反应详情

(3R,6S)-6-Methyl-1-{[(phenylmethyl)oxy]carbonyl}-3-piperidinecarboxylic acid (85 g, 307 mmol) in a 2 L RB flask was azeotroped with toluene (3×200 mL). The residue (an oil) was dissolved in 500 mL of t-butanol (anhydrous grade). To this solution was added triethylamine (64.1 mL, 460 mmol, 1.5 equiv) at room temperature in one portion. Diphenyl azidophosphate (110 g, 398 mmol, 1.3 equiv) was added via an addition funnel at room temperature portion-wise into this stirred mixture. Addition took 20 minutes. The resulting mixture (a light yellow clear solution) was stirred at room temperature for 30 minutes, followed by heating in an oil bath to 100° C. under reflux for 20 hours. LCMS showed conversion complete. The mixture was concentrated in vacuo to remove as much t-butanol as possible. The residue was diluted with EtOAc (1 L), which was washed with 200 mL of cold 2N HCl, followed by 200 mL of 2.5 N NaOH. The NaOH portion was salted with NaCl, and back extracted with EtOAc (400 mL). All the organic portions were combined, washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was taken up in hexane (500 mL) and EtOAc (20 mL). A waxy paste developed. The mixture was chilled in the refrigerator for 20 hours, resulting in a 2-phase mixture. The top layer was decanted off, and gave 42 g as an oil after concentration in vacuo, which would undergo further silica gel column purification. The waxy bottom component was taken up in CHCl3 (300 mL) and EtOAc (30 mL). The mixture was stirred for 5 minutes, and filtered. The filtrate was concentrated in vacuo to give an oil (150 g), which would undergo further silica gel column purification. The waxy solids (30 g) collected were identified as (PhO)2POOH, and were discarded. Silica gel column chromatography of the above two samples on multiple runs using gradient elution of 1% EtOAc in CHCl3 to 50% EtOAc in CHCl3 gave the title compound (88.28 g) as a thick clear syrup. LC-MS (ES) m/z=349 [M+H]+.

1. additionAddition
2. temperatureby heating in an oil bath to 100° C.
3. temperatureunder reflux for 20 hours
4. concentrationThe mixture was concentrated in vacuo
5. customto remove as much t-butanol as possible
6. additionThe residue was diluted with EtOAc (1 L), which
7. washwas washed with 200 mL of cold 2N HCl
8. extractionback extracted with EtOAc (400 mL)
9. washwashed with brine
10. dry with materialdried over MgSO4
11. filtrationfiltered
12. concentrationconcentrated in vacuo
13. temperatureThe mixture was chilled in the refrigerator for 20 hours
14. customresulting in a 2-phase mixture
15. customThe top layer was decanted off
16. customgave 42 g as an oil
17. concentrationafter concentration in vacuo, which
18. customsilica gel column purification
19. stirringThe mixture was stirred for 5 minutes
20. filtrationfiltered
21. concentrationThe filtrate was concentrated in vacuo