* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With palladium 10% on activated carbon; hydrogen In methanol for 4 h;
Step 1: 5-methyl-2-(trifluoromethyl) aniline Pd/C (0.2g, 10percentcontent) was added to 4-methyl-2-nitro-1-trifluoromethylbenzene (1g, 4.8mmol) in methanol (30mL) in a 100mL reaction flask. The reaction mixture was stirred for 4 hours under hydrogen atmosphereofl atmospheric pressure at 25°C. After completion of the reaction, the reaction solution was filtered and concentrated and the residue was separated and purified by column chromatography (ethyl acetate/petroleum ether=1:10) to obtain the title compound (0.68g, 80percent). (MS: [M+1] 176.2)
Reference：
[1] Patent: EP3150592, 2017, A1, . Location in patent: Paragraph 0133; 0134; 0135
[2] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 17, p. 3738 - 3743
2
[ 154057-13-3 ]
[ 107-06-2 ]
[ 116965-16-3 ]
Yield
Reaction Conditions
Operation in experiment
49%
With sodium hydroxide; sodium hypochlorite; sulfuric acid; tetrabutylammomium bromide In NaHCO3 (aqueous)
Step B 3-Nitro-4-(trifluoromethyl)benzoic acid To a rapidly stirred mixture of 1.00 g (4.88 mmol) of 2-nitro-4-methylbenzotrifluoride (from Step A), 236 mg (0.732 mmol) of tetra-n-butylammonium bromide, 51 mg (0.244 mmol) of ruthenium trichloride hydrate, and 2 mL of 1,2-dichloroethane were added five 5.8 -mL (approximately 22 mmol) portions of 13percent sodium hypochlorite solution (aqueous, approx. 3.8M) while monitoring and adjusting the pH. With each addition of sodium hypochlorite solution, 5N NaOH was added as necessary to maintain the pH between 8.5 and 10.5, and the next portion of sodium hypochlorite was added only when the pH was stable for about 5 minutes. The entire addition required approximately 2 hours, and the final pH was 10.3. After being stirred overnight at 45° C., the 2-phase mixture was cooled and separated. The aqueous phase was acidified to pH 3 by addition of 20percent sulfuric acid and extracted 3* with ethyl acetate. The combined organic extracts were washed with H2 O (3*), then with brine, and dried over anhydrous Na2 SO4. The residue obtained upon concentration was taken up in 5percent NaHCO3 (aqueous) adjusted to pH 9 with 5percent NaOH. The aqueous phase was washed twice with methylene chloride and then with ether. Next, the water phase was acidified with 20percent sulfuric acid and extracted with ethyl acetate as above to yield 563 mg (49percent) of the title compound as an off-white solid, mp 156°-158° C.; TLC in 1:1 hexane-EtOAc (at origin); mass spectrum (EI) m/e 235 (M+). 200 MHz 1 H NMR (CD3 OD) δ7.87 (d, J=8 Hz, 1H), 8.31 (d, J=8 Hz, 1H), 8.45 (s, 1H).
Reference：
[1] Patent: US5262412, 1993, A,
3
[ 1514-87-0 ]
[ 5326-34-1 ]
[ 154057-13-3 ]
Yield
Reaction Conditions
Operation in experiment
57%
With potassium fluoride; copper(I) iodide In N,N-dimethyl-formamide
Step A 2-Nitro-4-methylbenzotrifluoride A mixture of 6.00 g (27.8 mmol) of 4-bromo-3-nitrotoluene, 5.86 mL (8.03 g, 55.6 mmol) of methyl chlorodifluoroacetate, 1.93 g (33.4 mmol) of potassium fluoride, 5.31 g (27.8 mmol) of cuprous iodide, and 25 mL of dry DMF was stirred at 110° C. for 2 days. The cooled material was diluted with aqueous citric acid and extracted 3* with ethyl acetate. The combined organic extracts were washed with H2 O, then with brine, and dried over anhydrous Na2 SO4. The residue obtained upon concentration of the filtered solution was flash chromatographed 3* on silica gel (elution with 100:1 and 25:1 hexane-EtOAc) to give 3.25 g (57percent) of the title compound as a yellow liquid; homogeneous by TLC in 4:1 hexane-EtOAc; mass spectrum (EI) m/e 205 (M+). 400 MHz 1 H NMR (CDCl3) δ2.48 (s, 3H), 7.49 (d, J=8 Hz, 1H), 7.67 (s, 1H) overlapping 7.68 (d, J=8 Hz, 1H).
With potassium fluoride; copper(I) iodide; In N,N-dimethyl-formamide;
Step A 2-Nitro-4-methylbenzotrifluoride A mixture of 6.00 g (27.8 mmol) of 4-bromo-3-nitrotoluene, 5.86 mL (8.03 g, 55.6 mmol) of methyl chlorodifluoroacetate, 1.93 g (33.4 mmol) of potassium fluoride, 5.31 g (27.8 mmol) of cuprous iodide, and 25 mL of dry DMF was stirred at 110 C. for 2 days. The cooled material was diluted with aqueous citric acid and extracted 3* with ethyl acetate. The combined organic extracts were washed with H2 O, then with brine, and dried over anhydrous Na2 SO4. The residue obtained upon concentration of the filtered solution was flash chromatographed 3* on silica gel (elution with 100:1 and 25:1 hexane-EtOAc) to give 3.25 g (57%) of the title compound as a yellow liquid; homogeneous by TLC in 4:1 hexane-EtOAc; mass spectrum (EI) m/e 205 (M+). 400 MHz 1 H NMR (CDCl3) delta2.48 (s, 3H), 7.49 (d, J=8 Hz, 1H), 7.67 (s, 1H) overlapping 7.68 (d, J=8 Hz, 1H).
With sodium hydroxide; sodium hypochlorite; sulfuric acid; tetrabutylammomium bromide;ruthenium (III) chloride hydrate; In NaHCO3 (aqueous);
Step B 3-Nitro-4-(trifluoromethyl)benzoic acid To a rapidly stirred mixture of 1.00 g (4.88 mmol) of <strong>[154057-13-3]2-nitro-4-methylbenzotrifluoride</strong> (from Step A), 236 mg (0.732 mmol) of tetra-n-butylammonium bromide, 51 mg (0.244 mmol) of ruthenium trichloride hydrate, and 2 mL of 1,2-dichloroethane were added five 5.8 -mL (approximately 22 mmol) portions of 13% sodium hypochlorite solution (aqueous, approx. 3.8M) while monitoring and adjusting the pH. With each addition of sodium hypochlorite solution, 5N NaOH was added as necessary to maintain the pH between 8.5 and 10.5, and the next portion of sodium hypochlorite was added only when the pH was stable for about 5 minutes. The entire addition required approximately 2 hours, and the final pH was 10.3. After being stirred overnight at 45 C., the 2-phase mixture was cooled and separated. The aqueous phase was acidified to pH 3 by addition of 20% sulfuric acid and extracted 3* with ethyl acetate. The combined organic extracts were washed with H2 O (3*), then with brine, and dried over anhydrous Na2 SO4. The residue obtained upon concentration was taken up in 5% NaHCO3 (aqueous) adjusted to pH 9 with 5% NaOH. The aqueous phase was washed twice with methylene chloride and then with ether. Next, the water phase was acidified with 20% sulfuric acid and extracted with ethyl acetate as above to yield 563 mg (49%) of the title compound as an off-white solid, mp 156-158 C.; TLC in 1:1 hexane-EtOAc (at origin); mass spectrum (EI) m/e 235 (M+). 200 MHz 1 H NMR (CD3 OD) delta7.87 (d, J=8 Hz, 1H), 8.31 (d, J=8 Hz, 1H), 8.45 (s, 1H).
With palladium 10% on activated carbon; hydrogen; In methanol; under 760.051 Torr; for 4h;
Step 1: 5-methyl-2-(trifluoromethyl) aniline Pd/C (0.2g, 10%content) was added to 4-methyl-2-nitro-1-trifluoromethylbenzene (1g, 4.8mmol) in methanol (30mL) in a 100mL reaction flask. The reaction mixture was stirred for 4 hours under hydrogen atmosphereofl atmospheric pressure at 25C. After completion of the reaction, the reaction solution was filtered and concentrated and the residue was separated and purified by column chromatography (ethyl acetate/petroleum ether=1:10) to obtain the title compound (0.68g, 80%). (MS: [M+1] 176.2)
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