Potassium Phosphate, Tribasic → (R)-3-ethyl-7-fluoro-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-one

HRID 1056428Notes

Reaction equation

HRID 1056428 reaction equation
Br[C:2]1[C:3]([F:20])=[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]([CH2:17][CH3:18])[C:7]2=[O:19].[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.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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+]>[CH2:17]([N:8]1[C:7](=[O:19])[C:6]2[C:11](=[C:2]([C:28]3[NH:27][C:26]4[C@@H:22]([CH3:21])[NH:23][C:24](=[O:39])[C:25]=4[CH:29]=3)[C:3]([F:20])=[CH:4][CH:5]=2)[N:10]=[C:9]1[NH:12][C:13]1([CH3:16])[CH2:15][CH2:14]1)[CH3:18]

Participants

7

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 897939808-bromo-3-ethyl-7-fluoro-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-one

Product 1

HCID 89793983(R)-3-ethyl-7-fluoro-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-oneYield 70.8%

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-3-ethyl-7-fluoro-2-(1-methylcyclopropyl)amino)quinazolin-4(3H)-one (513a, 181.1 mg, 0.53 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; 174 mg, 0.665 mmol), potassium phosphate (339 mg, 1.597 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; 20.97 mg, 0.027 mmol) in a mixture of 1,4-dioxane (2.2 mL) and water (0.55 mL) was stirred under argon at 45° C. for 1.5 h. The reaction mixture was then concentrated onto silica gel and chromatographically purified (silica gel, 50-100% EtOAc/hexanes, then 0-10% MeOH/DCM). The isolated product was suspended in MeOH (2 mL), collected by vacuum filtration, washed with ethyl ether (5 mL), and dried in vacuo to provide (R)-3-ethyl-7-fluoro-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-one (148.2 mg, 0.375 mmol, 70% yield) as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 13.32 (1H, s), 7.90 (1H, s), 7.86 (1H, m, J=8.8, 6.3 Hz), 7.74 (1H, s), 7.11 (1H, dd, J=11.9, 8.8 Hz), 6.79 (1H, d, J=3.7 Hz), 4.66 (1H, q, J=6.3 Hz), 4.06 (2H, q, J=6.5 Hz), 1.54 (3H, s), 1.37 (3H, d, J=6.5 Hz), 1.15 (3H, t, J=6.9 Hz), 0.95-1.05 (2H, m), 0.86 (2H, d, J=2.0 Hz). 19F NMR (376 MHz, DMSO-d6) δ ppm −102.43 (1F, s). m/z (ESI, +ve) 395.9 (M+H)+.

Workup

  1. concentrationThe reaction mixture was then concentrated onto silica gel
  2. customchromatographically purified (silica gel, 50-100% EtOAc/hexanes
  3. filtrationcollected by vacuum filtration
  4. washwashed with ethyl ether (5 mL)
  5. customdried in vacuo

Sources & evidence

ORD record
ord-f394347e23e0471286ca8410a72909f4
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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