反应详情

A mixture of (6-chloro-5-methyl-pyrimidin-4-yl)-(2-fluoro-4-methanesulfonyl-phenyl)-amine (HCl salt, 1.76 g, 5.0 mmol) and 1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-ol (1.05 g, 5.0 mmol) in anhydrous THF (10 mL) was treated with potassium t-butoxide (20 mL, 20 mmol), placed under inert atmosphere, and refluxed for 4 hours, at which point the reaction had stalled at 60% conversion. The reaction mixture was cooled, quenched with water (30 mL), and extracted with ether (2×50 mL). The combined organic extract was rinsed with water (20 mL), followed by brine (20 mL), and was dried over MgSO4. After solvent removal, the residue was rinsed with boiling ether (2×20 mL), and the combined rinses were set aside to cool. Crystallization yielded a white solid (91% pure by LCMS) which was triturated in hot ether and filtered hot to furnish Compound A93 as a white solid in >95% purity (731 mg, 30% yield). This material was taken up in CH2Cl2 (10 mL), to which was added 1 N HCl/ether (1.5 mL). Upon solvent removal, a light gray foam was obtained (800 mg): 1H NMR (DMSO-d6) δ 10.26 (brs, 1 H), 8.77 (s, 1 H), 8.22 (s, 1 H), 7.83-7.71 (m, 3 H), 5.33 (m, 1 H), 3.75 (m, 2 H), 3.57 (m, 2 H), 3.37 (s, 3 H), 2.83 (m, 1 H), 2.13 (s, 3 H), 2.04 (m, 2 H), 1.78 (m, 2 H), 1.20 (d, 6 H, J=6.9 Hz), MS m/z 491.2 (M+).

1. temperaturerefluxed for 4 hours, at which
2. temperatureThe reaction mixture was cooled
3. customquenched with water (30 mL)
4. extractionextracted with ether (2×50 mL)
5. extractionThe combined organic extract
6. washwas rinsed with water (20 mL)
7. dry with materialwas dried over MgSO4
8. customAfter solvent removal
9. washthe residue was rinsed with boiling ether (2×20 mL)
10. temperatureto cool
11. customCrystallization
12. customyielded a white solid (91% pure by LCMS) which
13. customwas triturated in hot ether
14. filtrationfiltered hot
15. customto furnish Compound A93 as a white solid in >95% purity (731 mg, 30% yield)
16. customUpon solvent removal
17. customa light gray foam was obtained (800 mg)