* 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.
Reference：
[1] Journal of the American Chemical Society, 2009, vol. 131, # 31, p. 11049 - 11061
3
[ 328-75-6 ]
[ 105653-15-4 ]
[ 328-74-5 ]
Reference：
[1] Synthesis, 2006, # 19, p. 3316 - 3340
4
[ 328-75-6 ]
[ 75092-04-5 ]
[ 328-74-5 ]
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1980, vol. 16, p. 1031 - 1038[2] Zhurnal Organicheskoi Khimii, 1980, vol. 16, # 6, p. 1194 - 1202
5
[ 328-73-4 ]
[ 328-74-5 ]
Reference：
[1] Tetrahedron, 2010, vol. 66, # 38, p. 7642 - 7650
[2] Journal of Organic Chemistry, 2016, vol. 81, # 1, p. 330 - 335
6
[ 328-75-6 ]
[ 75092-05-6 ]
[ 328-74-5 ]
Reference：
[1] Journal of Organic Chemistry USSR (English Translation), 1980, vol. 16, p. 1031 - 1038[2] Zhurnal Organicheskoi Khimii, 1980, vol. 16, # 6, p. 1194 - 1202
7
[ 23165-29-9 ]
[ 328-74-5 ]
Yield
Reaction Conditions
Operation in experiment
187 mg
With triethylamine In dichloromethane; chloroform
General procedure: To a ice cooled solution of N-Boc-aminoacid (L-tertleucine, L-Leu, L-Val, L-Phe, L-Ala) 1mmol in DCM 10 ml, HOBt hydrate (0.153 g, 1 mmol) and DCC (0.205 g, 1 mmol) was added. Reaction mixture was stirred at 0°C through 30 minutes, and amine 7 a-g (2 mmol) was added. Resulting reaction mixture was stirred for 12 h and allowed to warm to room temperature. Then a few drops of acetic acid was added, solvents was removed under reduced pressure. Residue was dissolved in AcOEt and cooled to 4°C, precipitate of urea was removed by filtration. Organic phase was washed with aqueous solution of KHSO4 (10percent, 20ml) followed by aqueous solution of NaHCO3 (5percent, 20ml) and dried with MgSO4. Solvents were removed under reduced pressure and residue was dissolved in 10ml mixture of TFA:DCM (1:1). Progress of N-deprotection was monitored with TLC. Then mixture of TFA:DCM was evaporated and trifluoroacetate salt was dissolved in DCM 10 ml. To a resulted mixture NEt3 (0.303 g, 3 mmol) and chloroform solution of isothiocyanate 9a,b[2] was added dropwise. After completion of the reaction, the solvent was removed under vacuum, and the residue was purified with flash column chromatography. (S)-N-benzyl-2-(3-(3,5-bis(trifluoromethyl)phenyl)thioureido)-3,3-dimethylbutanamide (10a)Purification by flash column chromatography, (EtOAc/Hex, gradient elution 1:5 to 1:3),(187 mg, 38percent over two steps). white solid; mp 149–151 °C; [α]D26 −12.5° (c 0.4,CHCl3); 1H NMR (500 MHz, C6D6) δ 8.60 (s, 1H), 8.06 (d, J 9.2 Hz, 1H), 7.99 (s, 2H),7.42 (s, 1H), 6.96–6.90 (m, 4H), 6.89–6.84 (m, 1H), 5.51 (s, 1H), 5.02 (d, J 9.2 Hz,1H), 4.08 (dd, J2 14.7 Hz, J3 6.4 Hz, 1H), 3.88 (dd, J2 14.7 Hz, J3 5.3 Hz, 1H),0.97 (s, 9H); 13C NMR (CDCl3, 100 MHz): δ 181.9, 172.1, 139.9, 136.2, 131.7 (q, JC–F 33.3 Hz), 128.8, 127.9, 127.6, 124.2 (m), 123.0 (q, JC–F 271.1 Hz), 118.5 (m), 66.4, 44.2,35.1, 27.2; HRMS (ESI): m/z [MNa] calcd for C22H23F6N3OSNa: 514.1364; found:514.1368.
Reference：
[1] Journal of the American Chemical Society, 1946, vol. 68, p. 1602,1603
[2] Journal of the American Chemical Society, 1951, vol. 73, p. 3579
[3] Journal of the American Chemical Society, 1953, vol. 75, p. 4967
10
[ 402-31-3 ]
[ 328-74-5 ]
Reference：
[1] Journal of the American Chemical Society, 1953, vol. 75, p. 4967
Reference：
[1] Patent: US2547679, 1950, ,
[2] Collection of Czechoslovak Chemical Communications, 1987, vol. 52, # 5, p. 1340 - 1351
13
[ 328-74-5 ]
[ 349-58-6 ]
Reference：
[1] Patent: US2547679, 1950, ,
14
[ 328-74-5 ]
[ 328-73-4 ]
Reference：
[1] Organic Letters, 2017, vol. 19, # 10, p. 2518 - 2521
[2] Journal of the American Chemical Society, 1953, vol. 75, p. 4967
[3] Australian Journal of Chemistry, 1979, vol. 32, p. 1521 - 1530
[4] Organic Letters, 2018, vol. 20, # 17, p. 5167 - 5171
Reference：
[1] Journal of the American Chemical Society, 1990, vol. 112, # 12, p. 4976 - 4977
[2] Tetrahedron Letters, 1990, vol. 31, # 26, p. 3715 - 3718
[3] Journal of the American Chemical Society, 1982, vol. 104, # 8, p. 2183 - 2189
[4] Organic and Biomolecular Chemistry, 2010, vol. 8, # 23, p. 5324 - 5332
18
[ 13675-18-8 ]
[ 328-74-5 ]
[ 73852-19-4 ]
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 22, p. 6608 - 6612
19
[ 328-74-5 ]
[ 73852-19-4 ]
Reference：
[1] Chemistry - A European Journal, 2014, vol. 20, # 22, p. 6608 - 6612
20
[ 328-74-5 ]
[ 69807-91-6 ]
Reference：
[1] Advanced Synthesis and Catalysis, 2013, vol. 355, # 6, p. 1083 - 1088
[2] Tetrahedron Letters, 2014, vol. 55, # 10, p. 1702 - 1705
21
[ 321-14-2 ]
[ 328-74-5 ]
[ 978-62-1 ]
Yield
Reaction Conditions
Operation in experiment
85.5%
With phosphorus trichloride In toluene for 3 h; Heating / reflux
A mixture of 5-chlorosalicylic acid(6.90g, 40mmol), 3,5-bis(trifluoromethyl)aniline(9.16g, 40mmol), phosphorus trichloride(1.74mL, 20mmol) and toluene(80mL) was refluxed for 3 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate(240mL). After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(13.12g, 85.5percent) as a light yellow solid.1H-NMR(DMSO-d6): δ 7.05(1H, d, J=8.7Hz), 7.49(1H, dd, J=8.7, 2.7Hz), 7.85(1H, s), 7.87(1H, d, J=2.7Hz), 8.45(2H, s), 10.85(1H, s), 11.39(1H, s).
62%
With phosphorus trichloride In chlorobenzeneMicrowave irradiation
General procedure: All salicylanilides(1a-8d) were synthesized via a previously described microwave assisted (MicroSYNTH Milestone) method.25 Briefly,the appropriately substituted salicylic acid (1 eq) and the substituted aniline (1 eq) were suspended or dissolved in chlorobenzene(1 mL/0.15 mmol of acid). Phosphorus trichloride (PCl3) was added(0.5 eq) and the mixture was stirred (600 rpm) and radiated(530 W) for 30–60 min. The mixture was filtrated while hot and was let cool, initially at r.t. and overnight at 4 °C. The formed pre-cipitate was filtered and recrystallized with ethanol or mixture of hexane/AcOEt in order to afford the final compounds with yields of 41–83percent.
57%
With trichlorophosphate In toluene for 6 h; Inert atmosphere; Reflux
To 30 ml and of toluene were added 5-chlorosalicylic acid (862 mg, 5 mmol), 3,5-bis(trifluoromethyl)aniline (1.37 g, 6 mmol), and phosphoroustrichloride (755 mg, 5.5 mmol) in the presence of argon gas, followed by stirring for 6 hours through heat-reflux. Sodium hydrogen carbonate was added to the mixture to adjust pH to 7, followed by concentration under reduced pressure. The mixture was dissolved in 60 ml and of ethylacetate, which was washed with water (40 ml*2). The organic layer was concentrated under reduced pressure, followed by column chromatography to give 1.09 g of the target compound (yield: 57percent). m.p: 172-173° C.; 1H-NMR (300 MHz, DMSO-d6): δ 7.05 (1H, d, J=8.7 Hz), 7.49 (1H, dd, J=8.7, 2.7 Hz), 7.85 (1H, s), 7.87 (1H, d, J=2.7 Hz), 8.45 (2H, s), 10.85 (1H, s), 11.39 (1H, s).
28%
With pyridine; phosphorus trichloride In toluene for 12 h; Inert atmosphere; Reflux
General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley’s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6–7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).
28%
With pyridine; phosphorus trichloride In tolueneInert atmosphere; Reflux
Phosphorus trichloride (0.13ml, 1.5mmol) was added to a stirred solution of 3,5-bis(trifluoromethyl)aniline (0.47ml, 3mmol), a catalytic amount of pyridine and 5-chloro salicylic acid (621.3mg, 3.6mmol) in anhydrous toluene (10ml) in in a Radley’s Carousel reaction tube under an argon atmosphere. After the reaction mixture was refluxed for overnight, it was cooled to room temperature and aq. sodium bicarbonate was added dropwise until PH=6 - 7. After extracting with ethyl acetate, the organic layers was dried, dried (MgSO4) and concentrated in vacuo. After chromatography (EA-Hex, 1:10) of the crude product, and followed by recrystalization from EtOAc/hexane provided 2a as a white solid (320mg, 28percent). mp 172 - 173 oC. 1H NMR (DMSO-d6) δ 11.37(brs, 1H), 10.91(s, 1H), 8.43(s, 2H), 7.85-7.88(m, 2H), 7.49(dd, J1=8.7Hz, J2=2.9Hz, 1H), 7.05(d, J=8.7Hz, 1H).
Reference：
[1] Patent: EP1352650, 2003, A1,
[2] Patent: EP1512397, 2005, A1, . Location in patent: Page/Page column 77
[3] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 4, p. 1524 - 1532
[4] Patent: US2014/221411, 2014, A1, . Location in patent: Paragraph 0192; 0193
[5] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 1, p. 114 - 126
[6] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 6, p. 1748 - 1751
[7] Journal of Medicinal Chemistry, 2012, vol. 55, # 19, p. 8375 - 8391,17
[8] Journal of Medicinal Chemistry, 2012, vol. 55, # 19, p. 8375 - 8391
22
[ 328-74-5 ]
[ 268733-18-2 ]
Yield
Reaction Conditions
Operation in experiment
340 mg
With N-Bromosuccinimide In N,N-dimethyl-formamide at 50℃; for 1 h;
3,5-Bis(trifluoromethyl)aniline (2 g, 8.7 mmol, 1 equiv) was dissolved in DMF (6 mL, 1.5 M). N-bromosuccinimide (1.7 g, 9.6 mmol, 1.1 equiv) was added, and this mixture was stirred at 50 °C for one hour. After cooling to room temperature, water was added (100 mL) followed by extraction with EtOAc. The crude product was purified by column chromatography (1:10 → 1:5 EtOAc:Hex) to give 4-bromo-3,5-bis-(trifluoromethyl)-aniline (340 mg) & 2-bromo-3,5-bis-(trifluoromethyl)aniline (680 mg).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2013, vol. 23, # 6, p. 1748 - 1751
[2] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 1, p. 114 - 126
With triethylamine; In tetrahydrofuran; at 20℃; for 24.0h;Inert atmosphere;
A nitrogen atmosphere in Dry tetrahydrofuran (THF) 200 mL in 3,5-bis (trifluoromethyl) aniline (4 mL, 26 mmol, 1 eq) and the mixture, triethylamine (4.2 mL, 30 mmol, 1.2 eq) was slowly added.Was added over a period of about 3 minutes thiophosgene (0.78 mL, 10 mmol, 0.4 eq) to the solution, and reaction was allowed to stir at room temperature for 24 hours.After the reaction was terminated and the product extracted by the addition of 200 mL of distilled water and diethyl ether (200 mL X 3) After the solvent was removed.Then produce a white solid couple was recrystallized for a day at the after the extract was dissolved in dichloromethane refrigerator (0 ~ 5 ), filtered, and precipitated through a precipitation method using a n-hexane was dissolved in THF and filtered, the white solid state of 1,3-bis [3,5-bis (tri-fluoromethyl) phenyl] thiourea was obtained in a yield of 50%.
50%
With triethylamine; In tetrahydrofuran; at 20℃; for 24.0h;Inert atmosphere;
A nitrogen atmosphere in Dry tetrahydrofuran (THF) 200 mL in 3,5-bis (trifluoromethyl) aniline (4 mL, 26 mmol, 1 eq) and the mixture, triethylamine (4.2 mL, 30 mmol, 1.2 eq) was slowly added. Was added over a period of about 3 minutes thiophosgene (0.78 mL, 10 mmol, 0.4 eq) to the solution, and reaction was allowed to stir at room temperature for 24 hours. After the reaction was terminated and the product extracted by the addition of 200 mL of distilled water and diethyl ether (200 mL X 3) After the solvent was removed. After the after the extract was dissolved in dichloromethane refrigerator (0 ~ 5 ) produce a white solid recrystallized placed for one day in, by filtration, and precipitation was filtered through a precipitation method using a n-hexane was dissolved in THF, and whiteThe body state 1,3-bis [3,5-bis (tri-fluoromethyl) phenyl] thiourea was obtained in a yield of 50%.
N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxynicotineamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
With pyridine; phosphorus trichloride; In toluene;Inert atmosphere; Reflux;
General procedure: Phosphorus trichloride (0.13ml, 1.5mmol) was added to a stirred solution of 3,5-bis(trifluoromethyl)aniline (0.47ml, 3mmol), a catalytic amount of pyridine and 5-chloro salicylic acid (621.3mg, 3.6mmol) in anhydrous toluene (10ml) in in a Radley?s Carousel reaction tube under an argon atmosphere. After the reaction mixture was refluxed for overnight, it was cooled to room temperature and aq. sodium bicarbonate was added dropwise until PH=6 - 7. After extracting with ethyl acetate, the organic layers was dried, dried (MgSO4) and concentrated in vacuo. After chromatography (EA-Hex, 1:10) of the crude product, and followed by recrystalization from EtOAc/hexane provided 2a as a white solid (320mg, 28%).
47.6%
With pyridine; trichlorophosphate; In tetrahydrofuran; dichloromethane;
Example 24 N-[3,5-Bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxypyridine-3-carboxamide (Comopund No. 24). 5-Chloro-2-hydroxynicotinic acid(174mg, 1mmol), 3,5-bis(trifluoromethyl)aniline(275mg, 1.2mmol) and pyridine(316mg, 4mmol) were dissolved in tetrahydrofuran(20mL) and dichloromethane(10mL). Phosphorus oxychloride(0.112ml, 1.2mmol) was added, and the mixture was stirred at room temparature for 2 hours. The reaction mixture was poured into ethyl acetate(100mL) and 0.2 N hydrochloric acid(100mL), filtered through celite after stirring for 30 minutes, and the water layer of the filtrate was extracted with ethyl acetate. After the combined ethyl acetate layer was washed with water and brine one after another, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=2:1? 1:1) to give a light yellow solid. This was suspended and washed with ethanol under heating at reflux to give the title compound(183mg, 47.6%) as a white crystal. mp >270ØC. 1H-NMR(DMSO-d6): delta 7.83(1H, s), 8.15(1H, d, J=3.3Hz), 8.36(1H, d, J=3.0Hz), 8.40(2H, s), 12.43(1H, s).
47.6%
With pyridine; trichlorophosphate; In tetrahydrofuran; dichloromethane; at 20℃; for 2h;
Phosphorus oxychloride(0.112ml, 1.2mmol) was added to a solution of <strong>[38076-80-1]5-chloro-2-hydroxynicotinic acid</strong>(174mg, 1mmol), 3,5-bis(trifluoromethyl)aniline(275mg, 1.2mmol), pyridine(316mg, 4mmol) in tetrahydrofuran/dichloromethane(20mL+10mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ethyl acetate(100mL) and 0.2N hydrochloric acid(100mL), filtered through celite after stirring for 30 minutes, and the water layer was extracted with ethyl acetate. After the combined ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=2:1?1:1), washed with ethanol under suspension to give the title compound(183mg, 47.6%) as a white crystal. mp >270C.1H-NMR(DMSO-d6): delta 7.83(1H, s), 8.15(1H, d, J=3.3Hz), 8.36(1H, d, J=3.0Hz), 8.40(2H, s), 12.43(1H, s).
47.6%
With pyridine; trichlorophosphate; In tetrahydrofuran; dichloromethane; at 20℃; for 2h;
Phosphorus oxychloride(0.112ml, 1.2mmol) was added to a solution of <strong>[38076-80-1]5-chloro-2-hydroxynicotinic acid</strong>(174mg, 1mmol), 3,5-bis(trifluoromethyl)aniline(275mg, 1.2mmol), pyridine(316mg, 4mmol) in tetrahydrofuran/dichloromethane(20mL+10mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ethyl acetate(100mL) and 0.2N hydrochloric acid(100mL), filtered through celite after stirring for 30 minutes, and the water layer was extracted with ethyl acetate. After the combined ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=2:1?1:1), washed with ethanol under suspension to give the title compound(183mg, 47.6%) as a white crystal. mp >270C.1H-NMR(DMSO-d6): delta 7.83(1H, s), 8.15(1H, d, J=3.3Hz), 8.36(1H, d, J=3.0Hz), 8.40(2H, s), 12.43(1H, s).
47.6%
With pyridine; trichlorophosphate; In tetrahydrofuran; dichloromethane; at 20℃; for 2h;
5-Chloro-2-hydroxynicotinic acid(174mg, 1mmol), 3,5-bis(trifluoromethyl)aniline(275mg, 1.2mmol) and pyridine(316mg, 4mmol) were dissolved in tetrahydrofuran(20mL) and dichloromethane(10mL). Phosphorus oxychloride(0.112ml, 1.2mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ethyl acetate(100mL) and 0.2N hydrochloric acid(100mL), filtered through celite after stirring for 30 minutes, and the water layer of the filtrate was extracted with ethyl acetate. After the combined ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=2:1?1:1) to give a light yellow solid. This was suspended and washed with ethanol under heating at reflux to give the title compound(183mg, 47.6%) as a white crystal. mp >270C.1H-NMR(DMSO-d6): delta 7.83(1H, s), 8.15(1H, d, J=3.3Hz), 8.36(1H, d, J=3.0Hz), 8.40(2H, s), 12.43(1H, s).
47.6%
With trichlorophosphate; In tetrahydrofuran; dichloromethane; at 20℃; for 2h;
5-Chloro-2-hydroxynicotinic acid(174mg, 1mmol), 3,5-bis(trifluoromethyl)aniline(275mg, 1.2mmol) and pyridine(316mg, 4mmol) were dissolved in tetrahydrofuran(20mL) and dichloromethane(10mL). Phosphorus oxychloride(0.112ml, 1.2mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ethyl acetate(100mL) and 0.2N hydrochloric acid(100mL), filtered through celite after stirring for 30 minutes, and the water layer of the filtrate was extracted with ethyl acetate. After the combined ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=2:1?1:1) to give a light yellow solid. This was suspended and washed with ethanol under heating at reflux to give the title compound(183mg, 47.6%) as a white crystal. mp >270C.1H-NMR(DMSO-d6): delta 7.83(1H, s), 8.15(1H, d, J=3.3Hz), 8.36(1H, d, J=3.0Hz), 8.40(2H, s), 12.43(1H, s).
47.6%
With pyridine; trichlorophosphate; In tetrahydrofuran; dichloromethane; at 20℃; for 2h;
5-Chloro-2-hydroxynicotinic acid(174mg, 1mmol), 3,5-bis(trifluoromethyl)aniline(275mg, 1.2mmol) and pyridine(316mg, 4mmol) were dissolved in tetrahydrofuran(20mL) and dichloromethane(10mL). Phosphorus oxychloride(0.112ml, 1.2mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ethyl acetate(100mL) and 0.2N hydrochloric acid(100mL), filtered through celite after stirring for 30 minutes, and the water layer of the filtrate was extracted with ethyl acetate. After the combined ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=2:1?1:1) to give a light yellow solid. This was suspended and washed with ethanol under heating at reflux to give the title compound(183mg, 47.6%) as a white crystal. mp >270C.1H-NMR(DMSO-d6): delta 7.83(1H, s), 8.15(1H, d, J=3.3Hz), 8.36(1H, d, J=3.0Hz), 8.40(2H, s), 12.43(1H, s).
47.6%
With pyridine; trichlorophosphate; In tetrahydrofuran; dichloromethane; at 20℃; for 2h;
5-Chloro-2-hydroxynicotinic acid(174mg, 1mmol), 3,5-bis(trifluoromethyl)aniline(275mg, 1.2mmol) and pyridine(316mg, 4mmol) were dissolved in tetrahydrofuran(20mL) and dichloromethane(10mL). Phosphorus oxychloride(0.112ml, 1.2mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ethyl acetate(100mL) and 0.2N hydrochloric acid(100mL), filtered through celite after stirring for 30 minutes, and the water layer of the filtrate was extracted with ethyl acetate. After the combined ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel(n-hexane:ethyl acetate=2:1?1:1) to give a light yellow solid. This was suspended and washed with ethanol under heating at reflux to give the title compound(183mg, 47.6%) as a white crystal. mp >270C.1H-NMR(DMSO-d6): delta 7.83(1H, s), 8.15(1H, d, J=3.3Hz), 8.36(1H, d, J=3.0Hz), 8.40(2H, s), 12.43(1H, s).
Example 51 N-[3,5-Bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (Comopund No. 50). Using 5-chlorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound. Yield: 85.5percent. 1H-NMR(DMSO-d6): delta 7.05(1H, d, J=8.7Hz), 7.49(1H, dd, J=8.7, 2.7Hz), 7.85(1H, s), 7.87(1H, d, J=2.7Hz), 8.45(2H, s), 10.85(1H, s), 11.39(1H, s).
85.5%
With phosphorus trichloride; In toluene; for 3.0h;Heating / reflux;
A mixture of 5-chlorosalicylic acid(6.90g, 40mmol), 3,5-bis(trifluoromethyl)aniline(9.16g, 40mmol), phosphorus trichloride(1.74mL, 20mmol) and toluene(80mL) was refluxed for 3 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate(240mL). After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=4:1) to give the title compound(13.12g, 85.5percent) as a light yellow solid.1H-NMR(DMSO-d6): delta 7.05(1H, d, J=8.7Hz), 7.49(1H, dd, J=8.7, 2.7Hz), 7.85(1H, s), 7.87(1H, d, J=2.7Hz), 8.45(2H, s), 10.85(1H, s), 11.39(1H, s).
62%
With phosphorus trichloride; In chlorobenzene;Microwave irradiation;
General procedure: All salicylanilides(1a-8d) were synthesized via a previously described microwave assisted (MicroSYNTH Milestone) method.25 Briefly,the appropriately substituted salicylic acid (1 eq) and the substituted aniline (1 eq) were suspended or dissolved in chlorobenzene(1 mL/0.15 mmol of acid). Phosphorus trichloride (PCl3) was added(0.5 eq) and the mixture was stirred (600 rpm) and radiated(530 W) for 30?60 min. The mixture was filtrated while hot and was let cool, initially at r.t. and overnight at 4 °C. The formed pre-cipitate was filtered and recrystallized with ethanol or mixture of hexane/AcOEt in order to afford the final compounds with yields of 41?83percent.
57%
With trichlorophosphate; In toluene; for 6.0h;Inert atmosphere; Reflux;
To 30 ml and of toluene were added 5-chlorosalicylic acid (862 mg, 5 mmol), 3,5-bis(trifluoromethyl)aniline (1.37 g, 6 mmol), and phosphoroustrichloride (755 mg, 5.5 mmol) in the presence of argon gas, followed by stirring for 6 hours through heat-reflux. Sodium hydrogen carbonate was added to the mixture to adjust pH to 7, followed by concentration under reduced pressure. The mixture was dissolved in 60 ml and of ethylacetate, which was washed with water (40 ml*2). The organic layer was concentrated under reduced pressure, followed by column chromatography to give 1.09 g of the target compound (yield: 57percent). m.p: 172-173° C.; 1H-NMR (300 MHz, DMSO-d6): delta 7.05 (1H, d, J=8.7 Hz), 7.49 (1H, dd, J=8.7, 2.7 Hz), 7.85 (1H, s), 7.87 (1H, d, J=2.7 Hz), 8.45 (2H, s), 10.85 (1H, s), 11.39 (1H, s).
28%
With pyridine; phosphorus trichloride; In toluene; for 12.0h;Inert atmosphere; Reflux;
General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6?7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).
28%
With pyridine; phosphorus trichloride; In toluene;Inert atmosphere; Reflux;
Phosphorus trichloride (0.13ml, 1.5mmol) was added to a stirred solution of 3,5-bis(trifluoromethyl)aniline (0.47ml, 3mmol), a catalytic amount of pyridine and 5-chloro salicylic acid (621.3mg, 3.6mmol) in anhydrous toluene (10ml) in in a Radley?s Carousel reaction tube under an argon atmosphere. After the reaction mixture was refluxed for overnight, it was cooled to room temperature and aq. sodium bicarbonate was added dropwise until PH=6 - 7. After extracting with ethyl acetate, the organic layers was dried, dried (MgSO4) and concentrated in vacuo. After chromatography (EA-Hex, 1:10) of the crude product, and followed by recrystalization from EtOAc/hexane provided 2a as a white solid (320mg, 28percent). mp 172 - 173 oC. 1H NMR (DMSO-d6) delta 11.37(brs, 1H), 10.91(s, 1H), 8.43(s, 2H), 7.85-7.88(m, 2H), 7.49(dd, J1=8.7Hz, J2=2.9Hz, 1H), 7.05(d, J=8.7Hz, 1H).
N-[3,5-bis(trifluoromethyl)phenyl]-5-fluoro-2-hydroxybenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58.7%
Example 50 N-[3,5-Bis(trifluoromethyl)phenyl]-5-fluoro-2-hydroxybenzamide (Comopund No. 49). Using 5-fluorosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound. Yield: 58.7%. 1H-NMR(DMSO-d6):delta 7.04(1H, ddd, J=9.0, 4.5, 1.2Hz), 7.30-7.37(1H, m), 7.66(1H, ddd, J=9.0, 3.3, 1.2Hz), 7.84(1H, s), 8.46(2H, s), 10.85(1H, s), 11.21(1H, brs).
58.7%
With phosphorus trichloride; In chlorobenzene; for 3h;Heating / reflux;
A mixture of 5-fluorosalicylic acid(156mg, 1mmol), 3,5-bis(trifluoromethyl)aniline(229mg, 1mmol), phosphorus trichloride(44 mu L, 0.5mmol) and monochlorobenzene(5mL) was refluxed for 3 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate(50mL). After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=6:1) to give the title compound(215mg, 58.7%) as a white solid.1H-NMR(DMSO-d6):delta 7.04(1H, ddd, J=9.0, 4.5, 1.2Hz), 7.30-7.37(1H, m), 7.66(1H, ddd, J=9.0, 3.3, 1.2Hz), 7.84(1H, s), 8.46(2H, s), 10.85(1H, s), 11.21(1H, brs).
58.7%
With phosphorus trichloride; In chlorobenzene; for 3h;Heating / reflux;
A mixture of 5-fluorosalicylic acid(156mg, 1mmol), 3,5-bis(trifluoromethyl)aniline(229mg, 1mmol), phosphorus trichloride(44 mu L, 0.5mmol) and monochlorobenzene(5mL) was refluxed for 3 hours under argon atmosphere. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate(50mL). After the ethyl acetate layer was washed successively with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel(n-hexane:ethyl acetate=6:1) to give the title compound(215mg, 58.7%) as a white solid.1H-NMR(DMSO-d6):delta 7.04(1H, ddd, J=9.0, 4.5, 1.2Hz), 7.30-7.37(1H, m), 7.66(1H, ddd, J=9.0, 3.3, 1.2Hz), 7.84(1H, s), 8.46(2H, s), 10.85(1H, s), 11.21(1H, brs).
48%
With pyridine; phosphorus trichloride; In toluene;Inert atmosphere; Reflux;
General procedure: Phosphorus trichloride (0.13ml, 1.5mmol) was added to a stirred solution of 3,5-bis(trifluoromethyl)aniline (0.47ml, 3mmol), a catalytic amount of pyridine and 5-chloro salicylic acid (621.3mg, 3.6mmol) in anhydrous toluene (10ml) in in a Radley?s Carousel reaction tube under an argon atmosphere. After the reaction mixture was refluxed for overnight, it was cooled to room temperature and aq. sodium bicarbonate was added dropwise until PH=6 - 7. After extracting with ethyl acetate, the organic layers was dried, dried (MgSO4) and concentrated in vacuo. After chromatography (EA-Hex, 1:10) of the crude product, and followed by recrystalization from EtOAc/hexane provided 2a as a white solid (320mg, 28%).
With N-ethyl-N,N-diisopropylamine; In dichloromethane; water;
Step 6 Using a Phenyl Carbamate or Nitrophenyl Carbamate 3,5-Bis-(trifluoromethyl)aniline (2.0 g, 8.7 mmol) was dissolved in dichloromethane (80 mL) and N,N-diisopropylethylamine (1.6 mL, 9.6 mmol) was added followed by slow addition of phenyl chloroformate (1.1 mL, 8.7 mmol). The resulting mixture was stirred at room temperature for 16 hours. The mixture was successively washed with 1N hydrochloric acid (3*100 mL), water (3*100 mL), a mixture of water and saturated aqueous sodium hydrogen carbonate (1:1, 2*100 mL) and a mixture of water and saturated aqueous sodium chloride (1:1, 3*100 mL), dried (MgSO4) and concentrated in vacuo. The residue was crystallized from heptane containing a little diethyl ether to afford 1.3 g (43%) of (3,5-bis-trifluoromethylphenyl)<strong>[622-46-8]carbamic acid phenyl ester</strong> as a solid. Calculated for C15H9F6NO2: C, 51.59%; H, 2.60%; N, 4.01%. Found: C, 51.27%; H, 2.56%; N, 4.01%; C, 51.40%; H, 2.57%; N, 3.92%.
With N-chloro-succinimide; triethylamine; In tetrachloromethane; dichloromethane;
4.6-bis-(Trifluoromethyl)-1H-indol-2,3-dione Freshly prepared t BuOCl (2.2 g, 20 mmol) was added dropwise to a stirred cold (-65 C.) solution of 3,5-bis-(trifluoromethyl)aniline (4.58 g, 20 mmol) in anhydrous CH2 Cl2 (25 mL). After 10 minutes, neat ethyl (methylthio)acetate (2.68 g, 20 mmol) was added and the mixture; stirred at -65 C. for 1 hr. Triethylamine (2.68 g, 20 mmol) was added and then the mixture was allowed to warm to room temperature. The reaction mixture was quenched with water, the organic layer was separated and then rotary evaporated. The oily residue (6.35 g) was dissolved in hexanes and boiled for several hours and then allowed to cool. The precipitated beige solid was filtered and washed with hexanes to afford 3.67 g of pure (methylthio) indolone intermediate. N-chlorosuccinimide (1.31 g, 9.8 mmol) was added to a stirred solution of (methylthio) indolone (2.95 g, 9.4 mmol) in CCl4 (150 mL). The mixture was stirred at room temperature for 6.5 hours. The suspension was filtered, washed with CCl4 and the filtrate was rotary evaporated at 25-30 C. The residual light-brown oil was dissolved in a minimum volume (~5-10 mL) of CCl4 and kept in an ice bath. The precipitated last traces of succinimide were filtered and washed with hexanes.
With N-chloro-succinimide; triethylamine; In tetrachloromethane; dichloromethane;
4,6-bis-(Trifluoromethyl)-1H-indol-2,3-dione Freshly prepared t BuOCl (2.2 g, 20 mmol) was added dropwise to a stirred cold (-65 C.) solution of 3,5-bis-(trifluoromethyl)aniline (4.58 g, 20 mmol) in anhydrous CH2 Cl2 (25 mL). After 10 minutes, neat ethyl (methylthio)acetate (2.68 g, 20 mmol) was added and the mixture stirred at -65 C. for 1 hr. Triethylamine (2.68 g, 20 mmol) was added and then the mixture was allowed to warm to room temperature. The reaction mixture was quenched with water, the organic layer was separated and then rotary evaporated. The oily residue (6.35 g) was dissolved in hexanes and boiled for several hours and then allowed to cool. The precipitated beige solid was filtered and washed with hexanes to afford 3.67 g of pure (methylthio) indolone intermediate. N-chlorosuccinimide (1.31 g, 9.8 mmol) was added to a stirred solution of (methylthio) indolone (2.95 g, 9.4 mmol) in CCl4 (150 mL). The mixture was stirred at room temperature for 6.5 hours. The suspension was filtered, washed with CCl4 and the filtrate was rotary evaporated at 25-30 C. The residual light-brown oil was dissolved in a minimum volume (~5-10 mL) of CCl4 and kept in an ice bath. The precipitated last traces of succinimide were filtered and washed with hexanes.
N-[5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-3,5-bistrifluoromethylaniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triethylamine; In dichloromethane;
Example 113 N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-3,5-bistrifluoromethylaniline 3,5-Bistrifluoromethylaniline (0.368 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and <strong>[37091-73-9]2-chloro-1,3-dimethylimidazolinium chloride</strong> (0.271 g, 1.604 mmol) were added to a methylene chloride solution (20 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexane: ethyl acetate = 1:2) and then recrystallized from ether to obtain the titled compound (0.196 g, 0.335 mmol, 63percent).
N-[3,5-Bis(trifluoromethyl)phenyl]-3-hydroxyquinoxaline-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.7%
Example 29 N-[3,5-Bis(trifluoromethyl)phenyl]-3-hydroxyquinoxaline-2-carboxamide (Comopund No. 29). Using <strong>[1204-75-7]3-hydroxyquinoxaline-2-carboxylic acid</strong> and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound. Yield: 2.7%. 1H-NMR(DMSO-d6): delta 7.40-7.45(2H, m), 7.69(1H, td, J=8.4, 1.5Hz), 7.90-7.93(2H, m), 8.41(2H, s), 11.64(1H, s), 13.02(1H, s).
N-(3,5-bis(trifluoromethyl)phenyl)-5-bromo-2-hydroxybenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
88.5%
Example 52 N-[3,5-Bis(trifluoromethyl)phenyl]-5-bromo-2-hydroxybenzamide (Comopund No. 51). Using 5-bromosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound. Yield: 88.5%. 1H-NMR(DMSO-d6): delta 6.98(1H, d, J=8.8Hz), 7.59(1H, dd, J=8.8, 2.8Hz), 7.83(1H, s), 7.98(1H, d, J=2.8Hz), 8.43(2H, s), 10.82(1H, s), 11.37(1H, s).
83%
With phosphorus trichloride; In chlorobenzene;Microwave irradiation;
General procedure: All salicylanilides(1a-8d) were synthesized via a previously described microwave assisted (MicroSYNTH Milestone) method.25 Briefly,the appropriately substituted salicylic acid (1 eq) and the substituted aniline (1 eq) were suspended or dissolved in chlorobenzene(1 mL/0.15 mmol of acid). Phosphorus trichloride (PCl3) was added(0.5 eq) and the mixture was stirred (600 rpm) and radiated(530 W) for 30-60 min. The mixture was filtrated while hot and was let cool, initially at r.t. and overnight at 4 C. The formed pre-cipitate was filtered and recrystallized with ethanol or mixture of hexane/AcOEt in order to afford the final compounds with yields of 41-83%.
14%
With pyridine; phosphorus trichloride; In toluene;Inert atmosphere; Reflux;
General procedure: Phosphorus trichloride (0.13ml, 1.5mmol) was added to a stirred solution of 3,5-bis(trifluoromethyl)aniline (0.47ml, 3mmol), a catalytic amount of pyridine and 5-chloro salicylic acid (621.3mg, 3.6mmol) in anhydrous toluene (10ml) in in a Radley?s Carousel reaction tube under an argon atmosphere. After the reaction mixture was refluxed for overnight, it was cooled to room temperature and aq. sodium bicarbonate was added dropwise until PH=6 - 7. After extracting with ethyl acetate, the organic layers was dried, dried (MgSO4) and concentrated in vacuo. After chromatography (EA-Hex, 1:10) of the crude product, and followed by recrystalization from EtOAc/hexane provided 2a as a white solid (320mg, 28%).
With pyridine; phosphorus trichloride; In toluene; for 12h;Inert atmosphere; Reflux;
General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6-7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).
Example 95 N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-([(4-pyridin-2-yl)sulfamoyl]phenyl}diazenyl)benzamide (Comopund No. 94). Using 5-([(4-pyridin-2-yl)sulfamoyl]phenyl}diazenyl)salicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound. Yield: 7.9%. 1H-NMR(DMSO-d6): delta 6.87(1H, t, J=6.0Hz), 7.22(1H, d, J=8.7Hz), 7.21-7.23(1H, m), 7.77(1H, t, J=8.4Hz), 7.87(1H, s), 7.95-7.98(3H, m), 8.03-8.07(4H, m), 8.47(1H, d, J=2.4Hz), 8.49(2H, s), 11.14(1H, s), 12.03(1H, br).
(2) 4-Acetylamino-N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-methoxybenzamide. Using <strong>[24201-13-6]4-acetylamino-5-chloro-2-methoxybenzoic acid</strong> and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 24 gave the title compound. Yield: 23.8%. 1H-NMR(DMSO-d6):delta 2.17(3H, s), 3.89(3H, s), 7.77-7.82(3H, m), 8.45-8.49(2H, m), 9.66(1H, s), 10.68(1H, s).
(2) N-(3,5-Bis(trifluoromethyl)phenyl]-2-methoxy-5-sufamoylbenzamide. Using <strong>[22117-85-7]2-methoxy-5-sulfamoylbenzoic acid</strong> and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 24 gave the title compound. Yield: 24.2%. 1H-NMR(DMSO-d6): delta 3.97(3H, s), 7.38(2H, s), 7.39(1H, d, J=8.7Hz), 7.85(1H, s), 7.96(1H, dd, J=8.7, 2.4Hz), 8.06(1H, d, J=2.4Hz), 8.43(2H, s), 10.87(1H, s).
N-(3,5-bis(trifluoromethyl)phenyl)-2-hydroxy-5-methylbenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
54.9%
Example 56 N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-methylbenzamide (Comopund No. 55). Using 5-methylsalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound. Yield: 54.9%. 1H-NMR(DMSO-d6): delta 6.92(1H, d, J=8.7Hz), 7.28(1H, dd, J=8.7, 1.8Hz), 7.71(1H, d, J=1.8Hz), 7.82(1H, s), 8.47(2H, s), 10.80(1H, s), 11.14(1H, s).
22%
With pyridine; phosphorus trichloride; In toluene; for 12h;Inert atmosphere; Reflux;
General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6-7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).
22%
With pyridine; phosphorus trichloride; In toluene;Inert atmosphere; Reflux;
General procedure: Phosphorus trichloride (0.13ml, 1.5mmol) was added to a stirred solution of 3,5-bis(trifluoromethyl)aniline (0.47ml, 3mmol), a catalytic amount of pyridine and 5-chloro salicylic acid (621.3mg, 3.6mmol) in anhydrous toluene (10ml) in in a Radley?s Carousel reaction tube under an argon atmosphere. After the reaction mixture was refluxed for overnight, it was cooled to room temperature and aq. sodium bicarbonate was added dropwise until PH=6 - 7. After extracting with ethyl acetate, the organic layers was dried, dried (MgSO4) and concentrated in vacuo. After chromatography (EA-Hex, 1:10) of the crude product, and followed by recrystalization from EtOAc/hexane provided 2a as a white solid (320mg, 28%).
Example 53 N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide (Comopund No. 52). Using 5-iodosalicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound. Yield: 62.2%. 1H-NMR(DMSO-d6): delta 6.86(1H, d, J=8.4Hz), 7.74(1H, dd, J=8.7, 2.4Hz), 7.84(1H, s), 8.13(1H, d, J=2.1Hz), 8.84(2H, s), 10.82(1H, s), 11.41(1H, s).
With pyridine; phosphorus trichloride; In toluene; for 12h;Inert atmosphere; Reflux;
General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6-7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 80℃; for 0.5h;Microwave irradiation;
EXAMPLE 16; Synthesis of (E)-N-(3,5-bis(trifluoromethyl)phenyl)-4-(3-(4-fluorophenyl)acrylamido) piperidine-4-carboxamide (Compound 32) A. Synthesis of tert-butyl 4-((9H-fluoren-9-yl)methoxy)carbonylamino)-4-(3,5-bis(trifluoromethyl)phenylcarbamoyl)piperidine-1-carboxylate To a solution of 1-N-BOC-4-N-Fmoc-amino-4-carboxylic-piperidine (150 mg, 0.30 mmol), 3,5-bis(trifluoromethyl)aniline (0.15 mL, 0.96 mmol), diisopropylethylamine (DIPEA) (0.12 mL, 0.32 mmol) in DMF (2 mL) was added O-(7-azabenzotriazole-1yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (120 mg, 0.30 mmol). The solution was stirred in microwave for 0.5 hours at 80 C. and concentrated in vacuo. The residue was diluted with EtOAc, washed consecutively with saturated aqueous NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by flash column chromatography using 2:8 EtOAc-DCM to give desired compound (130 mg, 59%) as a white foam.
With dichlorotriphenylphosphorane; In tetrahydrofuran; for 2.0h;Inert atmosphere;
General procedure: To a stirred solution of <strong>[88598-08-7]furazancarboxylic acid</strong> 2 (2.6 mmol) and the appropriate aniline 3-14 (2.6 mmol) in dry THF (25 mL) Ph3PCl2 (5.46 mmol, 2.1 eq) was added portionwise under an inert atmosphere. The resulting suspension was stirred for 2 h, then poured into chilled 2 M HCl (50 mL). The mixture was extracted exhaustively with Et2O, then the collected organic layers were dried and concentrated under reduced pressure. The residue was purified by flash chromatography obtaining the title compound.
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 16h;
B. Synthesis ofN-(3,5-bis(trifluoromethyl)phenyl)-2-(2-oxopiperazin-l- yl)acetamide[00101] A 500 mL, single-necked, round-bottomed flask equipped with a magnetic stir bar was charged with 2-(4-tert-butoxycarbonyl)-2-oxopiperazin-l-yl)acetic acid (13.0 g, 50.3 mmol), 3,5-bis(trifluoromethyl)aniline (12.6 g, 55.3 mmol), and <9-(7- azabenzotriazol- 1 -yl)-N,NN',N'-tetramethylruonium hexafluorophosphate (HATU) (22.8 g, 60.0 mmol) in DMF (100 mL). Diisopropylethylamine (DIPEA) (10.3 g, 80.0 mmol) was added. The reaction mixture was stirred at room temperature for 16 h and then concentrated to -60 mL by rotary evaporation. Saturated NaHC03 aqueous solution (200 mL) was added, and the mixture was extracted with EtOAc (2 x 200 mL) and water (200 mL), and was dried over anhydrous Na2S04. After filtration, the filtrate was concentrated by rotary evaporation, and the residue was purified by flash chromatography on silica gel (CH2CI2, then EtOAc hexanes, 1 :1 in v/v) followed by recrystallization from CH2Cl2/hexanes to give a white solid (20. Og, 85%).[00102] The solid (17 g, 36.2 mmol) was treated with saturated HC1 in EtOAc (350 mL) for 10 min to affort the desired compound quantitatively. Purity (HPLC): 100%. 1H NMR (400 MHz, D20) δ 3.61 (t, 2H, J=5.4 Hz), 3.71 (t, 2H, J=5.4Hz), 3.96 (s, 2H), 4.32 (s, 2H), 7.73 (s, 1H), 7.88 (s, 2H). ES-MS m/z 370.2 (M+H). Anal. Cacld. For C]4H13F6N3O2-1.0HCl-0.63H2O: C, 40.37; H, 3.68; N, 10.09; CI 8.51. Found: C, 40.42; H, 3.75; N, 10.00; CI, 8.50.
With acetic acid; In 1-methyl-pyrrolidin-2-one; at 90℃; for 70h;
A mixture of 10.6 g (20 mmol) of 1,6,7,12-tetrachloroperylene-3,4:9,10-tetracarboxylic dianhydride, 100 ml of NMP, 12.8 g (56 mmol) of 3,5-bis(trifluoromethyl)aniline and 7.2 g (120 mmol) of acetic acid was heated to 90 C. for approx. 70 hours. The reaction mixture was allowed to cool and then poured onto 1000 ml of dilute hydrochloric acid, and the precipitate was filtered off, washed with water and dried under reduced pressure. The product was purified by chromatography on silica gel using a mixture of toluene and petroleum ether employing a concentration gradient. This gave 8.52 g (45%) of an orange powder.Rf(1:1 toluene:dichloromethane)=0.67
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 40℃; for 72h;
Example 2: Synthesis of N-(3,5-bis(trifluoromethyl)phenyl)-2-(pyrroLidin-3- yl)acetamide (7)[00149] 3,5-Bis(trifluoromethyl)aniline (1) (4.58 g, 20.0 mmol), N-Boc-3- pyrrolidine acetic acid (5) (4.0 g, 17.4 mmol), DIPEA (5.2 mL, 30 mmol) and HATU (9.5 g, 25 mmol) were stirred in DMF (40 mL) at 40C for 72 h. The reaction was diluted with saturated NH4C1 solution, extracted with Et20, washed with saturated NaHC03 solution, dried, and concentrated in vacuo. The residue was purified by automated column chromatography (0-40 % EtOAc, PE) to give tert-butyl 3-(2-(3,5- bis(trifluoromethyl)phenylamino)-2-oxoethyl)pyrrolidine- 1 -carboxylate (6) .
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 40℃; for 72h;
Example 3: Synthesis of 2-(azetidin-3-yI)-N-(3,5-bis(trifluoromethyI)phenyl)acetamide (10)[00151] 3,5-Bis(trifluoromethyl)aniline (1) (5.04 g, 22.0 mmol), 2-{-(tert- butoxycarbonyl)azetidin-3-yl)acetic acid (8) (4.5 g, 20.9 mmol), DIPEA (5.2 mL, 30 mmol) and HATU (10.6 g, 28 mmol) were stirred in DMF (40 mL) at 40C for 72 h. The reaction was diluted with saturated NH4C1 solution, extracted with Et20, washed with saturated NaHC03 solution, dried, concentrated in-vacuo and the residue purified by automated column chromatography (0-50 % EtOAc, PE) to provide tert-butyl 3-(2- (3,5-bis(trifluoromethyl)phenylamino)-2-oxoethyl)azetidine-l -carboxylate (9).
N-(3,5-bis(trifluoromethyl)phenyl)-3,5-dichloro-2-hydroxybenzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With pyridine; phosphorus trichloride; In toluene; for 12h;Inert atmosphere; Reflux;
General procedure: The salicylic acid (1.2 equiv) was added to a mixture of toluene (0.3 M), aniline (1.0 equiv), phosphorus trichloride (1.1 equiv), and pyridine (0.05 equiv) in a Radley?s Carousel reaction tube (modified from Itai et al.20). The mixture was refluxed under nitrogen for 12 h then cooled to room temperature. Aqueous sodium bicarbonate was added dropwise to attain pH 6-7. The resultant mixture was extracted with EtOAc. The organic extracts were combined, dried (MgSO4), and concentrated under vacuum. After chromatography (1:10 EtOAc:Hex) compounds were recrystallized (EtOAc/Hex).
2-bromo-3,5-bis(trifluoromethyl)-benzenamine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
340 mg; 680 mg
With N-Bromosuccinimide; In N,N-dimethyl-formamide; at 50℃; for 1.0h;
3,5-Bis(trifluoromethyl)aniline (2 g, 8.7 mmol, 1 equiv) was dissolved in DMF (6 mL, 1.5 M). N-bromosuccinimide (1.7 g, 9.6 mmol, 1.1 equiv) was added, and this mixture was stirred at 50 C for one hour. After cooling to room temperature, water was added (100 mL) followed by extraction with EtOAc. The crude product was purified by column chromatography (1:10 ? 1:5 EtOAc:Hex) to give 4-bromo-3,5-bis-(trifluoromethyl)-aniline (340 mg) & 2-bromo-3,5-bis-(trifluoromethyl)aniline (680 mg).
Freshly distilled chlorosulfonic acid (13.2 g, 0.1 mol, 1.0 equiv) was cooled to 15 C in an ice-water bath and 4-chloroanisole (27 mL, 0.2 mol, 2.0 equiv) was carefully added, keeping the temperature of the mixture below 50 C. The reaction mixture was carefully poured into 250 mL ice water. The resultant white solid (5-chloro-2-methoxybenzene-1-sulfonyl chloride) was filtered and dried. (0051) 3,5-Bis(trifluoromethyl)aniline (2.3 g, 10 mmol, 1.0 equiv) and 4-dimethylaminopyridine (50 mg, 0.4 mmol, 0.04 equiv) were dissolved in anhydrous pyridine (20 mL, 0.5 M). 5-Chloro-2-methoxybenzene-1-sulfonyl chloride (2.41 g, 10 mmol, 1 equiv) was added. The resulting mixture was stirred at room temperature (10 h). Water (20 mL) was added to quench the reaction. The precipitate formed was filtered and washed with water, cold THF, and Et2O to afford a brown solid (N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-methoxybenzene-sulfonamide). 1H NMR (300 MHz, DMSO-d6): delta 3.79 (s, 3H), 7.23 (d, J = 9.0 Hz, 1H), 7.66-7.68 (m, 3H), 7.75 (s, 1H), 7.81 (d, J = 2.6 Hz, 1H), 11.12(s, 1H). (0052) Boron tribromide (5 mL, 1.7 mmol, 1.7 equiv) was added to a solution of N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-methoxybenzenesulfonamide (434 mg, 1 mmol, 1.0 equiv) in DCM (5 mL, 0.2 M) at -70 C and allowed to warm to room temperature (12 h). The mixture was added dropwise to 10 mL ice water, with stirring continued for an additional 0.5 h. The mixture was cooled to room temperature and concentrated sodium hydroxide was added dropwise until the pH reached 6-7, followed by extraction with DCM. The organic extracts were combined, dried (MgSO4), concentrated under vacuum, and purified by chromatography (1:2 EtOAc:Hex) (340 mg, 81%). Slightly yellow solid. Mp 135-138 C. 1H NMR (300 MHz, DMSO-d6): delta 6.95 (d, J = 8.8 Hz, 1H), 7.49 (dd, J1 = 8.8 Hz, J2 = 2.3 Hz, 1H), 7.68-7.71 (m, 4H), 11.27 (s, 2H). IR (neat): 3354, 3238, 1413, 1374, 1276, 1125, 966, 826 cm-1. HRMS (APCI), m/z calcd for C14H8ClF6NO3S-H: 417.9766, found 417.9753.
With pyridine; phosphorus trichloride; In toluene;Inert atmosphere; Reflux;
General procedure: Phosphorus trichloride (0.13ml, 1.5mmol) was added to a stirred solution of 3,5-bis(trifluoromethyl)aniline (0.47ml, 3mmol), a catalytic amount of pyridine and 5-chloro salicylic acid (621.3mg, 3.6mmol) in anhydrous toluene (10ml) in in a Radley?s Carousel reaction tube under an argon atmosphere. After the reaction mixture was refluxed for overnight, it was cooled to room temperature and aq. sodium bicarbonate was added dropwise until PH=6 - 7. After extracting with ethyl acetate, the organic layers was dried, dried (MgSO4) and concentrated in vacuo. After chromatography (EA-Hex, 1:10) of the crude product, and followed by recrystalization from EtOAc/hexane provided 2a as a white solid (320mg, 28%).
N-(3,5-bis-trifluoromethyl-phenyl)-3-chloro-2-hydroxy-benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
59%
With pyridine; phosphorus trichloride; In toluene;Inert atmosphere; Reflux;
General procedure: Phosphorus trichloride (0.13ml, 1.5mmol) was added to a stirred solution of 3,5-bis(trifluoromethyl)aniline (0.47ml, 3mmol), a catalytic amount of pyridine and 5-chloro salicylic acid (621.3mg, 3.6mmol) in anhydrous toluene (10ml) in in a Radley?s Carousel reaction tube under an argon atmosphere. After the reaction mixture was refluxed for overnight, it was cooled to room temperature and aq. sodium bicarbonate was added dropwise until PH=6 - 7. After extracting with ethyl acetate, the organic layers was dried, dried (MgSO4) and concentrated in vacuo. After chromatography (EA-Hex, 1:10) of the crude product, and followed by recrystalization from EtOAc/hexane provided 2a as a white solid (320mg, 28percent).
General procedure: At room temperature, 3,5-bis(trifluoromethyl)aniline (5.0 mmol) was added to a solution of 2-hydroxybenzaldehyde (5.0 mmol) in ethanol (20 mL). After stirring for 2 h, solid was precipitated. Then the solid recrystallized with ethanol to obtain the corresponding pure product 1.
General procedure: To a solution of 3,4-dimethoxy-3-cyclobutane-1,2-dione (2.0 g,14.1 mmol) in MeOH (30 mL) was added 3,5-bis(trifluoromethyl)aniline or 9-amino(9-deoxy)epiquinine (15.5 mmol,1.1 equiv) at room temperature. The mixture was stirred at roomtemperature for 2 days. The reaction mixture was filtered andwashed with MeOH to give a yellow solid. The yellow solid(1.0 mmol) was then dissolved in MeOH (5 mL) and the correspondingsubstituted amine (1.1 mmol) was added. The solutionwas stirred at room temperature for 2 days. The reaction mixturewas filtered and the precipitate was washed with MeOH (5 mL).The crude product obtained was purified by recrystallization fromMeOH to give pure desired products V-VII.
N-((1H-benzo[d]imidazol-2-yl)methyl)-3,5-bis(trifluoromethyl)aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82.5%
With sodium carbonate; In ethanol; for 24h;Reflux;
General procedure: A mixture of compound 2 (1.669 g, 0.01 mol), 2-fluoroaniline (1.110 g, 0.01 mol) and sodium carbonate (1.276 g, 0.012 mol) in ethanol (20 mL) was refluxed for 24 h. Upon completion of the reaction, the solvent was evaporated. The residue was extracted with ethyl acetate (3 × 20 mL), and the organic phase was dried over anhydrous sodium sulphate and further purified by silica gel column chromatography (eluent, petroleum ether/ethyl acetate (5/1, V/V)) to afford the desired compound 3a as yellow solid. Yield: 73.1%;
A mixture of compound 1 (1.669 g, 0.01 mol) and 3,5-bis(trifluoromethyl)aniline (2.234 g, 0.01 mol) was refluxed in ethanol (20 mL). After 24 h, potassium carbonate (1.279 g, 0.012 mol) was added with continuous stirring for another 12 h. Upon completion of the reaction, the solvent was evaporated. The residue was extracted with ethyl acetate (3 × 20 mL), and the organic phase was dried over anhydrous sodium sulfate and further purified bysilica gel column chromatography (eluent, petroleum ether/ethyl acetate (5/1,V/V)) to afford the desired compound 2a as yellow solid
3-chloro-N-(3,5-bistrifluoromethylphenyl)picolinamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1.67 g
With pyridine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; at 20℃; for 2h;
Production Example 9 (1) [0718] A mixture of 1.15 g of 3,5-bistrifluoromethylaniline, 0.78 g of <strong>[57266-69-0]3-chloropicolinic acid</strong>, 1.15 g of EDCI hydrochloride, 0.06 g of HOBt and 10 mL of pyridine was stirred at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting solid was washed with hexane and dried to obtain 1.67 g of 3-chloro-N-(3,5-bistrifluoromethylphenyl)picolinamide. 3-Chloro-N-(3,5-bistrifluoromethylphenyl)picolinamide 1H-NMR (CDCl3) delta: 10.38 (1H, brs), 8.57 (1H, d), 8.30(2H, s), 7.94 (1H, d), 7.65 (1H, s), 7.51 (1H, dd).
dihydrobenzofuran-2-carboxylic acid N-(3,5-ditrifluoromethylphenyl)amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
43%
General procedure: To a mixture of 7 (1 eq) and 1,1?-carbodiimidazole (1.2 eq) in anhydrous THF was stirred for 1h then substituted aniline (0.9 eq) was added at room temperature. After stirring for 14 h, solvent was evaporated then the mixture acidified with 6N HCl to pH 2. The mixture was extracted with EtOAc (3 × 20 mL). The combined extracts were dried over anhydrous Na2SO4and the solvent was evaporated. After evaporation, the residue was purified by column chromatography (EtOAc/hexane = 1:3 - 1:50).
General procedure: To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (Ia) (0.2 mmol) in MeOH (0.25- 1 mL) the amine 2a-m was firstly added at room temperature. After the correspondingreaction time (ti) (see Table I), the amine 4a-n (0.2 mmol) was then added with MeOH (1.75-1 mL). After the corresponding reaction time (t2) (see Table I and Table Ibis), the product was purified by filtration or by column chromatography. Yields are reported in Table I and Table Ibis and pure compounds were obtained as stable solids.
General procedure: To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (Ia) (0.2 mmol) in MeOH (0.25- 1 mL) the amine 2a-m was firstly added at room temperature. After the correspondingreaction time (ti) (see Table I), the amine 4a-n (0.2 mmol) was then added with MeOH (1.75-1 mL). After the corresponding reaction time (t2) (see Table I and Table Ibis), the product was purified by filtration or by column chromatography. Yields are reported in Table I and Table Ibis and pure compounds were obtained as stable solids.
N-((1R,2R)-2-(2-(3,5-bis(trifluoromethyl)phenylamino)-3,4-dioxocyclobut-1-enylamino)cyclohexyl)-4-methylbenzenesulfonamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
General procedure: To a mixture of 3,4-dimethoxy-3-cyclobutene-1 ,2-dione (Ia) (0.2 mmol) in MeOH (0.25- 1 mL) the amine 2a-m was firstly added at room temperature. After the correspondingreaction time (ti) (see Table I), the amine 4a-n (0.2 mmol) was then added with MeOH (1.75-1 mL). After the corresponding reaction time (t2) (see Table I and Table Ibis), the product was purified by filtration or by column chromatography. Yields are reported in Table I and Table Ibis and pure compounds were obtained as stable solids.
tert-butyl (6R*,6aS*,9aS*)-6-((3,5-bis(trifluoromethyl)phenyl)amino)-6a,7,8,9a-tetrahydrodipyrrolo[2,3-b:3',2',1'-ij]quinoline-9(6H)-carboxylate[ No CAS ]
diethyl [[3,5‑bis(trifluoromethyl)phenyl]amino](4‑butoxyphenyl)methylphosphonate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
With tungstosulfonic acid; In neat (no solvent); at 20℃; for 0.333333h;Sonication; Green chemistry;
General procedure: A mixture of 3,5-bis(trifluoromethyl)aniline (1, 1 mmol),aryl aldehydes 2a-2j (1.0 mmol), diethyl phosphite (3,1.2 mmol), and TSA (5 mol%) was placed in a 25 cm3 flatbottomedconical flask and sonicated at ambient temperaturefor 10-30 min. The progress of the reaction was monitoredwith TLC using hexane and ethyl acetate (8:2) as the solvent.The reaction mixture was treated with 20 cm3 of ethylacetate and filtered through paper to remove catalyst residue.The catalyst residue was washed with ethanol and dried forreuse. The filtrate was quenched with 10 cm3 of water, followedby 5 cm3 brine solution dried over anhydrous sodiumsulfate, and evaporated in a rotary evaporator; the pure productswere obtained from ethanol by recrystallization.
General procedure: A dry, 50 mL round bottom flask was charged with a magnetic stir bar then sealed with a septum and flushed with nitrogen. To this was added the salicylic acid derivative (2.0 mmol) and dichloromethane (10 mL). While stirring, SOCl2 (10 mmol) was added dropwise, followed by dimethylformamide (0.05 mmol), and the mixture was allowed to stir at room temperature under nitrogen for 12 hours. At this point, the mixture was concentrated under vacuum to afford the solid acid chloride derivative which was used immediately without further purification. The flask containing the acid chloride was then re-sealed with a septum and placed under a nitrogen atmosphere, and its contents were re-suspended in fresh dichloromethane (20 mL). While stirring, the aniline derivative (4.0 mmol) was added and the resulting opaque mixture was stirred for an additional 18 h. At this point, the mixture was quenched with ice water (5 mL) and phases were separated using a separatory funnel. The aqueous layer was extracted twice with dichloromethane (20 mL) then the organic layers were combined and washed with brine (40 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated under vacuum to afford a crude solid residue. This residue was then re-suspended in dichloromethane (10 mL) and adsorbed onto silica gel (1 g), then chromatographed on a 12 g silica gel column using a solvent gradient of 0-40% ethyl acetate in hexanes over 25 min. The product-containing fractions were combined then concentrated under vacuum to afford the purified salicylamide derivative.
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