4-(4-Bromo-2-fluorobenzyl)morpholine

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

実験手順: 4-Bromo-2-fluorobenzyl bromide (3.0 g) and morpholine (2.15 ml) were stirred in dimethylformamide (30 ml) at ambient temperature for 18 h. The mixture was partitioned between diethyl ether (80 ml) and water (80 ml). The aqueous phase was extracted further with diethyl ether (80 ml) and the combined organic phases were dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 0-30% ethyl acetate/iso-hexane to give the product as a colourless oil (2.92 g). The mixture was partitioned between diethyl ether (80 ml) and water (80 ml) The aqueous phase was extracted further with diethyl ether (80 ml) the combined organic phases were dried (magnesium sulfate) concentrated in vacuo The residue was purified by column chromatography eluting with a gradient of 0-30% ethyl acetate/iso-hexane

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

実験手順: Analogously to example (4a), starting from 4-(4-bromo-2-fluoro-benzyl)-morpholine (274 mg; 1 mmol), bis(pinacolato)diboron (380 mg; 1.5 mmol), potassium acetate (294 mg; 3 mmol), bis(triphenylphosphine)palladium(II) dichloride (47 mg; 0.07 mmol) and from 5-(3,5-diethoxy-4-iodo-benzyl)-pyrimidine-2,4-diamine (example 1) (248 mg; 0.6 mmol), 166 mg (34%) 5-(2,6-diethoxy-3′-fluoro-4′-morpholin-4-ylmethyl-biphenyl-4-ylmethyl)-pyrimidine-2,4-diamine are obtained as a pale yellow powder. are obtained as a pale yellow powder

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

実験手順: Analogously to example (4a), starting from 4-(4-bromo-2-fluoro-benzyl)-morpholine (274 mg; 1 mmol), bis(pinacolato)diboron (380 mg; 1.5 mmol), potassium acetate (294 mg; 3 mmol), bis(triphenylphosphine)palladium(II) dichloride (47 mg; 0.07 mmol) and from 5-(3,5-diethoxy-4-iodo-benzyl)-pyrimidine-2,4-diamine (example 1) (248 mg; 0.6 mmol), 166 mg (34%) 5-(2,6-diethoxy-3′-fluoro-4′-morpholin-4-ylmethyl-biphenyl-4-ylmethyl)-pyrimidine-2,4-diamine are obtained as a pale yellow powder. are obtained as a pale yellow powder

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 4-bromo-1-(bromomethyl)-2-fluorobenzene (600 mg, 2.24 mmol) was dissolved in DMF (8 mL), and KI (400 mg, 2.46 mmol) was added and morpholine (0.78 mL, 8.96 mmol) was added, followed by stirring at 60° C. for 13 hours. When the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove DMF, and extracted two times or more with ethyl acetate and brine. The organic layer was treated with sodium sulfate to remove extra water, and then concentrated under reduced pressure, followed by column chromatography using 30% ethyl acetate/hexane, to give 4-(4-bromo-2-fluorobenzyl)morpholine (278 mg, 1.01 mmol) with a yield of 45%. KI (400 mg, 2.46 mmol) was added the reaction mixture was concentrated under reduced pressure to remove DMF extracted two times The organic layer was treated with sodium sulfate to remove extra water concentrated under reduced pressure

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

実験手順: 4-Bromo-2-fluorobenzyl bromide (3.0 g) and morpholine (2.15 ml) were stirred in dimethylformamide (30 ml) at ambient temperature for 18 h. The mixture was partitioned between diethyl ether (80 ml) and water (80 ml). The aqueous phase was extracted further with diethyl ether (80 ml) and the combined organic phases were dried (magnesium sulfate) and concentrated in vacuo. The residue was purified by column chromatography, eluting with a gradient of 0–30% ethyl acetate/iso-hexane to give the product as a colourless oil (2.92 g). The mixture was partitioned between diethyl ether (80 ml) and water (80 ml) The aqueous phase was extracted further with diethyl ether (80 ml) the combined organic phases were dried (magnesium sulfate) concentrated in vacuo The residue was purified by column chromatography eluting with a gradient of 0–30% ethyl acetate/iso-hexane