Potassium Phosphate, Tribasic → 2-(Tert-Butylamino)-3-Methyl-8-[(6r)-6-Methyl-4-Oxo-1,4,5,6-Tetrahydropyrrolo[3,4-B]pyrrol-2-Yl]quinazolin-4(3h)-One

HRID 1056326Notes

Reaction equation

HRID 1056326 reaction equation
[CH3:1][C@@H:2]1[C:6]2[NH:7][C:8](B3OC(C)(C)C(C)(C)O3)=[CH:9][C:5]=2[C:4](=[O:19])[NH:3]1.[C:20]([NH:24][C:25]1[N:34]([CH3:35])[C:33](=[O:36])[C:32]2[C:27](=[C:28](I)[CH:29]=[CH:30][CH:31]=2)[N:26]=1)([CH3:23])([CH3:22])[CH3:21].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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+].CCOC(C)=O.O>[C:20]([NH:24][C:25]1[N:34]([CH3:35])[C:33](=[O:36])[C:32]2[C:27](=[C:28]([C:8]3[NH:7][C:6]4[C@@H:2]([CH3:1])[NH:3][C:4](=[O:19])[C:5]=4[CH:9]=3)[CH:29]=[CH:30][CH:31]=2)[N:26]=1)([CH3:23])([CH3:22])[CH3:21]

Participants

8

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 897821382-(tert-butylamino)-8-iodo-3-methylquinazolin-4(3H)-one

Product 1

HCID 897820192-(Tert-Butylamino)-3-Methyl-8-[(6r)-6-Methyl-4-Oxo-1,4,5,6-Tetrahydropyrrolo[3,4-B]pyrrol-2-Yl]quinazolin-4(3h)-OneYield 73.7%

Reagents, catalysts & solvents 4

HCID 54751079XPhos PalladacycleCatalystHCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
45 °C

Procedure

A sealable tube (75 mL) was charged with (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) (2.00 g, 6.26 mmol), 2-(tert-butylamino)-8-iodo-3-methylquinazolin-4(3H)-one (701) (1.78 g, 5.01 mmol) and K3PO4 (3.98 g, 18.77 mmol) in 1,4-dioxane (16 mL)/water (4 mL). The mixture was bubbled with Argon for 3 min, then XPhos precatalyst II (Sigma-Aldrich; 0.24 g, 0.31 mmol) was added and the tube was sealed and heated in an oil bath at 45° C. for 90 min. The mixture was diluted with EtOAc (80 mL) and water (30 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (100 mL×2). The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified on a silica gel column (1-10% MeOH in DCM) to give (R)-2-(tert-butylamino)-3-methyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-one (1.35 g, 3.69 mmol, 59% yield) as a light brown crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.95 (1H, br.), 7.91 (2H, m), 7.62 (1H, s), 7.19 (1H, t, J=7.6 Hz), 6.73 (1H, m), 5.96 (1H, s), 4.54 (1H, q, J=6.4 Hz), 3.49 (3H, s), 1.52 (9H, s), 1.38 (3H, d, J=6.7 Hz). m/z (ESI, +ve ion) 366.2 (M+H)+.

Workup

  1. customThe mixture was bubbled with Argon for 3 min
  2. customthe tube was sealed
  3. customthe layers were separated
  4. extractionThe aqueous layer was extracted with EtOAc (100 mL×2)
  5. dry with materialThe combined organic layers were dried (MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was purified on a silica gel column (1-10% MeOH in DCM)

Sources & evidence

ORD record
ord-8bb55153438c44188256bfc2429ad1f2
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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