反应详情

To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate (70 g, crude, 0.1 mol) and DMAP (1.83 g, 15 mmol, 0.15 eq) in dry CH2Cl2 (150 mL), Et3N (12.1 g, 15.8 mL, 120 mmol) was added. The resulting mixture was cooled to 0˜5° C. using a ice-water bath, a solution of methyl chloroformate (11.28 g, 120 mmol, 1.2 eq) in dry CH2Cl2 (100 mL) was added drop wise. After addition, the reaction mixture was stirred for 3 h at 0˜5° C. TLC showed the starting material had disappeared. Water (80 mL) was added. The aqueous layer was extracted with CH2Cl2 (3×100 mL), the combined organic layers were washed with 10% citric acid (2×150 mL) and brine (100 mL), then dried over Na2SO4, filtered and concentrated to the crude product, which was purified by preparative HPLC to afford (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-(methoxycarbonylamino)ethoxy)-methyl)piperidine-1-carboxylate (10.7 g, the total yield for three steps is 25%). 1H NMR (400 MHz, CDCl3):1.12-1.40 (m, 4H), 1.43 (s, 9H), 1.64 (m, 2H), 2.82 (m, 2H), 3.25 (m, 2H), 3.61 (s, 3H), 3.74 (m, 1H), 4.05 (m, 1H), 4.16 (m, 1H), 7.22 (m, 1H), 7.32 (m, 3H).

1. temperatureThe resulting mixture was cooled to 0˜5° C.
2. additionAfter addition
3. extractionThe aqueous layer was extracted with CH2Cl2 (3×100 mL)
4. washthe combined organic layers were washed with 10% citric acid (2×150 mL) and brine (100 mL)
5. dry with materialdried over Na2SO4
6. filtrationfiltered
7. concentrationconcentrated to the crude product, which
8. customwas purified by preparative HPLC