2-amino-3-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:; See reaction.notes.procedure_details.

Procedure: A solution of 2-amino-3-methylphenol (3.6 g, 29.2 mmol) and diethyl squarate (5 g, 29.4 mmol) in dry ethanol (80 mL) was heated to reflux for two days, then allowed to stand at room temperature for 48 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was suspended in ethyl acetate (50 mL). Hexane (50 mL) was added to produce a slurry, which was filtered, and rinsed with three portions of hexane:ethyl acetate (1:1). The resulting solid was suspended in dichloromethane (200 mL) and methanol (20 mL), stirred at room temperature for 30 minutes, and filtered. The precipitate was suspended in hot dichloromethane, filtered hot, and dried to give 3-ethoxy-4-(2-hydroxy-6-methylphenylamino)-cyclobut-3-ene-1,2-dione, 1.56 g (6.3 mmol, 22%). to reflux for two days The reaction mixture was concentrated under reduced pressure Hexane (50 mL) was added to produce a slurry, which was filtered rinsed with three portions of hexane:ethyl acetate (1:1) filtered filtered hot dried

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

Procedure: 2-Amino-3-methyl-phenol (6.09 mmol) is heated with 3-formyl-benzoic acid methyl ester (6.09 mmol) in MeOH (6 mL) at 60° C. for 30 minutes. The solvent is removed from the mixture to obtain a dark red oil which is dissolved in dry CH2Cl2 (6 mL) at room temperature and treated with DDQ (6.4 mmol) for 16 hours. The mixture is diluted with EtOAc and poured onto saturated aqueous NaHCO3. The aqueous phase is further extracted with EtOAc and the combined organic phases are dried over Na2SO4. Filtration and removal of the solvent yields a residue which is purified by silica gel chromatography (5-10% EtOAc/hexane) to yield 3-(4-methyl-benzooxazol-2-yl)-benzoic acid methyl ester as a white solid: 1H NMR (400 MHz, CDCl3) 8.92 (d, J=1.6 Hz, 1H), 8.47 (dt, J1=7.8 Hz, J2=1.5 Hz, 1H), 8.2 (dt, J1=7.8 Hz, J2=1.4 Hz, 1H), 7.61 (t, J=7.9 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.27 (t, J=7.7 Hz, 1H), 7.17 (t, J=7.5 Hz, 1H), 3.99 (s, 3H), 2.69 (s, 3H); LC/MS (ES+): (M+1) 268.1. The solvent is removed from the mixture to obtain a dark red oil which The aqueous phase is further extracted with EtOAc the combined organic phases are dried over Na2SO4 Filtration and removal of the solvent yields a residue which is purified by silica gel chromatography (5-10% EtOAc/hexane)

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

Procedure: 2-Amino-3-methyl-phenol (6.09 mmol) is heated with 3-formyl-benzoic acid methyl ester (6.09 mmol) in MeOH (6 mL) at 60° C. for 30 minutes. The solvent is removed from the mixture to obtain a dark red oil which is dissolved in dry CH2Cl2 (6 mL) at room temperature and treated with DDQ (6.4 mmol) for 16 hours. The mixture is diluted with EtOAc and poured onto saturated aqueous NaHCO3. The aqueous phase is further extracted with EtOAc and the combined organic phases are dried over Na2SO4. Filtration and removal of the solvent yields a residue which is purified by silica gel chromatography (5-10% EtOAc/hexane) to yield 3-(4-methyl-benzooxazol-2-yl)-benzoic acid methyl ester as a white solid: 1H NMR (400 MHz, CDCl3) 8.92 (d, J=1.6 Hz, 1H), 8.47 (dt, J1=7.8 Hz, J2=1.5 Hz, 1H), 8.2 (dt, J1=7.8 Hz, J2=1.4 Hz, 1H), 7.61 (t, J=7.9 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.27 (t, J=7.7 Hz, 1H), 7.17 (t, J=7.5 Hz, 1H), 3.99 (s, 3H), 2.69 (s, 3H); LC/MS (ES+): (M+1) 268.1. The solvent is removed from the mixture to obtain a dark red oil which The aqueous phase is further extracted with EtOAc the combined organic phases are dried over Na2SO4 Filtration and removal of the solvent yields a residue which is purified by silica gel chromatography (5-10% EtOAc/hexane)

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

Procedure: 1,1′-Thiocarbonyldi-2(1H)-pyridone (0.086 g, 0.369 mmol) was added to a solution of cis-3-(4-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.150 g, 0.369 mmol) in pyridine (7 mL) at 0° C., and the mixture was stirred for 1 h at 0° C. The resulting orange solution was partitioned between dichloromethane (10 mL) and water (10 mL). The organic layer was separated and washed with 0.5 N HCl (10 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. 2-Amino-m-cresol (0.045 g, 0.369 mmol) was added to a suspension of the resulting orange solid and toluene (10 mL), and the mixture was heated at 80° C. for 1 h. 1,3-dicyclohexylcarbodiimide (0.114 g, 0.554 mmol) was added and the reaction mixture was heated at 80 C for an additional 18 h. The resulting orange brown solution was cooled to room temperature and concentrated to afford a light brown glassy solid. Purification by preparative HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 20 min at 21 mL/min using a 8μ Hypersil HS C18, 250×21 mm column, tr=8.1-10.3 min.) afforded cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4-methyl-1,3-benzoxazol-2-amine as an off-white solid (0.024 g, 12%): 1H NMR (DMSO-d6, 400 MHz) δ 10.81 (s, 1H), 8.24 (s, 1H), 7.96 (d, 2H), 7.66 (d, 2H), 7.33 (d, 1H), 7.06 (m, 2H), 4.80 (m, 1H), 3.391 (m, 1H), 2.67-2.10 (m, 18H), 1.71-1.60 (m, 4H); RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=7.57 min., 99%; m/z 538 (MH+). The resulting orange solution was partitioned between dichloromethane (10 mL) and water (10 mL) The organic layer was separated washed with 0.5 N HCl (10 mL) dried over anhydrous magnesium sulfate filtered concentrated the mixture was heated at 80° C. for 1 h the reaction mixture was heated at 80 C for an additional 18 h The resulting orange brown solution was cooled to room temperature concentrated to afford a light brown glassy solid Purification by preparative HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 20 min at 21 mL/min a 8μ Hypersil HS C18, 250×21 mm column, tr=8.1-10.3 min.

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

Procedure: 1,1′-Thiocarbonyldi-2(1H)-pyridone (0.086 g, 0.369 mmol) was added to a solution of cis-3-(4-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.150 g, 0.369 mmol) in pyridine (7 mL) at 0° C., and the mixture was stirred for 1 h at 0° C. The resulting orange solution was partitioned between dichloromethane (10 mL) and water (10 mL). The organic layer was separated and washed with 0.5 N HCl (10 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. 2-Amino-m-cresol (0.045 g, 0.369 mmol) was added to a suspension of the resulting orange solid and toluene (10 mL), and the mixture was heated at 80° C. for 1 h. 1,3-dicyclohexylcarbodiimide (0.114 g, 0.554 mmol) was added and the reaction mixture was heated at 80 C for an additional 18 h. The resulting orange brown solution was cooled to room temperature and concentrated to afford a light brown glassy solid. Purification by preparative HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 20 min at 21 mL/min using a 8μ Hypersil HS C18, 250×21 mm column, tr=8.1-10.3 min.) afforded cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4-methyl-1,3-benzoxazol-2-amine as an off-white solid (0.024 g, 12%): 1H NMR (DMSO-d6, 400 MHz) δ 10.81 (s, 1H), 8.24 (s, 1H), 7.96 (d, 2H), 7.66 (d, 2H), 7.33 (d, 1H), 7.06 (m, 2H), 4.80 (m, 1H), 3.391 (m, 1H), 2.67-2.10 (m, 18H), 1.71-1.60 (m, 4H); RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=7.57 min., 99%; m/z 538 (MH+). The resulting orange solution was partitioned between dichloromethane (10 mL) and water (10 mL) The organic layer was separated washed with 0.5 N HCl (10 mL) dried over anhydrous magnesium sulfate filtered concentrated the mixture was heated at 80° C. for 1 h the reaction mixture was heated at 80 C for an additional 18 h The resulting orange brown solution was cooled to room temperature concentrated to afford a light brown glassy solid Purification by preparative HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 20 min at 21 mL/min a 8μ Hypersil HS C18, 250×21 mm column, tr=8.1-10.3 min.

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

Procedure: A solution of 5-methoxy-2-methoxymethoxybenzaldehyde (F1) (2.77 g, 16.5 mmol) and 2-amino-m-cresol (2.03 g, 16.5 mmol) in benzene (70 mL) was refluxed for 15 h using an additional funnel to remove water. After the reaction mixture was cooled to room temperature, the solvent was removed in vacuo and the resulting residue was washed with ethanol to afford the objective compound as a orange solid (84%), which was used for next reaction without further purification: 1H-NMR (400 MHz, DMSO-d6) δ2.31 (s, 3H), 3.45 (s, 3H), 3.85 (s, 3H), 5.18 (s, 2H), 6.59 (s, 1H), 6.77 (d, 1H, J=8.0 Hz), 6.83 (d, 1H, J=8.0 Hz), 6.99 (t, 1H, J=8.0 Hz), 7.03 (dd, 1H, J=9.0, 2.5 Hz), 7.14 (d, 1H, J=9.0 Hz), 7.68 (s, 1H), 8.95 (s, 1H). to remove water the solvent was removed in vacuo the resulting residue was washed with ethanol

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

Procedure: Prepared by the method of Example 15a), from 2-amino-3-methylphenol (283 mg, 2.3 mmol) and 2-fluoro-5-nitrobenzoyl chloride (468 mg, 2.3 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.

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

Procedure: Prepared by the method of Example 15a), from 2-amino-3-methylphenol (283 mg, 2.3 mmol) and 2-fluoro-5-nitrobenzoyl chloride (468 mg, 2.3 mmol) the subtitle compound was obtained. The product was used directly in the next step without purification.