Ammonia → Triazolam

HRID 1730766Notes

Reaction equation

HRID 1730766 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH3:21])=[N:19][N:18]=[C:17]1[CH2:22]O.C([N:27](CC)CC)C.CS(Cl)(=O)=O.[I-].[K+].N>O1CCCC1.C(Cl)Cl>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]2[N:16]3[C:20]([CH3:21])=[N:19][N:18]=[C:17]3[CH2:22][N:27]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]=2[CH:14]=1

Participants

8

Reactant 5

HCID 222AmmoniaHCID 4875Potassium IodideHCID 8471TriethylamineHCID 31297Methanesulfonyl chloride2×HCID 64529502',5-Dichloro-2-(3-hydroxymethyl-5-methyl-4H-1,2,4-triazol-4-yl)benzophenone

Product 1

HCID 5556Triazolam

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Procedure

A suspension of 0.363 g. (1.00 mmol.) of 2',5-dichloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone in 5.0 ml. of methylene chloride was cooled to -20° C. in a Dry Ice/acetone bath and treated with 0.206 ml. (0.150 g., 1.50 mmol.) of triethylamine, followed by dropwise addition of 0.106 ml. (1.3 mmol.) of methanesulfonyl chloride. (Most of the starting material dissolved during the addition of the methanesulfonyl chloride.) During 15 minutes the temperature was gradually raised to 0°. The reaction mixture was quenched on ice and extracted with methylene chloride. The organic extracts were treated with a saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated in vacuo to yield an oil. The oil was dissolved in 5 ml. of freshly distilled tetrahydrofuran in a dry flask and treated first with 0.332 g. (2.00 mmol.) of potassium iodide, then ammonia (gas). After saturating the reaction mixture with ammonia, the mixture was warmed to room temperature (22°-24° C.) and stirred for 24 hours. The mixture was quenched in a saturated aqueous sodium hydroxide solution, extracted with chloroform, dried over anhydrous sodium sulfate and concentrated in vacuo to afford an oil. Crystallization from ethyl acetate and methanol/ethyl acetate yielded 25 mg. of a tan solid of melting point 210°-221° C. Recrystallization from ethyl acetate gave pure 8-chloro-1-methyl-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine of melting point 223°-225° C.

Workup

  1. additionA suspension of 0.363 g
  2. additiontreated with 0.206 ml
  3. temperature) During 15 minutes the temperature was gradually raised to 0°
  4. customThe reaction mixture was quenched on ice
  5. extractionextracted with methylene chloride
  6. additionThe organic extracts were treated with a saturated aqueous sodium bicarbonate solution
  7. dry with materialdried over anhydrous sodium sulfate
  8. concentrationconcentrated in vacuo
  9. customto yield an oil
  10. dissolutionThe oil was dissolved in 5 ml
  11. concentrationAfter saturating the reaction mixture with ammonia
  12. customThe mixture was quenched in a saturated aqueous sodium hydroxide solution
  13. extractionextracted with chloroform
  14. dry with materialdried over anhydrous sodium sulfate
  15. concentrationconcentrated in vacuo
  16. customto afford an oil
  17. customCrystallization from ethyl acetate and methanol/ethyl acetate
  18. customyielded 25 mg
  19. customRecrystallization from ethyl acetate

Sources & evidence

ORD record
ord-2708d4e415b04c5fbb65ae014af5ff74
Source dataset
uspto-grants-1976_11
Patent number
US03993660

Reaction notes

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