Benzonitrile, 4-amino-3-methyl-2-(trifluoromethyl)- (9CI)

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: To a stirred solution of 4-amino-3-methyl-2-(trifluoromethyl)benzonitrile (3.59 g, 17.9 mmol) in toluene (80 mL) was added benzophenone (3.59 g, 19.7 mmol) followed by PTSA monohydrate (0.035 g, 0.18 mmol). The reaction flask was fitted with a Dean-Stark trap and heated at reflux for 7 d. The reaction was concentrated and purified by SiO2 chromatography (5% EtOAc in hexanes) to afford 4-[(diphenylmethylidene)amino]-3-methyl-2-(trifluoromethyl)benzonitrile (5.16 g, 79%) as a yellow solid: 1H NMR (400 MHz, DMSO-d6): δ 7.71-7.01 (m, 10H), 7.65 (d, J=8.4 Hz, 1H), 6.95 (d, J=8.4 Hz, 1H), 2.30 (s, 3H). The reaction flask was fitted with a Dean-Stark trap heated at reflux for 7 d The reaction was concentrated purified by SiO2 chromatography (5% EtOAc in hexanes)

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The crude N-[4-cyano-2-methyl-3-(trifluoromethyl)phenyl]-2,2-dimethylpropanamide from Example 191B was dissolved in EtOH (5 mL) and conc. HCl (5 mL). The resulting mixture was heated to 70° C. for 20 min. The cooled reaction's pH was adjusted to ca. 8 with 6 N NaOH. EtOAc (20 mL) was added and the isolated organic portion was dried (Na2SO4), filtered, and concentrated to afford the title compound: MS (ES) m/z 201 (M+1). the isolated organic portion was dried (Na2SO4) filtered concentrated

反応条件: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The crude N-[4-cyano-2-methyl-3-(trifluoromethyl)phenyl]-2,2-dimethylpropanamide from Example 191B was dissolved in EtOH (5 mL) and conc. HCl (5 mL). The resulting mixture was heated to 70° C. for 20 min. The cooled reaction's pH was adjusted to ca. 8 with 6 N NaOH. EtOAc (20 mL) was added and the isolated organic portion was dried (Na2SO4), filtered, and concentrated to afford the title compound: MS (ES) m/z 201 (M+1). the isolated organic portion was dried (Na2SO4) filtered concentrated

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

実験手順: The title compound was prepared from 18D in a manner similar to that described in Experiment 2E.

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

実験手順: A solution of the mixed product from 18C (7.53 g, 26.5 mmol) in 120 mL of concentrated HCl/EtOH (1:1) was refluxed for 14 h. After cooling to rt, the solution was concentrated under reduced pressure. The resulting residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3 (2×) and brine (1×), dried (MgSO4), filtered and concentrated. The residue was chromatographed (silica gel), eluting with chloroform/MeOH (98:2) to furnish the title compound (4.62 g, 87%). MS (ES) m/z 201 [M+1]+. the solution was concentrated under reduced pressure The resulting residue was dissolved in EtOAc washed with saturated aqueous NaHCO3 (2×) and brine (1×) dried (MgSO4) filtered concentrated The residue was chromatographed (silica gel) eluting with chloroform/MeOH (98:2)

反応条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-amino-3-methyl-2-(trifluoromethyl)benzonitrile (CAS 573764-86-0, 2.0 g, 9.99 mmol) was dissolved in fluoroboric acid, HBF4 solution (15 mL) at −10° C. (ice/MeOH). To the pre-cooled solution was added NaNO2 (689 mg, 9.992 mmol) in 2 mL H2O drop by drop under constant stirring. The reaction mixture was allowed to stir for 15 min at −10° C. and filtered off. The white residue was washed with cold EtOH and cold ether to get the diazosalt as a white crystalline solid. The salt is dried over high vacuum for 4-5 h. to provide 1.9 g. The salt was heated up (>250° C.) and sublimed under reduced pressure to get the crude fluoro compound as an oil. The oil is chromatographed to get the pure 4-fluoro-3-methyl-2-(trifluoromethyl)benzonitrile as a clear oil (700 mg): 1H NMR (400 MHz, CDCl3, δ in ppm) 7.68 (dd, J=5.0, 9.0 Hz, 1H), 7.33 (t, J=9 Hz, 1H), 2.43 (quin, J=2 Hz, 3H). at −10° C. filtered off The white residue was washed with cold EtOH and cold ether to get the diazosalt as a white crystalline solid The salt is dried over high vacuum for 4-5 h. to provide 1.9 g The salt was heated up (>250° C.) sublimed under reduced pressure to get the crude fluoro compound as an oil The oil is chromatographed

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

実験手順: To a solution of 4-amino-3-methyl-2-(trifluoromethyl)benzonitrile (commercially available, for example from Sunshine Chemlab, Downington, Pa., USA, 500 mg, 2.50 mmol) and triethylamine (0.383 mL, 2.75 mmol) in dichloromethane (10 mL) was added 2-chloro-2-oxoethyl acetate (0.269 mL, 2.50 mmol) dropwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with DCM (100 ml) and water (50 ml) and aqueous was extracted with DCM (100 ml). The organics were combined, passed through a phase separator and concentrated to afford 710 mg of the title compound as a pale yellow powder. aqueous was extracted with DCM (100 ml) concentrated

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

実験手順: To a solution of 4-amino-3-methyl-2-(trifluoromethyl)benzonitrile (commercially available, for example from Sunshine Chemlab, Downington, Pa., USA, 500 mg, 2.50 mmol) and triethylamine (0.383 mL, 2.75 mmol) in dichloromethane (10 mL) was added 2-chloro-2-oxoethyl acetate (0.269 mL, 2.50 mmol) dropwise. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with DCM (100 ml) and water (50 ml) and aqueous was extracted with DCM (100 ml). The organics were combined, passed through a phase separator and concentrated to afford 710 mg of the title compound as a pale yellow powder. aqueous was extracted with DCM (100 ml) concentrated

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

実験手順: The title compound was prepared from 18D in a manner similar to that described in Experiment 2E.

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

実験手順: The title compound was prepared from 18D in a manner similar to that described in Experiment 2E.

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

実験手順: A solution of the mixed product from 18C (7.53 g, 26.5 mmol) in 120 mL of concentrated HCl/EtOH (1:1) was refluxed for 14 h. After cooling to rt, the solution was concentrated under reduced pressure. The resulting residue was dissolved in EtOAc, washed with saturated aqueous NaHCO3 (2×) and brine (1×), dried (MgSO4), filtered and concentrated. The residue was chromatographed (silica gel), eluting with chloroform/MeOH (98:2) to furnish the title compound (4.62 g, 87%). MS (ES) m/z 201 [M+1]+. the solution was concentrated under reduced pressure The resulting residue was dissolved in EtOAc washed with saturated aqueous NaHCO3 (2×) and brine (1×) dried (MgSO4) filtered concentrated The residue was chromatographed (silica gel) eluting with chloroform/MeOH (98:2)