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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 523290
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HRID 523290 반응식
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]
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6

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HCID 10796Cesium carbonateHCID 1177606764-bromo-3-cyano-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide2회HCID 1239796828-Fluoro-1-methyl-3-[2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]quinazoline-2,4-dione2회

생성물 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-carboxamide
수율 32.2%

시약·촉매·용매 2

HCID 178418807HCID 178418807, 화합물촉매HCID 312751,4-Dioxane용매

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온도
88 °C

실험 절차

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).

후처리

  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

출처 및 근거

ORD 기록
ord-618fc3e6ce7845ea8efcdef5547b6bd9
출처 데이터셋
uspto-grants-2016_05
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US09334290B2

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