Hydrochloric Acid → Naltrexone

HRID 2040749Notes

Reaction equation

HRID 2040749 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].C(N1[CH2:29][CH2:28][CH2:27]C1=O)C.C1(CBr)CC1.C(N(CC)C(C)C)(C)C.Cl>O>[CH:19]1[C:14]2[CH2:13][C@H:12]3[N:2]([CH2:1][CH:27]4[CH2:28][CH2:29]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

7

Reactant 5

HCID 313Hydrochloric AcidHCID 17595N-ethyl-2-pyrrolidoneHCID 81503BromomethylcyclopropaneHCID 81531DiisopropylethylamineHCID 1528625314-Hydroxymorphine-6-one

Product 1

HCID 5360515NaltrexoneYield 100.8%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
54.5 °C

Procedure

A mixture of noroxymorphone (62 Kg), N-ethyl-2-pyrrolidinone (186 kg), cyclopropymethyl bromide (37.8 kg) and N,N-diisopropylethylamine (36.2 kg) was heated to 52-57° C. for 24 hours and 45 min. The mixture was then diluted with a solution prepared by mixing hydrochloric acid 37% (30 kg) and water (82 kg). Low boiling compounds were removed by distillation under vacuum keeping the temperature below 70° C. After cooling to 25-30° C. the mixture was further diluted with water (1975 kg). Ammonium hydroxide 4% (206 kg) was then added over three hours till pH=9-10 to precipitate the product. The solid was filtered, washed with water (2×124 kg) and dried under vacuum at 60° C. obtaining 71.3 kg of naltrexone (molar yield 89.6%). HPLC analysis (% by area): naltrexone 99.45%, noroxymorphone 0.16%, 3-cyclopropylmethylnaltrexone 0.28%

Workup

  1. additionThe mixture was then diluted with a solution
  2. customprepared
  3. customwere removed by distillation under vacuum
  4. customthe temperature below 70° C
  5. temperatureAfter cooling to 25-30° C. the mixture
  6. additionwas further diluted with water (1975 kg)
  7. additionAmmonium hydroxide 4% (206 kg) was then added over three hours till pH=9-10
  8. customto precipitate the product
  9. filtrationThe solid was filtered
  10. washwashed with water (2×124 kg)
  11. customdried under vacuum at 60° C.

Sources & evidence

ORD record
ord-b24d7f8899f24029884c26f6c5d6b9a7
Source dataset
uspto-grants-2013_11
Patent number
US08580963B2

Reaction notes

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