Acetic Acid → Adinazolam

HRID 268532Notes

Reaction equation

HRID 268532 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]N)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1.C=O.[C:26]([BH3-])#[N:27].[Na+].[C:30](O)(=O)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:27]([CH3:26])[CH3:30])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:23]=1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 712FormaldehydeHCID 5003444Sodium cyanoborohydrideHCID 12611937Desmethyladinazolam

Product 1

HCID 37632AdinazolamYield 37.6%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent2×

Procedure

A solution of the crude 8-chloro-1-[(aminomethyl)]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine in acetonitrile is treated successively with 37% formalin (1.5 ml) and sodium cyanoborohydride (0.375 g). During the next 1 hour 20 minutes, 2 ml. of a 10% (v/v) solution of acetic acid in acetonitrile is added periodically, dropwise in such a manner that the temperature of the mixture remains between 25°-30° without external cooling. When the reaction is complete, the pH of the solution is about 6.8 and no further rise in temperature is noted after the addition of acid. The mixture is stirred for an additional 25 minutes and concentrated in vacuo. The residue is dissolved in methanol and concentrated. This residue is dissolved in methanol (30 ml), treated with 25% aqueous ethylenediamine (15 ml) and refluxed for 45 minutes. The mixture is cooled, diluted with water, saturated with sodium chloride and extracted with chloroform. The extract is washed (brine), dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on silica gel (100 g) with 2% methanol-98% chloroform. The resulting product is crystallized from ethyl acetate-Skellysolve B hexanes to give 8-chloro-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine in 2 crops: 330 mg. of melting point 170°-172.5°C; 67 mg. of melting point 168°-171°C (total yield 37.6%).

Workup

  1. customDuring the next 1 hour 20 minutes, 2 ml
  2. customremains between 25°-30° without external cooling
  3. additionafter the addition of acid
  4. concentrationconcentrated in vacuo
  5. dissolutionThe residue is dissolved in methanol
  6. concentrationconcentrated
  7. dissolutionThis residue is dissolved in methanol (30 ml)
  8. additiontreated with 25% aqueous ethylenediamine (15 ml)
  9. temperaturerefluxed for 45 minutes
  10. temperatureThe mixture is cooled
  11. additiondiluted with water, saturated with sodium chloride
  12. extractionextracted with chloroform
  13. washThe extract is washed (brine)
  14. dry with materialdried over anhydrous sodium sulfate
  15. concentrationconcentrated
  16. customThe residue is chromatographed on silica gel (100 g) with 2% methanol-98% chloroform
  17. customThe resulting product is crystallized from ethyl acetate-Skellysolve B hexanes

Sources & evidence

ORD record
ord-5928e4aaa4a7463c917503be9211309d
Source dataset
uspto-grants-1976_03
Patent number
US03947466

Reaction notes

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