2-氯-6-氟苯酚

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Chloro-6-fluorophenol (1.8 g, 12.33 mmol) was dissolved in dimethylformamide (DMF; 22 mL) and water (2.2 mL). Potassium carbonate (2.55 g, 18.5 mmol) and sodium chlorodifluoroacetate (4.7 g, 30.8 mmol) were then added and the solution was heated to 100° C. for 3 h. The cooled reaction mixture was then diluted with concentrated HCl (10 mL) and the resulting solution was stirred for 2 h. The reaction mixture was diluted with diethyl ether, washed with water, washed twice with 1M NaOH, washed once with brine, dried, filtered and concentrated under vacuum to yield the title compound (1 g, 41% yield) that was used in subsequent reactions without further purification. The cooled reaction mixture washed with water washed twice with 1M NaOH washed once with brine dried filtered concentrated under vacuum

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-Chloro-6-fluorophenol (1.8 g, 12.33 mmol) was dissolved in dimethylformamide (DMF; 22 mL) and water (2.2 mL). Potassium carbonate (2.55 g, 18.5 mmol) and sodium chlorodifluoroacetate (4.7 g, 30.8 mmol) were then added and the solution was heated to 100° C. for 3 h. The cooled reaction mixture was then diluted with concentrated HCl (10 mL) and the resulting solution was stirred for 2 h. The reaction mixture was diluted with diethyl ether, washed with water, washed twice with 1M NaOH, washed once with brine, dried, filtered and concentrated under vacuum to yield the title compound (1 g, 41% yield) that was used in subsequent reactions without further purification. The cooled reaction mixture washed with water washed twice with 1M NaOH washed once with brine dried filtered concentrated under vacuum

反应条件: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred mixture of potassium carbonate (25.04 g; 0.18 mol) in DMSO (200 ml) under an argon atmosphere was added an 8:2 mixture (25 g; 0.171 mol) (from Step 2A) of 4-chloro-2-fluorophenol (~20 g; 0.136 mol) and 2-chloro-6-fluorophenol (~5 g; 0.034 mol). To this mixture was added 4-fluoronitrobenzene (18.05 g; 0.128 mol) and the resulting mixture stirred at 100° C. for 30 minutes. At the end of this time, g.c. showed that the mixture contained (peak areas) ~10% of 2-chloro-6-fluorophenol, ~3% of a dichlorofluorophenol, a trace of 4-chloro-2-fluorophenol, and a single product peak. This mixture was poured into aqueous base (~1% NaOH) and the resulting mixture extracted with ether (2×300 ml). The ether extracts were combined, washed with water (an emulsion formed which required a little saturated aqueous NaCl to break), dried (MgSO4) and the solvent removed to give an orange-red oil (34 g). 19F NMR (CDCl3) showed that essentially a single isomer to be present. The material was subjected to Kugelrohr distillation (oven temp.=135°-145°) to give the desired product as a light yellow oil (32 g): RI=1.6038 @ 25° C. Recrystallization from hexane (freezer) gave the product as a white solid: m.p.=55°-57°C. the resulting mixture extracted with ether (2×300 ml) washed with water (an emulsion formed which dried (MgSO4) the solvent removed

反应条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To NaH (60 wt % in mineral oil; 0.071 g, 1.763 mmol) in 1 mL DMF was added 2-chloro-6-fluorophenol (0.258 g, 1.763 mmol). After 10 min, a clear/colorless solution resulted. 2-(2-Chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 0.075 g, 0.252 mmol) was added and the reaction became dark red. The reaction was heated at 70° C. for 1 h, then at 90° C. for 2 h, then at 110° C. for 14 h. The reaction was cooled to 0° C. and quenched with TFA (0.136 ml, 1.763 mmol), diluted with 1 mL DMSO, filtered, and purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 15-100% ACN/H2O with 0.1% TFA); product-containing fractions were concentrated in vacuo then treated with saturated aq. NaHCO3 and DCM. The organic layer was separated and the aq. layer was extracted 3×DCM. The combined organic extracts were then dried over Na2SO4, filtered, and concentrated in vacuo to give 2-(2-(2-chloro-6-fluorophenoxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.030 g, 0.074 mmol, 29% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.91 (1H, br. s), 8.57 (1H, d, J=8.8 Hz), 8.05-8.15 (1H, m), 7.84 (1H, dt, J=7.7, 0.8 Hz), 7.38-7.69 (5H, m), 6.87-6.91 (1H, m), 6.85 (1H, d, J=2.3 Hz), 3.32-3.38 (2H, m), 2.54-2.50 (2H, m). m/z (ESI, +ve) 408.2 (M+H)+. a clear/colorless solution resulted at 90° C. for 2 h at 110° C. for 14 h The reaction was cooled to 0° C. filtered purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 15-100% ACN/H2O with 0.1% TFA) product-containing fractions were concentrated in vacuo then treated with saturated aq. NaHCO3 and DCM The organic layer was separated the aq. layer was extracted 3×DCM The combined organic extracts were then dried over Na2SO4 filtered concentrated in vacuo

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4 g (56 mmol) of chlorine is introduced at this temperature. Then 60.5 g (540 mmol) of 2-fluorophenol are dropped in the solution over about 2 hours, while at the same rate 42 g (590 mmol) more chlorine is Introduced. After that 4 g more chlorine are introduced to complete the chlorination. is Introduced

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4 g (56 mmol) of chlorine is introduced at this temperature. Then 60.5 g (540 mmol) of 2-fluorophenol are dropped in the solution over about 2 hours, while at the same rate 42 g (590 mmol) more chlorine is Introduced. After that 4 g more chlorine are introduced to complete the chlorination. is Introduced

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 14.65 g (100 mmol) of 2-chloro-6-fluorophenol are dissolved in 50 ml of 2-propanol followed by the addition of 15.5 g (112 mmol) of potassium carbonate and 18.9 g (103 mmol) of 2-chloro-N-(4-methylphenyl)acetamide. The mixture is refluxed for 4 hours. At this time, the formation of 2-(2′-chloro-6′-fluorophenoxy)-N-(4-methylphenyl)acetamide is completed. 20 ml of sodium methylate solution 30% in methanol are slowly added. To maintain a temperature of at least 75° C., about 25 ml of solvent are distilled during the addition. The mixture is boiled 2 hours more to complete the formation of (2′-chloro-6′-fluorophenyl)-(4-methylphenyl)-amine. The mixture is refluxed for 4 hours are distilled during the addition

反应条件: temp:15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of 2-chloro-6-fluorophenol (1.0 g, 6.82 mmol) in concentrated acetic acid (3.0 mL) was cooled to 0° C. Fuming nitric acid (559 mg, 8.87 mmol) was added dropwise, maintaining the reaction temperature between 10 to 20° C. The reaction was allowed to stir at 0° C. for 3 h. The mixture was poured over ice and was allowed to warm to room temperature. The aqueous was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (1×50 mL), dried over Na2SO4, and evaporated under reduced pressure. The crude red solid was purified using the Biotage Quad 4 (25 M column) eluting with 9:1 Hexanes/EtOAc to afford the title compound as a yellow solid (326 mg, 1.70 mmol; 25% yield). 1H-NMR (DMSO-d6) δ 11.74 to 12.77 (broad s, 1H), 8.10 to 8.16 (m, 2H). The mixture was poured over ice to warm to room temperature The aqueous was extracted with EtOAc (3×50 mL) The combined organic layers were washed with brine (1×50 mL) dried over Na2SO4 evaporated under reduced pressure The crude red solid was purified eluting with 9:1 Hexanes/EtOAc

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Same procedure as example 6a starting from 2-chloro-6-fluorophenol and 2-chloro-N-(4-ethylphenyl)acetamide.