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Methanol → N-[5-chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxybenzene-1,3-diamine

HRID 1842741
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Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 1842741
[Cl:1][C:2]1[C:3]([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([CH3:37])[CH:29]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([N:18]3[CH2:22][CH2:21][C@@H:20]([N:23]([CH3:25])[CH3:24])[CH2:19]3)=[CH:11][C:10]=2[O:26][CH3:27])=[N:6][CH:7]=1.[NH4+].[Cl-].C(Cl)Cl.CO>C(O)C.O.[Fe]>[Cl:1][C:2]1[C:3]([C:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]([CH3:37])[CH:29]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([O:26][CH3:27])=[CH:11][C:12]([N:18]3[CH2:22][CH2:21][C@@H:20]([N:23]([CH3:25])[CH3:24])[CH2:19]3)=[C:13]([NH2:15])[CH:14]=2)=[N:6][CH:7]=1
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Komponenten

8

Edukt 4

HCID 887MethanolHCID 6344DichloromethaneHCID 25517Ammonium ChlorideHCID 712699515-chloro-N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-(1-methylindol-3-yl)pyrimidin-2-amine2×

Produkt 1

HCID 86677258N-[5-chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxybenzene-1,3-diamine
Ausbeute 33 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 23925IronKatalysatorHCID 702EthanolLösungsmittelHCID 962WaterLösungsmittel

Versuchsvorschrift

A mixture of 5-chloro-N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 86, 747 mg, 1.43 mmol), iron (479 mg, 8.59 mmol) and NH4Cl (53.6 mg, 1.00 mmol) in ethanol (48 mL) and water (16 mL) was heated at reflux for 3 h. The mixture was then cooled and concentrated in vacuo to give a thick slurry. CH2Cl2 (100 mL) and CH3OH (10 mL) were then added and the mixture was stirred for 0.25 h and then filtered. The filter cake was washed with further CH2Cl2 and MeOH and the combined organics were dried (MgSO4) and concentrated in vacuo. Purification by FCC (split into two batches), eluting with 1-9% methanolic ammonia in CH2Cl2 gave the title compound (230 mg, 33%) as a yellow gum which crystallised on standing, and (2nd batch) more of the title compound (329 mg, 47%) as a yellow gum; 1H NMR: (CDCl3) 1.87 (1H, ddt), 2.13 (1H, dtd), 2.29 (6H, s), 2.86 (1H, dq), 2.98-3.09 (2H, m), 3.20 (2H, dd), 3.66 (2H, s), 3.84 (3H, s), 3.88 (3H, s), 6.70 (1H, s), 7.25-7.35 (2H, m), 7.38 (1H, dd), 7.61 (1H, s), 8.10 (1H, s), 8.19 (1H, d), 8.32 (1H, s), 8.66 (1H, dd); m/z: ES+ MH+ 492.27.

Aufarbeitung

  1. temperaturewas heated
  2. temperatureat reflux for 3 h
  3. temperatureThe mixture was then cooled
  4. concentrationconcentrated in vacuo
  5. customto give a thick slurry
  6. filtrationfiltered
  7. washThe filter cake was washed with further CH2Cl2 and MeOH
  8. dry with materialthe combined organics were dried (MgSO4)
  9. concentrationconcentrated in vacuo
  10. customPurification
  11. customby FCC (split into two batches)
  12. washeluting with 1-9% methanolic ammonia in CH2Cl2

Quellen und Nachweise

ORD-Eintrag
ord-a77c44e892f64761a274294973d6f442
Quelldatensatz
uspto-grants-2015_02
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08946235B2

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