反应详情

A mixture of 6-bromo-4-(((3aS,4R,5R,6aS)-4-methyloctahydrocyclopenta-[c]pyrrol-5-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide TFA salt from Step 2 of Example 59 (22 mg, 0.045 mmol), 2-hydroxy-2-methylpropanoic acid (5.1 mg, 0.049 mmol), (benzotriazol-1-yloxy)tris(dimethylamine)phosphonium hexafluorophosphate (21.7 mg, 0.049 mmol) and N,N-diisopropylethylamine (0.023 mL, 0.134 mmol) in N,N-dimethylformamide (1 mL) was stirred at room temperature for 2 h. 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (19.8 mg, 0.089 mmol), 2.0 M aqueous K3PO4 (0.089 mL, 0.179 mmol) and PdCl2(dppf) (3.27 mg, 4.47 mmol) was added. The reaction vial was sealed under nitrogen and heated to 90° C. for 1 h. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 95:5 acetonitrile:water with 0.05% TFA; Gradient: 0-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (14 mg, 66% yield). 1H NMR (500 MHz, 1:1 mixture of methanol-d4/chloroform-d) d 8.64 (s, 1H), 8.13 (s, 1H), 7.98 (s, 1H), 7.86 (d, J=2.0 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 4.35-4.13 (m, 1H), 4.10-3.89 (m, 1H), 3.79-3.49 (m, 3H), 2.95-2.88 (m, 1H), 2.85-2.75 (m, 1H), 2.45-2.20 (m, 1H), 1.78-1.69 (m, 1H), 1.62-1.52 (m, 1H), 1.52-1.36 (m, 6H), 1.21 (d, J=6.9 Hz, 3H); MS (ES+) m/z: 479.2 (M+H); LC retention time: 1.135 min (analytical HPLC Method I).

1. customThe reaction
2. customvial was sealed under nitrogen
3. temperatureheated to 90° C. for 1 h
4. customThe crude material was purified via preparative LC/MS with the following conditions
5. waitGradient: 0-100% B over 25 minutes
6. customa 5-minute hold
7. additionFractions containing the desired product
8. customdried via centrifugal evaporation