4-amino-2,6-dibromophenol

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

Procedure: 2,6-Dibromo-4-aminophenol (0.6 g.) was dissolved in acetone (30 ml.) to which was added pyridine (0.32 ml.). Then dropwise and with stirring the solution was added to an acetone solution (10 ml.) containing acetylsalicyloyl chloride which was prepared from acetylsalicylic acid (0.38 g.). Then the reactant solution was evaporated to dryness under reduced pressure to give a residue which was dissolved in ethyl acetate. After washing first with water and then with 1 N hydrochloric acid, the solution was evaporated under reduced pressure to remove ethyl acetate. The residues were redissolved in a mixture of methanol and 2 N sodium hydroxide (10 ml. each). Stirring this solution for several hours and acidifying with 2 N hydrochloric acid precipitated the product which was recrystallized from aqueous methanol to give light brown crystals of 3,5-dibromo-2',4-dihydroxybenzanilide (0.88 g.). Yield: 78%. The compound melts at 182°-187° C. Then the reactant solution was evaporated to dryness under reduced pressure to give a residue which After washing first with water with 1 N hydrochloric acid, the solution was evaporated under reduced pressure to remove ethyl acetate The residues were redissolved in a mixture of methanol and 2 N sodium hydroxide (10 ml Stirring this solution for several hours precipitated the product which was recrystallized from aqueous methanol

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

Procedure: 4-Amino-2,6-dibromo-phenol (14.13 g, 52.9 mmol) was dissolved in acetone (425 mL) to give a dark brown solution. Potassium carbonate (21.95 g, 158.8 mmol) was added followed by iodomethane (3.46 mL, 55.6 mmol). The mixture was stirred at rt overnight. The acetone was removed under reduced pressure and the residue partitioned between EtOAc and water. Sodium metabisulphite and brine were added to aid separation of the layers. The mixture was extracted into EtOAc (4×150 mL). The combined organic layers were washed with sodium metabisuphite solution (saturated, aqueous) then brine, dried over Na2SO4 and concentrated under reduced pressure. A dark brown oil was obtained which crystallised upon standing. The mixture was purified by chromatography, Biotage SP4, 330 g Si cartridge, 20% EtOAc in cyclohexane. The relevant fractions were combined to give the desired compound as a brown solid, 11.31 g (76%). m/z: 280.03/282.00/284.02 [M+H]+. to give a dark brown solution The acetone was removed under reduced pressure the residue partitioned between EtOAc and water Sodium metabisulphite and brine were added separation of the layers The mixture was extracted into EtOAc (4×150 mL) The combined organic layers were washed with sodium metabisuphite solution (saturated, aqueous) brine, dried over Na2SO4 concentrated under reduced pressure A dark brown oil was obtained which crystallised The mixture was purified by chromatography, Biotage SP4, 330 g Si cartridge, 20% EtOAc in cyclohexane

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

Procedure: 2,6-Dibromo-4-aminophenol (0.6 g.) was dissolved in acetone (30 ml.) to which pyridine (0.32 ml.) was added. Then the solution was added by drops and with stirring to an acetone solution (10 ml.) containing acetylsalicyloyl chloride which was prepared from acetylsalicylic acid (0.38 g.). The resulting solution was evaporated to dryness under reduced pressure to give a residue which was dissolved in ethyl acetate. After washing first with water and then with 1N hydrochloric acid the solution was evaporated under reduced pressure to remove the ethyl acetate. The residue was redissolved in a mixture of methanol and 2 N sodium hydroxide (10 ml. each). Stirring this solution for several hours and acidifying with 2 N hydrochloric acid precipitated the product which was recrystallized from aqueous methanol to give light brown crystals of 3',5'-dibromo-2,4'-dihydroxybenzanilide (0.88 g.). Yield: 78%. The melting point of the compound is 182°-187° C. was added Then the solution was added by drops The resulting solution was evaporated to dryness under reduced pressure to give a residue which After washing first with water with 1N hydrochloric acid the solution was evaporated under reduced pressure to remove the ethyl acetate The residue was redissolved in a mixture of methanol and 2 N sodium hydroxide (10 ml precipitated the product which was recrystallized from aqueous methanol

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

Procedure: Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 15 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 320.3 mg (1.2 mmol) of 4-amino-2,6-dibromophenol to give 427.1 mg (89.2%) of the product as a gray solid, m.p.>250° C., mass (electrospray, m/e): M+H 479.7, 481.6.

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

Procedure: 2,6-Dibromo-4-aminophenol (0.6 g.) was dissolved in acetone (30 ml.) to which pyridine (0.32 ml.) was added. Then the solution was added by drops and with stirring to an acetone solution (10 ml.) containing acetylsalicyloyl chloride which was prepared from acetyl-salicylic acid (0.38 g.). The resulting solution was evaporated to dryness under reduced pressure to give a residue which was dissolved in ethyl acetate. After washing first with water and then with 1 N hydrochloric acid the solution was evaporated under reduced pressure to remove the ethyl acetate. The residue was redissolved in a mixture of methanol and 2 N sodium hydroxide (10 ml. each). Stirring this solution for several hours and acidifying with 2 N hydrochloric acid precipitated the product which was recrystallized from aqueous methanol to give light brown crystals of 3',5'-dibromo-2,4'-dihydroxybenzanilide (0.88 g.). Yield: 78%. The melting point of the compound is 182°-187° C. was added Then the solution was added by drops The resulting solution was evaporated to dryness under reduced pressure to give a residue which After washing first with water with 1 N hydrochloric acid the solution was evaporated under reduced pressure to remove the ethyl acetate The residue was redissolved in a mixture of methanol and 2 N sodium hydroxide (10 ml precipitated the product which was recrystallized from aqueous methanol

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

Procedure: 2,6-Dibromo-4-aminophenol (0.6 g.) was dissolved in acetone (30 ml.) to which pyridine (0.32 ml.) was added. Then the solution was added by drops and with stirring to an acetone solution (10 ml.) containing acetylsalicyloyl chloride which was prepared from acetyl-salicylic acid (0.38 g.). The resulting solution was evaporated to dryness under reduced pressure to give a residue which was dissolved in ethyl acetate. After washing first with water and then with 1 N hydrochloric acid the solution was evaporated under reduced pressure to remove the ethyl acetate. The residue was redissolved in a mixture of methanol and 2 N sodium hydroxide (10 ml. each). Stirring this solution for several hours and acidifying with 2 N hydrochloric acid precipitated the product which was recrystallized from aqueous methanol to give light brown crystals of 3',5'-dibromo-2,4'-dihydroxybenzanilide (0.88 g.). Yield: 78%. The melting point of the compound is 182°-187° C. was added Then the solution was added by drops The resulting solution was evaporated to dryness under reduced pressure to give a residue which After washing first with water with 1 N hydrochloric acid the solution was evaporated under reduced pressure to remove the ethyl acetate The residue was redissolved in a mixture of methanol and 2 N sodium hydroxide (10 ml precipitated the product which was recrystallized from aqueous methanol

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

Procedure: 2,6-Dibromo-4-aminophenol (0.6 g.) was dissolved in acetone (30 ml.) to which was added pyridine (0.32 ml.). Then dropwise and with stirring the solution was added to an acetone solution (10 ml.) containing acetylsalicyloyl chloride which was prepared from acetylsalicylic acid (0.38 g.). Then the reactant solution was evaporated to dryness under reduced pressure to give a residue which was dissolved in ethyl acetate. After washing first with water and then with 1 N hydrochloric acid, the solution was evaporated under reduced pressure to remove ethyl acetate. The residues were redissolved in a mixture of methanol and 2 N sodium hydroxide (10 ml. each). Stirring this solution for several hours and acidifying with 2 N hydrochloric acid precipitated the product which was recrystallized from aqueous methanol to give light brown crystals of 3,5-dibromo-2',4-dihydroxybenzanilide (0.88 g.). Yield: 78%. The compound melts at 182°-187° C. Then the reactant solution was evaporated to dryness under reduced pressure to give a residue which After washing first with water with 1 N hydrochloric acid, the solution was evaporated under reduced pressure to remove ethyl acetate The residues were redissolved in a mixture of methanol and 2 N sodium hydroxide (10 ml Stirring this solution for several hours precipitated the product which was recrystallized from aqueous methanol

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

Procedure: Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 15 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 320.3 mg (1.2 mmol) of 4-amino-2,6-dibromophenol to give 427.1 mg (89.2%) of the product as a gray solid, m.p.>250° C., mass (electrospray, m/e): M+H 479.7, 481.6.

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

Procedure: 4-Amino-2,6-dibromo-phenol (14.13 g, 52.9 mmol) was dissolved in acetone (425 mL) to give a dark brown solution. Potassium carbonate (21.95 g, 158.8 mmol) was added followed by iodomethane (3.46 mL, 55.6 mmol). The mixture was stirred at rt overnight. The acetone was removed under reduced pressure and the residue partitioned between EtOAc and water. Sodium metabisulphite and brine were added to aid separation of the layers. The mixture was extracted into EtOAc (4×150 mL). The combined organic layers were washed with sodium metabisuphite solution (saturated, aqueous) then brine, dried over Na2SO4 and concentrated under reduced pressure. A dark brown oil was obtained which crystallised upon standing. The mixture was purified by chromatography, Biotage SP4, 330 g Si cartridge, 20% EtOAc in cyclohexane. The relevant fractions were combined to give the desired compound as a brown solid, 11.31 g (76%). m/z: 280.03/282.00/284.02 [M+H]+. to give a dark brown solution The acetone was removed under reduced pressure the residue partitioned between EtOAc and water Sodium metabisulphite and brine were added separation of the layers The mixture was extracted into EtOAc (4×150 mL) The combined organic layers were washed with sodium metabisuphite solution (saturated, aqueous) brine, dried over Na2SO4 concentrated under reduced pressure A dark brown oil was obtained which crystallised The mixture was purified by chromatography, Biotage SP4, 330 g Si cartridge, 20% EtOAc in cyclohexane

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

Procedure: 2,6-Dibromo-4-aminophenol (0.6 g.) was dissolved in acetone (30 ml.) to which pyridine (0.32 ml.) was added. Then the solution was added by drops and with stirring to an acetone solution (10 ml.) containing acetylsalicyloyl chloride which was prepared from acetylsalicylic acid (0.38 g.). The resulting solution was evaporated to dryness under reduced pressure to give a residue which was dissolved in ethyl acetate. After washing first with water and then with 1N hydrochloric acid the solution was evaporated under reduced pressure to remove the ethyl acetate. The residue was redissolved in a mixture of methanol and 2 N sodium hydroxide (10 ml. each). Stirring this solution for several hours and acidifying with 2 N hydrochloric acid precipitated the product which was recrystallized from aqueous methanol to give light brown crystals of 3',5'-dibromo-2,4'-dihydroxybenzanilide (0.88 g.). Yield: 78%. The melting point of the compound is 182°-187° C. was added Then the solution was added by drops The resulting solution was evaporated to dryness under reduced pressure to give a residue which After washing first with water with 1N hydrochloric acid the solution was evaporated under reduced pressure to remove the ethyl acetate The residue was redissolved in a mixture of methanol and 2 N sodium hydroxide (10 ml precipitated the product which was recrystallized from aqueous methanol

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

Procedure: Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 15 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 320.3 mg (1.2 mmol) of 4-amino-2,6-dibromophenol to give 427.1 mg (89.2%) of the product as a gray solid, m.p.>250° C., mass (electrospray, m/e): M+H 479.7, 481.6.

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

Procedure: 2,6-Dibromo-4-aminophenol (0.6 g.) was dissolved in acetone (30 ml.) to which pyridine (0.32 ml.) was added. Then the solution was added by drops and with stirring to an acetone solution (10 ml.) containing acetylsalicyloyl chloride which was prepared from acetyl-salicylic acid (0.38 g.). The resulting solution was evaporated to dryness under reduced pressure to give a residue which was dissolved in ethyl acetate. After washing first with water and then with 1 N hydrochloric acid the solution was evaporated under reduced pressure to remove the ethyl acetate. The residue was redissolved in a mixture of methanol and 2 N sodium hydroxide (10 ml. each). Stirring this solution for several hours and acidifying with 2 N hydrochloric acid precipitated the product which was recrystallized from aqueous methanol to give light brown crystals of 3',5'-dibromo-2,4'-dihydroxybenzanilide (0.88 g.). Yield: 78%. The melting point of the compound is 182°-187° C. was added Then the solution was added by drops The resulting solution was evaporated to dryness under reduced pressure to give a residue which After washing first with water with 1 N hydrochloric acid the solution was evaporated under reduced pressure to remove the ethyl acetate The residue was redissolved in a mixture of methanol and 2 N sodium hydroxide (10 ml precipitated the product which was recrystallized from aqueous methanol