N-methyl-2-pyrrolidone → Naltrexone

HRID 659717Notes

Reaction equation

HRID 659717 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].CN1[CH2:28][CH2:27][CH2:26]C1=O.BrCC1CC1>O.CCN(CC)CC>[CH:19]1[C:14]2[CH2:13][C@H:12]3[N:2]([CH2:1][CH:26]4[CH2:27][CH2:28]4)[CH2:3][CH2:4][C@:5]45[C@H:6]([C:7]([CH2:9][CH2:10][C@@:11]34[OH:22])=[O:8])[O:21][C:16]([C:15]=25)=[C:17]([OH:20])[CH:18]=1

Participants

6

Reactant 3

HCID 13387N-methyl-2-pyrrolidoneHCID 81503BromomethylcyclopropaneHCID 1528625314-Hydroxymorphine-6-one2×

Product 1

HCID 5360515Naltrexone

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 8471TriethylamineSolvent2×

Conditions

Temperature
70 °C

Procedure

Naltrexone was prepared in high yield by direct N-alkylation of noroxymorphone with an alkyl halide in the presence of a protic solvent. Accordingly, 5.5 g of noroxymorphone, 16.5 mL of N-methyl-2-pyrrolidinone (NMP), and 1.65 mL of water were added to a flask (100 mL, 3 necked). The flask was flushed with nitrogen, and the reaction mixture was kept under nitrogen throughout the reaction. Next, 2.4 mL of bromomethylcyclopropane and 2.5 mL of triethylamine (NEt3) were added to the flask, which was then heated at 70° C. for 2 h. An additional 2.5 mL of NEt3 was added to the flask, and the mixture was heated at 70° C. for 7.5 h. HPLC analysis revealed that the reaction is completed with noroxymorphone at less than two percent or one percent and undesired side products such as quaternary ammonium salt and O-alkylation of phenol group were present at less than two percent or were undetectable. The mixture was cooled to room temperature, and water (82.5 g) was added to give a precipitate. The mixture was stirred for 1 h and then filtered. The solid was washed with water (2×5.5 mL) and dried under vacuum at 65° C. for 18 h to give 5.68 g of naltrexone as solid.

Workup

  1. customThe flask was flushed with nitrogen
  2. customthe reaction mixture was kept under nitrogen throughout the reaction
  3. temperaturethe mixture was heated at 70° C. for 7.5 h
  4. temperatureThe mixture was cooled to room temperature
  5. customto give a precipitate
  6. filtrationfiltered
  7. washThe solid was washed with water (2×5.5 mL)
  8. customdried under vacuum at 65° C. for 18 h

Sources & evidence

ORD record
ord-e54b0bd6b8e7443588d0269a4a336d02
Source dataset
uspto-grants-2011_12
Patent number
US08080661B2

Reaction notes

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