Trifluoroacetic acid → N-((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)-2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide

HRID 246399

Reaktionsgleichung

Reaktionsgleichung von HRID 246399
[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[N:7]=[C:6]2[C:13]1[N:14]=[C:15]2[C:21]([C:22]([NH:24][C@@H:25]3[CH2:30][CH2:29][O:28][CH2:27][C@@H:26]3[NH:31]C(=O)OC(C)(C)C)=[O:23])=[CH:20][N:19](COCC[Si](C)(C)C)[C:16]2=[N:17][CH:18]=1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:31][C@@H:26]1[C@H:25]([NH:24][C:22]([C:21]2[C:15]3[C:16](=[N:17][CH:18]=[C:13]([C:6]4[C:5]5[C:9](=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=5)[N:8]([CH3:12])[N:7]=4)[N:14]=3)[NH:19][CH:20]=2)=[O:23])[CH2:30][CH2:29][O:28][CH2:27]1

Komponenten

4

Edukt 2

HCID 6422Trifluoroacetic acidHCID 71289100tert-butyl (3R,4R)-4-(2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)tetrahydro-2H-pyran-3-ylcarbamate

Produkt 1

HCID 71280659N-((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)-2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamideAusbeute 64,8 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6344DichloromethaneLösungsmittel

Reaktionsbedingungen

Temperatur
25 °C

Versuchsvorschrift

To a pale yellow solution of tert-butyl (3R,4R)-4-(2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)tetrahydro-2H-pyran-3-ylcarbamate (115 mg, 176 μmol) in dichloromethane (3.00 mL) was added TFA (1.48 g, 1.00 mL, 13.0 mmol, Eq: 73.6), the reaction mixture turned dark red and was stirred at 25° C. overnight then concentrated. The residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1) and stirred at 25° C. for 3 h, then evaporated to a light yellow solid, dissolved in dichloromethane (added few drops MeOH and heating) and purified by chromatography (60 g column, 50 μm from Analogix, 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane. The pure product dissolved in dichloromethane/MeOH and most dichloromethane evaporated for solid formation, solid was separated by decantation and dried under high vacuum to give N-((3R,4R)-3-aminotetrahydro-2H-pyran-4-yl)-2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (48 mg, 114 μmol, 64.6%) as an off-white solid. MS (M+H)+=422 (100% purity); 1H NMR (DMSO-d6) δ: 9.05 (s, 1H), 8.45 (d, J=8.3 Hz, 1H), 8.39 (s, 1H), 8.17 (d, J=2.6 Hz, 1H), 7.70 (d, J=9.1 Hz, 1H), 7.31 (dd, J=9.1, 2.3 Hz, 1H), 4.23 (td, J=7.6, 4.0 Hz, 1H), 4.14 (s, 3H), 4.08 (q, J=5.3 Hz, 1H), 3.87 (s, 3H), 3.84 (br. s., 1H), 3.52-3.72 (m, 2H), 3.38-3.51 (m, 1H), 3.15 (d, J=4.9 Hz, 2H), 2.88 (br. s., 1H), 1.85-2.07 (m, 1H), 1.70 (d, J=11.7 Hz, 1H).

Aufarbeitung

  1. concentrationthen concentrated
  2. dissolutionThe residue was re-dissolved in 5 mL of a solution of (dichloromethane/MeOH/ammonium hydroxide; 60:10:1)
  3. stirringstirred at 25° C. for 3 h
  4. customevaporated to a light yellow solid
  5. dissolutiondissolved in dichloromethane (added few drops MeOH and heating)
  6. custompurified by chromatography (60 g column, 50 μm from Analogix, 0 to 5% over 15 min (MeOH containing 10% ammonium hydroxide)/dichloromethane
  7. dissolutionThe pure product dissolved in dichloromethane/MeOH
  8. custommost dichloromethane evaporated for solid formation, solid
  9. customwas separated by decantation
  10. customdried under high vacuum

Quellen und Nachweise

ORD-Eintrag
ord-05755730ef2b44b3a6cf45b390efb6f9
Quelldatensatz
uspto-grants-2014_02
Patentnummer
US08658646B2

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