3-amino-2-methylphenol

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:

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

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

Procedure: In a manner analogous to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reaction of 3-hydroxy-2-methylaniline (369 mg, 3 mmol) and 2,4-dichloro-5-fluoropyrimidine (100 mg, 0.6 mmol) gave N2,N4-bis(3-hydroxy-2-methylphenyl)-5-fluoro-2,4-pyrimidinediamine (180 mg, 88%). 1H NMR (acetone-d6): δ 2.14 (s, 3H), 2.22 (s, 3H), 6.61 (d, J=8.1 Hz, 1H), 6.78 (t, J=8.7 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H), 6.99 (d, J=9.0 Hz, 1H), 7.08 (t, J=7.8 Hz, 1H), 7.13 (dd, J=3.9, 8.4 Hz, 1H), 8.24 (d, J=5.1 Hz, 1H), 8.32 (br, 1H, NH), 8.57 (br, 1H, NH); LCMS: ret. time: 16.51 min.; purity: 90.47%; MS (m/e): 341.07 (MH+).

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

Procedure: To 3-amino-2-methylphenol (5.0 g, 41 mmol) in refluxing 6N HCl (100 mL) was added dropwise (E)-but-2-enal (5.7 g, 81 mmol) and the reaction was heated to reflux for 2 hours. After cooling, the reaction was neutralized with ammonium hydroxide and extracted with DCM. The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure to yield 2,8-dimethylquinolin-7-ol (9.0 g, 51% yield) as a brown solid. the reaction was heated to reflux for 2 hours After cooling extracted with DCM The combined organic phases were dried over MgSO4 filtered concentrated under reduced pressure

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

Procedure: 3-Amino-2-methylphenol (2.0 g; 16 mmol) and di-t-butylcarbonate were dissolved in THF (20 mL) and refluxed overnight. Evaporation of the solvent followed by flash chromatography (SiO2; EtOAc 5-30% in isohexane) afforded 2.48 g (69%) of the sub-title compound. refluxed overnight Evaporation of the solvent

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

Procedure: To a stirred solution of 3-amino-o-cresol (60 g) in anhydrous methanesulfonic acid (300 ml) was added N-chlorosuccinimide (68.3 g in five equal portions) over 2h and 10 min, keeping the reaction temperature between 10 and 12° C. by use of a cooling bath. The dark mixture was allowed to stir overnight and warm to room temperature. It was then added to 1000 ml water with stirring (final temperature approx. 51 ° C.). Concentrated ammonium hydroxide (370 ml) was added with stirring, keeping the temperature between 50 and 60° C. by use of a cooling bath. The product crystallized out near the end of the addition at 50-53° C. The product slurry was cooled to ice bath temperature and held for 1 h. The product, isolated in 70.5% yield by filtration, washing with ice water, and drying in vacuo at 50° C., was 98.44% pure by area-normalized HPLC with correction for relative response factors. It contained only 0.8% of the 6-chloro isomer and 0.68% of the 4,6-dichloro impurity. Recrystallization from isopropanol-water with charcoal treatment gave, in 94% recovery, purified product that was 99.67% pure by HPLC (mp 143-144° C.). the reaction temperature between 10 and 12° C. with stirring (final temperature approx. 51 ° C.) with stirring the temperature between 50 and 60° C. The product crystallized out near the end of the addition at 50-53° C The product slurry was cooled to ice bath temperature held for 1 h The product, isolated in 70.5% yield by filtration washing with ice water drying in vacuo at 50° C. Recrystallization from isopropanol-water with charcoal treatment gave, in 94% recovery purified product that

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

Procedure: 2-methyl-3-aminophenol (20.1 g, 0.163 mol) was dissolved in methylethylketone (MEK) (150 ml). Cesium carbonate (106 g, 0.326 mmol) was added in portions followed by dropwise addition of bromoacetonitrile (29.3 g, 0.245 mol) over 30 min. The mixture was stirred 14 hr at room temperature, then filtered through a coarse fritted funnel. The solids were washed with ethylacetate (2×100 ml) and the combined washings and filtrate were concentrated at reduced pressure to give 20.8 g (79% yield) of (2-methyl-3-aminophenoxy)acetonitrile which required no further purification. filtered through a coarse fritted funnel The solids were washed with ethylacetate (2×100 ml) the combined washings and filtrate were concentrated at reduced pressure

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

Procedure: 2-methyl-3-nitrophenol (25 g, 0.163 mol) was dissolved in 170 ml of absolute ethanol in a 11 Parr hydrogenation flask. The flask was purged with nitrogen. 10% palladium on charcoal (1.73 g, 1.6 mmol) was added and the mixture was hydrogenated (40 psi H2) for 1.5 hr in a Parr apparatus. The flask was evacuated and purged with nitrogen. The catalyst was removed by filtration through a Whatman GF/F filter. After removal of the ethanol at reduced pressure, 20.1 g (100% yield) of 2-methyl-3-aminophenol was obtained as a lightly brown solid. The flask was purged with nitrogen for 1.5 hr The flask was evacuated purged with nitrogen The catalyst was removed by filtration through a Whatman GF/F filter After removal of the ethanol at reduced pressure