反应详情

To a solution of (3S,4S)-tert-butyl 3-((3-carbamoyl-6-ethynylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate from Step 2 of Example 292 (71 mg, 0.179 mmol) in toluene (2 mL) and DMF (0.2 mL) was added azidobenzene (149 mg, 1.250 mmol). The flask was purged with nitrogen, and the reaction solution was stirred at room temperature for 1 hour, then warmed to 95° C. After stirring over two nights, the reaction was cooled to room temperature. The volatiles were removed in vacuo and the residue was diluted with 3 mL DMF and purified by via preparative HPLC with the following conditions: Column: Phenomenex Luna C18, 21.5×250 mm, 5-μm particles; Mobile Phase A: 10:90 methanol:water with 0.1% trifluoroacetic acid; Mobile Phase B: 90:10 methanol:water with 0.1% trifluoroacetic acid; Gradient: 30-100% B over 14 minutes, then a 2-minute hold at 100% B; Flow: 25 mL/min. Fractions containing the desired product were combined and concentrated via centrifugal evaporation to remove the methanol. The solution was neutralized with 1N NaOH, and was then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate. Filtration and evaporation afforded the title compound (41 mg, 42% yield). MS (ES+) m/z: 517.1 (M+H); LC retention time: 3.385 min (analytical LCMS Method J).

1. customThe flask was purged with nitrogen
2. temperaturewarmed to 95° C
3. stirringAfter stirring over two nights
4. temperaturethe reaction was cooled to room temperature
5. customThe volatiles were removed in vacuo
6. additionthe residue was diluted with 3 mL DMF
7. custompurified by via preparative HPLC with the following conditions
8. waitGradient: 30-100% B over 14 minutes
9. customa 2-minute hold
10. additionFractions containing the desired product
11. concentrationconcentrated via centrifugal evaporation
12. customto remove the methanol
13. customwas then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate
14. dry with materialThe organic layer was dried over sodium sulfate
15. filtrationFiltration and evaporation