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

HRID 523296
Notizen
Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 523296
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].[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+]>C1COCC1.O.CCOC(C)=O.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>[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:37]1[CH:38]=[CH:39][CH:40]=[C:35]([N:30]2[C:31](=[O:34])[CH:32]=[C:33]4[C:24]([Cl:23])=[CH:25][CH:26]=[CH:27][N:28]4[C:29]2=[O:51])[C:36]=1[CH3:50])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3
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Komponenten

8

Edukt 3

HCID 10796Cesium carbonateHCID 1177612874-bromo-3-chloro-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 865806943-chloro-4-(3-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide
Ausbeute 69,8 %

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 178418807HCID 178418807, VerbindungKatalysatorHCID 962WaterLösungsmittelHCID 8028TetrahydrofuranLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Reaktionsbedingungen

Temperatur
60 °C

Versuchsvorschrift

A mixture of 4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 3] (1.11 g, 2.91 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] (1.00 g, 2.42 mmol) and Cs2CO3 (1.58 g, 4.85 mmol) in THF (8 mL) and water (2 mL) was bubbled with argon for three min. The mixture was treated with PdCl2(dppf) DCM adduct (0.099 g, 0.121 mmol) and heated at 60° C. overnight. The cooled mixture was diluted with EtOAc and washed sequentially with water and brine. The combined aqueous layers were extracted with DCM containing a small amount of MeOH. The combined organic layers were dried and concentrated until a tan precipitate formed, which was removed by filtration. The filtrate was concentrated and purified by column chromatography on silica gel (120 g), eluting with EtOAc-DCM (sequentially 70%, 80%, and 100%), to give 3-chloro-4-(3-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) as a yellow solid (993 mg, 69% yield). The material was separated by chiral super-critical fluid chromatography as follows: column: CHIRALPAK® AD-H (3×25 cm, 5 μm); Mobile Phase: CO2-IPA (50:50) at 150 mL/min, 45° C., 100 bar; sample preparation: 5.6 mg/mL in MeOH-DCM (1:1); injection: 3 mL. The second peak eluting from the column provided 3-chloro-4-(R)-(3-(R)-(5-chloro-1,3-dioxo-1H-pyrido[1,2-c]pyrimidin-2(3H)-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Example 32]. Mass spectrum m/z 587 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 8.27 (s, 2H), 8.14 (s, 1H), 7.84 (d, J=1.1 Hz, 1H), 7.59 (d, J=6.8 Hz, 1H), 7.56-7.46 (m, 2H), 7.29 (dd, J=7.4, 1.2 Hz, 1H), 7.01 (dd, J=8.4, 1.5 Hz, 1H), 6.64 (d, J=8.6 Hz, 1H), 6.55 (t, J=7.3 Hz, 1H), 5.98 (s, 1H), 5.75 (s, 1H), 4.98 (s, 1H), 1.71 (s, 3H), 1.46-1.42 (m, 6H).

Aufarbeitung

  1. customwas bubbled with argon for three min
  2. washwashed sequentially with water and brine
  3. extractionThe combined aqueous layers were extracted with DCM containing a small amount of MeOH
  4. customThe combined organic layers were dried
  5. concentrationconcentrated until a tan precipitate
  6. customformed
  7. customwhich was removed by filtration
  8. concentrationThe filtrate was concentrated
  9. custompurified by column chromatography on silica gel (120 g)
  10. washeluting with EtOAc-DCM (sequentially 70%, 80%, and 100%),

Quellen und Nachweise

ORD-Eintrag
ord-cb1d3535067d47e7a19b1a1f590437a7
Quelldatensatz
uspto-grants-2016_05
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US09334290B2

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