N-(4-Methoxybenzyl)pyridin-2-amine → 6-chloro-N-(3-fluoropyridin-4-yl)-8-((4-methoxybenzyl)(pyridin-2-yl)amino)imidazo[1,2-b]pyridazine-3-carboxamide

HRID 1943402

Reaktionsgleichung

Reaktionsgleichung von HRID 1943402
[Cl:1][C:2]1[CH:3]=[C:4](Cl)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1.BrC1C2N(C(C(NC3C=CN=CC=3F)=O)=CN=2)N=C(Cl)C=1.[CH3:43][O:44][C:45]1[CH:58]=[CH:57][C:48]([CH2:49][NH:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=2)=[CH:47][CH:46]=1.CC(C)([O-])C.[K+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:50]([CH2:49][C:48]2[CH:47]=[CH:46][C:45]([O:44][CH3:43])=[CH:58][CH:57]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=2)[C:5]2[N:6]([C:8]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][C:15]=3[F:20])=[O:12])=[CH:9][N:10]=2)[N:7]=1

Komponenten

6

Edukt 4

HCID 97452N-(4-Methoxybenzyl)pyridin-2-amineHCID 23665647Potassium tert-butoxideHCID 596244958-Bromo-6-chloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamideHCID 596245496,8-Dichloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide

Produkt 1

HCID 596246786-chloro-N-(3-fluoropyridin-4-yl)-8-((4-methoxybenzyl)(pyridin-2-yl)amino)imidazo[1,2-b]pyridazine-3-carboxamideAusbeute 68,5 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8028TetrahydrofuranLösungsmittel2×

Versuchsvorschrift

To a suspension containing a mixture of 6,8-dichloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide and 8-bromo-6-chloro-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide 5A (1.2 g, 3.68 mmol) was added N-(4-methoxybenzyl)pyridin-2-amine (1.183 g, 5.52 mmol) in THF (36.8 mL) at 0° C. This mixture was charged with a 1M solution of potassium tert-butoxide (7.36 mL, 7.36 mmol), slowly via syringe. The dark suspension was stirred for 20 min at room temperature. Volatiles were removed in vacuo and the resulting residue was triturated with MeOH and cooled to 0° C. Filtration, with cold MeOH washes afforded a tan solid which was dissolved in THF and azeotroped with PhMe to remove residual MeOH, then dried in vacuo overnight, which afforded 6-chloro-N-(3-fluoropyridin-4-yl)-8-((4-methoxybenzyl)(pyridin-2-yl)amino)imidazo[1,2-b]pyridazine-3-carboxamide (1.31 g, 68.5% yield) as a tan solid. LC/MS, m/z 504.0 (M+1). HPLC Rt=4.265 min. YMC S5 ODS-A column (4.6×50 mm) 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.2% H3PO4). Solvent A: (10% MeOH, 90% H2O, 0.2% H3PO4). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% 1 min, flow rate 4 mL/min. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.02 (1H, d, J=2.27 Hz), 8.62 (1H, d, J=2.27 Hz), 8.35-8.48 (4H, m), 8.23 (1H, s), 7.67-7.83 (1H, m), 7.32 (2H, dd, J=8.56, 2.27 Hz), 7.24 (1H, dd, J=7.05, 5.29 Hz), 7.00 (1H, s), 6.79-6.89 (2H, m), 5.60 (2H, s), 3.62-3.72 (3H, s).

Aufarbeitung

  1. additionTo a suspension containing
  2. customVolatiles were removed in vacuo
  3. customthe resulting residue was triturated with MeOH
  4. temperaturecooled to 0° C
  5. filtrationFiltration
  6. customwith cold MeOH washes afforded a tan solid which
  7. customazeotroped with PhMe
  8. customto remove residual MeOH
  9. customdried in vacuo overnight, which

Quellen und Nachweise

ORD-Eintrag
ord-f84adea6c40a40c1a0aaf85734259dcc
Quelldatensatz
uspto-grants-2013_03
Patentnummer
US08389527B2

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