Triethylamine → (+)-N-[5-Cycloheptyl-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]N'[3-(N-methyl-N'-piperazinyl)phenyl]urea

HRID 743707Notes

Reaction equation

HRID 743707 reaction equation
[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[CH:3]=1.ClC(Cl)(O[C:19](=[O:25])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[NH2:34][CH:35]1[N:41]=[C:40]([CH:42]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[C:39]2[CH:49]=[CH:50][CH:51]=[CH:52][C:38]=2[N:37]([CH3:53])[C:36]1=[O:54]>O1CCCC1>[CH:42]1([C:40]2[C:39]3[CH:49]=[CH:50][CH:51]=[CH:52][C:38]=3[N:37]([CH3:53])[C:36](=[O:54])[CH:35]([NH:34][C:19]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([N:8]4[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]4)[CH:3]=3)=[O:25])[N:41]=2)[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48]1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 94429TriphosgeneHCID 115646133-(4-Methylpiperazin-1-yl)anilineHCID 214804643-amino-5-cycloheptyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one

Product 1

HCID 15840131(+)-N-[5-Cycloheptyl-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-3-yl]N'[3-(N-methyl-N'-piperazinyl)phenyl]ureaYield 139.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

1-Amino-3-(N-methyl-N'-piperazinyl)benzene (197 mg) in anhydrous tetrahydrofuran (30 ml) was cooled to 0° C. whereupon triphosgene (101 mg) was added. The mixture was stirred at 0° C. for 2 min, then triethylamine (430 μl) was added portionwise until pH8. The mixture was then stirred for a further 5 min, allowed to warm to 15° C., and then re-cooled to 0° C. Then a solution 3-amino-5-cycloheptyl-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one (200 mg) (Enantiomer A) in anhydrous tetrahydrofuran (10 ml) was added dropwise over 5 min. The mixture was stirred at 0° C. for 5 min, allowed to warm to room temperature and then stirred for a further 15 min. The undissolved material was removed by filtration. The filtrate was evaporated in vacuo and the residue partitioned between ethyl acetate (50 ml) and water (30 ml). The organic phase was separated, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel with dichloromethane:methanol (9:1) as eluant to afford the title compound (239 mg) as a colourless solid. Mp 160° C. (dec.). 1H NMR (250 MHz, D6-DMSO) δ 1.05-1.87 (11H, m), 1.88-2.04 (1H, m) 2.21 (3H, s), 2.36-2.47 (4H, m), 2.95-3.21 (5H, m), 3.36 (3H, s), 5.05 (1H, d, J=8 Hz), 6.50 (1H, dd, J=8.2 and 2.0 Hz), 6.61 (1H, d, J=8 Hz), 7.04 (1H, t, J=7.5 Hz), 7.13 (1H, s), 7.25 (1H, d, J=7.5 Hz), 7.39 (1H, t, J=7.0 Hz), 7.52-7.70 (2H, m), 7.76 (1H, d, J=8.0 Hz), 8.89 (1H, s).

Workup

  1. additionwas added
  2. stirringThe mixture was then stirred for a further 5 min
  3. temperatureto warm to 15° C.
  4. temperaturere-cooled to 0° C
  5. stirringThe mixture was stirred at 0° C. for 5 min
  6. temperatureto warm to room temperature
  7. stirringstirred for a further 15 min
  8. customThe undissolved material was removed by filtration
  9. customThe filtrate was evaporated in vacuo
  10. customthe residue partitioned between ethyl acetate (50 ml) and water (30 ml)
  11. customThe organic phase was separated
  12. dry with materialdried (Na2SO4)
  13. customevaporated
  14. customThe residue was chromatographed on silica gel with dichloromethane:methanol (9:1) as eluant

Sources & evidence

ORD record
ord-03ff3ba0a8ca4e9da29115e8d9d3fe3d
Source dataset
uspto-grants-1996_09
Patent number
US05556969

Reaction notes

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