反应详情

温度

60 °C

To a solution of ethyl 4-[2-[(2,4-dimethoxyphenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 56; 569.3 mg, 1.26 mmol) in tetrahydrofuran (5.0 mL) was added lithium borohydride (82.0 mg, 3.77 mmol) at 0° C. The reaction mixture was stirred at 60° C. for 1.5 hr. After cooling, the reaction mixture was quenched with water at 0° C. and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting crude butanol (MS Calcd.: 411; Found: 412 (M+H)) was subjected for the next step without further purification. To a solution of the crude material in pyridine (1.0 mL) was added methanesulfonyl chloride (490 μL, 6.28 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was quenched with aqueous sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The crude mesylate was subjected for the next step without further purification. To the crude material (MS Calcd.: 489; Found: 490 (M+H)) in NAN-dimethylformamide (1.0 mL) was added potassium carbonate (346.9 mg, 2.51 mmol). The reaction mixture was stirred at 60° C. for 19 hr. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-40% ethyl acetate/n-hexane gradient mixture. The resulting solid was washed with n-hexane to give the title compound as a colorless powder (144.5 mg, 0.367 mmol, 29%).

1. temperatureAfter cooling
2. customthe reaction mixture was quenched with water at 0° C.
3. extractionextracted with ethyl acetate (×3)
4. washThe combined organic layer was washed with brine
5. dry with materialdried over anhydrous magnesium sulfate
6. filtrationfiltered
7. concentrationconcentrated in vacuo
8. customThe resulting crude butanol (MS Calcd.: 411; Found: 412 (M+H)) was subjected for the next step without further purification
9. stirringThe reaction mixture was stirred at room temperature for 2 hr
10. customThe reaction mixture was quenched with aqueous sodium hydrogen carbonate
11. extractionextracted with ethyl acetate (×3)
12. washThe combined organic layer was washed with brine
13. dry with materialdried over anhydrous magnesium sulfate
14. filtrationfiltered
15. concentrationconcentrated in vacuo
16. customThe crude mesylate was subjected for the next step without further purification
17. stirringThe reaction mixture was stirred at 60° C. for 19 hr
18. temperatureAfter cooling
19. extractionextracted with ethyl acetate (×3)
20. washThe combined organic layer was washed with water (×2) and brine
21. dry with materialdried over anhydrous magnesium sulfate
22. filtrationfiltered
23. concentrationconcentrated in vacuo
24. customThe residue was purified by silica gel column chromatography
25. washeluting with a 10-40% ethyl acetate/n-hexane gradient mixture
26. washThe resulting solid was washed with n-hexane