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Example 16 2- (2, 3-D6hyl-4-nitro-phenylamino} 2-methyl-propan-1-ol Fuming nitric acid (1.4 g, 20.3 mmol) was cooled to 0°C and acetic anhydride (2.89 g, 28.4 mmol) was added. This solution was added to a cold (0°C) solution of 3-fluoro-1, 2- dimethylbenzene (1.0 g, 8.1 mmol) in acetic anhydride (4 ml) over 10 min. The reaction mixture was stirred for 25 min, poured slowly over ice and the water solution extracted with EtOAc (x 3). The collected organic phase was washed with diluted saturated aqueous solution of NaHCO3 followed by brine before evaporation to dryness. The residue was flash purified on a silica gel column using hexane as a mobile phase to give 2, 3-dimethyl-4-fluoro-1-nitro-benzene 0.74 g (54percent) as a yellow oil which crystallised upon standing. The fluoride (0.576 g, 3. 4 mmol) was mixed with 2-amino-2-methylpropanol (0.61 g, 6.8 mmol) in a tube, and the tube was sealed before immersing it into an oil bath and heating at 160°C for 5 days. TLC (Hexane) showed remaining starting material. The reaction mixture was cooled and diluted with EtOAc before purification by flash silica gel chromatography (dry application; 6: 4 hexane and EtOAc) to give 0.34 g (59percent recovery) of the starting material 2, 3-dimethyl-4-fluoro-1-nitro-benzene and 0.20 g (61percent based on recovered starting material) of the 2- (2, 3-dimethyl-4-nitro-phenylamino)-2-methyl- propan-1-ol.
Reference：
[1] Patent: WO2005/42464, 2005, A1, . Location in patent: Page/Page column 38-39
[2] Journal of the Chemical Society, 1963, p. 5554 - 5556
With nitric acid; acetic anhydride; at 0℃; for 0.583333h;
Example 16 2- (2, 3-D6hyl-4-nitro-phenylamino} 2-methyl-propan-1-ol Fuming nitric acid (1.4 g, 20.3 mmol) was cooled to 0°C and acetic anhydride (2.89 g, 28.4 mmol) was added. This solution was added to a cold (0°C) solution of 3-fluoro-1, 2- dimethylbenzene (1.0 g, 8.1 mmol) in acetic anhydride (4 ml) over 10 min. The reaction mixture was stirred for 25 min, poured slowly over ice and the water solution extracted with EtOAc (x 3). The collected organic phase was washed with diluted saturated aqueous solution of NaHCO3 followed by brine before evaporation to dryness. The residue was flash purified on a silica gel column using hexane as a mobile phase to give 2, 3-dimethyl-4-fluoro-1-nitro-benzene 0.74 g (54percent) as a yellow oil which crystallised upon standing. The fluoride (0.576 g, 3. 4 mmol) was mixed with 2-amino-2-methylpropanol (0.61 g, 6.8 mmol) in a tube, and the tube was sealed before immersing it into an oil bath and heating at 160°C for 5 days. TLC (Hexane) showed remaining starting material. The reaction mixture was cooled and diluted with EtOAc before purification by flash silica gel chromatography (dry application; 6: 4 hexane and EtOAc) to give 0.34 g (59percent recovery) of the starting material 2, 3-dimethyl-4-fluoro-1-nitro-benzene and 0.20 g (61percent based on recovered starting material) of the 2- (2, 3-dimethyl-4-nitro-phenylamino)-2-methyl- propan-1-ol.
2-(2,3-dimethyl-4-nitro-phenylamino)-2-methyl-propan-1-ol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
at 160℃; for 120h;
Example 16 2- (2, 3-D6hyl-4-nitro-phenylamino} 2-methyl-propan-1-ol Fuming nitric acid (1.4 g, 20.3 mmol) was cooled to 0C and acetic anhydride (2.89 g, 28.4 mmol) was added. This solution was added to a cold (0C) solution of 3-fluoro-1, 2- dimethylbenzene (1.0 g, 8.1 mmol) in acetic anhydride (4 ml) over 10 min. The reaction mixture was stirred for 25 min, poured slowly over ice and the water solution extracted with EtOAc (x 3). The collected organic phase was washed with diluted saturated aqueous solution of NaHCO3 followed by brine before evaporation to dryness. The residue was flash purified on a silica gel column using hexane as a mobile phase to give 2, 3-dimethyl-4-fluoro-1-nitro-benzene 0.74 g (54%) as a yellow oil which crystallised upon standing. The fluoride (0.576 g, 3. 4 mmol) was mixed with 2-amino-2-methylpropanol (0.61 g, 6.8 mmol) in a tube, and the tube was sealed before immersing it into an oil bath and heating at 160C for 5 days. TLC (Hexane) showed remaining starting material. The reaction mixture was cooled and diluted with EtOAc before purification by flash silica gel chromatography (dry application; 6: 4 hexane and EtOAc) to give 0.34 g (59% recovery) of the starting material 2, 3-dimethyl-4-fluoro-1-nitro-benzene and 0.20 g (61% based on recovered starting material) of the 2- (2, 3-dimethyl-4-nitro-phenylamino)-2-methyl- propan-1-ol.
With sodium hydrogencarbonate; In dimethyl sulfoxide; at 100℃; for 72h;
A mixture of <strong>[1736-87-4]1-fluoro-2,3-dimethyl-4-nitrobenzene</strong> (0.003 mol), 1 /-/-indole-3-ethanamine (0.0036 mol) and NaHCO3 (0.0039 mol) in DMSO (4ml) was stirred at 1000C for 3 days, then cooled to room temperature. H2O was added. The precipitate was filtered, washed with EtOH, then with diethyl ether and dried. A part of this fraction was dried at 600C for 18 hours under vacuo, yielding 0.052g of intermediate 15 (M. P.: 178C).
With potassium carbonate; In dimethyl sulfoxide; at 75℃; for 72h;
Intermediate C2: 4-(2,3-Dimethyl-4-nitrophenoxy)pyridin-2 -amine.Intermediate C2 To a stirred solution of <strong>[33631-05-9]2-aminopyridin-4-ol</strong> (600 mg, 5.5 mmol) and 1 -fluoro-2,3-dimethyl-4- nitrobenzene (570 mg, 3.37 mmol) in DMSO (4.0 mL) was added K2C03 (1.00 g, 7.20 mmol) and the reaction mixture heated to 75C for 3 days. The resulting mixture was cooled to RT and was partitioned between water (50 mL) and EtOAc (75 mL). The aq layer was separated and extracted with EtOAc (75 mL) and the combined organic extracts were washed with water (3 x 50 mL) and brine (50 mL) and then dried and evaporated in vacuo. The residue was recrystallized from DCM to afford the title compound, Intermediate C2, as a tan solid (25 mg, 28%): R' 1 .40 min (Method 2); m/z 260 (M+H)+ (ES+).
19%
To a suspension of <strong>[33631-05-9]2-aminopyridin-4-ol</strong> (339 mg, 3.07 mmol) in MeCN (4.0 ml.) at RT was added DBU (570 mul_, 3.78 mmol) and after 30 min a solution of 1-fluoro-2,3-dimethyl-4- nitrobenzene (400 mg, 2.36 mmol) in MeCN (2.0 ml.) was added dropwise. The reaction mixture was maintained at RT for 16 hr; DMF (2.0 ml.) was added and the mixture heated to 800C for 72 hr and then cooled to RT for 64 hr. The resulting mixture was evaporated in vacuo and the residue was partitioned between DCM (50 ml.) and brine (30 ml_). The organic layer was separated and dried (MgSO4) and was evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, EtOAc in isohexane, 20-100%, gradient elution and then SiO2, 12g, 50% EtOAc in isohexane, isocratic elution) to afford 4-(2,3-dimethyl-4- nitrophenoxy)pyridin-2-amine, as a yellow solid (1 17 mg, 19%); R' 1.47 min (Method 2); m/z 260 (M+H)+ (ES+).
Intermediate C3: 4-((2,3-Dimethyl-4-nitrophenoxy)methyl)pyridin-2 -amine.Intermediate C3To a stirred solution of <strong>[105250-17-7](2-aminopyridin-4-yl)methanol</strong> (1 .33 g, 10.8 mmol) in DMF (10 mL) at 0°C was added sodium hydride (60percent dispersion in mineral oil, 537 mg, 13.4 mmol) and the reaction mixture maintained at 0°C for 5 min and then warmed to RT for 1 hr. The mixture was re-cooled to 0°C, treated with a solution of 1 -fluoro-2,3-dimethyl-4-nitrobenzene (2.00 g, 12.0 mmol) in DMF (5.0 mL) and after 2 min was warmed to RT. After 20 hr the reaction mixture was diluted with saturated aq. NH4CI (50 mL) and extracted with EtOAc (2 x 100 mL) and then ether (100 mL). The combined organic extracts were dried and evaporated in vacuo to afford a red oil. The residue was diluted with acetonitrile (50 mL), upon which a brown precipitate formed. The precipitate was removed by filtration and the filtrate was evaporated in vacuo. This residue was purified by flash column chromatography (Si02, 80 g, MeOH in DCM, 0-5percent, gradient elution) to afford the title compound, Intermediate C3, as a yellow solid (1.19 g, 39percent); R' 1 .35 (Method 2); m/z 274 (M+H)+ (ES+).
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