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

HRID 1056418Notes

Reaction equation

HRID 1056418 reaction equation
[C:1]([NH:5][C:6]1[N:15]([CH2:16][CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:14](=[O:23])[C:13]2[C:8](=[C:9](I)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][C@@H:26]1[C:30]2[NH:31][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:33][C:29]=2[C:28](=[O:43])[NH:27]1.P([O-])([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+].O>[C:1]([NH:5][C:6]1[N:15]([CH2:16][CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:14](=[O:23])[C:13]2[C:8](=[C:9]([C:32]3[NH:31][C:30]4[C@@H:26]([CH3:25])[NH:27][C:28](=[O:43])[C:29]=4[CH:33]=3)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]

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)-one3×HCID 897821492-(tert-butylamino)-8-iodo-3-(3-(methylsulfonyl)propyl)quinazolin-4(3H)-one

Product 1

HCID 89783544(R)-2-(tert-butylamino)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(3-(methylsulfonyl)propyl)quinazolin-4(3H)-oneYield 80%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
45 °C

Procedure

A glass microwave reaction vessel was charged with 2-(tert-butylamino)-8-iodo-3-(3-(methylsulfonyl)propyl)quinazolin-4(3H)-one (105 mg, 0.227 mmol) and (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) (89 mg, 0.272 mmol) in 1,4-dioxane (1.0 mL)/water (0.2 mL) followed by potassium phosphate (0.056 mL, 0.680 mmol) and XPhos precatalyst II (8.92 mg, 0.011 mmol, Sigma Aldrich, St. Louis, Mo.). The reaction mixture was stirred and heated in an oil bath at 45° C. for 2 h, then another 0.3 equiv. of boronic ester 705 was added and the reaction was stirred at RT overnight. More boronic ester 705 (0.3 equiv) was added and the reaction was stirred at 45° C. for 1 h. The mixture was cooled to RT and diluted with water (15 mL). The suspension was filtered and the solid was purified with silica gel chromatography (eluted with 1-4% MeOH in DCM) to give (R)-2-(tert-butylamino)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(3-(methylsulfonyl)propyl)quinazolin-4(3H)-one (85 mg, 0.180 mmol, 80% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 472 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.83 (1H, s), 7.83-7.93 (2H, m), 7.60 (1H, s), 7.19 (1H, t, J=7.6 Hz), 6.68 (1H, d, J=1.4 Hz), 5.95 (1H, s), 4.52 (1H, q, J=6.6 Hz), 4.28 (2H, t, J=7.2 Hz), 3.21 (2H, t, J=7.5 Hz), 3.02 (3H, s), 2.00-2.10 (2H, m), 1.50 (9H, s), 1.36 (3H, d, J=6.7 Hz).

Workup

  1. customA glass microwave reaction vessel
  2. stirringthe reaction was stirred at RT overnight
  3. stirringthe reaction was stirred at 45° C. for 1 h
  4. temperatureThe mixture was cooled to RT
  5. filtrationThe suspension was filtered
  6. customthe solid was purified with silica gel chromatography (eluted with 1-4% MeOH in DCM)

Sources & evidence

ORD record
ord-a55cf7f849924b9b972a3d50093f9aef
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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