Potassium Phosphate, Tribasic → 2-(8-tert-Butyl-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-benzaldehyde

HRID 1879680Notes

Reaction equation

HRID 1879680 reaction equation
Br[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:21][C:14]=3[O:13][CH2:12][CH2:11]2)[C:3]=1[CH:4]=[O:5].[CH3:26][N:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([C:49]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[O:50])=[CH:45][N:44]=2)[C:28]1=[O:57].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)CCC.C(OCC)(=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[C:22]([C:20]1[CH:19]=[CH:18][C:15]2[C:16](=[O:17])[N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:2]([C:31]4[CH:30]=[C:29]([NH:42][C:43]5[CH:48]=[CH:47][C:46]([C:49]([N:51]6[CH2:56][CH2:55][O:54][CH2:53][CH2:52]6)=[O:50])=[CH:45][N:44]=5)[C:28](=[O:57])[N:27]([CH3:26])[CH:32]=4)[C:3]=3[CH:4]=[O:5])[CH2:11][CH2:12][O:13][C:14]=2[CH:21]=1)([CH3:23])([CH3:25])[CH3:24]

Participants

9

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 592164661-Methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-oneHCID 595485352-Bromo-6-(8-tert-butyl-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)benzaldehyde

Product 1

HCID 595485232-(8-tert-Butyl-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-benzaldehydeYield 97.9%

Reagents, catalysts & solvents 5

HCID 6505921(1E,4E)-1,5-diphenylpenta-1,4-dien-3-one; palladiumCatalystHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylCatalystHCID 2631-ButanolSolventHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

2-Bromo-6-(8-tert-butyl-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)benzaldehyde (109 mg, 0.27 mmol), 1-Methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (179 mg, 1.5 eq), XPHOS (8 mg, 0.06 eq), and potassium phosphate (115 mg, 2 eq) were taken up in n-butanol (2 mL) and water (0.5 mL) and a stream of argon was bubbled through the mixture for 10 minutes. Then the catalyst Pd(dba)2 (5 mg, 0.03 eq) was added and the reaction was placed under argon and stirred at 100° C. for 40 minutes. By TLC analysis the reaction was complete, so it was cooled to room temperature and diluted with ethyl acetate (150 mL) and water (50 mL). The layers were partitioned and then separated and the organic layer was further washed with water (3×50 mL) and then finally washed with brine (1×50 mL). The ethyl acetate layer was dried over magnesium sulfate, filtered and concentrated. Purification by Preparative Thin Layer Chromatography on silica gel eluting with 7% methanol in dichloromethane gave the title compound as an off-white powder (168 mg) (M+H)+=636.

Workup

  1. customwater (0.5 mL) and a stream of argon was bubbled through the mixture for 10 minutes
  2. temperaturewas cooled to room temperature
  3. customThe layers were partitioned
  4. customseparated
  5. washthe organic layer was further washed with water (3×50 mL)
  6. washfinally washed with brine (1×50 mL)
  7. dry with materialThe ethyl acetate layer was dried over magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customPurification by Preparative Thin Layer Chromatography on silica gel eluting with 7% methanol in dichloromethane

Sources & evidence

ORD record
ord-d134f8d49ff745fd9c6d3daaaa242233
Source dataset
uspto-grants-2012_11
Patent number
US08318719B2

Reaction notes

Loading…