反应详情

A solution of 1-{[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]methyl}cyclohexanol (prepared as described in Part A, 27.1 mmol), dibenzylamine (15.6 mL, 81.3 mmol), and triethylamine (5.67 mL, 40.7 mmol) in toluene (100 mL) was heated at reflux for 7 d. The volatiles were removed under reduced pressure and the residue was partitioned between chloroform (300 mL) and water (100 mL). The aqueous layer was extracted with chloroform (2×75 mL). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated to give a semi-solid. The semi-solid was triturated with 1:2 ethyl acetate/hexanes and filtered. The filtrate was concentrated to an orange oil that was purified on a Biotage (gradient elution, 0-30% ethyl acetate/hexanes) to yield an oil contained both product and dibenzylamine. The oil was dissolved in ethyl acetate (100 mL) and 1 M HCl in diethyl ether (50 mL) and methanol (100 mL) were added. The solution was stirred for 10 minutes and the solvent was removed in vacuo. The residue was triturated with 1:2 ethyl acetate/hexanes and filtered. The filtrate was concentrated, and the resulting oil was dissolved in chloroform (300 mL), washed with saturated aqueous sodium bicarbonate (50 mL), dried over MgSO4, filtered, and concentrated. The material was dissolved in ethyl acetate (400 mL) and washed with 10% aqueous citric acid (2×100 mL), saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo to yield 1-({[2-(dibenzylamino)-5,6-dimethyl-3-nitropyridin-4-yl]amino}methyl)cyclohexanol (10.14 g, 79% yield over two steps).

1. temperatureat reflux for 7 d
2. customThe volatiles were removed under reduced pressure
3. customthe residue was partitioned between chloroform (300 mL) and water (100 mL)
4. extractionThe aqueous layer was extracted with chloroform (2×75 mL)
5. washThe combined organic layers were washed with brine (50 mL)
6. dry with materialdried over MgSO4
7. filtrationfiltered
8. concentrationconcentrated
9. customto give a semi-solid
10. customThe semi-solid was triturated with 1:2 ethyl acetate/hexanes
11. filtrationfiltered
12. concentrationThe filtrate was concentrated to an orange oil that
13. customwas purified on a Biotage (gradient elution, 0-30% ethyl acetate/hexanes)
14. customto yield an oil
15. customthe solvent was removed in vacuo
16. customThe residue was triturated with 1:2 ethyl acetate/hexanes
17. filtrationfiltered
18. concentrationThe filtrate was concentrated
19. dissolutionthe resulting oil was dissolved in chloroform (300 mL)
20. washwashed with saturated aqueous sodium bicarbonate (50 mL)
21. dry with materialdried over MgSO4
22. filtrationfiltered
23. concentrationconcentrated
24. dissolutionThe material was dissolved in ethyl acetate (400 mL)
25. washwashed with 10% aqueous citric acid (2×100 mL), saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL)
26. dry with materialdried over MgSO4
27. filtrationfiltered
28. concentrationconcentrated in vacuo