Potassium Phosphate, Tribasic → (R)-7-fluoro-3-methyl-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 1056421Notes

Reaction equation

HRID 1056421 reaction equation
Br[C:2]1[C:3]([F:19])=[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]([CH3:17])[C:7]2=[O:18].[CH3:20][C@@H:21]1[C:25]2[NH:26][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:28][C:24]=2[C:23](=[O:38])[NH:22]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.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>[F:19][C:3]1[C:2]([C:27]2[NH:26][C:25]3[C@@H:21]([CH3:20])[NH:22][C:23](=[O:38])[C:24]=3[CH:28]=2)=[C:11]2[C:6]([C:7](=[O:18])[N:8]([CH3:17])[C:9]([NH:12][C:13]3([CH3:16])[CH2:15][CH2:14]3)=[N:10]2)=[CH:5][CH:4]=1

Participants

8

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 897822548-bromo-7-fluoro-3-methyl-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-one

Product 1

HCID 89783542(R)-7-fluoro-3-methyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-oneYield 14.4%

Reagents, catalysts & solvents 3

HCID 54751079XPhos PalladacycleCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
40 °C

Procedure

A mixture of 8-bromo-7-fluoro-3-methyl-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-one (510a, 88 mg, 0.270 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, 109 mg, 0.324 mmol), X-Phos precatalyst II (10.61 mg, 0.013 mmol), and potassium phosphate (172 mg, 0.809 mmol) in 1,4-dioxane (2.2 mL)/water (0.54 mL) was sparged with nitrogen for 3 min at RT; the red solution was then heated to 40° C. for 1 h when starting bromide and product were observed via LCMS. More (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 (120 mg) was added, and the red solution was stirred for another 1 h at 40° C. when more product was observed via LCMS. The reaction mixture was diluted with EtOAc (100 mL), added to a separatory funnel, and washed with saturated aqueous sodium bicarbonate (2×75 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 0-6% 2 M ammonia in MeOH/DCM to give (R)-7-fluoro-3-methyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2-((1-methylcyclopropyl)amino)quinazolin-4(3H)-one (510, 15 mg, 0.039 mmol, 14% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.83-0.89 (m, 2H) 0.96-1.05 (m, 2H) 1.38 (d, J=6.65 Hz, 3H) 1.54 (s, 3H) 3.38 (s, 3H) 4.66 (q, J=6.39 Hz, 1H) 6.80 (d, J=3.91 Hz, 1H) 7.11 (dd, J=11.93, 8.80 Hz, 1H) 7.75 (s, 1H) 7.84 (s, 1H) 7.85-7.90 (m, 1H) 13.39 (s, 1H). 19F NMR (376 MHz, DMSO-d6) δ ppm −102.44 (s, 1F). MS (ESI, pos. ion) m/z: 382.1 (M+1).

Workup

  1. customwas sparged with nitrogen for 3 min at RT
  2. additionMore (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 (120 mg) was added
  3. additionThe reaction mixture was diluted with EtOAc (100 mL)
  4. additionadded to a separatory funnel
  5. washwashed with saturated aqueous sodium bicarbonate (2×75 mL)
  6. customthe organic layer was separated
  7. dry with materialdried over Na2SO4
  8. concentrationconcentrated
  9. customwas purified

Sources & evidence

ORD record
ord-f8166a0fa09e456bb2be459a2ecda721
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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