Sodium Carbonate → HCID 59252987, compound

HRID 884752Notes

Reaction equation

HRID 884752 reaction equation
Br[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[C:5](=[O:13])[N:4]([NH:14][CH2:15][CH3:16])[C:3]=1[CH3:17].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[C:60](=O)([O-:62])[O-:61].[Na+].[Na+].[C]=O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:15]([NH:14][N:4]1[C:3]([CH3:17])=[C:2]([C:60]([OH:62])=[O:61])[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:13])[CH3:16]

Participants

7

Reactant 4

HCID 10340Sodium CarbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 59253057HCID 59253057, compoundHCID 178418416HCID 178418416, compound

Product 1

HCID 59252987HCID 59252987, compoundYield 15%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
122 °C

Procedure

A stirred suspension of 4-bromo-2-ethylamino-8-fluoro-3-methyl-2H-isoquinolin-1-one (1.526 g, 4.847 mmol), palladium acetate (108.8 mg, 0.4847 mmol), 4,5-bis-diphenylphosphanyl-9,9-dimethyl-9H-xanthene (=Xantphos, 280.5 mg, 0.4847 mmol) and sodium carbonate (1.541 g, 14.54 mmol) in toluene (10 mL) was filled with carbon monoxide to 5 bars (6 times). It was stirred on hot oil bath (122° C., P=6 bar) for 19 hours, allowed to cool and the excess CO was released. It was quenched with 20 ml EtOH, filtered and partitioned between 3:1 Ether-EtOAc (3×100 ml) and 5% aq. NaHCO3 (100 ml). Each organic layer was washed with 2×5 ml 5% aq. NaHCO3. The organic solution contained crude unreacted starting material (865 mg). The combined aq. solution was acidified with 3M aq. HCl (pH=0) at 0° C., extracted with ethyl acetate (4×50 ml), each organic layer was washed with sat. aq. NaCl (2×5 ml). The combined org. solution was dried (Na2SO4) and rotovaped to give the pure title compound (190 mg; yield=15%) as a dark solid. LC-MS (m/z) 265.2 (MH+), fragments: 221.4 (M—CO2), 178.7 (M—CO2-EtNH); tR0.74. 1H NMR (500 MHz, DMSO-d6): 1.09 (t, J=7.2 Hz, 3H, Me of Et), 2.51 (s, 3H, Me (overlapped with dmso-d5)), 2.9 (br., 2H, CH2 of Et), 3.4 (very br., H2O+CO2H), 6.18 (br., 1H, NH), 7.25 (dd, J=8.0 Hz, J (H—F)=11.7 Hz, 1H, C7H), 7.44 (d, J=8.2 Hz, C5H), 7.74 (dt, J (d, H—F)=5.1 Hz, J (t)=8.2 Hz, 1H, C6H). 19F NMR (470 MHz, CFCl3=0 ppm): −110.78 (dd, J=4.9 Hz, J=11.5 Hz). 13C APT (125 MHz, DMSO-d5=39.87 ppm): 12.89 (Me of Et), 17.18 (Me), 44.69 (CH2 of Et), 110.46 (s, C), 112.76 (d, J=5.8 Hz, C), 113.18 (d, J=21 Hz, C7H), 120.01 (d, J=3.6 Hz, C5H), 134.44 (d, J=9.9 Hz, C6H), 135.94 (C), 143.13 (C), 157.79 (d, J=4.8 Hz, C), 161.64 (d, J=262 Hz, C8-F), 168.57 (C).

Workup

  1. temperatureto cool
  2. customIt was quenched with 20 ml EtOH
  3. filtrationfiltered
  4. custompartitioned between 3:1 Ether-EtOAc (3×100 ml) and 5% aq. NaHCO3 (100 ml)
  5. washEach organic layer was washed with 2×5 ml 5% aq. NaHCO3
  6. customwas acidified with 3M aq. HCl (pH=0) at 0° C.
  7. extractionextracted with ethyl acetate (4×50 ml)
  8. washeach organic layer was washed with sat. aq. NaCl (2×5 ml)
  9. dry with materialsolution was dried (Na2SO4)

Sources & evidence

ORD record
ord-d9e86ff58f354050b9594531f947355a
Source dataset
uspto-grants-2012_08
Patent number
US08242134B2

Reaction notes

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