Ammonia → Alprazolam

HRID 1974055Notes

Reaction equation

HRID 1974055 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22]Br)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.[NH3:24]>O1CCCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]3[C:20]([CH3:21])=[N:19][N:18]=[C:17]3[CH2:22][N:24]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=2[CH:15]=1

Participants

5

Reactant 2

HCID 222AmmoniaHCID 126119365-chloro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone

Product 1

HCID 2118Alprazolam

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

A stirred suspension of 5-chloro-2-[3-(bromomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone (391 mg., 0.001 mole) in tetrahydrofuran (15 ml.) is cooled in an ice bath and treated with a saturated solution of ammonia in methanol (12.5 ml.). The resulting solution is allowed to warm to ambient temperature and stand for 24 hours. It is then concentrated in vacuo. The residue is suspended in water, treated with a little sodium bicarbonate and extracted with methylene chloride. The extract is washed with brine, dried with anhydrous potassium carbonate and concentrated. The residue is crystallized from methylene chloride-ethyl acetate to give 0.229 g. of crude product of melting point 227°-228.5° C. Recrystallization of this material from ethyl acetate gives three crops of 8-chloro-1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine: 0.142 g. of melting point 228°-229.5°, 0.053 g. of melting point 228.5°-229.5° C. and 0.021 g. of melting point 228°-229.5° C.

Workup

  1. temperatureis cooled in an ice bath
  2. concentrationIt is then concentrated in vacuo
  3. additiontreated with a little sodium bicarbonate
  4. extractionextracted with methylene chloride
  5. washThe extract is washed with brine
  6. dry with materialdried with anhydrous potassium carbonate
  7. concentrationconcentrated
  8. customThe residue is crystallized from methylene chloride-ethyl acetate
  9. customto give 0.229 g
  10. customRecrystallization of this material from ethyl acetate

Sources & evidence

ORD record
ord-400d35f12e9c45bcb054d5bf11b2ad72
Source dataset
uspto-grants-1976_12
Patent number
US04000151

Reaction notes

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