220587-29-1

216439-76-8

119771-23-2

Synthesis of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propionic acid from methyl (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propionate and ( S)-3-(4-boronic acid phenyl)-2-((tert-butoxycarbonyl)amino)propionic acid was performed in the following general steps: the above organic ester layer was stirred with an aqueous lithium hydroxide solution (23 g, dissolved in 500 mL of water) for 30 min at room temperature. The pH of the reaction mixture was adjusted to about 10 with 6N hydrochloric acid and subsequently filtered. The filter cake was washed with 200 mL of water. Acetonitrile was removed from the filtrate by distillation under reduced pressure to give an aqueous slurry (water was supplemented during distillation to a total volume of 950 mL). The slurry was filtered through a 20 micron cellulose pad and the filter cake was washed with 200 mL of water. The filtrate was washed with 500 mL of methyl tertiary butyl ether (MTBE) and then rediluted with 700 mL of MTBE. The mixture was acidified with 6N hydrochloric acid to pH about 4.5. The organic layer was washed with 500 mL of water and concentrated under reduced pressure to give the target acid compound as a brown oil (206 g, estimated purity of 95% based on NMR). The crude product can be used directly in the next step of the reaction. Alternatively, it can be purified by solvent recrystallization from MTBE/heptane mixture to give a white solid product containing a small amount of (S)-3-(4-boronic acid phenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid. Mass spectral (ESI) data: MH+ = 392.2, MNH4+ = 409.2, M2H+ = 783.4, M2NH4+ = 800.4. 1H NMR (CDCl3) δ 7.95 (br s, 1H), 7.76 (d, J = 7.8 Hz, 2H), 7.21 (d, J = 7.6 Hz, 2H), 5.03 (d, J = 7.8 Hz, 1H), 4.62 (m, 1H), 3.18 (m, 2H), 1.43 (s, 9H), 1.35 (s, 12H).13C NMR (CDCl3) δ 175.8, 155.7, 139.7, 135.4, 129.2, 84.2, 80.5, 54.5, 38.3, 28.7, 25.2.