O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate → n-[(2r)-2-({[4-((2r,3r)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}amino)-2-phenylacetyl]-d-alanine

Participants

Reaction Steps

(2R)-({[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}amino)(phenyl)acetic acid (0.040 g, 0.065 mmol) was dissolved in CH2Cl2 (5 ml). tert-Butyl D-alaninate hydrochloride (0.014 g, 0.078 mmol) and N-methyl-morphiline (0.020 g, 0.195 mmol) were added. After 5 minutes TBTU (0.027 g, 0.084 mmol) was added. The reaction was allowed to stir overnight and the resulting tert-butyl ester was purified on silica gel and eluted with EtOAc/CH2Cl2 (25/75). The pure fractions were concentrated. The residue was dissolved in CH2Cl2 (4 ml) and trifluoroacetic acid (0.5 ml). After 1.5 h at room temperature, full conversion to the corresponding acid was obtained. The reaction mixture was concentrated and the remaining TFA was removed through co-evaporation with toluene (3 ml). The crude acid was dissolved in MeOH (3 ml) and NaBH4 (0.010 g, 0.260 mmol) was added. Full conversion to the corresponding alcohol was obtained after 5 minutes. The reaction was quenched by the addition of 0.1M NH4OAc buffer (1 ml). The mixture was concentrated and the residue was purified by preparative HPLC using a gradient of 20-50% CH3CN in 0.1M NH4OAc buffer as mobile phase. Freeze-drying gave the title compound (0.024 g, 54%) as a colourless solid. M/z: 688.6 (M−1). 1H NMR [(CD3)2SO), 400 MHz] δ 1.10-1.24 (m, 3H), 2.89-2.94 (m, 2H), 3.99-4.08 (m, 1H), 4.26-4.30 (m, 1H), 4.60 (d, 1H), 4.64 (d, 1H), 4.70-4.78 (m, 1H), 5.02-5.08 (m, 1H), 5.53-5.56 (d, 1H), 6.94-7.40 (m, 17H), 8.39-8.59 (m, 2H).

Provenance & Evidence