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

HRID 1056280Notes

Reaction equation

HRID 1056280 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])[NH:8][C:7]2=[O:17].C([O-])([O-])=O.[K+].[K+].[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.O1CCOCC1>C(Cl)Cl.O>[C:13]([NH:12][C:9]1[NH:8][C:7](=[O:17])[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

7

Reactant 4

HCID 11430Potassium CarbonateHCID 312751,4-DioxaneHCID 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 1365008368-bromo-2-(tert-butylamino)quinazolin-4(3H)-one

Product 1

HCID 136500861(R)-2-(tert-butylamino)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-oneYield 8.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

Argon was bubbled into a mixture of 8-bromo-2-(tert-butylamino)quinazolin-4(3H)-one (408a, 62 mg, 0.21 mmol), K2CO3 (0.116 g, 0.84 mmol), dichlorobis(p-dimethylamino-phenylditbutylphosphine)palladium (ii) (Aldrich; 0.030 g, 0.042 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 (706; 0.110 g, 0.419 mmol) and 2 mL dioxane and 0.4 mL water for 1 min. The reaction was sealed and placed in a 100° C. oil bath for 30 min. The reaction was cooled and partitioned between sat'd aq. NH4Cl and DCM. The aqueous layer was extracted with 5% IPA/CHCl3 three times and the combined organics were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. This material was dissolved in DMSO, filtered, and purified by RPHPLC, Phenomenex Gemini 150×30 mm C18 column, 10-70% ACN/H2O with 0.1% TFA; product-containing fractions were treated with saturated aqueous NaHCO3 and DCM. The aqueous layer was extracted 3×DCM and combined organics dried over Na2SO4, filtered, and concentrated in vacuo to give 21 mg as a tan solid. The material was sonicated in 0.5 mL DCM for 2 min, then filtered, rinsing 2×DCM. The solid was collected and dried in vacuo to give (R)-2-(tert-butylamino)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-one (6 mg, 0.017 mmol, 8% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.21 (1H, br. s.), 10.63 (1H, s), 7.95 (1H, dd, J=7.6, 1.6 Hz), 7.82 (1H, dd, J=7.8, 1.6 Hz), 7.62 (1H, s), 7.16 (1H, t, J=7.7 Hz), 6.79 (1H, d, J=1.4 Hz), 6.30 (1H, s), 4.54 (1H, d, J=6.7 Hz), 1.47 (9H, s), 1.36 (3H, d, J=6.7 Hz). m/z (ESI, +ve ion) 352.1 (M+H)+.

Workup

  1. customThe reaction was sealed
  2. customplaced in a 100° C.
  3. customfor 30 min
  4. temperatureThe reaction was cooled
  5. custompartitioned between sat'd aq. NH4Cl and DCM
  6. extractionThe aqueous layer was extracted with 5% IPA/CHCl3 three times
  7. dry with materialthe combined organics were dried over anhydrous Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated in vacuo
  10. dissolutionThis material was dissolved in DMSO
  11. filtrationfiltered
  12. custompurified by RPHPLC, Phenomenex Gemini 150×30 mm C18 column, 10-70% ACN/H2O with 0.1% TFA
  13. additionproduct-containing fractions were treated with saturated aqueous NaHCO3 and DCM
  14. extractionThe aqueous layer was extracted 3×DCM
  15. dry with materialcombined organics dried over Na2SO4
  16. filtrationfiltered
  17. concentrationconcentrated in vacuo
  18. customto give 21 mg as a tan solid
  19. filtrationfiltered
  20. washrinsing 2×DCM
  21. customThe solid was collected
  22. customdried in vacuo

Sources & evidence

ORD record
ord-262ac899065c4275b2b39567add3a0e1
Source dataset
uspto-grants-2016_07
Patent number
US09394297B2

Reaction notes

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