2,6-Dimethyl-4-aminophenol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Using general hydrogenation conditions, 2,6-dimethyl-4-nitrophenol was reduced to 4-amino-2,6-dimethylphenol. In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 4-amino-2,6-dimethylphenol (823 mg, 6 mmol) and 2,4-dichloro-5-fluoropyrimidine (500 mg, 3 mmol) gave 2-chloro-N4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-4-pyrimidineamine. Compound 2-chloro-N4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-4-pyrimidineamine (500 mg, 1.87 mmol) and 3-(methoxycarbonylmethyleneoxy)aniline (500 mg, 2.76 mmol) reacted to give N4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (500 mg, 65%). 1H NMR (CD3OD): δ 2.16 (s, 6H), 3.76 (s, 3H), 4.51 (s, 2H), 6.79 (ddd, J=0.9, 2.4 and 8.1 Hz, 1H), 7.01-7.06 (m, 2H), 7.15 (s, 2H), 7.26 (t, J=8.1 Hz, 1H), 7.93 (d, J=5.7 Hz, 1H); 19F NMR (282 MHz, CD3OD): δ −163.31; LCMS: ret. time: 20.44 min.; purity: 84.25%; MS (m/e): 413.03 (MH+).

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Acetylsalicylic acid (50 mg.) and 4-amino-2,6-dimethylphenol (38 mg.) were dissolved in ethylene glycol (5 ml.) to which under cooling at 0° C. was added dicyclohexyl carbodiimide (65 mg.). After reaction for several hours the formed dicyclohexylurea was filtered off and the filtrate evaporated to dryness to give a powder which was dissolved in acetone (2 ml.); after adding 2 N sodium hydroxide (4 ml.), the solution was allowed to stand for several hours at room temperature. The addition of 2 N hydrochloric acid (20 ml.) gave a precipitate which was collected by filtration, washed with water and dried at 50° C. under reduced pressure to give solid 2',4-dihydroxy-3,5-dimethylbenzanilide as a powder which was then purified by column chromatography using Sephadex LH-20 resin and elution with methanol. The eluate was evaporated to dryness to give a solid which was recrystallized from aqueous acetone to give white crystals (57.8 mg.) of 2',4-dihydroxy-3,5-dimethylbenzanilide. Yield: 80.9%. Melting point: 142°-145° C. was filtered off the filtrate evaporated to dryness to give a powder which to stand for several hours at room temperature gave a precipitate which was collected by filtration washed with water dried at 50° C. under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-Hydroxy-4,6-dimethyl-1H-indole-2,3-dione was prepared from 3,5-dimethyl-4-hydroxyaniline according to Procedure A: 1H NMR (DMSO-d6): δ2.17 (s, 3H), 2.30 (s, 3H), 6.45 (s, 1H), 8.29 (s, 1H), 10.65 (s, 1H); ESI−MS m/z 190 (M−H)−. The isatin was combined with 4-methylphenylhydrazine hydrochloride according to Procedure H to provide the title compound in 41% yield. 1H NMR (DMSO-d6): δ2.15 (s, 3H), 2.24 (s, 3H), 2.43 (s, 3H), 6.46 (s, 1H), 7.16 (m, 4H), 7.88 (s, 1H), 10.64 (s, 1H), 12.85 (s,1H). APCI−MS m/z 294 (M−H, 45%).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 5-Hydroxy-4,6-dimethyl-1H-indole-2,3-dione was prepared from 4-hydroxy-3,5-dimethylaniline according to Procedure A. The title compound was prepared from 5-hydroxy-4,6-dimethyl-1H-indole-2,3-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G: mp>250° C.; 1H NMR (DMSO-d6): δ2.18 (s, 3H), 2.47 (s, 3H), 6.50 (s, 1H), 7.22 (s, 2H), 7.44 (d, J=8.7 Hz, 2H), 7.77 (d, J=8.7 Hz, 2H), 7.99 (s, 1H), 10.78(s, 1H), 12.98 (s,1H); APCI−MS: m/z 359 (M−H)−. Anal. Calcd for C16H16N4O4S.0.25 H2O: C, 52.67; H, 4.56; N, 15.35; S, 8.79. Found: C, 52.69; H, 4.47; N, 15.33; S, 8.87.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Using general hydrogenation conditions, 2,6-dimethyl-4-nitrophenol was reduced to 4-amino-2,6-dimethylphenol. In a manner analogous to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, the reaction of 4-amino-2,6-dimethylphenol (823 mg, 6 mmol) and 2,4-dichloro-5-fluoropyrimidine (500 mg, 3 mmol) gave 2-chloro-N4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-4-pyrimidineamine. Compound 2-chloro-N4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-4-pyrimidineamine (500 mg, 1.87 mmol) and 3-(methoxycarbonylmethyleneoxy)aniline (500 mg, 2.76 mmol) reacted to give N4-(3,5-dimethyl-4-hydroxyphenyl)-5-fluoro-N2-(3-methoxycarbonylmethyleneoxyphenyl)-2,4-pyrimidinediamine (500 mg, 65%). 1H NMR (CD3OD): δ 2.16 (s, 6H), 3.76 (s, 3H), 4.51 (s, 2H), 6.79 (ddd, J=0.9, 2.4 and 8.1 Hz, 1H), 7.01–7.06 (m, 2H), 7.15 (s, 2H), 7.26 (t, J=8.1 Hz, 1H), 7.93 (d, J=5.7 Hz, 1H); 19F NMR (282 MHz, CD3OD): δ −163.31; LCMS: ret. time: 20.44 min.; purity: 84.25%; MS (m/e): 413.03 (MH+).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Under argon gas stream, to a solution of 600 mg of 4-amino-2,6-dimethylphenol in 20 ml of tetrahydrofuran is added under ice-cooling 779 mg of 3-methoxycinnamic acid, and then 902 mg of dicyclohexylcarbodiimide and 118 mg of 1-hydroxybenzotriazole are added, followed by stirring at room temperature overnight. After ethyl acetate is added to the reaction mixture, the mixture is washed successively with 10 % hydrochloric acid, water, 5 % sodium hydrogen carbonate and water, and dried, followed by concentration. The residue is recrystallized from ethyl acetate-n-hexane to give 890 mg of 4-(3-methoxycinnamoyl)amino-2,6-dimethyl-phenol. the mixture is washed successively with 10 % hydrochloric acid, water, 5 % sodium hydrogen carbonate and water dried followed by concentration The residue is recrystallized from ethyl acetate-n-hexane