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USD 15-60
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Structure of 400-99-7 * Storage: {[proInfo.prStorage]}
* 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 Organic Chemistry, 1991, vol. 56, # 22, p. 6406 - 6411
2
[ 400-99-7 ]
[ 454-81-9 ]
Yield
Reaction Conditions
Operation in experiment
100%
With hydrogen In ethanol at 40℃;
Description 7. 2-Amino-4-(trifluoromethyl)phenol. (D7); A solution of 2-nitro-4-(trifluoromethyl)phenol (100 mg, 0.483 mmol) in ethanol (10 ml.) was pumped through an H-cube.(TM). hydrogenator CatCart (Pd/C, 30 x 4 mm) at a flow rate of 1 mL/min at 40 0C and 40 psi, topping up the solution with methanol (10 x 1 ml.) when it was running low. The collected solution was evaporated to dryness to give an off-white solid (88 mg, assume quantitative yield). The material was carried forward without further purification.(M + H)+ = 178.1H NMR δ (CDCI3): 6.76 (1 H, d, J = 8.4 Hz), 6.94 (1 H, d, J = 8.4 Hz), 6.98 (1 H, s).
100%
With hydrogen In ethanol at 40℃;
A solution of 2-nitro-4-(trifluoromethyl)phenol (100 mg, 0.483 mmol) in ethanol (10 mL) was pumped through an H-cube.(TM). hydrogenator CatCart (Pd/C, 30 x 4 mm) at a flow rate of 1 mL/min at 40 0C and 40 psi, topping up the solution with methanol (10 x 1 mL) when it was running low. The collected solution was evaporated to dryness to give an off-white solid (88 mg, assume quantitative yield). The material was carried forward without further purification.(M + H)+ = 178.1H NMR δ (CDCI3): 6.76 (1 H, d, J = 8.4 Hz), 6.94 (1 H, d, J = 8.4 Hz), 6.98 (1 H, s).
100%
With palladium 10% on activated carbon; hydrogen In methanol at 20℃;
0860] 2-Nitro-4-trifluoromethylphenol (340 μL, 2.41 mmol) was dissolved in methanol (50 mL) and processed through the H-Cube with a 10percent Pd/C Catalyst cartridge at ambient temperature and pressure. The eluent was concentrated under reduced pressure to provide 2-amino-4-trifluoromethylphenol as a light brown solid (438 mg, 100percent). (CI, m/z): [M+H]+ 178, [M−H]− 176; 1H NMR (CDCl3): δ 6.96 (d, J=2.0 Hz, 1H), 6.89-6.94 (m, 1H), 6.74 (d, J=8.2 Hz, 1H), 4.10 (br s, 2H).
67%
With ammonium formate In methanol at 85℃;
To a suspension of palladium hydroxide (3.05 g, 21.7 mmol) in methanol was added a methanol solution of 2-nitro-4-(trifluoromethyl)phenol (1.00 g, 4.8 mmol) followed by solid ammonium formate (3.04 g, 48.3 mmol). The mixture was heated at 85° C. and monitored by TLC. The completed reaction was allowed to cool to rt and was filtered through a pad of Celite.(R)., washing with ethyl acetate. The filtrate was concentrated under reduced pressure to provide the title compound (0.58 g, 67percent). LC-MS m/z 178.1 (MH+), retention time 0.55 minutes.
0.410 g
With palladium 10% on activated carbon; ammonium formate In methanol at 50℃; for 1 h;
mixture of compound 21 (0.500 g), ammonium formate (0.761 g), 10percent Pd / C (0.050 g) and methanol (12 mL) was stirred at 50 ° C. for 1 hour.The reaction mixture was filtered through celite, concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate.The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain compound 22 (0.410 g).
Reference：
[1] Patent: WO2009/37293, 2009, A1, . Location in patent: Page/Page column 52
[2] Patent: WO2009/37294, 2009, A1, . Location in patent: Page/Page column 93
[3] Patent: US2014/142114, 2014, A1, . Location in patent: Paragraph 0859; 0860
[4] Phosphorus, Sulfur and Silicon and the Related Elements, 2009, vol. 184, # 3, p. 651 - 659
[5] Patent: WO2005/85202, 2005, A1, . Location in patent: Page/Page column 53-54
[6] Organic Preparations and Procedures International, 2000, vol. 32, # 5, p. 485 - 488
[7] Patent: US2004/224997, 2004, A1, . Location in patent: Page 37
[8] Kogyo Kagaku Zasshi, 1959, vol. 62, p. 227,229[9] Chem.Abstr., 1962, vol. 57, p. 989
[10] Journal of the Chemical Society, 1954, p. 3852
[11] Journal of pharmaceutical sciences, 1968, vol. 57, # 10, p. 1763 - 1768
[12] Journal of pharmaceutical sciences, 1968, vol. 57, # 10, p. 1763 - 1768
[13] Journal of Heterocyclic Chemistry, 1993, vol. 30, # 3, p. 789 - 798
[14] Journal of Medicinal Chemistry, 1998, vol. 41, # 16, p. 3015 - 3021
[15] Medicinal Chemistry Research, 2000, vol. 10, # 1, p. 19 - 29
[16] Journal of Medicinal Chemistry, 2006, vol. 49, # 17, p. 5080 - 5092
[17] Bioorganic and Medicinal Chemistry, 2007, vol. 15, # 10, p. 3515 - 3523
[18] Patent: US4314065, 1982, A,
[19] Patent: US4164576, 1979, A,
[20] Patent: US4180572, 1979, A,
[21] Patent: US2008/305169, 2008, A1,
[22] Patent: WO2009/55357, 2009, A1, . Location in patent: Page/Page column 37
[23] Patent: EP2172453, 2010, A1, . Location in patent: Page/Page column 16
[24] Patent: US2007/10670, 2007, A1, . Location in patent: Page/Page column 102
[25] Patent: US2007/197512, 2007, A1, . Location in patent: Page/Page column 87
[26] European Journal of Medicinal Chemistry, 2012, vol. 56, p. 108 - 119
[27] Patent: JP2017/1991, 2017, A, . Location in patent: Paragraph 0192 - 0194
[28] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 14, p. 4001 - 4013
[29] Patent: US2008/64871, 2008, A1, . Location in patent: Page/Page column 65
3
[ 400-99-7 ]
[ 454-81-9 ]
Reference：
[1] Patent: US6262113, 2001, B1,
4
[ 400-99-7 ]
[ 7772-99-8 ]
[ 454-81-9 ]
Reference：
[1] Patent: US5886044, 1999, A,
5
[ 121-17-5 ]
[ 400-99-7 ]
Reference：
[1] Organic Letters, 2008, vol. 10, # 14, p. 3025 - 3028
[2] Phosphorus, Sulfur and Silicon and the Related Elements, 2009, vol. 184, # 3, p. 651 - 659
[3] Tetrahedron Letters, 2007, vol. 48, # 3, p. 473 - 476
[4] Journal of Organic Chemistry, 1971, vol. 36, # 1, p. 242 - 243
[5] Kogyo Kagaku Zasshi, 1959, vol. 62, p. 227,229[6] Chem.Abstr., 1962, vol. 57, p. 989
[7] Patent: US4314065, 1982, A,
[8] Patent: US4164576, 1979, A,
[9] Patent: US4180572, 1979, A,
[10] Patent: US4225731, 1980, A,
[11] Patent: EP2982670, 2016, A1,
6
[ 139-07-1 ]
[ 121-17-5 ]
[ 400-99-7 ]
Yield
Reaction Conditions
Operation in experiment
91%
With sodium hydroxide In hydrogenchloride; methanol
EXAMPLE 1 400 ml of methanol, 20 g of benzyldimethyldodecylammonium chloride and 180 g of 4-chloro-3-nitro-benzotrifluoride are initially introduced into the reaction flask, whilst stirring, and 400 g of 50percent strength sodium hydroxide solution are then added dropwise. The temperature rises to about 70° C. if the addition is carried out in the course of about 20 minutes. The mixture is then stirred at 65° C. for a further 4 hours and subsequently cooled by adding ice, and the pH is adjusted to 3 with concentrated hydrochloric acid. The phenol is driven over with steam and the phases are separated in the receiver by adding about 50 ml of concentrated hydrochloric acid. 156 g of 2-nitro-4-trifluoromethylphenol are obtained with a purity of more than 98.5percent, according to analysis by gas chromatography, which corresponds to a yield of 91percent of theory. Boiling point: 92°-95° C. at 15 mm, nD20: 1.5020.
Reference：
[1] Patent: US4225731, 1980, A,
7
[ 109-86-4 ]
[ 121-17-5 ]
[ 400-99-7 ]
Reference：
[1] Patent: US4225731, 1980, A,
8
[ 402-45-9 ]
[ 400-99-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 22, p. 6842 - 6851
[2] European Journal of Medicinal Chemistry, 2012, vol. 56, p. 108 - 119
9
[ 121-17-5 ]
[ 367-86-2 ]
[ 32137-19-2 ]
[ 394-25-2 ]
[ 40700-38-7 ]
[ 400-99-7 ]
Reference：
[1] Journal of Organic Chemistry, 1991, vol. 56, # 22, p. 6406 - 6411
10
[ 400-98-6 ]
[ 400-99-7 ]
Reference：
[1] Journal of the Chemical Society, 1954, p. 3852
[2] Ukrainskii Khimicheskii Zhurnal (Russian Edition), 1955, vol. 21, p. 81,83[3] Chem.Abstr., 1955, p. 8866
11
[ 400-99-7 ]
[ 122-51-0 ]
[ 1267217-46-8 ]
Yield
Reaction Conditions
Operation in experiment
40%
Stage #1: With palladium on activated charcoal; hydrogen In ethanol at 0 - 20℃; Inert atmosphere Stage #2: With toluene-4-sulfonic acid In ethanol for 3 h; Inert atmosphere; Reflux
2-nitro-4- (trifluoromethyl) phenol (500 mg, 2.41 mmol) palladium on carbon (200 mg) was added at 0 under an argon atmosphere in ethanol (10 ml) solution of. After hydrogen substitution, and stirred at room temperature overnight. After completion of the reaction, it was filtered through Celite, and the filtrate was concentrated under reduced pressure. to residue Triethyl orthoformate (2.4 ml, 14.5 mmol) in solution Para tosylic acid monohydrate (23 mg, 0.12 mmol) was added dropwise. Under an argon atmosphere, was stirred 3 h at reflux condition was solidified after completion of the reaction concentrated to dryness. The residue was purified by silica gel column chromatography (hexane / ethyl acetate),To give the title compound (182 mg, 40percent).
Reference：
[1] Patent: JP2016/124812, 2016, A, . Location in patent: Paragraph 0108
With hydrogen;palladium on activated charcoal; In ethanol; at 40℃; under 2068.65 Torr;
Description 7. 2-Amino-4-(trifluoromethyl)phenol. (D7); A solution of <strong>[400-99-7]2-nitro-4-(trifluoromethyl)phenol</strong> (100 mg, 0.483 mmol) in ethanol (10 ml.) was pumped through an H-cube hydrogenator CatCart (Pd/C, 30 x 4 mm) at a flow rate of 1 mL/min at 40 0C and 40 psi, topping up the solution with methanol (10 x 1 ml.) when it was running low. The collected solution was evaporated to dryness to give an off-white solid (88 mg, assume quantitative yield). The material was carried forward without further purification.(M + H)+ = 178.1H NMR delta (CDCI3): 6.76 (1 H, d, J = 8.4 Hz), 6.94 (1 H, d, J = 8.4 Hz), 6.98 (1 H, s).
100%
With hydrogen; In ethanol; at 40℃; under 2068.65 Torr;
A solution of <strong>[400-99-7]2-nitro-4-(trifluoromethyl)phenol</strong> (100 mg, 0.483 mmol) in ethanol (10 mL) was pumped through an H-cube hydrogenator CatCart (Pd/C, 30 x 4 mm) at a flow rate of 1 mL/min at 40 0C and 40 psi, topping up the solution with methanol (10 x 1 mL) when it was running low. The collected solution was evaporated to dryness to give an off-white solid (88 mg, assume quantitative yield). The material was carried forward without further purification.(M + H)+ = 178.1H NMR delta (CDCI3): 6.76 (1 H, d, J = 8.4 Hz), 6.94 (1 H, d, J = 8.4 Hz), 6.98 (1 H, s).
100%
With palladium 10% on activated carbon; hydrogen; In methanol; at 20℃; under 760.051 Torr;
0860] 2-Nitro-4-trifluoromethylphenol (340 muL, 2.41 mmol) was dissolved in methanol (50 mL) and processed through the H-Cube with a 10% Pd/C Catalyst cartridge at ambient temperature and pressure. The eluent was concentrated under reduced pressure to provide 2-amino-4-trifluoromethylphenol as a light brown solid (438 mg, 100%). (CI, m/z): [M+H]+ 178, [M-H]- 176; 1H NMR (CDCl3): delta 6.96 (d, J=2.0 Hz, 1H), 6.89-6.94 (m, 1H), 6.74 (d, J=8.2 Hz, 1H), 4.10 (br s, 2H).
67%
With ammonium formate;palladium dihydroxide; In methanol; at 85℃;
To a suspension of palladium hydroxide (3.05 g, 21.7 mmol) in methanol was added a methanol solution of <strong>[400-99-7]2-nitro-4-(trifluoromethyl)phenol</strong> (1.00 g, 4.8 mmol) followed by solid ammonium formate (3.04 g, 48.3 mmol). The mixture was heated at 85 C. and monitored by TLC. The completed reaction was allowed to cool to rt and was filtered through a pad of Celite, washing with ethyl acetate. The filtrate was concentrated under reduced pressure to provide the title compound (0.58 g, 67%). LC-MS m/z 178.1 (MH+), retention time 0.55 minutes.
In ethanol; water;
(b) 2-Amino-4-trifluoromethylphenol Sodium dithionite (97.0 g, 0.5 mole) was added in portions over a period of 6 hours to a solution of <strong>[400-99-7]2-nitro-4-trifluoromethylphenol</strong> (31 g, 0.15 mole) in a mixture of ethanol (120 ml) and water (90 ml), the solution being heated, with stirring, at a temperature of 55 C. during the addition. The mixture was filtered, the filtrate retained, and the collected solid was triturated with ethanol and refiltered. The solvent was removed from the combined filtrates by distillation under reduced pressure to give a yellow solid. The solid was dissolved in water, the aqueous solution extracted with diethyl ether (4*100 ml) and the combined ethereal phases were washed with brine. The ethereal phase was dried over anhydrous magnesium sulfate and the solvent evaporated to give a yellow solid which was recrystallized from petroleum ether (700 ml, bp 100-120 C.) to give the title compound as a pale yellow solid (10.6 g).
In ethanol;
82.2 g of 6A was dissolved in 300 ml of ethanol. 0.5 g of platinum oxide catalyst was added and the mixture was hydrogenated at 50 psig. Fresh portions of catalyst were added periodically. The reaction mixture was filtered, and the filtrate was concentrated. The residue was crystallized from water to give 2-amino-4-(trifluoromethyl)phenol (6B).
In ethanol;
82.2 g of 7A was dissolved in 300 ml of ethanol. 0.5 g of platinum oxide catalyst was added and the mixture was hydrogenated at 50 p.s.i.g. Fresh portions of catalyst were added periodically. The resulting mixture was filtered, and the solvent was evaporated from the filtrate. The residue was crystallized from water to give 2-amino-4-trifluoromethyl-phenol (7B).
palladium-carbon; In tetrahydrofuran;
Step 1 Production of 2-amino-4-trifluoromethylphenol 2-Nitro-4-trifluoromethylphenol (3.0951 g) was dissolved in tetrahydrofuran (15 mL). 7.5% Palladium-carbon (299.8 mg) was added to this solution and, under a hydrogen atmosphere, the mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the residue was washed with tetrahydrofuran. The filtrate and washing solution were combined and the mixture was concentrated under reduced pressure to give the title compound (2.6346 g) as a gray solid.
With hydrogen;palladium 10% on activated carbon; In ethanol; at 20℃; for 16h;
Method 5: Synthesis of (l,l-Dioxo-llambda6-thiomorpholin-4-yl)-[4-(5-trifluoromethyl- benzooxazol-2-yl) -[1,4] diazepan- 1 -yl] -methanone <n="38"/>Step 1: Synthesis of 2-Amino-4-(trifluoromethyl)phenol; To a solution of 5 g (24.1 mmol) of <strong>[400-99-7]2-nitro-4-(trifluoromethyl)phenol</strong> in ethanol (100 niL) is added 0.5 g of palladium on charcoal (10 wt%). The reaction mixture is reduced under hydrogen atmosphere at room temperature for 16 h with stirring. The catalyst is separated by filtration through Celite. The filtrate is concentrated under reduced pressure to afford 4.3 g of 2-amino-4-(trifluoromethyl)phenol. ES MS m/z =178 (M+H).
With hydrogen;palladium 10% on activated carbon; In tetrahydrofuran; at 20℃;
To a solution of 4-hydroxy-3-nitrobenzotrifluoride (1.00 g) in tetrahydrofuran (20 ml), 10% palladium on activated carbon (100 mg) was added and stirred overnight under a hydrogen atmosphere at room temperature. After the reaction mixture was filtered through celite, the solvent was distilled off under reduced pressure to give 2-amino-4-(trifluoromethyl)phenol (780 mg) as a gray powder. To a solution of 2-amino-4-(trifluoromethyl)phenol thus obtained (780 mg) in ethyl acetate (8 ml), water (8 ml) and sodium bicarbonate (739 mg) were added under ice cooling, followed by dropwise addition of chloroacetyl chloride (0.42 ml). After stirring at room temperature for 3 days, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure. The resulting residue was converted into a powder form by addition of chloroform and n-hexane, and then collected by filtration to give 2-chloro-N-[2-hydroxyphenyl-5-(trifluoromethyl)phenyl]acetamide (1.00 g) as a light-brown powder. To a solution of 2-chloro-N-[2-hydroxyphenyl-5-(trifluoromethyl)phenyl]acetamide thus obtained (1.00 g) in N,N-dimethylformamide (15 ml), potassium carbonate (708 mg) was added and stirred at room temperature for 2 hours. After insoluble materials were filtered off, the filtrate was diluted with ethyl acetate and the organic layer was washed twice with water. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to give 6-(trifluoromethyl)-2H-1,4-benzoxazin-3(4H)-one (860 mg) as a colorless powder. To a solution of 6-(trifluoromethyl)-2H-1,4-benzoxazin-3(4H)-one thus obtained (860 mg) in tetrahydrofuran (5 ml), borane-tetrahydrofuran complex (1.03M in tetrahydrofuran, 7.7 ml) was added and heated under reflux for 3.5 hours. After the reaction mixture was diluted with methanol and heated under reflux for 1 hour, 1M aqueous hydrochloric acid was added and heated under reflux for an additional 30 minutes. The reaction mixture was cooled to room temperature, followed by distilling off the solvent under reduced pressure. The resulting residue was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, dried over anhydrous sodium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate = 20:1 to 10:1) to give the titled compound, i.e., 6-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine (730 mg) as a colorless powder. 1H NMR (300 MHz, CHLOROFORM-D) delta 3.41-3.48 (m, 2 H), 3.90 (brs, 1H), 4.25-4.31 (m, 2 H), 6.79-6.85 (m, 2 H), 6.87-6.93 (m, 1 H).
With hydrogen;palladium-carbon; In tetrahydrofuran; at 20℃;
Step 1 Production of 2-amino-4-trifluoromethylphenol 2-Nitro-4-trifluoromethylphenol (3.0951 g) was dissolved in tetrahydrofuran (15 mL). 7.5% Palladium-carbon (299.8 mg) was added to this solution and, under a hydrogen atmosphere, the mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the residue was washed with tetrahydrofuran. The filtrate and washing solution were combined and the mixture was concentrated under reduced pressure to give the title compound (2.6346 g) as a gray solid.
With hydrogen;palladium-carbon; In tetrahydrofuran; at 1 - 40℃;
step 1 Production of 2-amino-4-trifluoromethylphenol 2-Nitro-4-trifluoromethylphenol (3.0951 g) was dissolved in tetrahydrofuran (15 mL). To this solution was added 7.5% palladium-carbon (299.8 mg), and the mixture was stirred overnight at room temperature under hydrogen atmosphere. The reaction mixture was filtered through celite, and concentrated under reduced pressure to give the title compound (2.6346 g) as a gray solid.
0.410 g
With palladium 10% on activated carbon; ammonium formate; In methanol; at 50℃; for 1h;
mixture of compound 21 (0.500 g), ammonium formate (0.761 g), 10% Pd / C (0.050 g) and methanol (12 mL) was stirred at 50 C. for 1 hour.The reaction mixture was filtered through celite, concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate.The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain compound 22 (0.410 g).
With palladium 10% on activated carbon; hydrogen; In ethanol; at 20℃; for 3h;
To a solution of <strong>[400-99-7]2-nitro-4-(trifluoromethyl)phenol</strong> (1.25 g, 6.0 mmol) in EtOH (30 mL) was added portionwisely 10% palladium-carbon (Pd/C) (0.5 g). The reaction mixture was stirred at rt. for 3 h under a hydrogen gas atmosphere. After completion of the reaction, the Pd/C catalyst was filtered off. To the resulting solution of 2-amino-4-trifluoromehylphenol was added potassium O-ethyl dithiocarbonate (1.06 g, 6.6 mmol). The reaction mixture was stirred at reflux temperature for 4 h and allowed to cool to rt. The solvent was evaporated under reduced pressure. The residue was adjusted to acidity by adding 1-N HCl solution, and extracted with AcOEt. The organic layer was washed with brine and dried over MgSO4. The solvent was evaporated under reduced pressure to give 7-(trifluoromethyl)-benzo[d]oxazole-2-thiol (0.78 g, 59%). Compound 19 was prepared from 7-(trifluoromethyl)benzo[d]-oxazole-2-thiol (11) in the same manner as in the preparation of 18 with ayield of 86% as colorless powdery crystals
With hydrogen;palladium-carbon; In tetrahydrofuran; at 0 - 40℃;
Step 1 Production of 2-amino-4-trifluoromethylphenol 2-Nitro-4-trifluoromethylphenol (3.0951 g) was dissolved in tetrahydrofuran (15 mL). 7.5% Palladium-carbon (299.8 mg) was added to this solution and, under a hydrogen atmosphere, the mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite, and the residue was washed with tetrahydrofuran. The filtrate and washing solution were combined and the mixture was concentrated under reduced pressure to give the title compound (2.6346 g) as a gray solid.
With caesium carbonate; In acetonitrile; at 90℃; for 6h;
Example C. 3- (2,6-Dichloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid[2-(2-nitro-4-trifluoromethyl-phenoxy)-ethyl]-amide. [00102] Step A:; <strong>[400-99-7]2-nitro-4-trifluoromethyl-phenol</strong> 7 (0.5 g, 2.42 mmol) and (2-Bromo- ethyl) -carbamic acid tert-butyl ester (0.54 g, 2.42 mmol) are dissolved in MeCN. Cs2C03 is added (1.58 g, 4.84 mmol) and the mixture is stirred at 90C for 6 hours. The mixture is then filtered, concentrated in vacuo, diluted with H20 and extracted three times with DCM. The organic layers are combined, dried (MgS04), filtered, and concentrated and the remainder purified by column chromatography using a DCM/MeOH gradient to afford intermediate 8 as a yellow solid: 'H-NMR (400 MHz, CDC13) No. = 8.42 (d, J = 1.1 Hz, 1H), 8.37 (m, NH), 7.58 (dd, J = 9.0 Hz, J = 2.0 Hz, 1H), 6.92 (d, J = 9.0 Hz, 1H), 4.29 (t, J = 5.5 Hz, 2H), 3.60 (q, J = 5.5 Hz, 2H), 1.42 (s, 9H). MS calculated for C9H10F3N2O3 (M-Boc+) 251.1, found 251.2.
With caesium carbonate; In acetonitrile; at 90℃; for 12h;
Step A:; <strong>[400-99-7]2-nitro-4-trifluoromethyl-phenol</strong> 7 (1.3 g, 6.3 mmol) and 1,2-dibromo ethane (2.71 mL, 31 mmol) are dissolved in MeCN. CS2C03 is added (4.1 g, 12.6 mmol) and the mixture is stirred at 90C for 12 hours. The mixture is then filtered, concentrated in vacuo, diluted with H20 and extracted three times with DCM. The organic layers are combined, dried (MgS04), filtered, and concentrated and the remainder purified by column chromatography using a hexanes/EtOAc gradient to afford intermediate 17 as a yellow solid: (at)H-NMR (400 MHz, CDC13) 8 = 8.06 (d, J = 2.0 Hz, 1H), 7.73 (dd, J = 8.8 Hz, J = 2.0 Hz, 1H), 7.12 (d, J = 8.8 Hz, 1H), 4.42 (t, J = 6.4 Hz, 2H), 3.63 (t, J = 6.4 Hz, 2H). MS calculated for C9H8BrF3NO3 (M+H+) 314.0, found 314.2.
With caesium carbonate; In acetonitrile; at 90℃; for 12h;
Example E2:; {3-Chloro-4-[5-methyl-4-(2-nitro-4-trifluoromethyl- phenoxymethyl)-isoxazol-3-yl]-phenyl}-acetic acid. [00120] Step A: 2-Butyne-1-01 (1.4 g, 20 mmol) is dissolved in ether (50 mL) and cooled to 0C. Triethylamine (3.3 mL, 24 mmol) is added to the solution. Methanesulfonyl chloride (1.6 mL, 22 mmol) is dissolved in ether (5 mL) and added dropwise to the reaction solution. The mixture is stirred for 30 minutes at 0C, then filtered and concentrated to give crude methanesulfonic acid but-2-ynyl ester 20 (2.96 g, 20 mmol, quant. ) as a colorless liquid: 'H-NMR (400 MHz, CDCl3) 8 = 4.79 (q, J = 2.4 Hz, 2H), 3.08 (s, 3H), 1.87 (t, J = 2.4 Hz, 3H). [00121] <strong>[400-99-7]2-nitro-4-trifluoromethyl-phenol</strong> 7 (4.1 g, 20 mmol) and methanesulfonic acid but-2-ynyl ester 20 (3.0 g, 20 mmol) are dissolved in MeCN. Cs2C03 is added (13.0 g, 40 mmol) and the mixture is stirred at 90C for 12 hours. The mixture is then filtered, concentrated in vacuo, diluted with H20 and extracted three times with DCM. The organic layers are combined, dried (MgS04), filtered, and concentrated and the remainder purified by column chromatography using a hexanes/EtOAc gradient to afford 1-but-2-ynyloxy-2- nitro-4-trifluoromethyl-benzene 21 as a yellow solid: 'H-NMR (400 MHz, CDC13) 8 = 8.06 (d, J = 1.7 Hz, 1H), 7.73 (dd, J = 8.8 Hz, J = 1.8 Hz, 1H), 7.30 (d, J = 8.8 Hz, 1H), 4.81 (q, J = 2.3 Hz, 2H), 1.79 (t, J = 2.3 Hz, 3H). MS calculated for CllHgF3N03 (M+H+) 260.1, found 260.3.
3-(2,6-dichloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid 2-(2-nitro-4-trifluoromethyl-phenoxy)-ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With triphenylphosphine; diethylazodicarboxylate; In dichloromethane; at 0 - 20℃; for 12h;
Step B:; 3- (2,6-Dichloro-phenyl)-5-methyl-isoxazole-4-carboxylic 2- hydroxy-ethyl ester 2 (25 mg, 0.079 mmol), triphenylphosphine (31 mg, 0.119 mmol) and 2- nitro-4-trifluoromethyl-phenol (19.6 mg, 0.095 mmol) are dissolved in DCM (1 mL) and cooled to 0C. Diethyl azodicarboxylate (27.5 mg, 0.158 mmol) is added dropwise, the solution is warmed to room temperature and stirred for 12 hours. Then the mixture is concentrated and purified on reverse phase HPLC (HzO/MeCN gradient) to afford the title compound Al as a yellow solid: MS calculated for C20H14Cl2F3N2O6 (M+H+) 505.0, found 505.0.
1-methyl-3-(2-nitro-4-trifluoro-methyl-phenoxymethyl)-piperidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 12h;
2-Nitro-4-trifluoromethyl-phenol (2.07 g,10 mmol) (1-methyl-piperidin-3-yl)-methanol (1.36 g,10.5 mmol) and triphenylphosphine (2.75 g, 10.5mmol), were diluted with 30 mL of THF and placedunder nitrogen. The reaction was cooled to 0°C,then DIAD (2.12 g, 10.5 mmol) was added dropwise in2 mL of THF. The reaction mixture was allowed tostir for 12 hours while warming to room temperature.The reaction mixture was diluted with ethyl acetate(100 mL) and HCl (50 mL of 2N). Aqueous layer waswashed with ethyl acetate (2 x 50 mL), then basifiedwith solid sodium hydroxide to pH=12. The productwas extracted with ethyl acetate (3 x 50 mL), Theorganic layer was washed with brine, dried overMgS04, filtered, and dried under reduced pressure.The product was purified by Biotage 40M cartridgeeluting with CH2Cl2/MeOH/NH4OH (90/8/2) to yield ayellow solid.
2-chloro-1-[3-(4-fluoro-benzyl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-ethanone[ No CAS ]
[ 400-99-7 ]
1-[3-(4-Fluoro-benzyl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-2-(2-nitro-4-trifluoromethyl-phenoxy)-ethanone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
With potassium iodide; potassium carbonate; In butanone;
1-[3-(4-Fluoro-benzyl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-2-(2-nitro-4-trifluoromethyl-phenoxy)-ethanone To a solution of 2-chloro-1-[3-(4-fluoro-benzyl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-ethanone (0.119, 0.37 mmol) in butanone (4 ml) is added <strong>[400-99-7]2-nitro-4-trifluoromethyl-phenol</strong> (0.300 g, 0.41 mmol), potassium carbonate (0.15 g, 1.09 mmol) and potassium iodide (0.18 g, 1.09 mmol). The resulting mixture is stirred at reflux for 7 hours. The reaction is then cooled, diluted with ethyl acetate and washed with brine. The organic layers are dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography gave the title compound (0.10 g, 58%). The title compounds for Examples 2-6 are prepared by a method analogous to that described in Example 1.
B) 2-bromo-6-nitro-4-(trifluoromethyl)phenol To a mixture of <strong>[400-99-7]2-nitro-4-(trifluoromethyl)phenol</strong> (4 g), iron(III) chloride (0.313 g) and acetic acid (24 mL) was added dropwise a solution of bromine (1.286 mL) in acetic acid (8 mL) at 0C. The reaction mixture was stirred at 40C for 2 hr, and then at room temperature for 5 hr. The reaction mixture was filtered through Celite, and the filtrate was diluted with ethyl acetate. The mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (5.37 g). 1H NMR (300 MHz, DMSO-d6) delta 8.26 (1H, dd, J = 2.3, 0.8 Hz), 8.32 (1H, dd, J = 2.3, 0.6 Hz)..The 1H of phenolic hydroxyl group was not observed.
With FeCl3; bromine; In acetic acid;
Step A 2-Bromo-4-trifluoromethyl-6-nitro-phenol 4.0 g of bromine in 7.3 mL of AcOH was added dropwise to a solution of 4.0 g of <strong>[400-99-7]2-nitro-4-trifluoromethyl-phenol</strong> and 300 mg FeCl3 in 23.1 mL of AcOH at 0 C. Reaction was then heated at 40 C. for 1.5 h. and then allowed to stir for 65 h at rt. Solvent was then removed, placed solid back into EtOAc, filtered through celite and concentrated in vacuo. 5 g of title compoundcompound was collected.
a) Preparation of 2-amino-4-trifluoromethylphenol A mixture of 4-trifluoromethyl-2-nitrophenol(1.0 g, 4.8 mmol) and tin (II) chloride (5.4 g, 24.2 mmol) in ethanol(150 mL) was heated at 80 C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2 Cl2) gave the desired product(708 mg, 83%). 1 H NMR (CD3 OD): delta 6.87 (s, 1H), 6.80 (d, 1H), 6.69 (d, 1H).
With calcium carbonate; In (2S)-N-methyl-1-phenylpropan-2-amine hydrate; hexane; N,N-dimethyl-formamide;
(1) To a mixture of 10 g of <strong>[400-99-7]2-nitro-4-trifluoromethylphenol</strong>, 8.0 g of anhydrous calcium carbonate and 30 ml of N,N-dimethylformamide was added dropwise a solution of 8.8 g of 2-bromoisobutyraldehyde in 23 ml of N,N-dimethylformamide and the mixture was stirred at room temperature for 4 days. The reaction mixture was then poured in ice-water and extracted with toluene. The organic layer was washed with 0.5 N aqueous sodium hydroxide solution and water in that order and dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was chromatographed on a silica gel column and elution was carried out with hexane-ethyl acetate (3:1). The Crystals from the elude were recrystallized from 15 ml of hexane twice to give 4.428 g of 2-(2-nitro-4-trifluoromethylphenoxy)isobutyraldehyde.
a) 7-Cyanomethoxy-4-trifluoromethylindole This compound was prepared from <strong>[400-99-7]2-nitro-4-trifluoromethylphenol</strong> by the methods described in Examples 1a part (i), 3a part (ii) and 1a part (vi).
a) 7-Cyanomethoxy-4-trifluoromethylindole This compound was prepared from 2-nitro-4-trifluoro-methylphenol by the methods described in Examples 1a part (i), 3a part (ii) and 1a part (vi).
With sodium hydroxide; In hydrogenchloride; methanol;
EXAMPLE 1 400 ml of methanol, 20 g of benzyldimethyldodecylammonium chloride and 180 g of 4-chloro-3-nitro-benzotrifluoride are initially introduced into the reaction flask, whilst stirring, and 400 g of 50% strength sodium hydroxide solution are then added dropwise. The temperature rises to about 70 C. if the addition is carried out in the course of about 20 minutes. The mixture is then stirred at 65 C. for a further 4 hours and subsequently cooled by adding ice, and the pH is adjusted to 3 with concentrated hydrochloric acid. The phenol is driven over with steam and the phases are separated in the receiver by adding about 50 ml of concentrated hydrochloric acid. 156 g of 2-nitro-4-trifluoromethylphenol are obtained with a purity of more than 98.5%, according to analysis by gas chromatography, which corresponds to a yield of 91% of theory. Boiling point: 92-95 C. at 15 mm, nD20: 1.5020.
aqueous benzyldodecyldimethylammonium chloride[ No CAS ]
[ 109-86-4 ]
[ 121-17-5 ]
[ 400-99-7 ]
Yield
Reaction Conditions
Operation in experiment
92%
With hydrogenchloride; potassium hydroxide;
EXAMPLE 6 45 g of 4-chloro-3-nitro-benzotrifluoride and 10 ml of 50% strength aqueous benzyldodecyldimethylammonium chloride are initially introduced into 150 ml of ethylene glycol monomethyl ether, and 100 g of 50% strength potassium hydroxide solution are added dropwise in the course of about 30 minutes, up to a temperature of 65 C. The mixture is then stirred at 65 C. for 6 hours and subsequently cooled and rendered acid with concentrated hydrochloric acid, and about 500 ml of distillate are driven over with steam. The organic phase is separated off and washed with 20 ml of dilute hydrochloric acid, and the organic phase is again separated off and dried with sodium sulphate. 38 g of 2-nitro-4-trifluoromethylphenol are obtained, which corresponds to a yield of 92% of theory.
a) Preparation of 2-amino-4-trifluoromethylphenol A mixture of 4-trifluoromethyl-2-nitrophenol (1.0 g, 4.8 mmol) and tin (It) chloride (5.4 g, 24.2 mmol) in ethanol (150 mL) was heated at 80 C. under argon. After 2 hours, the starting material had disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2Cl2) gave the desired product (708 mg, 83%). 1H NMR (CD3OD): d 6.87 (s, 1H), 6.80 (d, 1H), 6.69 (d, 1H).
With nitric acid; acetic acid; at 20 - 40℃; for 1h;
General procedure: An appropriate phenol (3) (150 mmol) was dissolved in glacial acetic acid (50 mL), and the solution was stirred and maintained at 40 C. Then, a solution containing 11 mL of 65% HNO3 and 30 mL of glacial acetic acid was added drop wise over 15 min. The mixture was stirred at r.t. for 45 min and poured into ice-water (400 mL). The aqueous mixture was extracted four times with CHCl3 (100 mL). Next, the organic phases were collected, dried with Na2SO4, evaporated and purified by column chromatography (4a, 4c, 4e) or crystallisation from ethanol (4b). Compound 4d was used for the next step without further purification [17].
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