Reaction #663737

Reaction equation

carbamoyl chloride

Potassium bis(trimethylsilyl)amide

Sodium bicarbonate

DCM trifluoroacetic acid

Oxycodone

→

oxycodone

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

Solvents

THF

THF

Conditions

Workup

1. 1
   Otherin dry
2. 2
   Otherdegassed 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
   ConcentrationThe mixture was concentrated in vacuo to half of its initial volume
6. 6
   workup.ADDITIONEtOAc (50 mL) was added
7. 7
   Otherlayers were separated
8. 8
   WashThe organic phase was further washed with water (3×20 mL), brine (40 mL)
9. 9
   Concentrationwas concentrated
10. 10
    OtherThe residue was purified by silica gel chromatography
11. 11
    Otherto afford a white foam in 55% yield (7.0 g, 13.4 mmol)
12. 12
    workup.STIRRINGstirred for 1 h
13. 13
    ConcentrationThe solution was then concentrated in vacuo

Procedure

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.

Source