反应详情

(3R)-Piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (2.64 g, 11.5 mmol), benzotriazo-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 1.1 eq., 5.61 g) and 1-hydroxybenzotriazole hydrate (0.1 eq., 180 mg) were dissolved in anhydrous dichloromethane (30 mL) under nitrogen and morpholine (1.1 eq., 1.11 mL) was added followed by triethylamine (3 eq., 4.82 mL). The solution briefly came to reflux and was then allowed to stir for 16 hr at ambient temperature. The solution was washed with 0.2M sodium hydroxide solution (×2), dried over anhydrous sodium sulfate and the solvent was removed under vacuum. The residue was dissolved in anhydrous toluene and the solvent again removed under vacuum. The product was purified by chromatography on silica gel eluting with a 5% to 10% methanol in dichloromethane gradient. The product was dissolved in ethyl acetate (30 mL), saturated with hydrogen chloride at −78° C. then stirred at room temperature for 1 hr. The solvent was evaporated in a stream of dry nitrogen. The solid residue was dissolved in water (˜5 mL) followed by sodium hydroxide (1 g). Xylene was added and the solvent was removed under vacuum. The residue was extracted with dichloromethane, the organic solution was filtered through Celite® and the solvent was evaporated under vacuum to give the title compound as a colorless oil which crystallized on refrigeration (2.25 g, 100%).

1. temperatureto reflux
2. washThe solution was washed with 0.2M sodium hydroxide solution (×2)
3. dry with materialdried over anhydrous sodium sulfate
4. customthe solvent was removed under vacuum
5. dissolutionThe residue was dissolved in anhydrous toluene
6. customthe solvent again removed under vacuum
7. customThe product was purified by chromatography on silica gel eluting with a 5% to 10% methanol in dichloromethane gradient
8. dissolutionThe product was dissolved in ethyl acetate (30 mL), saturated with hydrogen chloride at −78° C.
9. stirringthen stirred at room temperature for 1 hr
10. customThe solvent was evaporated in a stream of dry nitrogen
11. dissolutionThe solid residue was dissolved in water (˜5 mL)
12. additionXylene was added
13. customthe solvent was removed under vacuum
14. extractionThe residue was extracted with dichloromethane
15. filtrationthe organic solution was filtered through Celite®
16. customthe solvent was evaporated under vacuum