Potassium Phosphate, Tribasic → 3-chloro-4-(3-(6, 8-difluoro-2,4-dioxo-1,2-dihydroquinazolin-3 (4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide

HRID 523288Notes

Reaction equation

HRID 523288 reaction equation
Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[Cl:22].[F:23][C:24]1[CH:25]=[C:26]2[C:31](=[C:32]([F:34])[CH:33]=1)[NH:30][C:29](=[O:35])[N:28]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38](B3OC(C)(C)C(C)(C)O3)[C:37]=1[CH3:51])[C:27]2=[O:52].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].BrC1C2C3C(=CC(C(O)(C)C)=CC=3)NC=2C(C(N)=O)=CC=1Cl.C1COCC1>[Cl:22][C:3]1[CH:4]=[C:5]([C:19]([NH2:21])=[O:20])[C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]=1[C:38]1[CH:39]=[CH:40][CH:41]=[C:36]([N:28]2[C:27](=[O:52])[C:26]4[C:31](=[C:32]([F:34])[CH:33]=[C:24]([F:23])[CH:25]=4)[NH:30][C:29]2=[O:35])[C:37]=1[CH3:51])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3

Participants

7

Reactant 3

HCID 62657Potassium Phosphate, TribasicHCID 1177612874-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamideHCID 1233570346,8-difluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione2×

Product 1

HCID 865820283-chloro-4-(3-(6, 8-difluoro-2,4-dioxo-1,2-dihydroquinazolin-3 (4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamideYield 71%

Reagents, catalysts & solvents 3

HCID 1177612874-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamideCatalystHCID 178454861HCID 178454861, compoundCatalystHCID 8028TetrahydrofuranSolvent

Procedure

A mixture of 4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 3] (10 mg, 0.026 mmol), 6,8-difluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 16] (14.1 mg, 0.034 mmol), 1,1′-bis(di-tert-butylphosphino)ferrocene palladium(II) chloride (12.8 mg, 0.020 mmol) and THF (2 mL) in a reaction vial was treated with 2 M aqueous K3PO4 (0.039 mL, 0.079 mmol). The vial was sealed and subjected to three evacuate-fill cycles with nitrogen. The mixture was stirred at room temperature overnight. The phases of the mixture were separated, the aqueous phase was extracted twice with EtOAc, and the combined organic phases were dried and concentrated. The residue was purified by column chromatography on silica gel (40 g), eluting with EtOAc -hexanes (gradient from 80-100%). The isolated material was triturated with MeOH to give a solid after filtration. The filtrate was concentrated and subjected to column chromatography on silica (40 g), eluting with DCM-MeOH—NH4OH (gradient from 90:9:1-97:2.7:0.3) to give additional solid. The two solids were combined to provide 3-chloro-4-(3-(6,8-difluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) as a pale yellow solid (164 mg, 71% yield). Mass spectrum m/z 571 (M+H—H2O)+. 1H NMR (500 MHz, MeOH-d4) δ 8.04 (d, J=2.0 Hz, 1H), 7.70-7.68 (m, 1H), 7.65 (dd, J=7.2, 3.2 Hz, 1H), 7.57-7.52 (m, 1H), 7.43-7.34 (m, 3H), 7.18-7.07 (m, 1H), 6.90 (dd, J=8.4, 3.0 Hz, 1H), 1.84 (s, 3H), 1.62-1.56 (m, 6H).

Workup

  1. customThe vial was sealed
  2. customevacuate-fill cycles with nitrogen
  3. customThe phases of the mixture were separated
  4. extractionthe aqueous phase was extracted twice with EtOAc
  5. customthe combined organic phases were dried
  6. concentrationconcentrated
  7. customThe residue was purified by column chromatography on silica gel (40 g)
  8. washeluting with EtOAc -hexanes (gradient from 80-100%)
  9. customThe isolated material was triturated with MeOH
  10. customto give a solid
  11. filtrationafter filtration
  12. concentrationThe filtrate was concentrated
  13. washeluting with DCM-MeOH—NH4OH (gradient from 90:9:1-97:2.7:0.3)
  14. customto give additional solid

Sources & evidence

ORD record
ord-73f2c4b380ee4bd2b2695358ab85b71d
Source dataset
uspto-grants-2016_05
Patent number
US09334290B2

Reaction notes

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