H-ASP(OET)-OET HCL

White to off-white powder

The N-Boc-protected (5)-2-amino-l, 4-butandiol 7 was prepared from aspartic acid in 3 steps in 95% overall yield using previously reported methods, shown in Scheme 7 below.General procedure: A mixture of alanine (3.56 g, 0.04 mol) in ethanol (30 mL), with thionyl chloride (3.6 mL) dropwise added at -5 C, was refluxed in ethanol at 78 C under stirring within 1.5 h. Subsequently, the solution was distilled in vacuum to afford Alanine ethyl ester hydrochloride 2a in >80% yield. The physical constants of 2a-2l are identical with the corresponding data in reference [24].To a slurry of LAH (3.0 g, 78.4 mmol) in dry THF (30 mL) was added a solution of l-aspartic acid diethyl ester hydrochloride 13 (7.5 g, 62.7 mmol) in dry THF (50 mL) dropwise at 0 C under a nitrogen atmosphere. Then the solution was heated to reflux and stirred for 1 h. The reaction was cooled to 0 C with ice-water and MeOH (25 mL) was added carefully. After being stirred for 10 min, AcOH (6 mL) and 12 (14.9 g, 94.05 mmol) were added. The reaction was allowed to warm to room temperature and stirred for 12 h. Then conc. H2SO4 (17 mL) was added slowly, and the reaction was heated to reflux for 12 h. The reaction was cooled to 0 C and diluted with saturated NaCl solution (200 mL) and EtOAc (200 mL) and then separated. The aqueous layer was extracted with EtOAc (3 * 100 mL). The combined organic layers were washed with saturated aqueous NaHCO3 solution (100 mL), dried over anhydrous MgSO4 and evaporated under reduced pressure. The resulting crude product was purified by column chromatography on silica gel (1:2 petroleum ether:AcOEt) to give 14 (5.9 g, 32.6 mmol, 52%) as a white solid. Data for 14: Rf 0.22 (1:3 petroleum ether:EtOAc); mp: 68-69 C; [alpha]D25 -39.6 (c 1.6, MeOH); 1H NMR (400 MHz, CDCl3) delta 7.10 (d, J = 3.8, 1 H), 7.00 (s, 1 H), 6.35-6.25 (m, 1 H), 4.70 (dd, J = 11.6, 3.1, 1 H), 4.57-4.42 (m, 1 H), 3.89-3.78 (m, 1 H), 3.61 (ddd, J = 10.9, 8.5, 4.4, 1 H), 2.08 (ddd, J = 11.0, 8.9, 5.0, 2 H), 1.70 (s, 1 H); 13C NMR (100 MHz, CDCl3) delta 159.0, 124.9, 118.4, 118.0, 110.7, 70.0, 58.3, 50.4, 34.5; IR (thin film): numax 3450, 2941, 2877, 1686, 1535, 1471, 1405, 1335, 1211, 1109, 1070, 760; HRMS (ESI): Calcd for C9H11NO3Na [M+Na]+ 204.0631, found: 204.0629.