopropyl formaldehyde (0.24 mol, purity 99%) and 119.4 g of methanol were sequentially added. Hydrogen was introduced to a pressure of 1.0 MPa, and reacted at 40° C. for 12 h. After the reaction, the reaction solution was filtered, and the filter residue was washed with 20 g methanol. The filtrate was combined, and the solvent was removed under reduced pressure. The resultant was dried to obtain 43.2 g of methyl 3-[(cyclopropylmethyl)amino]-2-fluorobenzoate with a content of 98.5% (external standard method, the same below) and a yield of 95.4% (mass yield, the same below).

[0053] Characterization data: LC/MS [M+1]: m/z=224.

[0054] .sup.1H NMR (400 MHz, CDCl.sub.3) 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

[0055] In this Example, ethyl 3-[(cyclopropylmethyl)amino]-2-fluorobenzoate was prepared according to the following scheme:

##STR00011##

[0056] In a 500 mL autoclave, 43.0 g (0.2 mol, purity 99%) of ethyl 2-fluoro-3-nitrobenzoate, 0.42 g of 5% platinum carbon catalyst, 8.52 g (0.14 mol, purity 99%) of acetic acid, 19.6 g of cyclopropyl formaldehyde (0.28 mol, purity 99%) and 213 g of ethanol were sequentially added. Hydrogen was introduced to a pressure of 2.0 MPa, and reacted at 60° C. for 14 h. After the reaction, the reaction solution was filtered and the filter residue was wash with 20 g ethanol. The filtrate was combined, and the solvent was removed under reduced pressure. The resultant was dried to obtain 45. 1g of ethyl 3-[(cyclopropylmethyl)amino]-2-fluorobenzoate with a content of 98.0% and a yield of 95.4%.

[0057] Characterization data: LC/MS [M+1]: m/z=238.

EXAMPLE 3

[0058] In this Example, propyl 3-[(cyclopropylmethyl)amino]-2-fluorobenzoate was prepared according to the following scheme:

##STR00012##

[0059] In a 500 mL autoclave, 45.9 g (0.2 mol, purity 99%) of propyl 2-fluoro-3-nitrobenzoate, 0.91 g of 5% platinum carbon catalyst, 18.16 g (0.30 mol, purity 99%) of acetic acid, 22.4 g of cyclopropyl formaldehyde (0.32 mol, purity 99%) and 136.2 g of ethyl acetate were sequentially added. Hydrogen was introduced to a pressure of 3.0 MPa, and reacted at 100° C. for 16 h. After the reaction, the reaction solution was filtered and the filter residue was washed with 20 g ethyl acetate. The filtrate was combined, and the solvent was removed under reduced pressure. The resultant 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%.

[0060] Characterization data: LC/MS [M+1]1: m/z=252.

EXAMPLE 4

[0061] In this Example, isopropyl 3-[(cyclopropylmethyl)amino]-2-fluorobenzoate was prepared according to the following scheme:

##STR00013##

[0062] In a 500 mL autoclave, 45.9 g (0.2 mol, purity 99%) of isopropyl 2-fluoro-3-nitrobenzoate, 0.91 g of 5% platinum carbon catalyst, 9.08 g (0.15mol, purity 99%) of acetic acid, 16.8 g of cyclopropyl formaldehyde (0.24 mol, purity 99%) and 227 g of ethyl acetate were sequentially added. Hydrogen was introduced to a pressure of 2.0 MPa, and reacted at 60° C. for 12 h. After the reaction, the reaction solution was filtered and the filter residue was washed with 20 g ethyl acetate. The filtrate was combined, and the solvent was removed under reduced pressure. The resultant was dried to obtain 48.0 g of isopropyl 3-[(cyclopropylmethyl)amino]-2-fluorobenzoate with a content of 97.8% and a yield of 93.5%.

EXAMPLE 5-1

[0063] In this Example, an N-cyclopropylmethyl aniline compound was prepared according to the following scheme:

##STR00014##

[0064] In a 500 mL autoclave, 50.1 g (0.1 mol, purity 99%) 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, purity 99%) of propionic acid, 9.8 g of cyclopropyl formaldehyde (0.14 mol, purity 99%) and 248 g of methanol were sequentially added. Hydrogen was introduced to a pressure of 3.0 MPa, and reacted at 40° C. for 16 h. After the reaction, the reaction solution was filtered, and the filter residue was washed with 20 g methanol. The filtrate was combined, and the solvent was removed under reduced pressure. After drying, 50.4 g solid was obtained with a content of 98.4% and a yield of 95.4%.

[0065] Characterization data: LC/MS [M+1]: m/z=521.

[0066] .sup.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=4.4 Hz, 2H).

EXAMPLE 5-2

[0067] In this Example, an N-cyclopropylmethyl aniline compound was prepared according to the following scheme:

##STR00015##

[0068] The preparation method differs from that of Example 5-1 only in that 0.49 g of the 5% platinum-carbon catalyst was replaced with a 5% palladium-carbon catalyst with equal mass, and other conditions remained unchanged. The yield was 81.2%.

EXAMPLE 5-3

[0069] In this Example, an N-cyclopropylmethyl aniline compound was prepared according to the following scheme:

##STR00016##

[0070] The preparation method differs from that of Example 5-1 only in that 0.49 g of the 5% platinum-carbon catalyst was replaced with a 5% Raney nickel catalyst with equal mass, and other conditions remained unchanged. The yield was 73.5%.

EXAMPLE 5-4

[0071] In this Example, an N-cyclopropylmethyl aniline compound was prepared according to the following scheme:

##STR00017##

[0072] The preparation method differs from that of Example 5-1 only in that 2.48 g of propionic acid was replaced with formic acid with equal mass, and other conditions remain unchanged. The yield was 83.6%.

EXAMPLE 5-5

[0073] In this Example, an N-cyclopropylmethyl aniline compound was prepared according to the following scheme:

##STR00018##

[0074] The preparation method differs from that of Example 5-1 only in that: 2.48 g of propionic acid was replaced by 36% hydrochloric acid with equal mass, and other conditions remained unchanged. The yield was 56.2%.

EXAMPLE 6

[0075] In this Example, an N-cyclopropylmethyl aniline compound was prepared according to the following scheme:

##STR00019##

[0076] In a 500 mL autoclave, 62.8 g (0.1 mol, purity 99%) 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, purity 99%) of acetic acid, 11.2 g of cyclopropyl formaldehyde (0.16 mol, purity 99%) and 311 g of toluene were sequentially added. Hydrogen was introduced to a pressure of 1.0 MPa and reacted at 60° C. for 14 h. After the reaction, the reaction solution was filtered, and the filter residue was washed with 20 g toluene. The filtrate was combined, and the solvent was removed under reduced pressure. After drying, 62.6 g solid was obtained with a content of 97.6% and a yield of 94.6%.

[0077] Characterization data: LC/MS [M+1]: m/z=647.

[0078] .sup.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

[0079] In this Example, an N-cyclopropylmethyl aniline compound was prepared according to the following scheme:

##STR00020##

[0080] In a 500 mL autoclave, 57.9 g (0.1 mol, purity 99%) 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, purity 99%) of propionic acid, 9.8 g of cyclopropyl formaldehyde (0.14 mol, purity 99%) and 171.6 g of ethyl acetate were sequentially added. Hydrogen was introduced to a pressure of 2.0 MPa, and reacted at 100° C. for 16 h. After the reaction, the reaction solution was filtered, and the filter residue was washed with 20 g ethyl acetate. The filtrate was combined, and the solvent was removed under reduced pressure. After drying, 57.8 g solid was obtained with a content of 98.0% and a yield of 94.9%.

[0081] Characterization data: LC/MS [M+1]: m/z=598.

[0082] .sup.1H NMR(400 MHz, DMSO-d6) data (δ[ppm]): .sup.1 H 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

[0083] In this Example, an N-cyclopropylmethyl aniline compound was prepared according to the following scheme:

##STR00021##

[0084] In a 1000 mL autoclave, 59.7 g (0.1 mol, purity 99%) 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, purity 99%) of acetic acid, 9.8 g of cyclopropyl formaldehyde (0.14 mol, purity 99%) and 472 g of methanol were sequentially added. Hydrogen was introduced to a pressure of 3.0 MPa, and reacted at 60° C. for 12 h. After the reaction, the reaction solution was filtered, and the filter residue was washed with 20 g methanol. The filtrate was combined, and the solvent was removed under reduced pressure. After drying, 59.7 g solid was obtained with a content of 98.2% and a yield of 95.3%.

[0085] Characterization data: LC/MS [M+1]1: m/z=616.

[0086] .sup.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

[0087] In this Example, an N-cyclopropylmethyl aniline compound was prepared according to the following scheme:

##STR00022##

[0088] In a 500 mL autoclave, 40.0 g (0.2 mol, purity 99%) of 2-fluoro-N-methyl-3-nitrobenzamide, 0.2 g of 5% platinum carbon catalyst, 7.96 g (0.13 mol, purity 99%) of acetic acid, 16.8 g of cyclopropyl formaldehyde (0.24 mol, purity 99%) and 119.4 g of methanol were sequentially added. Hydrogen was introduced to a pressure of 1.0 MPa, and reacted at 40° C. for 12 h. After the reaction, the reaction solution was filtered, and the filter residue was washed with 20 g methanol. The filtrate was combined, and the solvent was removed under reduced pressure. After drying, 42.8 g solid was obtained with a content of 98.5% and a yield of 94.9%.

[0089] Applicant has stated that although the preparation method for the N-cyclopropylmethyl aniline compound of the present disclosure is described through the embodiments described above, the present disclosure is not limited to the embodiments described above, which means that implementation of the present disclosure does not necessarily depend on the embodiments described above. It should be apparent to those skilled in the art that any improvements made to the present disclosure, and equivalent replacements of various raw materials, the addition of adjuvant ingredients and the selection of specific manners, etc. in the present disclosure all fall within the protection scope and the scope of disclosure of the present disclosure.

[0090] The preferred embodiments of the present disclosure are described in detail above. However, the present disclosure is not limited to the specific details in the above-mentioned embodiments. Within the scope of the technical concept of the present disclosure, various simple modifications can be made to the technical solution of the present disclosure. These simple modifications all belong to the protection scope of the present disclosure.

[0091] In addition, it should be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the combination method will not be explained separately.