Cyclopropanecarboxylic acid → (S)-8-chloro-1-[5-(cyclopropyl)-1,2,4-oxadiazol-3-yl]-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one

HRID 867550Notes

Reaction equation

HRID 867550 reaction equation
[CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.[Cl:7][C:8]1[C:13]2[C:14](=[O:29])[N:15]3[CH2:28][CH2:27][CH2:26][C@H:16]3[C:17]3[N:18]([CH:19]=[N:20][C:21]=3[C:22](=[N:24]O)[NH2:23])[C:12]=2[CH:11]=[CH:10][CH:9]=1>CN(C)C=O>[Cl:7][C:8]1[C:13]2[C:14](=[O:29])[N:15]3[CH2:28][CH2:27][CH2:26][C@H:16]3[C:17]3[N:18]([CH:19]=[N:20][C:21]=3[C:22]3[N:24]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[O:6][N:23]=3)[C:12]=2[CH:11]=[CH:10][CH:9]=1

Participants

4

Reactant 2

HCID 15655Cyclopropanecarboxylic acidHCID 53703069(S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamidoxime

Product 1

HCID 54012187(S)-8-chloro-1-[5-(cyclopropyl)-1,2,4-oxadiazol-3-yl]-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

17.0 g (105 mmol) of N,N'-carbonyldiimidazole are added portionwise to a solution of 8.61 g (100 mmol) of cyclopropanecarboxylic acid in 30 ml of N,N-dimethylformamide. The mixture is stirred at room temperature for 1 hour and then heated rapidly to 50°. The solution obtained is added to a suspension of 33.1 g (100 mmol) of (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamidoxime in 100 ml of N,N-dimethylformamide and the mixture is heated to 90° for 2.5 hours. The solvent is removed on a rotary evaporator and is replaced by 100 ml of acetic acid. After stirring at 120° for 2.5 hours the mixture is again evaporated, the residue is dissolved in methylene chloride and washed with saturated sodium bicarbonate solution. The organic phase is dried over magnesium sulphate and concentrated. By chromatography of the oily residue on silica gel while eluting with ethyl acetate and recrystallization from alcohol and a small amount of methylene chloride there is obtained (S)-8-chloro-1-[5-(cyclopropyl)-1,2,4-oxadiazol-3-yl]-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 236°-237°

Workup

  1. temperatureheated rapidly to 50°
  2. customThe solution obtained
  3. temperaturethe mixture is heated to 90° for 2.5 hours
  4. customThe solvent is removed on a rotary evaporator
  5. stirringAfter stirring at 120° for 2.5 hours the mixture
  6. customis again evaporated
  7. dissolutionthe residue is dissolved in methylene chloride
  8. washwashed with saturated sodium bicarbonate solution
  9. dry with materialThe organic phase is dried over magnesium sulphate
  10. concentrationconcentrated
  11. washBy chromatography of the oily residue on silica gel while eluting with ethyl acetate and recrystallization from alcohol

Sources & evidence

ORD record
ord-1ac2b008adfd4bbe8d9f85adc7dc5cec
Source dataset
uspto-grants-1988_10
Patent number
US04775671

Reaction notes

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