Acetohydrazide → Brotizolam

HRID 1816516Notes

Reaction equation

HRID 1816516 reaction equation
[Br:1][C:2]1[S:19][C:5]2[NH:6][C:7](=O)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[C:26]([NH:29][NH2:30])(=O)[CH3:27].[OH-].[Na+]>N1C=CC=CC=1.ClCCl.O1CCCC1.O>[CH3:27][C:26]1[N:6]2[C:5]3[S:19][C:2]([Br:1])=[CH:3][C:4]=3[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])=[N:9][CH2:8][C:7]2=[N:30][N:29]=1

Participants

9

Reactant 4

HCID 14039AcetohydrazideHCID 14798Sodium HydroxideHCID 24819Phosphorus pentachlorideHCID 1354301237-bromo-5-(2-chlorophenyl)-1,3-dihydro-2H-thieno(2,3-e)(1,4)diazepin-2-one

Product 1

HCID 2451Brotizolam

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 1049PyridineSolventHCID 6344DichloromethaneSolvent2×HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
10 °C

Procedure

A suspension of 50 g (0.14 mol) of (1) in 2.5 ml of pyridine and 200 ml of dichloromethane is added dropwise to a suspension of 36 g (0.183 mol) of phosphorus pentachloride in 250 ml of dichloromethane at 5-10° C. with cooling. The mixture is stirred for 1 hour at 10° C. and a solution of 17 g (0.28 mol) of acetic acid hydrazide in 170 ml of tetrahydrofuran, heated to 40-50° C., is added dropwise with cooling at 10-20° C. The mixture is then stirred for 1 hour at ambient temperature and then refluxed for 5 to 18 hours. It is then cooled to ambient temperature, 380 ml water are added with cooling and the mixture is adjusted to an alkaline pH with 45% sodium hydroxide solution. The phases are separated and the aqueous phase is extracted with 100 ml of dichloromethane. 5 g of activated charcoal are added to the combined organic phases which are then stirred for 10 minutes, filtered and evaporated to dryness in vacuo. The residue is taken up in 750 ml of boiling methylethylketone, 5 g of activated charcoal are added and the resulting mixture is refluxed for another 10 min. The suspension is filtered, then 570 ml of solvent are distilled off. The mixture is allowed to cool slowly to ambient temperature and then cooled to 5° C. and stirred for 2 hours at this temperature. The product that crystallises out is filtered off, washed with 30 ml of cold methylethylketone and 50 ml of cold ethyl acetate and dried overnight at 60° C. in vacuo. Yield: 36.6 g (66%) of brotizolam.

Workup

  1. temperaturewith cooling
  2. additionis added dropwise
  3. temperaturewith cooling at 10-20° C
  4. stirringThe mixture is then stirred for 1 hour at ambient temperature
  5. temperaturerefluxed for 5 to 18 hours
  6. temperatureIt is then cooled to ambient temperature
  7. temperaturewith cooling
  8. customThe phases are separated
  9. extractionthe aqueous phase is extracted with 100 ml of dichloromethane
  10. addition5 g of activated charcoal are added to the combined organic phases which
  11. stirringare then stirred for 10 minutes
  12. filtrationfiltered
  13. customevaporated to dryness in vacuo
  14. addition5 g of activated charcoal are added
  15. temperaturethe resulting mixture is refluxed for another 10 min
  16. filtrationThe suspension is filtered
  17. distillation570 ml of solvent are distilled off
  18. temperatureto cool slowly to ambient temperature
  19. temperaturecooled to 5° C.
  20. stirringstirred for 2 hours at this temperature
  21. customThe product that crystallises out
  22. filtrationis filtered off
  23. washwashed with 30 ml of cold methylethylketone and 50 ml of cold ethyl acetate
  24. customdried overnight at 60° C. in vacuo

Sources & evidence

ORD record
ord-dd1f6088494a479c8c71c4765eaaca0d
Source dataset
uspto-grants-2005_04
Patent number
US06884886B2

Reaction notes

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