反应详情

5-Cyclohexyl-1,3-dihydro-1-(2-methylpropyl)-3(R,S)-[(benzyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one (1.0 g, 2.23 mmol) was dissolved in formic acid/methanol (130 ml of a 4.5% (v/v) solution), and added over 5 min to a stirred suspension of 10% palladium on carbon (0.36 g, 36% (w/w)) in formic acid/methanol (27 ml of a 4.5% (v/v) solution). After 4 h at room temperature the catalyst was filtered off and washed sequentially with methanol and acetone. The flitrate was evaporated in vacuo and the solid residue partitioned between ethyl acetate (500 ml) and 10% sodium carbonate solution (500 ml). The organic phase was dried (Na2SO4) and evaporated to give a clear oil, which was used without further purification. To a suspension of 5-(3-aminophenyl)tetrazole hydrochloride (0.29 g, 1.45 mmol) in tetrahydrofuran (10 ml) was added triethylamine (0.4 ml, 2.9 mmol). The mixture was cooled in an ice bath and triphosgene (0.14 g, 0.48 mmol) added, followed by triethylamine (0.3 ml, 2.2 mmol). The ice bath was removed and the mixture stirred at room temperature for 30 min. A solution of the aminobenzodiazepine (0.35 g, 1.11 mmol), from the above procedure, in tetrahydrofuran (15 ml) was added dropwise to the mixture. The reaction mixture was stirred at room temperature for 2 h, then diluted with ethyl acetate (30 ml) followed by 20% aqueous acetic acid (30 ml). After stirring for a further 15 min a white precipitate was filtered off and washed with ethyl acetate. The solid was suspended in methanol (20 ml), heated to 50° C., then filtered hot to afford N-[3(R,S)-5-cyclohexyl-2,3-dihydro-1-(2-methylpropyl )-2-oxo-1H-1,4-benzodiazepin-3-yl] N'-[3-tetrazol-5-ylphenyl]urea (280 mg, 39%) as a white solid. mp 188°-190° C. 1H NMR (360 MHz, D6 -DMSO) δ 0.65 (3H, d, J=7 Hz), 0.76 (3H, d, J=7 Hz), 0.99-1.96 (11H, m), 2.97 (1H, m), 3.62 (1H, dd, J=14 and 5 Hz), 4.15 (1H, dd, J=14 and 9 Hz), 5.05 (1H, m), 7.36-7.69 (7H, m), 7.78 (1H, d, J=8 Hz), 8.15 (1H, s), 9.23 (1H, s).

1. filtrationAfter 4 h at room temperature the catalyst was filtered off
2. washwashed sequentially with methanol and acetone
3. customThe flitrate was evaporated in vacuo
4. customthe solid residue partitioned between ethyl acetate (500 ml) and 10% sodium carbonate solution (500 ml)
5. dry with materialThe organic phase was dried (Na2SO4)
6. customevaporated
7. customto give a clear oil, which
8. customwas used without further purification
9. temperatureThe mixture was cooled in an ice bath
10. customThe ice bath was removed
11. stirringThe reaction mixture was stirred at room temperature for 2 h
12. stirringAfter stirring for a further 15 min a white precipitate
13. filtrationwas filtered off
14. washwashed with ethyl acetate
15. temperatureheated to 50° C.
16. filtrationfiltered hot