Potassium Phosphate, Tribasic → HCID 46908893, compound

HRID 2069731Notes

Reaction equation

HRID 2069731 reaction equation
Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[O:12][CH2:13][CH2:14][N:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:16]([C:20]1[CH:21]=[C:22]2[C:27](=[C:28]([F:30])[CH:29]=1)[C:26](=[O:31])[N:25]([C:32]1[CH:42]=[CH:41][CH:40]=[C:39](B3OC(C)(C)C(C)(C)O3)[C:33]=1[CH2:34][O:35]C(=O)C)[N:24]=[CH:23]2)([CH3:19])([CH3:18])[CH3:17].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)CCC.O.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd]>[C:16]([C:20]1[CH:21]=[C:22]2[C:27](=[C:28]([F:30])[CH:29]=1)[C:26](=[O:31])[N:25]([C:32]1[CH:42]=[CH:41][CH:40]=[C:39]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[O:12][CH2:13][CH2:14][N:15]=4)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=3)[C:33]=1[CH2:34][OH:35])[N:24]=[CH:23]2)([CH3:19])([CH3:17])[CH3:18]

Participants

7

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 594737692-(6-(tert-Butyl)-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetateHCID 59473789HCID 59473789, compound

Product 1

HCID 46908893HCID 46908893, compoundYield 11.8%

Reagents, catalysts & solvents 2

HCID 1542701,5-Diphenylpenta-1,4-dien-3-one;palladiumCatalystHCID 22253497Water butanolSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 5-bromo-3-(4,5-dihydro-oxazol-2-ylamino)-1-methyl-1H-pyridin-2-one (111 mg, 0.41 mmol), acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (201 mg, 0.41 mmol), X-Phos (15 mg, 0.033 mmol) and potassium phosphate tribasic (174 mg, 0.82 mmol) was taken up in n-butanol/water (4:1, 8.1 mL) and vacuum degassed. Palladium(0) bis(dibenzylideneacetone) (10 mg, 0.02 mmol) was added and the mixture was vacuum degassed and then heated to 100° C. under argon atmosphere. After 3 hours the material was cooled to ambient. The material was taken up in dichloromethane (40 mL) and water (40 mL) and shaken in a separatory funnel. The dichloromethane phase was collected and washed with brine solution (40 mL). The aqueous phase was back extracted with methylene chloride (2×30 mL) and the organic phases combined, dried over magnesium sulfate, filtered and stripped. Residual n-butanol was removed on the pump/rotary evaporator. Chromatography (Preparative TLC [3 plates], 11% methanol/dichloromethane—methanol contains 5% triethylamine) provided semi-pure product. The material was chromatographed a second time (Preparative TLC [2 plates], using 12% methanol/dichloromethane—methanol contains 5% triethylamine) which provided the title compound as an off-white crystalline solid (25 mg). (M+H)+=518 m/e; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.38 (s, 9 H) 3.56 (s, 3 H) 3.69-3.83 (m, 2 H) 4.25 (t, J=8.5 Hz, 2 H) 4.29-4.36 (m, 2 H) 4.65 (m, 1 H) 7.35-7.54 (m, 5 H) 7.74 (dd, J=13.3, 1.7 Hz, 1 H) 7.87 (d, J=1.7 Hz, 1 H) 8.49 (d, J=2.6 Hz, 1 H)

Workup

  1. customvacuum degassed
  2. customdegassed
  3. temperatureAfter 3 hours the material was cooled
  4. customThe dichloromethane phase was collected
  5. washwashed with brine solution (40 mL)
  6. extractionThe aqueous phase was back extracted with methylene chloride (2×30 mL)
  7. dry with materialdried over magnesium sulfate
  8. filtrationfiltered
  9. customResidual n-butanol was removed on the pump/rotary evaporator
  10. customChromatography (Preparative TLC [3 plates], 11% methanol/dichloromethane—methanol contains 5% triethylamine) provided semi-pure product
  11. customThe material was chromatographed a second time (Preparative TLC [2 plates], using 12% methanol/dichloromethane—methanol contains 5% triethylamine) which

Sources & evidence

ORD record
ord-b2aa6df7c60b4161aa9acf70429fd650
Source dataset
uspto-grants-2012_10
Patent number
US08299077B2

Reaction notes

Loading…