Diisopropylethylamine → 5-Chloro-N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-(1H-indol-3-yl)pyrimidin-2-amine

HRID 1842749

Reaktionsgleichung

Reaktionsgleichung von HRID 1842749
[CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.[Cl:9][C:10]1[C:11]([C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][CH:30]=2)=[N:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[C:20](F)=[CH:19][C:18]=2[O:27][CH3:28])=[N:14][CH:15]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.CO>[Cl:9][C:10]1[C:11]([C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:31][CH:30]=2)=[N:12][C:13]([NH:16][C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[C:20]([N:5]3[CH2:6][CH2:7][C@@H:3]([N:2]([CH3:8])[CH3:1])[CH2:4]3)=[CH:19][C:18]=2[O:27][CH3:28])=[N:14][CH:15]=1

Komponenten

6

Edukt 3

HCID 81531DiisopropylethylamineHCID 2758521(3R)-(+)-3-(Dimethylamino)pyrrolidineHCID 712408945-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine2×

Produkt 1

HCID 712700765-Chloro-N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-(1H-indol-3-yl)pyrimidin-2-amineAusbeute 96 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 887MethanolLösungsmittelHCID 31374DimethylacetamideLösungsmittel

Reaktionsbedingungen

Temperatur
140 °C

Versuchsvorschrift

(R)-(+)-3-(Dimethylamino)pyrrolidine (0.111 mL, 0.87 mmol) was added to a suspension of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1H-indol-3-yl)pyrimidin-2-amine (Intermediate 76, 300 mg, 0.73 mmol) and DIPEA (0.151 mL, 0.87 mmol) in DMA (3 mL) and the mixture was heated at 140° C. in a microwave for 0.5 h. The mixture was then diluted with CH3OH and absorbed onto an SCX column. The column was washed with CH3OH and eluted with 1:1 methanolic ammonia in CH2Cl2. Appropriate fractions were concentrated and further purification by FCC, eluting with 1.5% 7N methanolic ammonia in CH2Cl2 gave the title compound (353 mg, 96%) as an orange foam; 1H NMR: 1.78-1.91 (1H, m), 2.16-2.27 (7H, m), 2.70-2.85 (1H, m), 3.12-3.29 (3H, m), 3.41-3.55 (1H, m), 3.89 (3H, s), 6.57 (1H, s), 6.95 (1H, t), 7.17 (1H, t), 7.46 (1H, d), 8.09 (1H, s), 8.24 (1H, br s), 8.37 (1H, s), 8.50 (1H, d), 8.54 (1H, s), 11.88 (1H, s); m/z: ES+ MH+ 508.5.

Aufarbeitung

  1. customabsorbed onto an SCX column
  2. washThe column was washed with CH3OH
  3. washeluted with 1:1 methanolic ammonia in CH2Cl2
  4. concentrationAppropriate fractions were concentrated
  5. customfurther purification by FCC
  6. washeluting with 1.5% 7N methanolic ammonia in CH2Cl2

Quellen und Nachweise

ORD-Eintrag
ord-caed72c4107f477691772c6b806c7622
Quelldatensatz
uspto-grants-2015_02
Patentnummer
US08946235B2

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