Sodium Hydroxide → (R)-2-(tert-butylamino)-8-(6-ethyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-methylquinazolin-4(3H)-one

HRID 1056406Notes

Reaction equation

HRID 1056406 reaction equation
C(C1C=CC(C2C=CC=CC=2)=C(C(C)C)C=1C(C)C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:30]([C@@H:32]1[C:36]2[NH:37][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:39][C:35]=2[C:34](=[O:49])[NH:33]1)[CH3:31].[C:50]([NH:54][C:55]1[N:64]([CH3:65])[C:63](=[O:66])[C:62]2[C:57](=[C:58](I)[CH:59]=[CH:60][CH:61]=2)[N:56]=1)([CH3:53])([CH3:52])[CH3:51].[OH-].[Na+]>O1CCOCC1.O.CCOCC.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]>[C:50]([NH:54][C:55]1[N:64]([CH3:65])[C:63](=[O:66])[C:62]2[C:57](=[C:58]([C:38]3[NH:37][C:36]4[C@@H:32]([CH2:30][CH3:31])[NH:33][C:34](=[O:49])[C:35]=4[CH:39]=3)[CH:59]=[CH:60][CH:61]=2)[N:56]=1)([CH3:53])([CH3:52])[CH3:51]

Participants

10

Reactant 5

HCID 14798Sodium HydroxideHCID 62657Potassium Phosphate, TribasicHCID 30344661,1'-Biphenyl, tris(1-methylethyl)-HCID 897821382-(tert-butylamino)-8-iodo-3-methylquinazolin-4(3H)-one2×HCID 89793814(R)-6-ethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one

Product 1

HCID 89793815(R)-2-(tert-butylamino)-8-(6-ethyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-methylquinazolin-4(3H)-oneYield 52.6%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 3283Diethyl EtherSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of 2-(dicyclohexylphosphino)-2′,4′,6%-tri-isopropyl1,1′-biphenyl (Strem Chemicals, 16.02 mg, 0.034 mmol), tris(dibenzylideneacetone)dipalladium (0) (Strem Chemicals, 15.38 mg, 0.017 mmol), potassium phosphate tribasic (Sigma Aldrich, 267 mg, 1.260 mmol), (R)-6-ethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (505g, 232 mg, 0.840 mmol) and 2-(tert-butylamino)-8-iodo-3-methylquinazolin-4(3H)-one (Intermediate 701, 150 mg, 0.420 mmol) in 1,4-dioxane (4 mL), water (1.20 mL) in a sealed glass tube was heated at 80° C. for 1.5 h. The reaction mixture was treated with 1N NaOH and extracted with EtOAc (2×50 mL), washed with brine and dried over MgSO4, filtered and concentrated. The crude reaction mixture was chromatographed on an ISCO Combiflash RF (40 g Thomson SingleStep column, using a gradient of 0-10% MeOH in DCM) affording a dark brown oil. It was suspended in Et2O with sonication and filtered and washed with Et2O and dried in the vacuum oven at 34° C. for 2 h affording (R)-2-(tert-butylamino)-8-(6-ethyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-methylquinazolin-4(3H)-one (505, 83.8 mg, 0.221 mmol, 52.6% yield) as a tan amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.83 (1H, br. s.), 7.89 (2H, d, J=7.2 Hz), 7.65 (1H, br. s.), 7.18 (1H, br. s.), 6.71 (1H, br. s.), 5.94 (1H, br. s.), 4.45 (1H, br. s.), 3.48 (3H, br. s.), 1.84 (1H, br. s.), 1.61 (1H, br. s.), 1.50 (9H, br. s.), 0.85 (3H, br. s.). m/z (ESI, +ve) 380.0 (M+1)+.

Workup

  1. extractionextracted with EtOAc (2×50 mL)
  2. washwashed with brine
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude reaction mixture
  7. customwas chromatographed on an ISCO Combiflash RF (40 g Thomson SingleStep column
  8. customaffording a dark brown oil
  9. filtrationfiltered
  10. washwashed with Et2O
  11. customdried in the vacuum oven at 34° C. for 2 h

Sources & evidence

ORD record
ord-362a27c20d4540f9a00a6f6265206ec1
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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