Diisopropylethylamine → (3aS,4R,5R,6aS)-tert-butyl 5-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

Participants

Reaction Conditions

Reaction Steps

A mixture of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 2, 5.05 g, 18.40 mmol), crude tert-butyl 5-amino-4-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Intermediate 7, 7.07 g) and N,N-diisopropylethylamine (12.85 mL, 73.6 mmol) in N-methylpyrrolidinone (80 mL) was heated to 95° C. for 5 h. The mixture was diluted with ethyl acetate (600 mL), washed with water, brine, dried (MgSO4) and concentrated. Silica gel chromatography, eluting with 0-60% ethyl acetate in hexanes, gave the desired product as a racemic mixture (3.1 g). This mixture was resolved using preparative SFC using the following conditions: Column: ChiralPak AD-H 25×3 cm, 5 μm; Column Temp: 40° C.; Flow rate: 130 mL/min; Mobile Phase: CO2/methanol=50/50; Injection Volume: 5 mL (22.2 mg/mL, 3 g solid in 75 mL methanol and 60 mL chloroform); Detector Wavelength: 263 nm. The first eluted enantiomer was the desired (3aS,4R,5R,6aS)-tert-butyl 5-((6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-methylhexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.35 g). 1H NMR (400 MHz, chloroform-d) δ ppm 10.40 (1 H, d, J=8.36 Hz), 7.88 (1 H, s), 7.58 (1 H, d, J=1.76 Hz), 6.83 (1 H, d, J=1.76 Hz), 5.64 (2 H, br. s.), 3.86-4.08 (1 H, m), 3.49-3.67 (1 H, m), 3.38-3.50 (2 H, m), 3.14-3.34 (1 H, m), 2.74-2.82 (1 H, m), 2.55-2.68 (1 H, m), 2.18-2.40 (1 H, m), 1.59-1.90 (2 H, m), 1.51 (9 H, s), 1.08-1.19 (3 H, m); MS (ES+) m/z: 478.2, 480.2 (M+H).

Provenance & Evidence