反应详情

To a stirring solution of 6-bromo-2-tetralone (1.0 g, 0.00444 mol, 1 eq.) in methanol (139 ml) was added ammonium acetate (3.4218 g, 0.04444 mol, 10 eq.). The reaction mixture then stirred over 1 h at RT. Sodium cyanoborohydride (0.335 g, 0.00533 mol, 12 eq.) was then added to the reaction mixture at RT and then stirred for 20 h. The solvent of the reaction mixture was evaporated under reduced pressure. The residue then dissolved in water (50 ml) and acidified by 1(N)HCl solution up to PH˜2. The aqueous part was extracted with DCM (2×50 ml). The aqueous part was then basified with 1(N) NaOH solution up to PH˜10. The aqueous part was extracted with DCM (2×100 ml). The combined organic part was washed with brine (30 ml), dried over Na2SO4, and evaporated under reduced pressure to get the product 6-bromo-1,2,3,4-tetrahydro-2-napthyl amine. 2. To a stirring solution of 6-bromo-1,2,3,4-tetrahydro-2-napthyl amine (0.5 g, 0.00221 mol, 1 eq.) in DCM (15 ml), triethyl amine (0.9 ml, 0.00663 mol, 3 eq.) was added at RT. The reaction mixture was then stirred at RT for 20 min. The reaction mixture was cooled to 0° C. and boc-anhydride (0.578 g, 0.002654 mol, 1.2 eq.) was added slowly. The reaction mixture was stirred for 1 h at RT. The reaction mixture was diluted with DCM (70 ml) and washed by water (2×30 ml) and by brine (20 ml). The organic layer then was dried over Na2SO4, evaporated in reduced pressure to get the crude material, which is purified by column chromatography (silica gel 100-200; 5% ethyl acetate/hexane). 3. A stirring solution of step-2 compound (0.7 gm, 0.002147 mol, 1 eq) in dry THF (28 ml) was cooled to −78° C. n-Buli (2M) solution (2.147 ml, 0.004294 mol, 2 eq) was added to the reaction mixture drop wise under argon atmosphere. The reaction mixture was then stirred over 45 min at −78° C. DMF (0.6636 ml, 0.008588 mol, 4 eq) was added to the reaction mixture at −78° C. The reaction mixture was slowly warmed to RT over 1 h. The reaction mixture was quenched by saturated ammonium chloride solution (10 ml). The aqueous part was extracted with ethyl acetate (2×30 ml). The combined organic part was washed with brine (20 ml). The organic layer then was dried over Na2SO4, evaporated in reduced pressure to get the crude material, which is purified by column chromatography (silica gel 100-200; 10% ethyl acetate/hexane). 4. To a stirring solution of step-3 compound (1.0 g, 0.003636 mol, 1 eq.) in DCM (20 ml) was added methylamine hydrochloride (0.3558 g, 0.004363 mol, 1.2 eq) at RT and then the reaction mixture was stirred for 2 h at RT. Na(OAc)3BH (2.31 g, 0.0109 mol, 3 eq) was then added to the reaction mixture at RT. The reaction mixture was stirred for 16 h at RT. The reaction mixture was diluted with DCM (50 ml) and organic part washed with water (2×20 ml) and brine (20 ml). The organic layer then was dried over Na2SO4, evaporated under reduced pressure to get the crude material, which is purified by column chromatography (silica gel 100-200; 5% methanol/DCM) to desired product. 5. To a solution of step-4 product (0.45 g, 0.0015 mol) in water (9 ml), NaHCO3 (0.26 g, 0.003 mol, 2 eq.) was added. A solution of Fmoc-Cl (0.6 g, 0.00225 mol, 1.5 eq.) in dioxane (9 ml) was added at 5° C. and then the reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was concentrated under reduced pressure. The concentrated mass was diluted with water and extracted with ethyl acetate (3×50 ml). The combined organic layer was dried with Na2SO4 and concentrated under reduced pressure to give the crude product. The crude product was purified using column chromatography (silica gel 100-200; 15% ethyl acetate/hexane) to give the desired product.

1. temperatureThe reaction mixture was cooled to 0° C.
2. stirringThe reaction mixture was stirred for 1 h at RT
3. washwashed by water (2×30 ml) and by brine (20 ml)
4. dry with materialThe organic layer then was dried over Na2SO4
5. customevaporated in reduced pressure
6. customto get the crude material, which
7. customis purified by column chromatography (silica gel 100-200; 5% ethyl acetate/hexane)
8. additionwas added to the reaction mixture drop wise under argon atmosphere
9. stirringThe reaction mixture was then stirred over 45 min at −78° C
10. temperatureThe reaction mixture was slowly warmed to RT over 1 h
11. customThe reaction mixture was quenched by saturated ammonium chloride solution (10 ml)
12. extractionThe aqueous part was extracted with ethyl acetate (2×30 ml)
13. washThe combined organic part was washed with brine (20 ml)
14. dry with materialThe organic layer then was dried over Na2SO4
15. customevaporated in reduced pressure
16. customto get the crude material, which
17. customis purified by column chromatography (silica gel 100-200; 10% ethyl acetate/hexane)
18. stirringthe reaction mixture was stirred for 2 h at RT
19. stirringThe reaction mixture was stirred for 16 h at RT
20. washwashed with water (2×20 ml) and brine (20 ml)
21. dry with materialThe organic layer then was dried over Na2SO4
22. customevaporated under reduced pressure
23. customto get the crude material, which
24. customis purified by column chromatography (silica gel 100-200; 5% methanol/DCM) to desired product
25. stirringthe reaction mixture was stirred at 0° C. for 2 h
26. concentrationThe reaction mixture was concentrated under reduced pressure
27. additionThe concentrated mass was diluted with water
28. extractionextracted with ethyl acetate (3×50 ml)
29. dry with materialThe combined organic layer was dried with Na2SO4
30. concentrationconcentrated under reduced pressure
31. customto give the crude product
32. customThe crude product was purified