Isobutyl iodide → 5-Cyclohexyl-1,3-dihydro-1-(2-methylpropyl)-3(R,S)-[(benzyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one

HRID 2379316Notes

Reaction equation

HRID 2379316 reaction equation
[CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:18])[CH:9]([NH:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH2:33][CH:34]([CH3:36])[CH3:35]>CN(C)C=O>[CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:10](=[O:18])[CH:9]([NH:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

5

Reactant 3

HCID 10556Isobutyl iodideHCID 24758Sodium hydrideHCID 135413400Z-(R,S)-3-amino-5-cyclohexyl-2-oxo-1,4-benzodiazepine

Product 1

HCID 189577795-Cyclohexyl-1,3-dihydro-1-(2-methylpropyl)-3(R,S)-[(benzyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-oneYield 56%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A solution of 5-cyclohexyl-1,3-dihydro-3(R,S)-[ (benzyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one(7.0 g, 18 mmol)in dimethylformamide (84 ml), under an atmosphere of nitrogen, was treated with sodium hydride (0.77 g of a 55-60% dispersion in mineral oil, 18 mmol) in one portion, at -10° C. After 30 min at -10° C., 1-iodo-2-methylpropane (2.3 ml, 19.8 mmol) was added in one portion and the solution allowed to reach 0° C. over 2 h, then stirred at ambient temperature overnight. After this time the solvent was removed under reduced pressure, and the crude residue partitioned between water (500 ml) and dichloromethane (500 ml). The organic phase was separated and the aqueous phase extracted with dichloromethane (2×500 ml). The combined organic layers were washed with brine (500 ml), dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica gel, using 2:1 petrol:ethyl acetate as the eluant, to afford the title compound (4.5 g, 56%) as a white solid. mp 148°-150° C. 1H NMR (360 MHz, CDCl3) δ 0.73 (3H, d, J=7 Hz), 0.79 (3H, d, J=7 Hz), 1.14-2.09 (11H, m), 2.80 (1H, m), 3.42 (1H, dd, J=14 and 5 Hz), 4.27 (1H, dd, J=14 and 9 Hz), 5.10 (3H, m), 6.55 (1H, d, J=8 Hz), 7.23-7.34 (8H, m), 7.45 (1H, t, J=8 Hz), 7.56 (1H, d, J=8 Hz).

Workup

  1. customat -10° C
  2. waitto reach 0° C. over 2 h
  3. customAfter this time the solvent was removed under reduced pressure
  4. customthe crude residue partitioned between water (500 ml) and dichloromethane (500 ml)
  5. customThe organic phase was separated
  6. extractionthe aqueous phase extracted with dichloromethane (2×500 ml)
  7. washThe combined organic layers were washed with brine (500 ml)
  8. dry with materialdried (MgSO4)
  9. customevaporated in vacuo
  10. customThe residue was chromatographed on silica gel

Sources & evidence

ORD record
ord-b42841a9010b4778a1258210d67a47a9
Source dataset
uspto-grants-1994_11
Patent number
US05360802

Reaction notes

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