تفاعل #69467

ord-6c347fd2053c4b53bdc6763a8606b949

معادلة التفاعل

O=C([O-])[O-].[Cs+].[Cs+]
cesium carbonate
O=C(c1cc(C2CCCN2)c2oc(N3CCOCC3)cc(=O)c2c1)N1CCOCC1
6-(morpholine-4-carbonyl)-2-morpholino-8-(pyrrolidin-2-yl)-4H-chromen-4-one
CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
(9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine)
Fc1cc(F)cc(Br)c1
1-bromo-3,5-difluorobenzene
O=C(c1cc([C@H]2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1)N1CCOCC1
desired product
O=C(c1cc([C@H]2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1)N1CCOCC1
8-[(2R)-1-(3,5-difluorophenyl)pyrrolidin-2-yl]-6-(morpholine-4-carbonyl)-2-morpholino-chromen-4-one
O=C(c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1)N1CCOCC1
8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-6-(morpholine-4-carbonyl)-2-morpholino-4H-chromen-4-one
المردود 149.9%

المذيبات

ظروف التفاعل

درجة الحرارة
100°CELSIUS
الظروف التفصيلية
See reaction.notes.procedure_details.

المعالجة

  1. 1
    أخرىwas bubbled with nitrogen for 10 minutes
  2. 2
    أخرىthe mixture bubbled with nitrogen for 2 minutes
  3. 3
    درجة الحرارةUpon cooling to room temperature the mixture
  4. 4
    أخرىwas partitioned between DCM (500 mL) and water (250 mL)
  5. 5
    غسيلThe organic phase was washed with brine
  6. 6
    تجفيفdried with magnesium sulfate
  7. 7
    ترشيحfiltered
  8. 8
    تركيزconcentrated under reduced pressure
  9. 9
    أخرىto give a brown gum
  10. 10
    أخرىThe gum was purified by flash column chromatography on silica using gradient elution (0% methanol/DCM to 5% methanol/DCM)

الإجراء التجريبي

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.

المصدر

DOI: 10.6084/m9.figshare.5104873.v1براءة الاختراع: US08530470B2uspto-grants-2013_09