Acetonitrile, 2-(methylamino)- → N-cyanomethyl-2-hydroxy-2-{3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridine-5-yl]-phenyl}-N-methyl-acetamide

HRID 886617

Reaktionsgleichung

Reaktionsgleichung von HRID 886617
[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[N:19][N:18](CO)[C:15]3=[N:16][CH:17]=2)[CH:7]=1)[C:3]([OH:5])=O.[CH3:31][NH:32][CH2:33][C:34]#[N:35].C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[C:34]([CH2:33][N:32]([CH3:31])[C:3](=[O:5])[CH:2]([OH:1])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[C:14]3[C:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])=[N:19][NH:18][C:15]3=[N:16][CH:17]=2)[CH:7]=1)#[N:35]

Komponenten

6

Edukt 3

HCID 36652Acetonitrile, 2-(methylamino)-HCID 81531DiisopropylethylamineHCID 59825038hydroxy-{3-[1-hydroxymethyl-3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid

Produkt 1

HCID 178489384N-cyanomethyl-2-hydroxy-2-{3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridine-5-yl]-phenyl}-N-methyl-acetamideAusbeute 53 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 6228DimethylformamideLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Versuchsvorschrift

A mixture of hydroxy-{3-[1-hydroxymethyl-3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid (0.1 g, 0.25 mmol), methylaminoacetonitrile (20 μl, 0.27 mmol), diisopropylethylamine (DIEA, 87 μl, 0.48 mmol), N,N,N′,N′,-Tetramethyl-O-(7-azabenotriazol-1-yl)uronium hexafluorophosphate (HATU, 101 mg, 0.27 mmol) in DMF (3 ml) was stirred at room temperature overnight. The reaction mixture was dissolved in 10 ml ethyl acetate and subsequently extracted with 1N HCl, saturated NaHCO3, brine, dried with Na2SO4, concentrated to dryness. The crude was purified by silica gel chromatography. The resulting material was dissolved in 3 ml of methanol, aqueous NaOH was added (1 ml, 2 N in H2O) and the mixture stirred overnight at room temperature. The solvent was removed under reduced pressure and the crude was neutralized with 500 μl of 1N HCl and purified by mass-triggered reverse phase HPLC to afford N-cyanomethyl-2-hydroxy-2-{3-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridine-5-yl]-phenyl}-N-methyl-acetamide as a yellow powder (56 mg, 53% yield). 1H NMR (500 MHz, DMSO-d6) δ 3.02 (s, 3H), 3.87 (s, 3H), 4.14 (s, 2H), 5.55 (s, 1H), 7.10 (m, 1H), 7.23 (d, 1H), 7.40 (d, 1H), 7.45-7.52 (m, 2H), 7.66 (d, 1H), 7.72 (m, 2H), 8.32 (s, 1H), 8.33 (s, 1H). MS: m/z 427.5 (M+H+).

Aufarbeitung

  1. extractionsubsequently extracted with 1N HCl, saturated NaHCO3, brine
  2. dry with materialdried with Na2SO4
  3. concentrationconcentrated to dryness
  4. customThe crude was purified by silica gel chromatography
  5. dissolutionThe resulting material was dissolved in 3 ml of methanol
  6. additionaqueous NaOH was added (1 ml, 2 N in H2O)
  7. stirringthe mixture stirred overnight at room temperature
  8. customThe solvent was removed under reduced pressure
  9. custompurified by mass-triggered reverse phase HPLC

Quellen und Nachweise

ORD-Eintrag
ord-ba58d341247946c7ba054bbaea5b696e
Quelldatensatz
uspto-grants-2012_08
Patentnummer
US08242280B2

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