Potassium Phosphate, Tribasic → (R)-3-cyclopropyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2-((1-methylcyclopropyl)amino)quinazolin-4(1H)-one

HRID 1056380Notes

Reaction equation

HRID 1056380 reaction equation
Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1([CH3:16])[CH2:15][CH2:14]1)[N:8]([CH:17]1[CH2:19][CH2:18]1)[C:7]2=[O:20].[CH3:21][C@@H:22]1[C:26]2[NH:27][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:29][C:25]=2[C:24](=[O:39])[NH:23]1.[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.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[CH:17]1([N:8]2[C:7](=[O:20])[C:6]3[C:11](=[C:2]([C:28]4[NH:27][C:26]5[CH:22]([CH3:21])[NH:23][C:24](=[O:39])[C:25]=5[CH:29]=4)[CH:3]=[CH:4][CH:5]=3)[NH:10][C@H:9]2[NH:12][C:13]2([CH3:16])[CH2:15][CH2:14]2)[CH2:19][CH2:18]1

Participants

6

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 89781988(R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-oneHCID 897937848-bromo-3-cyclopropyl-2-((1-methylcyclopropyl)amino)-quinazolin-4(3H)-one

Product 1

HCID 118512008(R)-3-cyclopropyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2-((1-methylcyclopropyl)amino)quinazolin-4(1H)-oneYield 59%

Reagents, catalysts & solvents 2

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylCatalystHCID 54751079XPhos PalladacycleCatalyst

Conditions

Temperature
45 °C

Procedure

A microwave tube was charged with 8-bromo-3-cyclopropyl-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-one (492a; 170 mg, 0.51 mmol), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705; 167 mg, 0.64 mmol), X-Phos pre-catalyst II generation (Sigma-Aldrich; 20 mg, 0.025 mmol) and K3PO4 (Sigma-Aldrich; 324 mg, 1.53 mmol). The tube was sealed and purged with argon for 5 min. 1,4-Dioxane (1.4 mL) and water (0.35 mL) were added and Ar (g) was bubbled through the mixture for 5 min. The tube was sealed and heated in an oil bath at 45° C. for 90 min. The reaction was then cooled to RT and EtOAc and water were added. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude material was absorbed onto a plug of silica gel and purified by silica gel chromatography (0-10% MeOH in CH2Cl2), to provide (R)-3-cyclopropyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2-((1-methylcyclopropyl)amino)quinazolin-4(1H)-one (492) (117 mg, 0.30 mmol, 59% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.01 (s, 1H), 8.09 (dd, J=7.63, 1.37 Hz, 1H), 7.77 (dd, J=7.73, 1.27 Hz, 1H), 7.68 (s, 1H), 7.59 (s, 1H), 7.13 (t, J=7.73 Hz, 1H), 6.93 (d, J=0.98 Hz, 1H), 4.63 (q, J=6.46 Hz, 1H), 2.67-2.74 (m, 1H), 1.55 (s, 3H), 1.36 (d, J=6.65 Hz, 3H), 1.19-1.27 (m, 2H), 0.99-1.04 (m, 2H), 0.83-0.88 (m, 2H), 0.73 (dd, J=3.91, 2.54 Hz, 2H). m/z (ES, +ve) 390.0 (M+H)+.

Workup

  1. customThe tube was sealed
  2. custompurged with argon for 5 min
  3. addition1,4-Dioxane (1.4 mL) and water (0.35 mL) were added
  4. customAr (g) was bubbled through the mixture for 5 min
  5. customThe tube was sealed
  6. temperatureThe reaction was then cooled to RT
  7. additionEtOAc and water were added
  8. customThe layers were separated
  9. extractionthe aqueous layer was extracted with EtOAc (2×)
  10. dry with materialThe combined organic layers were dried over anhydrous Na2SO4
  11. filtrationfiltered
  12. concentrationconcentrated
  13. customThe crude material was absorbed onto a plug of silica gel
  14. custompurified by silica gel chromatography (0-10% MeOH in CH2Cl2)

Sources & evidence

ORD record
ord-9c744102f858402f95f7c0de41085375
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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