Carbamic chloride → Trifluoroacetic acid

HRID 454796

Reaction equation

HRID 454796 reaction equation
[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:34](Cl)(=O)[NH2:35].[C:38](=[O:41])(O)[O-:39].[Na+].C(Cl)Cl.[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49]>C1COCC1>[F:46][C:47]([F:52])([F:51])[C:48]([OH:50])=[O:49].[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].[CH3:1][N:2]([CH2:3][CH2:34][NH2:35])[C:38](=[O:41])[O-:39]

Participants

9

Reactant 5

HCID 68048Carbamic chlorideHCID 516892Sodium BicarbonateHCID 3251421Potassium bis(trimethylsilyl)amideHCID 5284603OxycodoneHCID 21863450Trifluoroacetic acid methylene chloride

Product 3

HCID 6422Trifluoroacetic acidHCID 5284603OxycodoneHCID 86667877N-methyl-N-(2-amino)ethylcarbamate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-10 °C

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 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 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) 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 in vacuo 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.

Workup

  1. customin dry
  2. customdegassed tetrahydrofuran (120 mL)
  3. stirringThe mixture was stirred at −5° C. for 30 min
  4. stirringThe reaction was stirred at room temperature for 2 h
  5. concentrationThe mixture was concentrated in vacuo to half of its initial volume
  6. additionEtOAc (50 mL) was added
  7. customlayers were separated
  8. washThe organic phase was further washed with water (3×20 mL) and brine (40 mL)
  9. concentrationwas concentrated
  10. customThe residue was purified by silica gel chromatography
  11. customto afford a white foam in 55% yield (7.0 g, 13.4 mmol)
  12. stirringstirred for 1 h
  13. concentrationThe solution was then concentrated in vacuo

Sources & evidence

ORD record
ord-caad387da98346c4992eaabad07cf6b4
Source dataset
uspto-grants-2013_07
Patent number
US08497237B2

Linked notes

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