Hydrazine hydrate (1:1) → Alprazolam

HRID 1764514

Reaction equation

HRID 1764514 reaction equation
[NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:4]=2[N:3]=1.Cl.[CH3:21][C:22]1[NH:23]C=CN=1.O.NN.C([O-])([O-])(OCC)C>C(O)C.CO>[Cl:19][C:16]1[CH:17]=[CH:18][C:4]2[N:3]3[C:22]([CH3:21])=[N:23][N:1]=[C:2]3[CH2:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]=2[CH:15]=1

Participants

7

Reactant 4

HCID 24654Hydrazine hydrate (1:1)HCID 165626N-Desmethyl-N(4)-desoxychlordiazepoxideHCID 5216292-Methylimidazole hydrochlorideHCID 86598186Ethyl ortho-acetate

Product 1

HCID 2118Alprazolam

Reagents, catalysts & solvents 2

HCID 702EthanolSolventHCID 887MethanolSolvent2×

Procedure

To a suspension of 1.35 parts of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine in 25 parts by volume of methanol are added 0.6 part of 2-methylimidazole hydrochloride and 6 parts by volume of 1 mole methanol solution of hydrazine hydrate. The mixture is stirred at room temperature for 1.5 hours, followed by addition of 4.8 parts of ethyl orthoacetate and 10 parts by volume of ethanol containing 10% hydrogen chloride. The mixture is refluxed for 30 minutes, followed by evaporation of the solvent. The residue is neutralized with saturated aqueous sodium bicarbonate and extracted with methylene chloride. The methylene chloride extract is washed with water and dried over sodium sulfate, followed by evaporation of the solvent. The residue is purified by means of silica gel column-chromatography to give 8-chloro-1-methyl-6-phenyl-4H-s-triazolo [4,3-a][1,4] benzodiazepine. Recrystallization from a mixture of acetone and n-hexane affords colorless needles. Melting point: 225° C to 226° C.

Workup

  1. temperatureThe mixture is refluxed for 30 minutes
  2. customfollowed by evaporation of the solvent
  3. extractionextracted with methylene chloride
  4. extractionThe methylene chloride extract
  5. washis washed with water
  6. dry with materialdried over sodium sulfate
  7. customfollowed by evaporation of the solvent
  8. customThe residue is purified by means of silica gel column-chromatography

Sources & evidence

ORD record
ord-6b343a50e8d947faa2445817e7501c13
Source dataset
uspto-grants-1978_09
Patent number
US04116956

Linked notes

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