反应详情

温度

2.5 °C

To a solution of (R)-tert-butyl 3-((R)-(2-aminoethoxy)(5-fluoro-2-methylphenyl)methyl)piperidine-1-carboxylate (3.1 g, 8.5 mmol) and DMAP (0.54 g) in dry CH2Cl2 (45 mL), Et3N (2.58 g, 3.6 mL) was added. The resulting mixture was cooled to 0-5° C. under ice-water bath, a solution of methyl chloroformate (4.0 g, 43 mmol, 5 eq) in dry CH2Cl2 (50 mL) was added dropwise. After addition, the reaction mixture was stirred for 1-2 h at 0-5° C. The reaction was quenched with water (50 mL). The aqueous layer was extracted with CH2Cl2 (3×30 mL), the combined organic layers were washed with 10% citric acid (2×50 mL) and brine, then dried over Na2SO4, filtered and concentrated to the crude product, which was purified by preparative HPLC to afford (R)-tert-butyl 3-((R)-(5-fluoro-2-methylphenyl)(2-(methoxycarbonylamino)ethoxy)methyl)piperidine-1-carboxylate (400 mg, HPLC≧98%). 1H NMR (CDCl3) δ 7.2 (m, 1H), 7.1 (m, 1H), 6.9 (m, 1H), 4.4 (m, 1H), 4.1 (m, 1H), 3.7 (m, 1H), 3.6 (s, 3H), 3.2 (m, 2H), 2.9 (m, 2H), 2.3 (s, 3H), 1.75 (m, 1H), 1.6 (m, 1H), 1.4 (s, 9H), 1.25 (m, 2H).

1. additionAfter addition
2. customThe reaction was quenched with water (50 mL)
3. extractionThe aqueous layer was extracted with CH2Cl2 (3×30 mL)
4. washthe combined organic layers were washed with 10% citric acid (2×50 mL) and brine
5. dry with materialdried over Na2SO4
6. filtrationfiltered
7. concentrationconcentrated to the crude product, which
8. customwas purified by preparative HPLC