4-溴-2,6-二氟苯腈

反应条件: temp:0.00; pressure:0.00; stir:

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

实验步骤: KOtBu (11.8 g) is added to a flask charged with a stir bar and dry NMP (40 mL) and chilled to −10° C. under argon atmosphere. A solution of ethyl (4-ethyl-phenyl)-acetate (10.1 g) and 1-bromo-4-cyano-3,5-difluoro-benzene (11.5 g) in NMP (40 mL) is added at such a rate that the reaction temperature maintains below 10° C. After stirring for 1 hour at room temperature, methanol (50 mL) and 1 M aqueous sodium hydroxide solution (39 mL) are added and the resulting mixture is stirred overnight at 100° C. Then, 4 M aqueous hydrochloric acid (100 mL) is added and the mixture is stirred for another h at 100° C. The methanol fraction is evaporated, water (200 mL) is added to the residue and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are washed twice with water, twice with brine and dried (MgSO4). The solvent is evaporated and the residue is washed with methanol. The insoluble residue is separated by filtration and dried to give the white product. charged with a stir bar maintains below 10° C the resulting mixture is stirred overnight at 100° C the mixture is stirred for another h at 100° C The methanol fraction is evaporated water (200 mL) is added to the residue the resulting mixture is extracted with ethyl acetate The combined organic extracts are washed twice with water, twice with brine dried (MgSO4) The solvent is evaporated the residue is washed with methanol The insoluble residue is separated by filtration dried to give the white product

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

实验步骤: KOtBu (11.8 g) is added to a flask charged with a stir bar and dry NMP (40 mL) and chilled to −10° C. under argon atmosphere. A solution of ethyl (4-ethyl-phenyl)-acetate (10.1 g) and 1-bromo-4-cyano-3,5-difluoro-benzene (11.5 g) in NMP (40 mL) is added at such a rate that the reaction temperature maintains below 10° C. After stirring for 1 hour at room temperature, methanol (50 mL) and 1 M aqueous sodium hydroxide solution (39 mL) are added and the resulting mixture is stirred overnight at 100° C. Then, 4 M aqueous hydrochloric acid (100 mL) is added and the mixture is stirred for another h at 100° C. The methanol fraction is evaporated, water (200 mL) is added to the residue and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are washed twice with water, twice with brine and dried (MgSO4). The solvent is evaporated and the residue is washed with methanol. The insoluble residue is separated by filtration and dried to give the white product. charged with a stir bar maintains below 10° C the resulting mixture is stirred overnight at 100° C the mixture is stirred for another h at 100° C The methanol fraction is evaporated water (200 mL) is added to the residue the resulting mixture is extracted with ethyl acetate The combined organic extracts are washed twice with water, twice with brine dried (MgSO4) The solvent is evaporated the residue is washed with methanol The insoluble residue is separated by filtration dried to give the white product

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

实验步骤: A solution of 3-bromobenzaldehyde (1, 18.5 g, 100 mmol), propane-1,3-diol (9.1 g, 120 mmol) and p-toluenesufonic acid monohydrate (0.1 g, 0.5 mmol) in toluene (200 mL) was refluxed with azeotropical removal of water using a Dean-Stark water separator for 15.5 h. The reaction mixture was cooled to room temperature, washed with 5% potassium carbonate solution (100 mL) and water (2×100 mL), dried over sodium sulfate and filtered. The filtrate was concentrated to afford the title compound (24.8 g, 100%): 1H NMR (500 MHz, CDCl3) δ 7.66 (t, J=1.8 Hz, 1H), 7.46 (ddd, J=7.9, 2.0, 1.1 Hz, 1H), 7.40 (br d, J=7.9 Hz, 1H), 7.23 (t, J=7.9 Hz, 1H), 5.46 (s, 1H), 4.28-4.25 (m, 2H), 4.00-3.95 (m, 2H), 2.26-2.17 (m, 1H), 1.47-1.43 (m, 1H); ESI MS m/z 243, 245 [M+H]+. washed with 5% potassium carbonate solution (100 mL) and water (2×100 mL) dried over sodium sulfate filtered The filtrate was concentrated

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

实验步骤: A solution of 3-bromobenzaldehyde (1, 18.5 g, 100 mmol), propane-1,3-diol (9.1 g, 120 mmol) and p-toluenesufonic acid monohydrate (0.1 g, 0.5 mmol) in toluene (200 mL) was refluxed with azeotropical removal of water using a Dean-Stark water separator for 15.5 h. The reaction mixture was cooled to room temperature, washed with 5% potassium carbonate solution (100 mL) and water (2×100 mL), dried over sodium sulfate and filtered. The filtrate was concentrated to afford the title compound (24.8 g, 100%): 1H NMR (500 MHz, CDCl3) δ 7.66 (t, J=1.8 Hz, 1H), 7.46 (ddd, J=7.9, 2.0, 1.1 Hz, 1H), 7.40 (br d, J=7.9 Hz, 1H), 7.23 (t, J=7.9 Hz, 1H), 5.46 (s, 1H), 4.28-4.25 (m, 2H), 4.00-3.95 (m, 2H), 2.26-2.17 (m, 1H), 1.47-1.43 (m, 1H); ESI MS m/z 243, 245 [M+H]+. washed with 5% potassium carbonate solution (100 mL) and water (2×100 mL) dried over sodium sulfate filtered The filtrate was concentrated

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

实验步骤: To a solution of 4-bromo-2,6-difluorobenzonitrile (1, 15.0 g, 69 mmol) in THF (100 mL) at 0° C. was slowly added sodium methoxide (25% wt in methanol, 14.9 g, 69 mmol) and the mixture was stirred at room temperature for 16 h. The mixture was concentrated and partitioned between dichloromethane (500 mL) and water (250 mL). The organic extracts were dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel chromatography eluting with ethyl acetate in hexane (0-100%) to afford the title compound (15.2 g, 99%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 7.01-6.99 (m, 1H), 6.94 (s, 1H), 3.96 (s, 1H). at 0° C. The mixture was concentrated partitioned between dichloromethane (500 mL) and water (250 mL) The organic extracts were dried (MgSO4) filtered concentrated The residue was purified by silica gel chromatography eluting with ethyl acetate in hexane (0-100%)

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

实验步骤: The title compound was prepared from 4-bromo-2,6-difluorobenzonitrile (2.5 g, 11.47 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.51 g, 12.61 mmol) using the method of Example 34(a) producing 3.61 g of title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.52-1.67 (m, 3H), 1.81-1.87 (m, 1H), 1.95-1.99 (m, 1H), 2.33-2.41 (m, 1H), 3.59-3.65 (m, 1H), 3.94-3.98 (m, 1H), 5.36-5.39 (m, 1H), 6.77 (d, 1H), 7.62 (s, 1H), 7.64 (s, 1H), 7.66 (d, 1H).

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

实验步骤: To a solution of 4-bromo-2,6-difluoro-benzonitrile (15.0 g, 68.8 mmol) in tetrahydrofuran (150 ml) is added sodium methoxide (4.5 g, 82.6 mmol) at room temperature and the mixture is stirred for 16 h. The reaction mixture is concentrated under reduced pressure and the resulting solid is purified by column chromatography (silica gel, 5% ethyl acetate/hexane) to obtain 4-bromo-2-fluoro-6-methoxy-benzonitrile (8.5 g, 36.9 mmol, 53%). The reaction mixture is concentrated under reduced pressure the resulting solid is purified by column chromatography (silica gel, 5% ethyl acetate/hexane)

反应条件: temp:2.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: A solution of compound 1 (11.50 g, 0.076 mol) in ethanol (90 ml) was added dropwise to a stirred mixture of compound 7 (15.0 g, 0.069 mol) and tetrakis(triphenylphosphine)palladium(O) (2.38 g, 2.06 mmol) in benzene (130 ml) and 2M-sodium carbonate (100 ml) at room temperature under dry nitrogen. The stirred mixture was heated under reflux (90°-95° C.) for 4.5 h (i.e., until glc analysis revealed absence of starting material). The mixture was cooled and stirred for 1 h at room temperature with 30% hydrogen peroxide (2 ml). The mixture was further cooled to 2° C., and the product was filtered off and washed with water. The product was dried (CaCl2) in vacuo to give fawn-coloured needles. The stirred mixture was heated under reflux (90°-95° C.) for 4.5 h (i.e., until glc analysis revealed absence of starting material) The mixture was cooled the product was filtered off washed with water The product was dried (CaCl2) in vacuo to give fawn-coloured needles

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

实验步骤: To a 500-mL RBF was added NaH (0.660 g, 27.5 mmol) and THF (100 mL). To this solution was added benzyl alcohol (2.385 mL, 22.94 mmol) in THF slowly via syringe, with external cooling (ice bath) when necessary. After the addition, the reaction mixture was stirred for 1 hour at room temperature. At this time, the mixture was transferred via syringe slowly to a solution of 4-bromo-2,6-difluorobenzonitrile (5 g, 22.94 mmol) in THF at 0° C. The solution was allowed to warm to room temperature and stirred over the weekend. The reaction was poured into water (50 mL), and extracted with EtOAc (3×100 mL). The organic layers were combined and dried over Na2SO4. The dried solution was filtered, and the filtrate was concentrated in vacuo to yield a pale yellow solid which was purified by flash chromatography (gradient elution 0-30% EtOAc in hexanes) to afford the title compound (3.911 g) as a white fluffy solid. 1H NMR (400 MHz, DMSO-d6): δ 5.35 (s, 2H), 7.27-7.66 (m, 7H). with external cooling (ice bath) when necessary After the addition to warm to room temperature stirred over the weekend extracted with EtOAc (3×100 mL) dried over Na2SO4 The dried solution was filtered the filtrate was concentrated in vacuo to yield a pale yellow solid which was purified by flash chromatography (gradient elution 0-30% EtOAc in hexanes)

反应条件: temp:150.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: Five batches of the below reaction were run in sequence in a microwave reactor: To a 5-mL microwave vial was added 4-bromo-2,6-difluorobenzonitrile (3 g, 13.76 mmol), hydrazine (0.864 mL, 27.5 mmol), Hunig's base (4.81 mL, 27.5 mmol) and ethanol (10 mL). The vial was capped and stirred for 10 minutes at 150° C. in a microwave reactor. The reaction mixture was cooled (ice-water bath) and a yellow precipitate formed. The yellow precipitates were collected, combined and the solids were washed with cold ethanol to yield pale yellow rods of the title compound (13.0 g). LC-MS (ES) m/z=230 and 232 (1:1 intensity) [M+H]+. Five batches of the below reaction were run in sequence in a microwave reactor The vial was capped a yellow precipitate formed The yellow precipitates were collected the solids were washed with cold ethanol

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a stirred solution of 4-bromo-2,6-difluorobenzamide (9 5 g) in DMF (1 L) at 0° C. was added cyanuric chloride (82 g) slowly, and the reaction mixture was stirred at 0° C. for 4 hours. Water (5 L) was added slowly to the reaction, and it was extracted with EtOAc (2 L). The organic layer was separated, dried over MgSO4, filtered and evaporated under vacuum to afford the crude product, which was purified by chromatography (SiO2, 300-400 mesh, petroleum ether:EtOAc=200:1) to provide 47 g of pure title compound and 17 g of impure title compound. 1H NMR (300 MHz, DMSO-d6): δ 7.90 (m, 2H). was extracted with EtOAc (2 L) The organic layer was separated dried over MgSO4 filtered evaporated under vacuum to afford the crude product, which was purified by chromatography (SiO2, 300-400 mesh, petroleum ether:EtOAc=200:1)