Sodium Hydroxide → (R)-8-(6-(2-(benzyloxy)ethyl)-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2-(tert-butylamino)-3-methylquinazolin-4(3H)-one

HRID 1056397Notes

Reaction equation

HRID 1056397 reaction equation
C(C1C=CC(C2C=CC=CC=2)=C(C(C)C)C=1C(C)C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:30]([O:37][CH2:38][CH2:39][C@@H:40]1[C:44]2[NH:45][C:46](B3OC(C)(C)C(C)(C)O3)=[CH:47][C:43]=2[C:42](=[O:57])[NH:41]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[C:58]([NH:62][C:63]1[N:72]([CH3:73])[C:71](=[O:74])[C:70]2[C:65](=[C:66](I)[CH:67]=[CH:68][CH:69]=2)[N:64]=1)([CH3:61])([CH3:60])[CH3:59].[OH-].[Na+]>O1CCOCC1.O.C(Cl)Cl.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>[CH2:30]([O:37][CH2:38][CH2:39][C@@H:40]1[C:44]2[NH:45][C:46]([C:66]3[CH:67]=[CH:68][CH:69]=[C:70]4[C:65]=3[N:64]=[C:63]([NH:62][C:58]([CH3:59])([CH3:60])[CH3:61])[N:72]([CH3:73])[C:71]4=[O:74])=[CH:47][C:43]=2[C:42](=[O:57])[NH:41]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1

Participants

11

Reactant 5

HCID 14798Sodium HydroxideHCID 62657Potassium Phosphate, TribasicHCID 30344661,1'-Biphenyl, tris(1-methylethyl)-HCID 897821382-(tert-butylamino)-8-iodo-3-methylquinazolin-4(3H)-oneHCID 123869201(R)-6-(2-(benzyloxy)ethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one

Product 1

HCID 118511955(R)-8-(6-(2-(benzyloxy)ethyl)-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2-(tert-butylamino)-3-methylquinazolin-4(3H)-oneYield 49.1%

Reagents, catalysts & solvents 5

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 887MethanolSolventHCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

A mixture of 2-(dicyclohexylphosphino)-2′,4′,6%-tri-isopropyl1,1′-biphenyl(Strem Chemicals, Newburyport, Mass., 110 mg, 0.23 mmol), tris(dibenzylideneacetone)dipalladium (0) (Strem Chemicals, Newburyport, Mass., 105 mg, 0.115 mmol), potassium phosphate tribasic (1.83 g, 8.63 mmol), (R)-6-(2-(benzyloxy)ethyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (503a, 1.10 g, 2.88 mmol) and 2-(tert-butylamino)-8-iodo-3-methylquinazolin-4(3H)-one (701) (830 mg, 2.32 mmol) in 1,4-dioxane (12 mL), water (3.60 mL) in a sealed glass tube was heated in a heating block at 80° C. for 2 h. The reaction mixture was treated with 1 N NaOH and extracted with EtOAc (2×50 mL), washed with brine and dried over MgSO4, filtered and concentrated. The crude reaction mixture was chromatographed on an ISCO Combiflash RF (40 g Thomson SingleStep column, using a gradient of 20-100% EtOAc in hexanes then 0-10% MeOH in DCM) affording (R)-8-(6-(2-(benzyloxy)ethyl)-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)-2-(tert-butylamino)-3-methylquinazolin-4(3H)-one (503b, 555 mg, 1.14 mmol, 40% yield) as a dark brown oil. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.01 (1H, dd, J=7.9, 1.5 Hz), 7.89 (1H, dd, J=7.5, 1.5 Hz), 7.19-7.28 (3H, m), 7.08-7.17 (3H, m), 6.69 (1H, s), 4.75 (1H, dd, J=6.7, 5.1 Hz), 4.45 (2H, q, J=11.3 Hz), 3.70-3.77 (1H, m), 3.62-3.70 (1H, m), 3.55 (3H, s), 2.19-2.31 (1H, m), 1.98-2.09 (1H, m), 1.54 (9H, s). m/z (ESI, +ve) 486.0 (M+1)′.

Workup

  1. extractionextracted with EtOAc (2×50 mL)
  2. washwashed with brine
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude reaction mixture
  7. customwas chromatographed on an ISCO Combiflash RF (40 g Thomson SingleStep column

Sources & evidence

ORD record
ord-10f021a632f142218093b935a4fd19cb
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

Loading…