Trifluoroacetic acid → 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-amino-cyclohexyl)-amide

HRID 246350Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 246350
C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[C:34]5[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=5)[N:28]([CH3:36])[N:27]=4)[N:24]=3)[NH:19][CH:18]=2)=[O:16])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.C1CCCCC1>ClCCl.CO>[NH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([C:26]4[C:34]5[C:29](=[CH:30][C:31]([Cl:35])=[CH:32][CH:33]=5)[N:28]([CH3:36])[N:27]=4)[N:24]=3)[NH:19][CH:18]=2)=[O:16])[CH2:9]1

Komponenten

6

Edukt 3

HCID 6422Trifluoroacetic acidHCID 8078CyclohexaneHCID 71279706tert-butyl 3-(2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)cyclohexylcarbamate

Produkt 1

HCID 712805442-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-amino-cyclohexyl)-amideAusbeute 33,7 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 887MethanolLösungsmittelHCID 6344DichloromethaneLösungsmittel2×

Versuchsvorschrift

The less polar, diastereomer B of (3-{[2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-cyclohexyl)-carbamic acid tert-butyl ester (66 mg, 126 μmol) isolated from Example 276 was dissolved in dichloromethane (5 mL) and treated with TFA (1.48 g, 1 mL, 13.0 mmol). After 18 h at room temperature the solvents were evaporated and the residue dissolved in dichloromethane/MeOH, adsorbed on silica gel and purified by chromatography (25 g column, 50 μm from Thomson, 0 to 5% MeOH containing 10% ammonium hydroxide) in dichloromethane, 20 min gradient) to give an off white residue that was dissolved in dichloromethane containing few drops of MeOH. Cyclohexane was added to promote solid formation. The precipitate was separated by decanting the mother liquor and dried under high vacuum to give 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (3-amino-cyclohexyl)-amide (diastereomer B) (18 mg, 33.7%) as a white solid. MS (M+H)+=424; 1H NMR (DMSO-d6) δ: 9.02 (s, 1H), 8.42 (s, 1H), 8.37 (d, J=8.7 Hz, 1H), 8.05 (d, J=7.9 Hz, 1H), 7.98 (s, 1H), 7.30 (d, J=10.2 Hz, 1H), 4.36 (br. s., 1H), 4.16 (s, 3H), 3.33 (br. s., 1H), 3.13 (br. s., 1H), 2.54 (br. s., 1H), 1.79 (br. s., 1H), 1.59-1.71 (m, 2H), 1.53 (d, J=9.4 Hz, 1H), 1.38 (s, 1H), 1.32 (s, 1H).

Aufarbeitung

  1. customAfter 18 h at room temperature the solvents were evaporated
  2. dissolutionthe residue dissolved in dichloromethane/MeOH
  3. custompurified by chromatography (25 g column, 50 μm from Thomson, 0 to 5% MeOH containing 10% ammonium hydroxide) in dichloromethane, 20 min gradient)
  4. customto give an off white residue that
  5. customThe precipitate was separated
  6. customby decanting the mother liquor
  7. customdried under high vacuum

Quellen und Nachweise

ORD-Eintrag
ord-393228839ee94bb9852bd8dc854fe497
Quelldatensatz
uspto-grants-2014_02
Patentnummer
US08658646B2

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