Potassium Phosphate, Tribasic → HCID 89783447, compound

HRID 1056433Notes

Reaction equation

HRID 1056433 reaction equation
Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[N:8]([CH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[C:7]2=[O:23].[CH3:24][C@@H:25]1[C:29]2[NH:30][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:32][C:28]=2[C:27](=[O:42])[NH:26]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>[C:13]([NH:12][C:9]1[N:8]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:7](=[O:23])[C:6]2[C:11](=[C:2]([C:31]3[NH:30][C:29]4[C@@H:25]([CH3:24])[NH:26][C:27](=[O:42])[C:28]=4[CH:32]=3)[CH:3]=[CH:4][CH:5]=2)[N:10]=1)([CH3:16])([CH3:15])[CH3:14]

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 89782141HCID 89782141, compound

Product 1

HCID 89783447HCID 89783447, compoundYield 12.5%

Reagents, catalysts & solvents 3

HCID 54751079XPhos PalladacycleCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
40 °C

Procedure

A mixture of 8-bromo-2-(tert-butylamino)-3-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (515d, 70 mg, 0.184 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, 93 mg, 0.276 mmol), X-Phos precatalyst II (7.24 mg, 9.20 μmol), and potassium phosphate (117 mg, 0.552 mmol) in 1,4-dioxane (1.5 mL)/water (0.4 mL) was sparged with nitrogen for 3 min at RT; the reaction mixture was stirred at 40° C. for 1.5 h. The reaction mixture was diluted with EtOAc (100 mL), added to a separatory funnel, and washed with saturated aqueous NaHCO3 (3×75 mL); the organic layer was separated, dried over Na2SO4, and concentrated. The crude product was loaded onto the column and was purified via automated flash chromatography (silica gel) with 0-6% 2 M ammonia in MeOH/DCM to give (R)-2-(tert-butylamino)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)quinazolin-4(3H)-one (515, 10 mg, 0.023 mmol, 12% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.52 (d, J=6.65 Hz, 3H) 1.65 (s, 9H) 1.85 (d, J=11.15 Hz, 2H) 2.33-2.48 (m, 2H) 3.61 (t, J=11.54 Hz, 2H) 4.17 (dd, J=11.74, 4.50 Hz, 2H) 4.65 (q, J=6.72 Hz, 1H) 4.88 (s, 1H) 5.59-5.68 (m, 1H) 5.70 (s, 1H) 6.82 (d, J=1.17 Hz, 1H) 7.21 (t, J=7.73 Hz, 1H) 8.00 (dd, J=7.73, 1.47 Hz, 1H) 8.04 (dd, J=7.83, 1.37 Hz, 1H) 12.27 (br. s., 1H). MS (ESI, pos. ion) m/z: 436.1 (M+1).

Workup

  1. customwas sparged with nitrogen for 3 min at RT
  2. additionThe reaction mixture was diluted with EtOAc (100 mL)
  3. additionadded to a separatory funnel
  4. washwashed with saturated aqueous NaHCO3 (3×75 mL)
  5. customthe organic layer was separated
  6. dry with materialdried over Na2SO4
  7. concentrationconcentrated
  8. customwas purified

Sources & evidence

ORD record
ord-760ad74d38734c668c94b4ed542aeb13
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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