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

HRID 523290Notes

Reaction equation

HRID 523290 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[C:22]#[N:23].[F:24][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]2[C:34]=1[N:33]([CH3:35])[C:32](=[O:36])[N:31]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39](B3OC(C)(C)C(C)(C)O3)[C:38]=1[CH3:52])[C:30]2=[O:53].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>[C: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:39]1[CH:40]=[CH:41][CH:42]=[C:37]([N:31]2[C:30](=[O:53])[C:29]4[C:34](=[C:25]([F:24])[CH:26]=[CH:27][CH:28]=4)[N:33]([CH3:35])[C:32]2=[O:36])[C:38]=1[CH3:52])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3)#[N:23]

Participants

6

Reactant 3

HCID 10796Cesium carbonateHCID 1177606764-bromo-3-cyano-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide2×HCID 1239796828-Fluoro-1-methyl-3-[2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]quinazoline-2,4-dione2×

Product 1

HCID 865805333-cyano-4-(3-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamideYield 32.2%

Reagents, catalysts & solvents 2

HCID 178418807HCID 178418807, compoundCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
88 °C

Procedure

A mixture of 4-bromo-3-cyano-7-(2-hydroxypropan-2-yl)-9H -carbazole-1-carboxamide [Intermediate 23] (0.400 g, 1.08 mmol), 8-fluoro-1-methyl-3-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)quinazoline-2,4(1H,3H)-dione [Intermediate 2] (0.573 g, 1.40 mmol), Cs2CO3 (0.700 g, 2.15 mmol), and dioxane (5 mL) was subjected to 3 evacuate-fill cycles with nitrogen. The mixture was treated with PdCl2(dppf) DCM adduct (0.053 g, 0.064 mmol) and subjected to 2 more evacuate-fill cycles with nitrogen. The mixture was heated at 88° C. for 2 days. The cooled mixture was diluted with EtOAc, washed sequentially with water and brine, and dried and concentrated. The residue was purified by column chromatography on silica gel, eluting with EtOAc-hexanes (sequentially 50%, 75%, 85% and 100%). The resulting impure product was purified by reverse-phase preparative HPLC to give 3-cyano-4-(3-(8-fluoro-1-methyl-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 (0.200 g, 32% yield). Mass spectrum m/z 576 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H), 8.45 (s, 1H), 8.35 (br. s., 1H), 8.00-7.94 (m, 1H), 7.92 (s, 1H), 7.77-7.68 (m, 2H), 7.60-7.52 (m, 2H), 7.41 (dd, J=6.6, 2.2 Hz, 1H), 7.38-7.29 (m, 1H), 7.13 (t, J=10.1 Hz, 1H), 6.85 (t, J=8.1 Hz, 1H), 5.05 (d, J=2.0 Hz, 1H), 3.74 (dd, J=8.1, 2.6 Hz, 3H), 1.73 (s, 3H), and 1.48-1.43 (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 column chromatography on silica gel
  8. washeluting with EtOAc-hexanes (sequentially 50%, 75%, 85% and 100%)
  9. customThe resulting impure product was purified by reverse-phase preparative HPLC

Sources & evidence

ORD record
ord-618fc3e6ce7845ea8efcdef5547b6bd9
Source dataset
uspto-grants-2016_05
Patent number
US09334290B2

Reaction notes

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