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Cesium carbonate → 4-(3-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide

HRID 523295
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 523295
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].[Cl:23][C:24]1[C:33]2[N:28]([C:29](=[O:51])[N:30]([C:35]3[CH:40]=[CH:39][CH:38]=[C:37](B4OC(C)(C)C(C)(C)O4)[C:36]=3[CH3:50])[C:31](=[O:34])[CH:32]=2)[CH:27]=[CH:26][CH:25]=1.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>[Cl:23][C:24]1[C:33]2[N:28]([C:29](=[O:51])[N:30]([C:35]3[C:36]([CH3:50])=[C:37]([C:2]4[C:14]5[C:13]6[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:16])[CH3:17])=[CH:11][CH:12]=6)[NH:7][C:6]=5[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=4[F:22])[CH:38]=[CH:39][CH:40]=3)[C:31](=[O:34])[CH:32]=2)[CH:27]=[CH:26][CH:25]=1
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Komponenten

6

Edukt 3

HCID 10796Cesium carbonateHCID 1177610104-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide2×HCID 1238892435-Chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione(racemic)2×

Produkt 1

HCID 1177712284-(3-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
Ausbeute 8,5 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 178418807HCID 178418807, VerbindungKatalysatorHCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
52 °C

Versuchsvorschrift

A mixture of 4-bromo-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 27] (0.098 g, 0.268 mmol), 5-chloro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione [Intermediate 33] (0.144 g, 0.349 mmol), Cs2CO3 (0.175 g, 0.537 mmol), and dioxane (1.6 mL) was subjected to three evacuate-fill cycles with nitrogen. The mixture was treated with PdCl2(dppf) DCM adduct (0.013 g, 0.016 mmol) and subjected to two more evacuate-fill cycles with nitrogen. The mixture was heated at 52° 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. The residue was partitioned between EtOAc and water, and the organic layer was washed with brine. The aqueous layers were extracted with EtOAc, and the combined organic layers were dried and concentrated. The residue was purified twice by column chromatography on silica gel, eluting with EtOAc-hexanes (sequentially 50%, 65% and 75%) to give 4-(3-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-3-fluoro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) as a yellow solid (0.013 g, 8% yield). Mass spectrum m/z 571, 573 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ 11.39 (d, J=5.3 Hz, 1H), 8.30-8.24 (m, 1H), 8.21 (br. s., 1H), 7.95 (dd, J=10.5, 1.7 Hz, 1H), 7.84 (s, 1H), 7.60 (d, J=7.2 Hz, 2H), 7.55-7.47 (m, 2H), 7.42-7.39 (m, 1H), 7.04-6.99 (m, 1H), 6.93 (d, J=8.6 Hz, 0.6H), 6.84 (d, J=8.6 Hz, 0.4H), 6.57 (td, J=7.3, 3.5 Hz, 1H), 6.00 (d, J=8.6 Hz, 1H), 4.98 (s, 1H), 1.78 (d, J=1.9 Hz, 3H), and 1.45 (d, J=3.9 Hz, 6H).

Aufarbeitung

  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
  10. customThe residue was partitioned between EtOAc and water
  11. washthe organic layer was washed with brine
  12. extractionThe aqueous layers were extracted with EtOAc
  13. customthe combined organic layers were dried
  14. concentrationconcentrated
  15. customThe residue was purified twice by column chromatography on silica gel
  16. washeluting with EtOAc-hexanes (sequentially 50%, 65% and 75%)

Quellen und Nachweise

ORD-Eintrag
ord-b68f4311750340b1afe4da1a767afdd9
Quelldatensatz
uspto-grants-2016_05
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US09334290B2

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