Реакция #69467

Уравнение реакции

cesium carbonate

6-(morpholine-4-carbonyl)-2-morpholino-8-(pyrrolidin-2-yl)-4H-chromen-4-one

(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine)

1-bromo-3,5-difluorobenzene

→

desired product

8-[(2R)-1-(3,5-difluorophenyl)pyrrolidin-2-yl]-6-(morpholine-4-carbonyl)-2-morpholino-chromen-4-one

8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-6-(morpholine-4-carbonyl)-2-morpholino-4H-chromen-4-one

Выход 149.9%

Растворители

dioxane

Условия реакции

Обработка

1. 1
   Другоеwas bubbled with nitrogen for 10 minutes
2. 2
   Другоеthe mixture bubbled with nitrogen for 2 minutes
3. 3
   ТемператураUpon cooling to room temperature the mixture
4. 4
   Другоеwas partitioned between DCM (500 mL) and water (250 mL)
5. 5
   ПромывкаThe organic phase was washed with brine
6. 6
   Сушкаdried with magnesium sulfate
7. 7
   Фильтрацияfiltered
8. 8
   Концентрированиеconcentrated under reduced pressure
9. 9
   Другоеto give a brown gum
10. 10
    ДругоеThe gum was purified by flash column chromatography on silica using gradient elution (0% methanol/DCM to 5% methanol/DCM)

Методика

6-(morpholine-4-carbonyl)-2-morpholino-8-(pyrrolidin-2-yl)-4H-chromen-4-one (296 g, 716 mmol), 1-bromo-3,5-difluorobenzene (173 g, 895 mmol) and cesium carbonate (700 g, 2148 mmol) suspended in dioxane (3 L) was bubbled with nitrogen for 10 minutes. diacetoxypalladium (8.04 g, 36 mmol) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (41.4 g, 72 mmol) were added and the mixture bubbled with nitrogen for 2 minutes then heated at 100° C. for 2 hours. Upon cooling to room temperature the mixture was partitioned between DCM (500 mL) and water (250 mL). The organic phase was washed with brine and dried with magnesium sulfate, filtered and concentrated under reduced pressure to give a brown gum. The gum was purified by flash column chromatography on silica using gradient elution (0% methanol/DCM to 5% methanol/DCM). The desired product, 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-6-(morpholine-4-carbonyl)-2-morpholino-4H-chromen-4-one (282 g, 75%), was thus isolated as a pale yellow dry film. Mass Spectrum: m/z [M+H]+=526. More material was made by repeating this reaction.

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