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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 523288
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HRID 523288 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[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
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참가 물질

7

반응물 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)-dione2회

생성물 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-carboxamide
수율 71%

시약·촉매·용매 3

HCID 1177612874-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide촉매HCID 178454861HCID 178454861, 화합물촉매HCID 8028Tetrahydrofuran용매

실험 절차

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).

후처리

  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

출처 및 근거

ORD 기록
ord-73f2c4b380ee4bd2b2695358ab85b71d
출처 데이터셋
uspto-grants-2016_05
DOI
10.6084/m9.figshare.5104873.v1
특허 번호
US09334290B2

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