Cesium carbonate → 3-fluoro-4-(3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3 (4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide

HRID 523292Notes

Reaction equation

HRID 523292 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[F:22].[F:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[NH:32][C:31](=[O:34])[N:30]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37](B3OC(C)(C)C(C)(C)O3)[C:36]=1[CH3:50])[C:29]2=[O:51].C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[F: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:37]1[CH:38]=[CH:39][CH:40]=[C:35]([N:30]2[C:29](=[O:51])[C:28]4[C:33](=[C:24]([F:23])[CH:25]=[CH:26][CH:27]=4)[NH:32][C:31]2=[O:34])[C:36]=1[CH3:50])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 1177610104-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide2×HCID 1231490768-fluoro-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 865824873-fluoro-4-(3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3 (4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamideYield 18.3%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
88 °C

Procedure

A mixture of 4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H -carbazole-1-carboxamide [Intermediate 27] (0.104 g, 0.285 mmol), 8-fluoro-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 17] (0.147 g, 0.370 mmol), Cs2CO3 (0.186 g, 0.570 mmol), and dioxane (1.6 mL) was subjected to 3 evacuate-fill cycles with nitrogen. The mixture was treated with PdCl2(dppf) DCM adduct (14 mg, 0.017 mmol), and subjected to two more evacuate-fill cycles with nitrogen. The mixture was heated at 88° C. overnight. The cooled mixture was diluted with EtOAc, washed sequentially with water and brine, and dried and concentrated. The residue was purified by reverse phase preparative HPLC. The appropriate fractions were treated with saturated aqueous NaHCO3 and concentrated to an aqueous residue which was extracted with EtOAc. The organic layer was washed with brine. The combined aqueous layers were extracted with EtOAc, and the combined organic layers were dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes (sequentially 50%, 65% and 75%), to provide 3-fluoro-4-(3-(8-fluoro-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 white solid (0.029 g, 18% yield). Mass spectrum m/z 537 (M+H—H2O)+. 1H NMR (500 MHz, DMSO-d6) δ 11.81 (br. s., 1H), 11.39 (d, J=1.4 Hz, 1H), 8.21 (br. s., 1H), 7.95 (dd, J=10.7, 2.1 Hz, 1H), 7.86-7.80 (m, 2H), 7.64 (t, J=9.2 Hz, 1H), 7.59 (br. s., 1H), 7.53-7.50 (m, 2H), 7.42-7.38 (m, 1H), 7.26-7.20 (m, 1H), 7.07-6.99 (m, 1H), 6.97-6.88 (m, 1H), 4.98 (d, J=9.7 Hz, 1H), 1.81-1.75 (m, 3H), and 1.48-1.41 (m, 6H).

Workup

  1. customevacuate-fill cycles with nitrogen
  2. custommore evacuate-fill cycles with nitrogen
  3. additionThe cooled mixture was diluted with EtOAc
  4. washwashed sequentially with water and brine
  5. customdried
  6. concentrationconcentrated
  7. customThe residue was purified by reverse phase preparative HPLC
  8. additionThe appropriate fractions were treated with saturated aqueous NaHCO3
  9. concentrationconcentrated to an aqueous residue which
  10. extractionwas extracted with EtOAc
  11. washThe organic layer was washed with brine
  12. extractionThe combined aqueous layers were extracted with EtOAc
  13. customthe combined organic layers were dried
  14. concentrationconcentrated
  15. customThe residue was purified by column chromatography on silica gel
  16. washeluting with EtOAc-hexanes (sequentially 50%, 65% and 75%),

Sources & evidence

ORD record
ord-1d537c2b0e524fd5a0a53f6ec98fbbbc
Source dataset
uspto-grants-2016_05
Patent number
US09334290B2

Reaction notes

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