반응 단계
To a solution of (2R,4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester (prepared by using the procedure described in US005217996) (200 mg, 0.486 mmol) in DMF (3 mL) are added EDC-HCl (112 mg, 0.583 mmol) and HOAt (79 mg, 0.583 mmol) at room temperature. After stirring for 10 minutes, 3-aminopropionitrile (41 mg, 0.583 mmol) and triethylamine (0.081 mL, 0.583 mmol) is added and stirred overnight. Additional EDC-HCl (66 mg, 0.292 mmol), HOAt (40 mg, 0.292 mmol), aminopropionitrile (21 mg, 0.292 mmol), and triethylamine (0.081 mL, 0.583 mmol) are added. After stirring for 1 hour, the reaction mixture is heated to 50° C. and stirred for 5 hours. The reaction mixture is diluted with ethyl acetate and washed with H2O and brine. The organic layer is dried over Na2SO4 and concentrated. The residue is purified by silica gel column chromatography to give (2R,4S)-5-biphenyl-4-yl-4-[3-(2-cyano-ethylcarbamoyl)-propionylamino]-2-methyl pentanoic acid ethyl ester. HPLC Retention time 1.37 minutes (condition B); MS 464 (M+1); 1H NMR (400 MHz, CDCl3) δ ppm 1.17 (d, J=7.33 Hz, 3H), 1.25 (t, J=7.07 Hz, 3H), 1.51 (ddd, J=4.29, 0.85, 14.14 Hz, 1H), 1.95 (ddd, J=4.29, 9.60, 13.89 Hz, 1H), 2.41-2.59 (m, 5H), 2.58 (t, J=6.57 Hz, 2H), 2.83 (d, J=6.57 Hz, 2H), 3.45 (ddd, J=2.53, 8.00, 12.0 Hz, 2H), 4.14 (ddd, J=2.53, 8.00, 14.01 Hz, 2H), 4.21-4.31 (m, 1H), 5.64 (d, J=9.09 Hz, 1H), 6.60-6.67 (m, 1H), 7.24 (d, J=8.34 Hz, 2H), 7.34 (t, J=7.33 Hz, 1H), 7.43 (t, J=7.83 Hz, 2H), 7.53 (d, J=8.34 Hz, 2H), 7.58 (d, J=7.07 Hz, 2H).
