2-amino-6-chlorophenol

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

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

Procedure: When 2-amino-6-chlorophenol and 2-amino-4,6-dichlorophenol are used in place of o-aminophenol and when p-toluyl chloride is used in place of 3-fluoro-p-toluyl chloride in the above example, there is obtained 3'-chloro-2'-hydroxy-p-toluanilide and 3',5'-dichloro-2'-hydroxy-p-toluanilide, respectively.

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

Procedure: When 2-amino-6-chlorophenol and 2-amino-4,6-dichlorophenol are used in place of o-aminophenol and when p-toluyl chloride is used in place of 3-fluoro-p-toluyl chloride in the above example, there is obtained 3'-chloro-2'-hydroxy-p-toluanilide and 3',5'-dichloro-2'-hydroxy-p-toluanilide, respectively.

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

Procedure: Cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-7-chloro-1,3-benzoxazol-2-amine was prepared from cis-3-(4-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.245 mmol) and 2-amino-6-chlorophenol (0.053 g, 0.367 mmol) in a manner similar to that used in the synthesis of 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 (PH4052419F). The compound was formed as an off-white solid (0.018 g, 13%): 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, 100 Å, 5 μm, 250×4.6 mm column) tr=7.78 min., 94%; m/z 558 (MH+).

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

Procedure: 2-amino-6-methylphenol was prepared from 2-methyl-6-nitrophenol (0.500 g, 3.26 mmol) in a manner similar to that described for 2-amino-6-chlorophenol. The compound was formed as a black solid (0.030 g, 8%). 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, 100 Å, 5 μm, 250×4.6 mm column) tr=5.78 min., 86%; m/z 123 (MH+).

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

Procedure: 2-amino-6-methylphenol was prepared from 2-methyl-6-nitrophenol (0.500 g, 3.26 mmol) in a manner similar to that described for 2-amino-6-chlorophenol. The compound was formed as a black solid (0.030 g, 8%). 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, 100 Å, 5 μm, 250×4.6 mm column) tr=5.78 min., 86%; m/z 123 (MH+).

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

Procedure: 2-amino-4,6-dichlorophenol was prepared from 2,4-dichloro-6-nitrophenol (0.625 g, 2.40 mmol) in a manner similar to that described for 2-amino-6-chlorophenol. The compound was formed as a black solid (0.044 g, 10%). 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, 100 Å, 5 μm, 250×4.6 mm column) tr=9.033 min., 74%; m/z 177 (MH+).

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

Procedure: 2-amino-4,6-dichlorophenol was prepared from 2,4-dichloro-6-nitrophenol (0.625 g, 2.40 mmol) in a manner similar to that described for 2-amino-6-chlorophenol. The compound was formed as a black solid (0.044 g, 10%). 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, 100 Å, 5 μm, 250×4.6 mm column) tr=9.033 min., 74%; m/z 177 (MH+).

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

Procedure: A solution of 2-chloro-6-nitrophenol (1.210 g, 6.972 mmol) in ethanol (50 mL) was treated with iron powder (1.947 g, 34.86 mmol) and concentrated HCl (3 mL). The yellow mixture was heated to reflux for 18 h and then cooled to room temperature. The reaction mixture was filtered through a pad of Celite, and the filtrate was neutralized with satd aq NaHCO3 solution. The resulting gray suspension was filtered through a pad of Celite, and the filtrate was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to give a black solid. Trituration with heptane afforded 2-amino-6-chlorophenol (0.577 g, 58%) as a dark brown solid. 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, 100 Å, 5 μm, 250×4.6 mm column) tr=7.30 min., 91%; m/z 143 (MH+). The yellow mixture was heated to reflux for 18 h The reaction mixture was filtered through a pad of Celite The resulting gray suspension was filtered through a pad of Celite the filtrate was extracted with ethyl acetate (3×20 mL) The combined organic layers were washed with brine dried over anhydrous magnesium sulfate filtered concentrated to give a black solid

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

Procedure: A solution of 2-chloro-6-nitrophenol (1.210 g, 6.972 mmol) in ethanol (50 mL) was treated with iron powder (1.947 g, 34.86 mmol) and concentrated HCl (3 mL). The yellow mixture was heated to reflux for 18 h and then cooled to room temperature. The reaction mixture was filtered through a pad of Celite, and the filtrate was neutralized with satd aq NaHCO3 solution. The resulting gray suspension was filtered through a pad of Celite, and the filtrate was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to give a black solid. Trituration with heptane afforded 2-amino-6-chlorophenol (0.577 g, 58%) as a dark brown solid. 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, 100 Å, 5 μm, 250×4.6 mm column) tr=7.30 min., 91%; m/z 143 (MH+). The yellow mixture was heated to reflux for 18 h The reaction mixture was filtered through a pad of Celite The resulting gray suspension was filtered through a pad of Celite the filtrate was extracted with ethyl acetate (3×20 mL) The combined organic layers were washed with brine dried over anhydrous magnesium sulfate filtered concentrated to give a black solid

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

Procedure: An ambient solution of 2-amino-6-chlorophenol (0.86 g, 6.0 mmol) and 3-chloro-4-bromophenyl isothiocyanate (1.49 g, 6.0 mmol) in tetrahydrofuran (20 mL) was stirred for 16 h. The reaction was cooled (0° C.), and LiOH.H2O (0.521 g, 12.41 mmol) was added, followed by the drop wise addition of 30% H2O2 (3.41 mL, 31.0 mmol) over 15 minutes. The reaction was warmed to room temperature and stirred for 16 h. The reaction was then quenched by the addition of 20% aqueous sodium sulfite solution (50 mL) and ethyl acetate (75 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×75 mL). The combined organics were dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 gel, eluting with 25% ethyl acetate in hexane, to give the title compound. MS (ESI) m/z 359[M+H]+. was added The reaction was then quenched by the addition of 20% aqueous sodium sulfite solution (50 mL) and ethyl acetate (75 mL) The layers were separated the aqueous was extracted with additional ethyl acetate (2×75 mL) The combined organics were dried with anhydrous Na2SO4 filtered concentrated under reduced pressure The residue was purified by chromatography on SiO2 gel eluting with 25% ethyl acetate in hexane

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

Procedure: Cis-N2-(4-{4-Amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-7-chloro-1,3-benzoxazol-2-amine was prepared from cis-3-(4-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.100 g, 0.245 mmol) and 2-amino-6-chlorophenol (0.053 g, 0.367 mmol) in a manner similar to that used in the synthesis of 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 (PH4052419F). The compound was formed as an off-white solid (0.018 g, 13%): 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, 100 Å, 5 μm, 250×4.6 mm column) tr=7.78 min., 94%; m/z 558 (MH+).