反应详情

温度

0 °C

To a solution of 3(R,S)-[(benzyloxycarbonyl)amino]-5-cycloheptyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one (1.26 g) at 0° C., under an atmosphere of nitrogen, was added sodium hydride (125 mg of a 50% dispersion in mineral oil). After stirring for 1 h at 0° C. 2-methylpropyl iodide (399 μl) was added and the mixture allowed to warm to ambient temperature over 3 h. More sodium hydride (16 mg of a 50% dispersion in mineral oil) followed by 2-methylpropyl iodide (40 μl) was added and the solution stirred at room temperature for 18 h. More sodium hydride (103 mg of a 50% dispersion in mineral oil) followed by 2-methylpropyl iodide (210 μl) was added and the solution stirred for 4 h at room temperature. The solvent was then evaporated in vacuo and the residue partitioned between dichloromethane (30 ml) and water (30 ml). The organic phase was separated and the aqueous layer washed further with dichloromethane (3×20 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4) and evaporated under reduced pressure. The residue was azeotroped with toluene (2×20 ml), then chromatographed on silica gel using 4:1 petrol:ethyl acetate as the eluant. The product was isolated as a viscous oil which solidified on addition of petrol:ethyl acetate (4:1) (20 ml). After evaporation of the solvent the resultant solid was triturated with petrol (60/80) and the title compound (830 mg) isolated as a white solid. 1H NMR (360 MHz, CDCl3) δ 0.73 (3H, d, J=6.6 Hz), 0.79 (3H, d, J=6.6 Hz), 1.43-1.83 (12H, m), 2.06-2.20 (1H, m), 2.94-3.06 (1H, m), 3.43 (1H, dd, J=13.8 and 5 Hz), 4.27 (1H, dd, J=13.8 and 9.3 Hz), 5.10 (3H, m), 6.56 (1H, d, J=8.2 Hz), 7.24=7.35 (7H, m), 7.49 (1H, dd, J=8.4 and 8.4 Hz), 7.58 (1H, d, J=7.9 Hz). MS (CI, NH3) 462 (M+).

1. temperatureto warm to ambient temperature over 3 h
2. additionwas added
3. stirringthe solution stirred at room temperature for 18 h
4. additionwas added
5. stirringthe solution stirred for 4 h at room temperature
6. customThe solvent was then evaporated in vacuo
7. customthe residue partitioned between dichloromethane (30 ml) and water (30 ml)
8. customThe organic phase was separated
9. washthe aqueous layer washed further with dichloromethane (3×20 ml)
10. washThe combined organic layers were washed with brine (20 ml)
11. dry with materialdried (MgSO4)
12. customevaporated under reduced pressure
13. customThe residue was azeotroped with toluene (2×20 ml)
14. customchromatographed on silica gel using 4:1 petrol
15. customThe product was isolated as a viscous oil which
16. customAfter evaporation of the solvent the resultant solid
17. customwas triturated with petrol (60/80)