反応 #663737

反応方程式

carbamoyl chloride

Potassium bis(trimethylsilyl)amide

Sodium bicarbonate

DCM trifluoroacetic acid

Oxycodone

→

oxycodone

N-methyl-N-(2-amino)ethylcarbamate-2TFA

溶媒

THF

THF

反応条件

後処理

1. 1
   その他in dry
2. 2
   その他degassed tetrahydrofuran (120 mL)
3. 3
   workup.STIRRINGThe mixture was stirred at −5° C. for 30 min
4. 4
   workup.STIRRINGThe reaction was stirred at room temperature for 2 h
5. 5
   濃縮The mixture was concentrated in vacuo to half of its initial volume
6. 6
   workup.ADDITIONEtOAc (50 mL) was added
7. 7
   その他layers were separated
8. 8
   洗浄The organic phase was further washed with water (3×20 mL), brine (40 mL)
9. 9
   濃縮was concentrated
10. 10
    その他The residue was purified by silica gel chromatography
11. 11
    その他to afford a white foam in 55% yield (7.0 g, 13.4 mmol)
12. 12
    workup.STIRRINGstirred for 1 h
13. 13
    濃縮The solution was then concentrated in vacuo

実験手順

Oxycodone free base (6.5 g, 20.6 mmol) was dissolved in dry, degassed tetrahydrofuran (120 mL), and the mixture was cooled to −10° C. using dry ice/acetone bath. Potassium bis(trimethylsilyl)amide (KHMDS) (103.0 mL, 51.6 mmol, 0.5 M in toluene) was added via cannula. The mixture was stirred under N2 at below −5° C. for 30 min. N,N-Bis(tert-butyl)N′-2-(chlorocarbonyl(methyl)amino)ethylcarbamate (8.0 g, 23.7 mmol), (E-8) prepared as described in the Example herein, in THF (30 mL) was then added via cannula over 15 min. The mixture was stirred at −5° C. for 30 min. Another portion of carbamoyl chloride (4.0 g, 11.9 mmol) in THF (10 mL) was added. The reaction was stirred at room temperature for 2 h. Sodium bicarbonate (10 mL, sat. aq.) was added. The mixture was concentrated in vacuo to half of its initial volume. EtOAc (50 mL) was added and layers were separated. The organic phase was further washed with water (3×20 mL), brine (40 mL) and then was concentrated. The residue was purified by silica gel chromatography, using DCM/MeOH (gradient 100/1 to 100/15) to afford a white foam in 55% yield (7.0 g, 13.4 mmol). This material was dissolved in a 1:1 mixture of DCM/trifluoroacetic acid (TFA) (20 mL/20 mL) at room temperature and stirred for 1 h. The solution was then concentrated in vacuo to afford oxycodone 6-(N-methyl-N-(2-amino)ethylcarbamate-2TFA as a thick oil (7.3 g, 11.4 mmol, 99% purity). MS: (m/z) calc: 415.2, observed (M+H+) 416.5. The oxycodone 6-(N-methyl-N-(2-amino)ethylcarbamate-2TFA (E-9) was used without further purification.

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