反应详情

温度

40 °C

To a suspension of (E)-(R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid [2(ii-a)] (200 g, 524.3 mmol) in degassed ethanol (900 ml) at 40° C. a solution of diiodo(p-cymene)ruthenium(II) dimer (0.052 g, 0.0524 mmol) and (αR,αR)-2,2′-bis(α-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphine]ferrocene (=Mandyphos SL-M004-1) (0.116 g, 0.110 mmol) is added in degassed ethanol (100 ml). The solution is degassed using vacuum and a pressure of 20 bar hydrogen applied. The mixture is stirred at 40° C. for 6 h. Vessel is then purged with nitrogen. Ethanol (700 ml) is removed by distillation. Isopropyl acetate (600 ml) is added. Solvent (600 ml) is removed by distillation. Isopropyl acetate (600 ml) is added. Solvent (600 ml) is removed by distillation. Isopropyl acetate (300 ml) is added and the solution is heated to reflux. Heptane fraction (1200 ml) is added and the mixture is cooled to room temperature. The solid is collected by filtration and washed with heptane fraction-isopropyl acetate 2:1 mixture (360 ml). The solid is dried overnight at 50° C. under 1-50 mbar vacuum to afford the title compound as a white/off-white solid [Ratio 2(i-a): 2(i-b) 99:1, as determined by HPLC analysis]. Mpt 146-147° C.; δH (500 MHz; DMSO) 1.07 (3H, d, J 7.0, 1-CH3), 1.34 (9H, s, (CH3)3), 1.38 (1H, m, 3-HA), 1.77 (1H, m, 3-HB), 2.43 (1H, m, 2-H), 2.70 (2H, d, J 7.0, 5-H), 3.69 (1H, m, 4-H), 6.74 (1H, d, J 9.0, NH), 7.27 (2H, d, J 8.0, Ar-ortho-H(Ph)), 7.36 (1H, t, J 7.0, Ar-(Ph)-para-H), 7.46 (2H, t, J 7.5, Ar-(Ph)-meta-H), 7.57 (2H, d, J 8.0, Ar-meta-H(Ph), 7.64 (2H, d, J 7.5, Ar-(Ph)-ortho-H), 12.01 (1H, s, CO2H); δC (500 MHz, DMSO) 18.1 (1-CH3), 28.3 [(CH3)3], 35.9 (2-C), 37.9 (3-C), 40.7 (5-C), 50.0 (4-C), 77.4 [(C(CH3)3], 126.3, 126.5, 127.2, 128.9, 129.8 (Ar—CH), 137.7 (Ar-ipso-C(Ph)), 138.3 (Ar-para-C(Ph)), 140.1 (Ar-(Ph)-ipso-C), 155.2 (NCO), 177.2 (CO2H); m/z (+ESI) 406 ([MNa]+, 6%), 384 ([MH]+, 31), 328 (100), 284 (19); Found: [MH]+, 384.21691. C23H30NO4 requires MH 384.21693.

1. customThe solution is degassed
2. customVessel is then purged with nitrogen
3. customEthanol (700 ml) is removed by distillation
4. additionIsopropyl acetate (600 ml) is added
5. customSolvent (600 ml) is removed by distillation
6. additionIsopropyl acetate (600 ml) is added
7. customSolvent (600 ml) is removed by distillation
8. additionIsopropyl acetate (300 ml) is added
9. temperaturethe solution is heated to reflux
10. additionHeptane fraction (1200 ml) is added
11. temperaturethe mixture is cooled to room temperature
12. filtrationThe solid is collected by filtration
13. washwashed with heptane fraction-isopropyl acetate 2:1 mixture (360 ml)
14. customThe solid is dried overnight at 50° C. under 1-50 mbar vacuum