1,3-Dichloroacetone → 8-chloro-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol

HRID 566289

Reaction equation

HRID 566289 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[CH2:21][C:22]([CH2:24]Cl)=O.C(=O)([O-])[OH:27].[Na+]>O1CCOCC1>[Cl:19][C:16]1[CH:17]=[CH:18][C:4]2[N:3]3[CH:24]=[C:22]([CH2:21][OH:27])[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

5

Reactant 3

HCID 107931,3-DichloroacetoneHCID 165626N-Desmethyl-N(4)-desoxychlordiazepoxideHCID 516892Sodium Bicarbonate

Product 1

HCID 212659938-chloro-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanolYield 28.2%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Conditions

Temperature
98 °C

Procedure

A solution of 10.9 g of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine (K. Meguro, H. Tawada & Y. Kuwada, Yakugaku Zasshi, 1973, 93, 1253-1262) and 5.2 g of 1,3-dichloroacetone in 200 ml of dioxan was treated with 3.13 g of anhydrous sodium hydrogen carbonate and stirred at 98° C. for 22 h. After cooling the inorganic salts were filtered off, the filtrate was treated with 0.93 g of p-toluenesulphonic acid and stirred at 98° C. for 1.5 h. 74.5 ml of 1N aqueous sodium hydroxide solution and 2.5 g of active charcoal were added to this solution and the mixture was stirred at 80° C. for 2 h. After cooling the mixture was filtered over Dicalite and the filtrate was concentrated in a vacuum. The residue was taken up in dichloromethane and water and the aqueous phase was extracted four times with chloroform. The chloroform was evaporated in a vacuum. The residue (about 8 g) was crystallized from ethyl acetate. The crystals (7.3 g) were filtered off, dissolved in dichloromethane and chromatographed over 180 g of silica gel. The desired product was eluted with dichloromethane containing 2 to 4% ethanol and was recrystallized from ethyl acetate/ethanol 2:1. There were obtained 3.4 g of 8-chloro-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol of m.p. 203-204° C., which was converted into the hydrochloride, m.p. 252-254° C.

Workup

  1. temperatureAfter cooling the inorganic salts
  2. filtrationwere filtered off
  3. additionthe filtrate was treated with 0.93 g of p-toluenesulphonic acid
  4. stirringstirred at 98° C. for 1.5 h
  5. addition74.5 ml of 1N aqueous sodium hydroxide solution and 2.5 g of active charcoal were added to this solution
  6. stirringthe mixture was stirred at 80° C. for 2 h
  7. temperatureAfter cooling the mixture
  8. filtrationwas filtered over Dicalite
  9. concentrationthe filtrate was concentrated in a vacuum
  10. extractionwater and the aqueous phase was extracted four times with chloroform
  11. customThe chloroform was evaporated in a vacuum
  12. customThe residue (about 8 g) was crystallized from ethyl acetate
  13. filtrationThe crystals (7.3 g) were filtered off
  14. dissolutiondissolved in dichloromethane
  15. customchromatographed over 180 g of silica gel
  16. washThe desired product was eluted with dichloromethane containing 2 to 4% ethanol
  17. customwas recrystallized from ethyl acetate/ethanol 2:1

Sources & evidence

ORD record
ord-fd01a11ba3f44fd4bd75d9145f17f41b
Source dataset
uspto-grants-2001_01
Patent number
US06174881B1

Linked notes

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