反应详情

A mixture of 4-(((3S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-3-yl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylic acid (120 mg, 0.297 mmol), EDC (68.4 mg, 0.357 mmol) and 1-hydroxybenzotriazole (54.7 mg, 0.357 mmol) in DMF (2 mL) was stirred at rt for 30 minutes. (Z)—N′-hydroxyacetimidamide (48.5 mg, 0.654 mmol) was added and the reaction mixture was stirred for 30 min at rt and 3 hr at 125° C. for 5 hr. After cooling to rt, The reaction mixture was partitioned between EtOAc (30 ml) and saturated NaHCO3 solution (30 ml). The organic layer was washed with saturated NaHCO3 solution (30 ml), 10% LiCl solution (2×30 ml) and brine (30 ml). After drying (MgSO4) and filtration, the organic layer was concentrated to a yellow oil that was chromatographed on a 12 gm ISCO silica gel cartridge, eluting with a 0-100% EtOAc/Hex gradient. The pure fractions were concentrated to afford (3S,4S)-tert-butyl 3-((3-carbamoyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-methylpyrrolidine-1-carboxylate (50 mg, 0.110 mmol, 36.9% yield) as an off-white solid. 1H NMR (400 MHz, METHANOL-d4) δ 8.27 (s, 2H), 7.48 (s, 1H), 3.88-3.50 (m, 4H), 3.21 (td, J=10.3, 4.4 Hz, 1H), 2.72 (d, J=6.4 Hz, 1H), 2.43 (s, 3H), 1.45 (d, J=13.6 Hz, 9H), 1.18 (d, J=6.8 Hz, 3H). MS (ES+) m/z: 442.2 (M+H); LC retention time: 2.991 min (analytical HPLC Method O).

1. stirringthe reaction mixture was stirred for 30 min at rt and 3 hr at 125° C. for 5 hr
2. temperatureAfter cooling to rt
3. customThe reaction mixture was partitioned between EtOAc (30 ml) and saturated NaHCO3 solution (30 ml)
4. washThe organic layer was washed with saturated NaHCO3 solution (30 ml), 10% LiCl solution (2×30 ml) and brine (30 ml)
5. customAfter drying
6. filtration(MgSO4) and filtration
7. concentrationthe organic layer was concentrated to a yellow oil that
8. customwas chromatographed on a 12 gm ISCO silica gel cartridge
9. washeluting with a 0-100% EtOAc/Hex gradient
10. concentrationThe pure fractions were concentrated