1,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride → (S)-5-(2,4-difluorophenoxy)-1-(2-hydroxy-2-methylpropyl)-N-(2-oxopyrrolidin-3-yl)-1H-indazole-6-carboxamide

HRID 912464Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 912464
[F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([OH:16])=O)[N:10]([CH2:17][C:18]([OH:21])([CH3:20])[CH3:19])[N:9]=[CH:8]2.[NH2:27][C@H:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33].Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[C:14]([NH:27][C@H:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33])=[O:16])[N:10]([CH2:17][C:18]([OH:21])([CH3:19])[CH3:20])[N:9]=[CH:8]2

Komponenten

6

Edukt 3

HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 12430456(3S)-3-aminopyrrolidin-2-oneHCID 67417664HCID 67417664, Verbindung

Produkt 1

HCID 24865102(S)-5-(2,4-difluorophenoxy)-1-(2-hydroxy-2-methylpropyl)-N-(2-oxopyrrolidin-3-yl)-1H-indazole-6-carboxamideAusbeute 34 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 142844-(Dimethylamino)pyridineKatalysatorHCID 6228DimethylformamideLösungsmittel

Versuchsvorschrift

5-(2,4-Difluorophenoxy)-1-(2-hydroxy-2-methylpropyl)-1H-indazole-6-carboxylic acid (200 mg, 0.552 mmol) was dissolved in N,N-dimethylformamide (2 mL). To his was added (S)-3-aminopyrrolidin-2-one (4a) (111 mg, 1.10 mmol), 4-(dimethylamino)pyridine (6.7 mg, 0.055 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (116 mg, 0.607 mmol) successively, and the reaction mixture was allowed to stir at ambient temperature for 16 hours. The reaction mixture was partitioned between water and ethyl acetate, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography on a silica gel column, eluting with 100% acetone to yield pure (S)-5-(2,4-difluorophenoxy)-1-(2-hydroxy-2-methylpropyl)-N-(2-oxopyrrolidin-3-yl)-1H-indazole-6-carboxamide (Ij) (83 mg, 34%). Mass spec: 445 (M+1). 1H NMR (CDCl3) δ 8.39 (s, 1H), 8.26 (brd, 1H), 7.93 (s, 1H), 7.18 (m, 1H), 7.04 (s, 1H), 7.02 (m, 1H), 6.92 (m, 1H), 6.04 (br, 1H), 4.59 (ddd, 1H), 4.37 (s, 2H), 3.64 (brs, 1H), 3.45 (m, 2H), 2.87 (m, 1H), 2.09 (m, 1H), 1.21 (s, 3H), 1.12 (s, 3H).

Aufarbeitung

  1. customThe reaction mixture was partitioned between water and ethyl acetate
  2. extractionthe aqueous layer was extracted twice with ethyl acetate
  3. dry with materialThe combined organic layers were dried over anhydrous sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude product was purified by flash chromatography on a silica gel column
  7. washeluting with 100% acetone

Quellen und Nachweise

ORD-Eintrag
ord-cad4c8ec642c4e3ba532e9f71d06bfbf
Quelldatensatz
uspto-grants-2011_09
Patentnummer
US08026233B2

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