Potassium Phosphate, Tribasic → HCID 89783717, compound

HRID 1056286Notes

Reaction equation

HRID 1056286 reaction equation
[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC1(C)C(C)(C)OB([C:51]2[NH:59][C:58]3[CH2:57][CH2:56][NH:55][C:54](=[O:60])[C:53]=3[CH:52]=2)O1.Br[C:63]1[CH:64]=[CH:65][CH:66]=[C:67]2[C:72]=1[N:71]=[C:70]([NH:73][CH:74]([CH3:76])[CH3:75])[N:69]([C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][N:78]=1)[C:68]2=[O:83]>O1CCOCC1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:76][CH:74]([NH:73][C:70]1[N:69]([C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][N:78]=2)[C:68](=[O:83])[C:67]2[C:72](=[C:63]([C:51]3[NH:59][C:58]4[CH2:57][CH2:56][NH:55][C:54](=[O:60])[C:53]=4[CH:52]=3)[CH:64]=[CH:65][CH:66]=2)[N:71]=1)[CH3:75]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 89781930HCID 89781930, compoundHCID 897834962-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-YL)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-C]pyridin-4-one

Product 1

HCID 89783717HCID 89783717, compoundYield 7.7%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

Pd2dba3 (8.67 mg, 9.46 μmol, Strem Chemicals, MA), K3PO4 (161 mg, 0.757 mmol), XPhos (9.02 mg, 0.019 mmol, Strem Chemicals, MA), and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (248 mg, 0.946 mmol, 609) was sealed in a 5 mL conical microwave tube and evacuated and backfilled with nitrogen 3×. 8-Bromo-2-(isopropylamino)-3-(pyridin-2-yl)quinazolin-4(3H)-one (68 mg, 0.189 mmol, 415d) was added as a solution in 1,4-dioxane (0.7 mL). Water (0.2 mL) was added, and the mixture was stirred at 80° C. for 2 h. The material was cooled to RT and concentrated under reduced pressure. It was taken up in DMSO, filtered, and purified by reverse-phase preparative HPLC using an Xbridge column, 0.1% TFA in CH3CN/H2O, gradient 5% to 50% over 12 min. The product fractions were dried in a Genevac EZ-2 evaporator at 55° C. The material was solublized in 1:1 MeOH:DCM, and the free base was generated using a Si-carbonate cartridge (Silicycle, pre-washed with MeOH). The filtrate was concentrated under reduced pressure to give 2-((1-methylethyl)amino)-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)-3-(2-pyridinyl)-4(3H)-quinazolinone as a pale yellow solid (6 mg, 7%). 1H NMR (DMSO-d6) δ ppm 12.11 (1H, br. s.), 8.70 (1H, d, J=4.5 Hz), 8.06-8.12 (1H, m), 8.04 (1H, d, J=8.2 Hz), 7.78 (1H, d, J=7.0 Hz), 7.59-7.65 (2H, m), 7.18 (1H, t, J=7.7 Hz), 7.08 (1H, s), 6.97 (1H, br. s.), 5.84 (1H, d, J=7.4 Hz), 4.18-4.29 (1H, m), 4.11 (1H, br. s.), 3.14-3.19 (2H, m), 2.86 (2H, t, J=6.9 Hz), 1.18-1.25 (6H, m). m/z (ESI, +ve) 415.0 (M+H)+.

Workup

  1. customevacuated
  2. temperatureThe material was cooled to RT
  3. concentrationconcentrated under reduced pressure
  4. filtrationfiltered
  5. custompurified by reverse-phase preparative HPLC
  6. customover 12 min
  7. customThe product fractions were dried in a Genevac EZ-2 evaporator at 55° C
  8. washa Si-carbonate cartridge (Silicycle, pre-washed with MeOH)
  9. concentrationThe filtrate was concentrated under reduced pressure

Sources & evidence

ORD record
ord-f0308007721d414b90a60f4cc063ccbc
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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