Réaction #2446111

Équation de réaction

Potassium bis(trimethylsilyl)amide

Sodium bicarbonate

DCM trifluoroacetic acid

carbamoyl chloride

Oxycodone

→

oxycodone

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

TFA

Solvants

THF

THF

Conditions de réaction

Traitement

1. 1
   Autrein dry
2. 2
   Autredegassed 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 under vacuum to half of its initial volume
6. 6
   workup.ADDITIONEtOAc (50 mL) was added
7. 7
   Autrelayers were separated
8. 8
   LavageThe organic phase was further washed with water (3×20 mL) and brine (40 mL)
9. 9
   Concentrationwas concentrated
10. 10
    AutreThe residue was purified by silica gel chromatography
11. 11
    Autreto 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 under vacuum

Mode opératoire

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 a 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), (Compound C) 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 under vacuum 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) and 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 under vacuum to afford a TFA salt of oxycodone 6-(N-methyl-N-(2-amino)ethylcarbamate (Compound KC-19) as a thick oil (7.3 g, 11.4 mmol, 99% purity). MS: (m/z) calc: 415.2, observed (M+H+) 416.5.

Source