Potassium Phosphate, Tribasic → HCID 89782039, compound

HRID 1056412Notes

Reaction equation

HRID 1056412 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]([CH3:16])([CH3:15])[CH3:14])[N:8]([CH:17]1[CH2:20][CH2:19][CH2:18]1)[C:7]2=[O:21].[CH3:22][C@@H:23]1[C:27]2[NH:28][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:30][C:26]=2[C:25](=[O:40])[NH:24]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO.C(Cl)Cl>O1CCOCC1.O.CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+]>[C:13]([NH:12][C:9]1[N:8]([CH:17]2[CH2:20][CH2:19][CH2:18]2)[C:7](=[O:21])[C:6]2[C:11](=[C:2]([C:29]3[NH:28][C:27]4[C@@H:23]([CH3:22])[NH:24][C:25](=[O:40])[C:26]=4[CH:30]=3)[CH:3]=[CH:4][CH:5]=2)[N:10]=1)([CH3:16])([CH3:15])[CH3:14]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 21226129Dichloromethane methanolHCID 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 89793968HCID 89793968, compound

Product 1

HCID 89782039HCID 89782039, compoundYield 70.2%

Reagents, catalysts & solvents 3

HCID 72376365[2-(2-Aminophenyl)phenyl]-chloro-palladium dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphaneCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
45 °C

Procedure

A solution of 8-bromo-2-(tert-butylamino)-3-cyclobutylquinazolin-4(3H)-one (254.1 mg, 0.725 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 (Example 705; 238 mg, 0.907 mmol), potassium phosphate (462 mg, 2.176 mmol), and chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) (XPhos precatalyst, 2nd generation; Aldrich; 28.6 mg, 0.036 mmol) in a mixture of 1,4-dioxane (3.0 mL) and water (0.750 mL) was stirred under argon at 45° C. for 1 h. The reaction mixture was then concentrated onto silica gel and chromatographically purified (silica gel, 50-100% EtOAc/hexanes, then 0-10% MeOH/DCM) to provide (R)-2-(tert-butylamino)-3-cyclobutyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-one (206.3 mg, 0.509 mmol, 70% yield) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.95 (1H, s), 7.87 (1H, dd, J=7.7, 0.9 Hz), 7.80 (1H, dd, J=7.7, 0.9 Hz), 7.61 (1H, s), 7.13 (1H, t, J=7.7 Hz), 6.72 (1H, s), 5.81 (1H, s), 4.48-4.64 (2H, m), 2.63 (2H, td, J=11.3, 5.0 Hz), 2.01-2.18 (2H, m), 1.56-1.70 (2H, m), 1.48 (9H, s), 1.36 (3H, d, J=6.7 Hz). m/z (ESI, +ve) 406.0 (M+H)+.

Workup

  1. concentrationThe reaction mixture was then concentrated onto silica gel
  2. customchromatographically purified (silica gel, 50-100% EtOAc/hexanes

Sources & evidence

ORD record
ord-6c75695eb1b440b49b9ace38b22fa268
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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