Ethyl Acetate → 3-(S)-(2-(S)-Benzyloxycarbonylamino-4,4-dimethyl-pentanoylamino)-4-(5-fluoro-2,3-dihydro-indol-1-yl)-butyric acid tert-butyl ester

Participants

Reaction Steps

A sample of the product of step A (1.3 g, 3.0 mmol) was treated with 20% Pd(OH)2 on carbon (260 mg) and methanol (2 mL). The atmosphere in the reaction was exchanged for hydrogen by sparging the solution with a long needle for 3 minutes and the reaction was stirred under 1 atmosphere of hydrogen for 2 hours. The atmosphere was exchanged back to nitrogen by again sparging the solution with a long needle for 3 minutes. The reaction mixture was filtered through celite and the solvent was removed. The resulting oil was treated with Cbz-tBu-ala DCHA salt (1.8 g, 3.7 mmol), HATU (1.4 g, 3.8 mmol) and DMF (2 mL). The reaction was then treated with diisopropylethylamine (1.2 g, 9.2 mmol) and stirred overnight. The reaction was diluted with ethyl acetate and extracted with water twice and 1 M NaOH once. The organics were then dried over MgSO4 and the solvent was removed. The residue was purified over silica gel using a gradient of 0 to 100% ethyl acetate in hexane to afford 1.3 g (77%) of the title material as a solid; 1H NMR (CDCl3, 400 MHz) δ 0.92 (s, 9H), 1.39 (dd, 1H, J1=5.8, J2=14.4), 1.44 (s, 9H), 1.82 (dd, 1H, J1=3.7, J2=14.5), 2.51 (dd, 1H, J1=5.5, J2=16.2), 2.61 (dd, 1H, J1=4.7, J2=16.3), 2.92 (dd, 1H, J1=J2=8.2), 3.07 (dd, 1H, J1=7.4, J2=13.6), 3.17 (dd, 1H, J1=6.0, J2=13.8), 3.28-3.47 (m, 2H), 4.09-4.17 (m, 1H), 4.33-4.43 (m, 1H), 4.98-5.13 (m, 3H), 6.40 (dd, 1H, J1=4.0, J2=8.4), 6.69-6.84 (m, 3H), 7.26-7.37 (m, 5H); HPLC-MS calcd. for C31H42FN3O5 (M+H+) 556.3, found 556.5.

Provenance & Evidence