反应详情

A 1000 mL flask was charged with the product from Example 1B (47.8 g, 0.31 mol), 1,1′-carbonyldiimidazole (60.8 g, 0.37 mol) and 500 mL of ethyl acetate. The mixture was stirred at ambient temperature for 2 hours then (2S)-2-aminopropanamide hydrochloride (46.7 g, 0.70 mol, commercially available from Aldrich) and 30 mL of water were charged to the flask. The reaction mixture was heated at 65° C. for 19 hours. After cooling to ambient temperature, the reaction flask was charged with 500 mL of water and stirred for 4 hours resulting in formation of a crystalline solid. The solid was filtered, rinsed with 100 mL of ethyl acetate, and dried to provide the title compound in 97% diastereomeric excess (de) as determined by HPLC: Zobax RX-C8 column, 5 μm, 4.6×250 mm; detector λ=205 nm, eluted with 15% CH3CN/0.03 M KH2PO4 for 10 minutes then 35% CH3CN/0.03 M KH2PO4 over 15 minutes; retention time 20.01 minutes. Stereochemistry was determined by x-ray crystallography. X-ray data: MW=224.30, C12H20N2O2, crystal dimensions 0.40X0.40X0.40 mm, primitive orthorhombic, P212121 (#19), a=6.9845(9) Å, b=8.642(1) Å, c=22.081(3) Å, V=1332.8(3) Å3, Z=4, Dcalc=1.118 g/cm3. Crystallographic data were collected using MoKα graphite monochromated radiation (λ=0.71069 Å). Refinement of the structure using full matrix least squares refinement of 2049 observed reflections (I>3.00σ(I)) and 145 variable parameters and converged with unweighted and weighted agreement factors of R=0.068 and Rw=0.075. 1H NMR (DMSO-d6, 300 MHz) δ 8.00 (d, 1H), 7.19 (s, 1H), 6.91 (s, 1H), 4.22 (p, 1H), 1.50 (dd), 1.3-1.6 (m, 10H), 1.19 (d, 3H), 0.85 (dd), 0.59 (dd, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 174.1, 169.8, 47.9, 37.0, 28.3, 28.1, 26.7, 25.9, 25.2, 25.2, 18.5, 18.1; MS m/z 225 (M+H)+.

1. temperatureThe reaction mixture was heated at 65° C. for 19 hours
2. temperatureAfter cooling to ambient temperature
3. stirringstirred for 4 hours
4. customresulting in formation of a crystalline solid
5. filtrationThe solid was filtered
6. washrinsed with 100 mL of ethyl acetate
7. customdried