4-amino-2-fluoro-3-methylbenzonitrile

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of dimethyl sulfoxide (400 mL) and potassium nitrite (22.67 g, 266 mmol) was stirred to dissolve potassium nitrite and 4-amino-2-fluoro-3-methylbenzonitrile (10 g, 66.6 mmol) and copper(I) bromide (1.911 g, 13.32 mmol) were added. Aqueous 48% hydrogen bromide (33 mL, 266 mmol), diluted with dimethyl sulfoxide (200 mL), was added dropwise and the reaction stirred for 2 h. After complete conversion of starting material, the reaction mixture was poured into iced-cold water and neutralized to pH 7 with cold concentrated sodium hydroxide. The resulting solid was collected by filtration to give the desired product (11.4 g, 53.3 mmol, 80% yield) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ (ppm) 7.47 (d, J=9.37 Hz, 1H), 7.33 (t, 1H), 2.39 (d, J=2.34 Hz, 3H). were added was added dropwise the reaction stirred for 2 h The resulting solid was collected by filtration

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-bromo-3-fluoro-2-methylaniline (23 g, 113 mmol) and cyanocopper (20.19 g, 225 mmol) N,N-dimethylformamide (200 mL) was heated to 140° C. for 7 h. After the mixture was cooled to room temperature filtered and poured into a reparatory funnel containing water and ethyl acetate (1:1). Layers were separated and the organic layer was concentrated under reduced pressure. Flash chromatography (0-50% ethyl acetate in hexane) gave the desired product (11.4 g, 76 mmol, 67% yield) as a brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ (ppm) 7.22 (t, 1H), 6.45 (d, J=8.59 Hz, 1H), 4.23 (br. s., 2H), 2.07 (s, 3H); MS (ESI) m/z 151.1 [M+1]+. After the mixture was cooled to room temperature filtered poured into a reparatory funnel containing water and ethyl acetate (1:1) Layers were separated the organic layer was concentrated under reduced pressure

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-bromo-3-fluoro-2-methylaniline (23 g, 113 mmol) and cyanocopper (20.19 g, 225 mmol) N,N-dimethylformamide (200 mL) was heated to 140° C. for 7 h. After the mixture was cooled to room temperature filtered and poured into a reparatory funnel containing water and ethyl acetate (1:1). Layers were separated and the organic layer was concentrated under reduced pressure. Flash chromatography (0-50% ethyl acetate in hexane) gave the desired product (11.4 g, 76 mmol, 67% yield) as a brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ (ppm) 7.22 (t, 1H), 6.45 (d, J=8.59 Hz, 1H), 4.23 (br. s., 2H), 2.07 (s, 3H); MS (ESI) m/z 151.1 [M+1]+. After the mixture was cooled to room temperature filtered poured into a reparatory funnel containing water and ethyl acetate (1:1) Layers were separated the organic layer was concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Fluoro-4-isocyanato-3-methylbenzonitrile was prepared from 4-amino-2-fluoro-3-methyl-benzonitrile (72D) following a procedure analogous to the procedure used in the preparation of compound 2E (Example 2).

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Fluoro-4-isocyanato-3-methylbenzonitrile was prepared from 4-amino-2-fluoro-3-methyl-benzonitrile (72D) following a procedure analogous to the procedure used in the preparation of compound 2E (Example 2).

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: N-(4-cyano-3-fluoro-2-methyl-phenyl)-acetamide (72C) (450 mg, 2.34 mmol) was dissolved in 1:1 conc. HCl/EtOH (20 mL,) and the mixture was refluxed for 1 h. The reaction was cooled to rt and concentrated. The residue was dissolved in EtOAc (30 mL), washed with sat. aq. NaHCO3 and brine, dried (MgSO4), filtered and concentrated. The residue was recrystallized from EtOAc/Hexane to provide the title compound (340 mg). LC/MS: m/z 151 [M+H]+ the mixture was refluxed for 1 h concentrated The residue was dissolved in EtOAc (30 mL) washed with sat. aq. NaHCO3 and brine dried (MgSO4) filtered concentrated The residue was recrystallized from EtOAc/Hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of dimethyl sulfoxide (400 mL) and potassium nitrite (22.67 g, 266 mmol) was stirred to dissolve potassium nitrite and 4-amino-2-fluoro-3-methylbenzonitrile (10 g, 66.6 mmol) and copper(I) bromide (1.911 g, 13.32 mmol) were added. Aqueous 48% hydrogen bromide (33 mL, 266 mmol), diluted with dimethyl sulfoxide (200 mL), was added dropwise and the reaction stirred for 2 h. After complete conversion of starting material, the reaction mixture was poured into iced-cold water and neutralized to pH 7 with cold concentrated sodium hydroxide. The resulting solid was collected by filtration to give the desired product (11.4 g, 53.3 mmol, 80% yield) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ (ppm) 7.47 (d, J=9.37 Hz, 1H), 7.33 (t, 1H), 2.39 (d, J=2.34 Hz, 3H). were added was added dropwise the reaction stirred for 2 h The resulting solid was collected by filtration

反応条件: temp:140.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 4-bromo-3-fluoro-2-methylaniline (23 g, 113 mmol) and cyanocopper (20.19 g, 225 mmol) N,N-dimethylformamide (200 mL) was heated to 140° C. for 7 h. After the mixture was cooled to room temperature filtered and poured into a separatory funnel containing water and ethyl acetate (1:1). Layers were separated and the organic layer was concentrated under reduced pressure. Flash chromatography (0-50% ethyl acetate in hexane) gave the desired product (11.4 g, 76 mmol, 67% yield) as a brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ (ppm) 7.22 (t, 1H), 6.45 (d, J=8.59 Hz, 1H), 4.23 (br. s., 2H), 2.07 (s, 3H); MS (ESI) m/z 151.1[M+1]+. After the mixture was cooled to room temperature filtered poured into a separatory funnel containing water and ethyl acetate (1:1) Layers were separated the organic layer was concentrated under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 2-Fluoro-4-isocyanato-3-methylbenzonitrile was prepared from 4-amino-2-fluoro-3-methyl-benzonitrile (72D) following a procedure analogous to the procedure used in the preparation of compound 2E (Example 2).

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: N-(4-cyano-3-fluoro-2-methyl-phenyl)-acetamide (72C) (450 mg, 2.34 mmol) was dissolved in 1:1 conc. HCl/EtOH (20 mL), and the mixture was refluxed for 1 h. The reaction was cooled to rt and concentrated. The residue was dissolved in EtOAc (30 mL), washed with sat. aq. NaHCO3 and brine, dried (MgSO4), filtered and concentrated. The residue was recrystallized from EtOAc/Hexane to provide the title compound (340 mg). LC/MS: m/z 151 [M+H]+ the mixture was refluxed for 1 h concentrated The residue was dissolved in EtOAc (30 mL) washed with sat. aq. NaHCO3 and brine dried (MgSO4) filtered concentrated The residue was recrystallized from EtOAc/Hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: N-(4-cyano-3-fluoro-2-methyl-phenyl)-acetamide (72C) (450 mg, 2.34 mmol) was dissolved in 1:1 conc. HCl/EtOH (20 mL), and the mixture was refluxed for 1 h. The reaction was cooled to rt and concentrated. The residue was dissolved in EtOAc (30 mL), washed with sat. aq. NaHCO3 and brine, dried (MgSO4), filtered and concentrated. The residue was recrystallized from EtOAc/Hexane to provide the title compound (340 mg). LC/MS: m/z 151 [M+H]+ the mixture was refluxed for 1 h concentrated The residue was dissolved in EtOAc (30 mL) washed with sat. aq. NaHCO3 and brine dried (MgSO4) filtered concentrated The residue was recrystallized from EtOAc/Hexane