Method for preparing an N-cyclopropylmethyl aniline compound

Abstract

Provided is a method for preparing an N-cyclopropylmethyl aniline compound, which comprises reacting a compound represented by Formula IV with cyclopropyl formaldehyde in the presence of metal zinc and an acid to generate an N-cyclopropylmethyl aniline compound represented by Formula I. The method of the present disclosure has mild reaction conditions, short reaction time, a high yield, simple processes, simple operations and low costs, and is more applicable to industrial production.

Claims

1. A method for preparing an N-cyclopropylmethyl aniline compound, comprising reacting a compound represented by Formula IV with cyclopropyl formaldehyde in the presence of metal zinc and an acid to generate an N-cyclopropylmethyl aniline compound represented by Formula I according to the following scheme: ##STR00019## wherein R is alkyloxy or ##STR00020## wherein R.sub.1 is methoxy or fluorine, R.sub.2 is fluorine or trifluoromethyl, R.sub.3 is any one of H, fluorine, chlorine, bromine, iodine, nitro or trifluoromethyl, and R.sub.4 is any one of trifluoromethyl, trifluoromethoxy or difluoromethoxy.

2. The method according to claim 1, wherein R is C1-C6 alkyloxy.

3. The method according to claim 2, wherein R is methoxy, ethoxy, propoxy or isopropoxy.

4. The method according to claim 1, wherein R is ##STR00021## wherein R.sub.1 is fluorine, R.sub.2 is fluorine, R.sub.3 is H, bromine or iodine, and R.sub.4 is any one of trifluoromethyl, trifluoromethoxy or difluoromethoxy.

5. The method according to claim 1, wherein the metal zinc is zinc powder or a metal zinc bulk.

6. The method according to claim 5, wherein the metal zinc is zinc powder.

7. The method according to claim 1, wherein the acid is an inorganic acid or an organic acid.

8. The method according to claim 7, wherein the acid is formic acid, acetic acid, hydrochloric acid or sulfuric acid.

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

10. The method according to claim 1, wherein the molar ratio of the compound represented by Formula IV to the metal zinc is 1:(1-4).

11. The method according to claim 1, wherein the molar ratio of the compound represented by Formula IV to the acid is 1:(1-4).

12. The method according to claim 1, wherein the reaction is carried out in a solvent which is any one of an alcohol solvent, an ester solvent, an ether solvent or a halogenated hydrocarbon solvent.

13. The method according to claim 12, wherein the alcohol solvent is any one or a combination of at least two selected from the group consisting of methanol, ethanol and isopropanol.

14. The method according to claim 12, wherein the ester solvent is ethyl acetate and/or butyl acetate.

15. The method according to claim 12, wherein the ether solvent is any one or a combination of at least two selected from the group consisting of diethyl ether, methyl tert-butyl ether and tetrahydrofuran.

16. The method according to claim 12, wherein the halogenated hydrocarbon solvent is dichloromethane and/or dichloroethane.

17. The method according to claim 12, wherein the mass ratio of the compound represented by Formula IV to the solvent is 1:(2-8).

18. The method according to claim 1, wherein the reaction is carried out at a temperature of 35 C. to 80 C.

19. The method according to claim 1, wherein the reaction is carried out for 2 to 5 hours.

20. The method according to claim 1, comprising reacting a compound represented by Formula IV with cyclopropyl formaldehyde in a molar ratio of 1:(1-3) in the presence of metal zinc and an acid at 35 C. to 80 C. for 2 to 5 hours to obtain an N-cyclopropylmethyl aniline compound represented by Formula I, wherein the molar ratio of the compound represented by Formula IV to the metal zinc is 1:(1-4), and the molar ratio of the compound represented by Formula IV to the acid is 1:(1-4).

Description

DETAILED DESCRIPTION

(1) The technical embodiments of the present disclosure are further described below through specific embodiments. Those skilled in the art should understand that the embodiments are merely used to help understand the present disclosure and should not be regarded as specific limitations on the present disclosure.

Example 1

(2) In this Example, 3-[(cyclopropylmethyl)amino]-2-fluoro-N-[4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-2-(trifluoromethyl)phenyl]benzamide was prepared according to the following reaction scheme:

(3) ##STR00008##

(4) To a reaction flask equipped with a mechanical stirrer and a thermometer 47.1 g (0.1 mol) of 3-amino-2-fluoro-N-[4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-2-(trifluoromethyl)phenyl]benzamide, 14.0 g (0.2 mol) of cyclopropyl formaldehyde, 150 g of ethyl acetate and 13.0 g (0.2 mol) of zinc powder were sequentially added, followed by dropwise addition of 12 g (0.2 mol) of acetic acid at 60 C. After the dropwise addition was finished, the mixture was stirred for 3 hours. After the reaction was finished, the mixture was filtered. The filter cake was rinsed with 20 g of ethyl acetate. The filtrate was desolventized under reduced pressure and dried to obtain 51.2 g of 3-[(cyclopropylmethyl)amino]-2-fluoro-N-[4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-2-(trifluoromethyl)phenyl]benzamide in purity 98.7% and yield 97.2%.

(5) Characterization data:

(6) LC/MS [M+1]: m/z=521.

(7) 1H NMR (400 MHz, DMSO-d6) data ([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 2

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

(9) ##STR00009##

(10) To a reaction flask equipped with a mechanical stirrer and a thermometer 17.1 g (0.1 mol) of methyl 3-amino-2-fluoro-benzoate, 21.0 g (0.3 mol) of cyclopropyl formaldehyde, 136 g of methanol and 26.0 g (0.4 mol) of zinc powder were sequentially added, followed by dropwise addition of 24 g (0.4 mol) of acetic acid at 40 C. After the dropwise addition was finished, the mixture was stirred for 5 hours. After the reaction was finished, the reaction solution was filtered. The filter cake was rinsed with 20 g of methanol. The filtrate was desolventized under reduced pressure and dried to obtain 21.5 g of methyl 3-[(cyclopropylmethyl)amino]-2-fluorobenzoate in purity 98.5% and yield 95.0%.

(11) Characterization data:

(12) LC/MS [M1]: m/z=224.

(13) 1H NMR (400 MHz, CDCl.sub.3) data ([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 3

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

(15) ##STR00010##

(16) To a reaction flask equipped with a mechanical stirrer and a thermometer 18.5 g (0.1 mol) of ethyl 3-amino-2-fluoro-benzoate, 21.0 g (0.3 mol) of cyclopropyl formaldehyde, 74 g of ethanol and 19.5 g (0.3 mol) of zinc powder were sequentially added, followed by dropwise addition of 30.4 g (0.3 mol) of hydrochloric acid at 60 C. After the dropwise addition was finished, the mixture was stirred for 3 hours, After the reaction was finished, the reaction solution was filtered. The filter cake was rinsed with 20 g of ethanol. The filtrate was desolventized under reduced pressure and dried to obtain 21.6 g of ethyl 3-[(cyclopropylmethyl)amino]-2-fluorobenzoate in purity 98.0% and yield 89.3%.

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

Example 4

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

(19) ##STR00011##

(20) To a reaction flask equipped with a mechanical stirrer and a thermometer 19.9 g (0.1 mol) of propyl 3-amino-2-fluoro-benzoate, 14 g (0.2 mol) of cyclopropyl formaldehyde, 60 g of diethyl ether and 13 g (0.2 mol) of zinc powder were sequentially added, followed by dropwise addition of 24 g (0.4 mol) of acetic acid at 35 C. After the dropwise addition was finished, the mixture was stirred for 5 hours. After the reaction was finished, the reaction solution was filtered. The filter cake was rinsed with 20 g of diethyl ether. The filtrate was desolventized under reduced pressure and dried to obtain 21.2 g of propyl 3-[(cyclopropylmethyl)amino]-2-fluorobenzoate in purity 97.3% and yield 82.2%.

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

Example 5

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

(23) ##STR00012##

(24) To a reaction flask equipped with a mechanical stirrer and a thermometer 19.9 g (0.1 mol) of isopropyl 3-amino-2-fluoro-benzoate, 21.0 g (0.3 mot) of cyclopropyl formaldehyde, 80 g of isopropanol and 19.5 g (0.3 mol) of zinc powder were sequentially added, followed by dropwise addition of 18 g (0.3 mol) of acetic acid at 60 C. After the dropwise addition was finished, the mixture was stirred for 3 hours. After the reaction was finished, the reaction solution was filtered. The filter cake was rinsed with 20 g of isopropanol. The filtrate was desolventized under reduced pressure and dried to obtain 22.0 g of isopropyl 3-[(cyclopropylmethyl)amino]-2-fluorobenzoate in purity 97.6% and yield 85.5%.

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

Example 6

(26) In this Example, 3-[(cyclopropylmethyl)amino]-N-[2-iodo-4-[1,1,1,2,3,3-heptafluoroprop-2-yl]-6-(trifluoromethyl)phenyl]-2-fluorobenzamide was prepared according to the following reaction scheme:

(27) ##STR00013##

(28) To a reaction flask equipped with a mechanical stirrer and a thermometer 29.6 g (0.05 mol) of 3-amino-2-fluoro-N-[2-iodo-4-[1,1,1,2,3,3-heptafluoroprop-2-yl]-6-(trifluoromethyl)phenyl]benzamide, 10.5 g (0.15 mol) of cyclopropyl formaldehyde, 48.8 g of dichloromethane and 13 g (0.2 mol) of zinc powder were sequentially added, followed by dropwise addition of 10.0 g (0.1 mol) of sulfuric acid at 40 C. After the dropwise addition was finished, the mixture was stirred for 5 hours. After the reaction was finished, the reaction solution was filtered. The filter cake was rinsed with 10 g of dichloromethane. The filtrate was desolventized under reduced pressure, diluted with 50 ml of water, adjusted with 30% sodium hydroxide to pH 89, cooled to 0 C., filtered and dried to obtain 29.4 g of 3-[(cyclopropylmethyl)amino]-N-[2-iodo-4-[1,1,1,2,3,3,3-heptafluoroprop-2-yl]-6-(trifluoromethyl)phenyl]-2-fluorobenzamide in purity 98.3% and yield 89.5%.

(29) Characterization data:

(30) LC/MS [M+1]: m/z=647.

(31) 1H NMR (400 MHz, DMSO-d6) data ([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

(32) In this Example, 3-[(cyclopropylmethyl)amino]-N-[2-bromo-4-[1,1,1,2,3,3,3-heptafluoroprop-2-yl]-6-(difluoromethoxy)phenyl]-2-fluorobenzamide was prepared according to the following reaction scheme:

(33) ##STR00014##

(34) To a reaction flask equipped with a mechanical stirrer and a thermometer 27.2 g (0.05 mol) of 3-amino-N-[2-chloro-4-[1,1,1,2,3,3,3-heptafluoroprop-2-yl]-6-(difluoromethoxy)phenyl]-2-fluorobenzamide, 7 g (0.1 mol) of cyclopropyl formaldehyde, 75 g of dichloroethane and 3.3 g (0.05 mol) of zinc powder were sequentially added, followed by dropwise addition of 3 g (0.05 mol) of acetic acid at 80 C. After the dropwise addition was finished, the mixture was stirred for 2 hours. After the reaction was finished, the reaction solution was filtered. The filter cake was rinsed with 10 g of dichloroethane. The filtrate was desolventized under reduced pressure, diluted with 25 ml of water, adjusted with 30% sodium hydroxide to pH 89, cooled to 0 C., filtered and dried to obtain 27.6 g of 3-[(cyclopropylmethyl)amino]-N-[2-bromo-4-[1,1,1,2,3,3,3-heptafluoroprop-2-yl]-6-(difluoromethoxy)phenyl]-2-fluorobenzamide in purity 98.1% and yield 90.6%.

(35) Characterization data:

(36) LC/MS [M+1]: m/z=598.

(37) 1H NMR (400 MHz, DMSO-d6) data ([ppm]): .sup.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

(38) In this Example, 3-[(cyclopropylmethyl)amino]-N-[2-bromo-4-[1,1,1,2,3,3,3-heptafluoroprop-2-yl]-6-(trifluoromethyl)phenyl]-2-fluorobenzamide was prepared according to the following reaction scheme:

(39) ##STR00015##

(40) To a reaction flask equipped with a mechanical stirrer and a thermometer 27.3 g (0.05 mol) of 3-amino-N-[2-bromo-4-[1,1,1,2,3,3,3-heptafluoroprop-2-yl]-6-(trifluoromethyl)phenyl]-2-fluorobenzamide, 7 g (0.1 mop of cyclopropyl formaldehyde, 75 g of isopropanol and 3.3 g (0.05 mol) of zinc powder were sequentially added, followed by dropwise addition of 10.2 g (0.1 mol) of hydrochloric acid at 60 C. After the dropwise addition was finished, the mixture was stirred for 3 hours. After the reaction was finished, the reaction solution was filtered. The filter cake was rinsed with 10 g of isopropanol. The filtrate was desolventized under reduced pressure and dried to obtain 7.7.2 g of 3-[(cyclopropylmethyl)amino]-N-[2-bromo-4-[1,1,1,2,3,3,3-heptafluoroprop-2-yl]-6-(trifluoromethyl)phenyl]-2-fluorobenzamide in purity 97.8% and yield 88.8%.

(41) Characterization data:

(42) LC/MS [M+1]: m/z=600.

(43) 1H NMR (400 MHz, DMSO-d6) data ([ppm]): 10.54 (s, 1H), 8.42 (s, 1H), 7.96 (s, 1H), 7.10 (t, J=8.0 Hz, 1H), 6.96-6.91 (m, 1H), 6.83-6.79 (m, 1H), 5.79-5.75 (m, 1H) 3.03 (t, J=6.2 Hz, 2H), 1.14-1.05 (m, 1H), 0.48-0.43 (m, 2H), 0.29-0.2 (m, 2H).

Example 9

(44) In this Example, 3-[(cyclopropylmethyl)amino]-N-[2-bromo-4-[1,1,1,2,3,3,3-heptafluoroprop-2-yl]-6-(trifluoromethoxy)phenyl]-2-fluorobenzamide was prepared according to the following reaction scheme:

(45) ##STR00016##

(46) To a reaction flask equipped with a mechanical stirrer and a thermometer 28.05 g (0.05 mol) of 3-amino-N-[2-bromo-4-[1,1,1,2,3,3,3-heptafluoroprop-2-yl]-6-(trifluoromethoxy)phenyl]-2-fluorobenzamide, 7 g (0.05 mol) of cyclopropyl formaldehyde, 60 g of butyl acetate and 6.5 g (0.1 mol) of zinc powder were sequentially added, followed by dropwise addition of 5.2 g (0.1 mol) of formic acid at 80 C. After the dropwise addition was finished, the mixture was stirred for 2 hours. After the reaction was finished, the reaction solution was filtered. The filter cake was rinsed with 20 g of butyl acetate. The filtrate was desolventized under reduced pressure and dried to obtain 26.0 of 3-[(cyclopropylmethyl)amino]-N-[2-bromo-4-[1,1,1,2,3,3,3-heptafluoroprop-2-yl]-6-(trifluoromethoxy)phenyl]-2-fluorobenzamide in purity 97.0% and yield 82.0%.

(47) Characterization data:

(48) LC/MS [M+1]: m/z=616.

(49) 1H NMR (400 MHz, DMSO-d6) data ([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 10

(50) In this Example, 3-[(cyclopropylmethyl)amino]-2-fluoro-N-[2-nitro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)phenyl]benzamide was prepared according to the following reaction scheme:

(51) ##STR00017##

(52) To a reaction flask equipped with a mechanical stirrer and a thermometer 25.8 g (0.05 mol) of 3-amino-2-fluoro-N-[2-nitro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)phenyl]benzamide, 7.0 g (0.1 mol) of cyclopropyl formaldehyde, 103 g of tetrahydrofuran, and 6.5 g (0.1 mol) of zinc powder were sequentially added, followed by dropwise addition of 10.5 g (0.2 mol) of formic acid at 60 C. After the dropwise addition was finished, the mixture was stirred for 3 hours. After the reaction was finished, the reaction solution was filtered. The filter cake was rinsed with 10 g of tetrahydrofuran. The filtrate was desolventized under reduced pressure and dried to obtain 25.4 g of 3-[(cyclopropylmethyl)amino]-2-fluoro-N-[2-nitro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-6-(trifluoromethyl)phenyl]benzamide in purity 98.1% and yield 88.2%.

(53) Characterization data:

(54) LC/MS [M+1]: m/z=566.

(55) 1H NMR (400 MHz, DMSO-d6) data ([ppm]): 10.53 (s, 1H), 8.45 (s, 1H), 8.02 (s, 1H), 7.12 (t, J=8.0 Hz, 1H), 6.97-6.93 (m, 1H), 6.86-6.80 (m, 1H), 5.78-5.75 (m, 1H), 3.05 (m, 2H), 1.16-1.09 (m, 1H), 0.49-0.43 (m, 2H), 0.30-0.24 (m, 2H).

Example 11

(56) In this Example, 3-[(cyclopropylmethyl)amino]-2-fluoro-N-[4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-2,6-bis(trifluoromethyl)phenyl]benzamide was prepared according to the following reaction scheme:

(57) ##STR00018##

(58) To a reaction flask equipped with a mechanical stirrer and a thermometer 27.0 g (0.05 mol) of 3-amino-2-fluoro-N-[4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-2,6-bis(trifluoromethyl)phenyl]benzamide, 10.5 g (0.15 mol) of cyclopropyl formaldehyde, 135 g of methyl tert-butyl ether and 13.0 g (0.2 mol) of zinc powder were sequentially added, followed by dropwise addition of 12 g (0.2 mol) of acetic acid at 60 C. After the dropwise addition was finished, the mixture was stirred for 3 hours. After the reaction was finished, the reaction solution was filtered. The filter cake was rinsed with 10 g of methyl tert-butyl ether. The filtrate was desolventized under reduced pressure and dried to obtain 26.5 g of 3-[(cyclopropylmethyl)amino]-2-fluoro-N-[4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]-2,6-bis(trifluoromethyl)phenyl]benzamide in purity 97.6% and yield 88.0%.

(59) Characterization data:

(60) LC/MS [M1]: m/z=589.

(61) 1H NMR (400 MHz, DMSO-d6) data ([ppm]): 10.55 (s, 1H), 8.43 (s, 1H), 8.06 (s, 1H), 7.14 (t, J=8.0 Hz, 1H), 6.99-6.95 (m, 1H), 6.86-6.81 (m, 1H) 5.79-5.75 (m, 1H), 3.06 (m, 2H), 1.17-1.11 (m, 1H), 0.48-0.42 (m, 2H), 0.31-0.24 (m, 2H).

(62) The 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 disclosure scope of the present disclosure.