Triethylamine → Naltrexone

HRID 1850096Notes

Reaction equation

HRID 1850096 reaction equation
[CH:1]1([CH2:4]Br)C[CH2:2]1.CCN(CC)CC.[CH3:13][N:14]1[C@@H:24]2[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[C:28]4[O:33][C@H:18]5[C:19]([CH:21]=[CH:22][C@:23]2([OH:34])[C@:17]5([C:27]=34)[CH2:16][CH2:15]1)=[O:20]>CN1CCCC1=O.ClCCl>[CH:31]1[C:26]2[CH2:25][C@H:24]3[N:14]([CH2:13][CH:1]4[CH2:4][CH2:2]4)[CH2:15][CH2:16][C@:17]45[C@H:18]([C:19]([CH2:21][CH2:22][C@@:23]34[OH:34])=[O:20])[O:33][C:28]([C:27]=25)=[C:29]([OH:32])[CH:30]=1

Participants

6

Reactant 3

HCID 8471Triethylamine2×HCID 81503BromomethylcyclopropaneHCID 1528625314-Hydroxymorphine-6-one

Product 1

HCID 5360515NaltrexoneYield 87%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
70 °C

Procedure

Cyclopropylmethyl bromide (64 mg; 0.479 mmol) and Et3N (45 μl; 0.327 mmol) were added to a suspension of noroxymorphone (Example 5, 100 mg; 0.348 mmol) in a mixture of N-Methyl-2-pyrrolidone (NMP)/H2O (10:1; 0.35 mL). The reaction vessel was purged with argon and the reaction mixture was stirred at 70° C. for 2 h. At that time, additional Et3N (45 μl; 0.327 mmol) was added and the mixture was stirred for an additional 6 h at 70° C. The reaction mixture was then cooled to room temperature, diluted with dichloromethane (15 mL) and washed with saturated NaHCO3 (3×3 mL). The aqueous layer was re-extracted with dichloromethane (5 mL) and the combined organic layers were dried over MgSO4. Column chromatography of the residue (dichloromethane/methanol 4:1) afforded 103 mg (87%) of naltrexone as a white solid: mp 173-175° C. (acetone), mp 159-161° C. (MeOH), [lit. mp 174-176° C. (acetone)]xvii identical in all respects to the material described in the literature.xviii

Workup

  1. customThe reaction vessel was purged with argon
  2. stirringthe mixture was stirred for an additional 6 h at 70° C
  3. temperatureThe reaction mixture was then cooled to room temperature
  4. washwashed with saturated NaHCO3 (3×3 mL)
  5. extractionThe aqueous layer was re-extracted with dichloromethane (5 mL)
  6. dry with materialthe combined organic layers were dried over MgSO4

Sources & evidence

ORD record
ord-4e2e0a887a6049d6bd6983442f05f009
Source dataset
uspto-grants-2015_02
Patent number
US08957072B2

Reaction notes

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