4-bromo-2,6-difluoroaniline

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 348 g trisodiumphosphate dodecahydrate (Merck KGaA, Art. No.106 578) were dissolved in 500 ml of distilled water. Then 8.563 g bis(triphenylphosphine) palladium (Merck KGaA, Art. No. 804 174) and 0.611 g hydaziniumhydroxide (Merck KGaA, Art. No. 804 604) were added. The suspension was stirred for 5 minutes. Then, 126.886 g 4-bromo-2,6-difluoro-aniline, prepared in house, were added. Next 100 g of the p-n-propylphenyl boronic acid, prepared as described above, dissolved in 600 ml dried tetrahydrafurane (Merck KGaA, Art. No.108 107) was added dropwise. The reaction mixture was heated 6 hours under reflux. The organic layer was separated, dried over Na2SO4 and it's solvent evaporated. The isolated crude product (150 g of 4′-n-propyl-3,5-difluoro-biphenyl-4-ylamine was used for the next step of the reaction without further purificatoin. 804 604) were added were added dissolved in 600 ml dried tetrahydrafurane (Merck KGaA, Art. No.108 107) was added dropwise The reaction mixture was heated 6 hours under reflux The organic layer was separated dried over Na2SO4 evaporated

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Sodium hydride (60%, 612 mg, 15.3 mmol) was added to a solution of 4-bromo-2,6-difluoroaniline (2.77 g, 6.65 mmol) in DMF (80 ml). After stirring for 30 minutes at ambient temperature, 7-benzyloxy-4-chloro-6-methoxyquinazoline (2 g, 6.65 mmol), (prepared, for example, as described in WO 97/22596, Example 1, but the free base was generated prior to use), was added and stirring was maintained for 4 hours. The mixture was partitioned between ethyl acetate and water (200 ml). The organic layer was separated, washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was triturated with isopropanol, collected by filtration, washed with ether and dried under vacuum to give 7-benzyloxy-4-(4-bromo-2,6-difluoroanilino)-6-methoxyquinazoline (1.95 g, 62%). was added stirring was maintained for 4 hours The mixture was partitioned between ethyl acetate and water (200 ml) The organic layer was separated washed with water, brine dried (MgSO4) the volatiles were removed by evaporation The residue was triturated with isopropanol collected by filtration washed with ether dried under vacuum

反応条件: temp:0.00; pressure:0.00; stir:

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Sodium hydride (60%, 612 mg, 15.3 mmol) was added to a solution of 4-bromo-2,6-difluoroaniline (2.77 g, 6.65 mmol) in DMF (80 ml). After stiffing for 30 minutes at ambient temperature, 7-benzyloxy-4-chloro-6-methoxyquinazoline (2 g, 6.65 mmol), (prepared, for example, as described in WO 97/22596, Example 1, but the free base was generated prior to use), was added and stirring was maintained for 4 hours. The mixture was partitioned between ethyl acetate and water (200 ml). The organic layer was separated, washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was triturated with isopropanol, collected by filtration, washed with ether and dried under vacuum to give 7-benzyloxy-4-(4-bromo-2,6-difluoroanilino)-6-methoxyquinazoline (1.95 g, 62%). was added was maintained for 4 hours The mixture was partitioned between ethyl acetate and water (200 ml) The organic layer was separated washed with water, brine dried (MgSO4) the volatiles were removed by evaporation The residue was triturated with isopropanol collected by filtration washed with ether dried under vacuum

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Under argon, sodium hydride (60%, 372 mg, 9.3 mmol) was added to a solution of 4-bromo-2,6-difluoroaniline (1.67 g, 8.08 mmol) in DMF. After stirring for 30 minutes at ambient temperature, 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (1.3 g, 4.04 mmol) was added and stirring was continued for a further 20 hours. The mixture was poured onto water (130 ml) and extracted with ethyl acetate. The organic layers were washed with water, brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was purified by column chromatography on silica, eluting with methylene chloride/methanol (95/5) followed by methylene chloride/methanol containing ammonia (1%) (90/10). The fractions containing the expected product were combined and evaporated. The residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum at 50° C. to give 4-(4-bromo-2,6-difluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (1.4 g, 70%). stirring was continued for a further 20 hours The mixture was poured onto water (130 ml) extracted with ethyl acetate The organic layers were washed with water, brine dried (MgSO4) the volatiles were removed by evaporation The residue was purified by column chromatography on silica eluting with methylene chloride/methanol (95/5) containing ammonia (1%) (90/10) The fractions containing the expected product evaporated The residue was triturated with ether collected by filtration washed with ether dried under vacuum at 50° C.

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 132 g of 4-bromo-2,6-difluoroaniline, 70 g of copper (I) cyanide and 444 ml of N-methylpyrrolidone were mixed in a flask and refluxed for 3 hours. The reaction solution was poured into a solution including 266 g of iron (III) chloride, 85 ml of concentrated hydrochloric acid and 315 ml of water. The solution was extracted with chloroform and washed with water and an aqueous 10% solution of potassium hydroxide. The chloroform was distilled off. The residue was distillated under a reduced pressure (bp: 90°-110° C./4 mmHg) and recrystallized from a solvent mixture of hexane and chloroform, to yield 56 g of 4-cyano-2,6-difluoroaniline. refluxed for 3 hours The reaction solution was poured into a solution The solution was extracted with chloroform washed with water The chloroform was distilled off recrystallized from a solvent mixture of hexane and chloroform

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 300 g of bromine was added drop-wise to 231 g of 2,6-difluoroaniline dissolved in 400 ml of chloroform. The mixture was refluxed for one hour and the reaction solution was poured into an aqueous 10% solution of potassium hydroxide. The potassium hydroxide was extracted with chloroform and the organic layer was washed with an aqueous 10% solution of potassium hydroxide and water. The chloroform was distilled off and the residue was distilled under reduced pressure (bp: 70°-80° C./4 mmHg) and recrystallized from hexane, to yield 292 g of 4-bromo-2,6-difluoroaniline. The mixture was refluxed for one hour The potassium hydroxide was extracted with chloroform the organic layer was washed with an aqueous 10% solution of potassium hydroxide and water The chloroform was distilled off the residue was distilled under reduced pressure (bp: 70°-80° C./4 mmHg) recrystallized from hexane

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 300 g of bromine was added drop-wise to 231 g of 2,6-difluoroaniline dissolved in 400 ml of chloroform. The mixture was refluxed for one hour and the reaction solution was poured into an aqueous 10% solution of potassium hydroxide. The potassium hydroxide was extracted with chloroform and the organic layer was washed with an aqueous 10% solution of potassium hydroxide and water. The chloroform was distilled off and the residue was distilled under reduced pressure (bp: 70°-80° C./4 mmHg) and recrystallized from hexane, to yield 292 g of 4-bromo-2,6-difluoroaniline. The mixture was refluxed for one hour The potassium hydroxide was extracted with chloroform the organic layer was washed with an aqueous 10% solution of potassium hydroxide and water The chloroform was distilled off the residue was distilled under reduced pressure (bp: 70°-80° C./4 mmHg) recrystallized from hexane