Formic Acid → 6-Ketonalbuphine

HRID 2276792Notes

Reaction equation

HRID 2276792 reaction equation
[CH3:1][N:2]1[C@@H:12]2[CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[C:16]4[O:21][C@H:6]5[C:7]([CH:9]=[CH:10][C@:11]2([OH:22])[C@:5]5([C:15]=34)[CH2:4][CH2:3]1)=[O:8].[CH2:23]1[CH2:26][CH2:25][CH:24]1C=O.C(O)=O.C(N(CC)CC)C>CO.CC1C=CC(C(C)C)=CC=1.CC1C=CC(C(C)C)=CC=1.Cl[Ru]Cl.Cl[Ru]Cl>[CH:23]1([CH2:1][N:2]2[CH2:3][CH2:4][C@@:5]34[C:15]5[C:14]6[CH2:13][C@@H:12]2[C@:11]3([OH:22])[CH2:10][CH2:9][C:7](=[O:8])[C@@H:6]4[O:21][C:16]=5[C:17]([OH:20])=[CH:18][CH:19]=6)[CH2:26][CH2:25][CH2:24]1

Participants

7

Reactant 4

HCID 284Formic Acid2×HCID 8471TriethylamineHCID 12431621CyclobutanecarbaldehydeHCID 1528625314-Hydroxymorphine-6-one2×

Product 1

HCID 444650036-KetonalbuphineYield 94%

Reagents, catalysts & solvents 2

HCID 10908223Dichloro(p-cymene)ruthenium(II) dimerCatalystHCID 887MethanolSolvent2×

Procedure

A mixture of Noroxymorphone (8.8 g, 30.6 mmol) in methanol (250 mL) was degassed for 20 minutes. 2-cyclobutanecarbaldehyde (7.7 g, 91.5 mmol) was added and the mixture heated at reflux for 1 hour. The reaction mixture was cooled to ambient temperature. In a separate flask formic acid (14.0 g, 306 mmol) was added slowly to a solution of triethylamine (12.4 g, 123 mmol) in methanol (40 mL). The formic acid solution was stirred for 5 minutes before being added to the solution containing Noroxymorphone along with dichloro(p-cymene)ruthenium(II) dimer (53 mg). The reaction was heated at reflux for a further 2.5 hours. The reaction was concentrated under reduced pressure then partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous phase was extracted with further ethyl acetate then the organic layers combined and dried (MgSO4). Filtration and removal of the solvent under reduced pressure gave (4R,4aS,7aR,12bS)-3-(cyclobutylmethyl)-4a,9-dihydroxy-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one (10.2 g, 94% yield); LC/MS (M+H)+=356.2.

Workup

  1. customwas degassed for 20 minutes
  2. temperaturethe mixture heated
  3. temperatureat reflux for 1 hour
  4. additionbefore being added to the solution
  5. temperatureThe reaction was heated
  6. temperatureat reflux for a further 2.5 hours
  7. concentrationThe reaction was concentrated under reduced pressure
  8. customthen partitioned between ethyl acetate and saturated sodium bicarbonate solution
  9. extractionThe aqueous phase was extracted with further ethyl acetate
  10. dry with materialdried (MgSO4)
  11. filtrationFiltration and removal of the solvent under reduced pressure

Sources & evidence

ORD record
ord-b36251ef23384656af0de22cd59291f3
Source dataset
uspto-grants-2015_09
Patent number
US09133125B2

Reaction notes

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