反应详情

温度

-78 °C

To a stirred solution of oxalyl chloride (0.28 ml, 2.3 mmol) in CH2Cl2 (20.0 ml) was added DMSO (0.39 ml) at −78° C. After 5 minutes, to the mixture was added 1-tert-butoxycarbonyl-4-fluoro-2-pyrrolidinylmethanol (500 mg, 2.28 mmol) in CH2Cl2 (5.0 ml). The mixture was stirred for 30 minutes at −78° C., and triethylamine (1.6 ml) was added. The mixture was stirred for 30 minutes at −78° C., and stirred for 30 minutes at room temperature. Water was added to the mixture, and extracted with CH2Cl2. The organic layer was dried over Na2SO4, and concentrated in vacuo. The crude product was used to the subsequent reaction without further purification. To a stirred solution of the crude product, methyl 4-aminobenzoate(302 mg, 2.0 mmol), and AcOH (0.13 ml) in DCE (10 ml) was added NaBH(OAc)3 (656 mg, 3.09 mmol) at 0° C. The reaction mixture was stirred at room temperature for 18 hr. The mixture was concentrated in vacuo. Sat. NaHCO3 was added to the residue, and extracted with CH2Cl2. The extract was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with EtOAc-n-hexane (1:3, v/v) as eluent to give methyl 4-(1-tert-butoxycarbonyl-4-fluoro-2-pyrrolidinyl)methylaminobenzoate (541 mg, 77%) as a pale yellow oil. 1H-NMR (CDCl3) δ 1.55–1.59 (m, 1H), 2.16–2.27 (m, 1H), 2.89–3.03 (m, 2H), 3.19–3.28 (m, 2H), 3.69–3.73 (m, 1H), 3.84 (s, 3H), 5.15 and 5.29 (each s, total 1H), 6.55–6.58 (m, 2H), 7.84–7.86 (m, 2H).

1. stirringThe mixture was stirred for 30 minutes at −78° C.
2. stirringstirred for 30 minutes at room temperature
3. extractionextracted with CH2Cl2
4. dry with materialThe organic layer was dried over Na2SO4
5. concentrationconcentrated in vacuo
6. customThe crude product was used to the subsequent reaction without further purification
7. stirringThe reaction mixture was stirred at room temperature for 18 hr
8. concentrationThe mixture was concentrated in vacuo
9. additionSat. NaHCO3 was added to the residue
10. extractionextracted with CH2Cl2
11. washThe extract was washed with brine
12. dry with materialdried over Na2SO4
13. concentrationconcentrated in vacuo
14. customThe residue was purified by column chromatography on silica gel with EtOAc-n-hexane (1:3