Trifluoroacetic acid → HCID 178462170, Verbindung

HRID 1943411Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1943411
F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:35][C:36]2[CH:37]=[C:38]([N:55]([CH:65]3[CH2:67][CH2:66]3)CC3C=CC(OC)=CC=3)[C:39]3[N:40]([C:42]([C:45]([NH:47][C:48]4[CH:53]=[CH:52][N:51]=[CH:50][C:49]=4[F:54])=[O:46])=[CH:43][N:44]=3)[N:41]=2)[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.C(OC([NH:84][C@@H:85]([CH3:89])[C:86](O)=[O:87])=O)(C)(C)C.C(O)(C(F)(F)F)=O>CN(C=O)C>[NH2:84][C@H:85]([C:86]([NH:28][C@H:29]1[CH2:30][CH2:31][C@H:32]([NH:35][C:36]2[CH:37]=[C:38]([NH:55][CH:65]3[CH2:67][CH2:66]3)[C:39]3[N:40]([C:42]([C:45]([NH:47][C:48]4[CH:53]=[CH:52][N:51]=[CH:50][C:49]=4[F:54])=[O:46])=[CH:43][N:44]=3)[N:41]=2)[CH2:33][CH2:34]1)=[O:87])[CH3:89]

Komponenten

7

Edukt 5

HCID 6422Trifluoroacetic acidHCID 81531DiisopropylethylamineHCID 85082Tert-butoxycarbonylalanineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 178490952HCID 178490952, Verbindung

Produkt 1

HCID 178462170HCID 178462170, VerbindungAusbeute 42,9 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6228DimethylformamideLösungsmittel

Versuchsvorschrift

BOP (62.5 mg, 0.141 mmol) was added to a solution of 6-((trans)-4-aminocyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 8B (20 mg, 0.047 mmol), DIEA (0.0062 mL, 0.035 mmol) and (S)-2-(tert-butoxycarbonylamino)propanoic acid (17.83 mg, 0.094 mmol) in DMF (1 mL). The clear reaction mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated down, dissolved in CH2Cl2 (0.50 mL) and TFA (0.545 mL, 7.07 mmol) and stirred at rt for 30 min. The reaction mixture was concentrated and purified with HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 20% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA)) to isolate the title compound, 6-((trans-4-(L-alanylamino)cyclohexyl)amino)-8-(cyclopropylamino)-N-(3-fluoro-4-pyridinyl)imidazo[1,2-b]pyridazine-3-carboxamide (10 mg, 42.8%), as a white solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=1.41 (M+H=496.3). 1H NMR (400 MHz, MeOD) δ ppm 8.85 (1H, t, J=6.55 Hz), 8.69 (1H, d, J=3.53 Hz), 8.48 (1H, d, J=6.04 Hz), 8.13 (1H, s), 6.11 (1H, s), 3.97 (1H, d, J=4.28 Hz), 3.87 (1H, q, J=7.13 Hz), 3.72 (1H, br. s.), 2.59 (1H, td, J=6.80, 3.53 Hz), 2.21 (2H, br. s.), 1.99 (2H, br. s.), 1.32-1.62 (7H, m), 0.78-0.96 (2H, m), 0.55-0.76 (2H, m).

Aufarbeitung

  1. concentrationThe reaction mixture was concentrated down
  2. dissolutiondissolved in CH2Cl2 (0.50 mL)
  3. concentrationThe reaction mixture was concentrated
  4. custompurified with HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 20% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA))

Quellen und Nachweise

ORD-Eintrag
ord-eafa05e03d0b42a7a4fddee89106bd55
Quelldatensatz
uspto-grants-2013_03
Patentnummer
US08389527B2

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