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

HRID 1056275Notes

Reaction equation

HRID 1056275 reaction equation
CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[CH3:35][C@@H:36]1[C:40]2[NH:41][C:42](B3OC(C)(C)C(C)(C)O3)=[CH:43][C:39]=2[C:38](=[O:53])[NH:37]1.Br[C:55]1[CH:56]=[CH:57][CH:58]=[C:59]2[C:64]=1[N:63]=[C:62]([NH:65][C:66]([CH3:69])([CH3:68])[CH3:67])[N:61]([CH:70]([CH3:72])[CH3:71])[C:60]2=[O:73].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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].CO>[C:66]([NH:65][C:62]1[N:61]([CH:70]([CH3:71])[CH3:72])[C:60](=[O:73])[C:59]2[C:64](=[C:55]([C:42]3[NH:41][C:40]4[C@@H:36]([CH3:35])[NH:37][C:38](=[O:53])[C:39]=4[CH:43]=3)[CH:56]=[CH:57][CH:58]=2)[N:63]=1)([CH3:69])([CH3:68])[CH3:67]

Participants

9

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 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 897820438-bromo-2-(tert-butylamino)-3-isopropylquinazolin-4(3H)-one

Product 1

HCID 89784686(R)-2-(tert-butylamino)-3-isopropyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-oneYield 69%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

Argon was bubbled into a mixture of Pd2dba3 (Strem, 7.45 mg, 8.13 μmol), Xphos (Strem; 7.75 mg, 0.016 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; 0.085 g, 0.325 mmol), 8-bromo-2-(tert-butylamino)-3-isopropylquinazolin-4(3H)-one (0.055 g, 0.163 mmol), potassium phosphate (0.10 g, 0.488 mmol) in 1 mL dioxane and 0.2 mL water for 1 min. The reaction was sealed and heated to 80° C. for 2 h. The reaction was cooled and transferred to a RBF with some MeOH and adsorbed onto 0.7 g silica gel and dried in vacuo. The material was purified by silica gel chromatography (12 g column) using 0-100% 90/10 DCM/MeOH in DCM. The product-containing fractions were concentrated to afford (R)-2-(tert-butylamino)-3-isopropyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-one (0.044 g, 0.112 mmol, 69% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.78 (1H, s), 7.84 (2H, ddd, J=14.9, 7.6, 1.6 Hz), 7.59 (1H, s), 7.15 (1H, t, J=7.7 Hz), 6.63 (1H, d, J=1.6 Hz), 5.72 (1H, s), 4.94 (1H, quin, J=6.7 Hz), 4.51 (1H, q, J=6.8 Hz), 3.17 (3H, s), 1.52 (6H, d, J=6.8 Hz), 1.48 (9H, s), 1.36 (3H, d, J=6.7 Hz). m/z (ESI, +ve ion) 394.1 (M+H)+.

Workup

  1. customThe reaction was sealed
  2. temperatureThe reaction was cooled
  3. customdried in vacuo
  4. customThe material was purified by silica gel chromatography (12 g column)
  5. concentrationThe product-containing fractions were concentrated

Sources & evidence

ORD record
ord-56fb52bc2b7b41c89fc1e1f8be9dfde6
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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