反应详情

A solution of Boc carbamate 2 (759 mg, 2.0 mmol) and TFA (764 mg, 6.70 mmol) in CH2Cl1 (3 g) was aged at 40° C. for 1.5 h. The volatiles were removed under a stream of nitrogen (40° C.), and the residue was dissolved in CH2Cl2 (3 g). DIEA (491 mg, 3.80 mmol), HOBT (41 mg, 0.30 mmol), DCC (516 mg, 2.5 mmol) and DMAP (12 mg, 0.10 mmol) were added sequentially, and the mixture was aged for 20 h at 25° C. Oxalic acid dihydrate (250 mg) and MTBE (5 mL) were added, and the mixture was aged for 1 h. The mixture was filtered from the dicyclohexyl urea (DCU), and the filter cake was washed with a mixture of CH2Cl2 (2 mL) and MTBE (15 mL). The filtrate was washed with saturated aqueous NaH2PO4 (2×10 mL), water (10 mL), saturated aqueous NaHCO3 (10 mL), water (10 mL), and saturated aqueous NaCl (10 mL). The organic phase was dried over MgSO4 and evaporated. The residue was purified by chromatography (silica, gradient elution, 10% MTBE in hexane then MTBE to provide piperidone 3 (366 mg, 70%).: 13C NMR (62.9 MHz, CDCl3) δ 172.8, 170.5, 136.6, 130.6, 128.1, 126.6, 61.5, 54.8, 42.0, 40.5, 28.9, 19.5, 14.0. Chiral supercritical phase HPLC indicated 3 to be >99.5 % ee. HPLC conditions: Sumichiral AG OA3200 250×4.6 mm column, isocratic elution, 16% MeOH in supercritical CO2 at 300 bar, 2.0 mL/min flow at 35° C. with detection at 210 nm. Retention times: (R)-3=2.35 min., (S)-3=2.87 min.

1. customThe volatiles were removed under a stream of nitrogen (40° C.)
2. dissolutionthe residue was dissolved in CH2Cl2 (3 g)
3. waitthe mixture was aged for 1 h
4. filtrationThe mixture was filtered from the dicyclohexyl urea (DCU)
5. washthe filter cake was washed with a mixture of CH2Cl2 (2 mL) and MTBE (15 mL)
6. washThe filtrate was washed with saturated aqueous NaH2PO4 (2×10 mL), water (10 mL), saturated aqueous NaHCO3 (10 mL), water (10 mL), and saturated aqueous NaCl (10 mL)
7. dry with materialThe organic phase was dried over MgSO4
8. customevaporated
9. customThe residue was purified by chromatography (
10. washsilica, gradient elution, 10% MTBE in hexane