4-Methylmorpholine → N2-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-L-glutaminyl-D-tyrosine

Participants

Reaction Steps

N2-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-hydroxyethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}-L-glutamine (22 mg, 0.0359 mmol), tert-butyl D-tyrosinate hydrochloride (10 mg, 0.0421 mmol) and N-methylmorpholine (14 mg, 0.138 mmol) were dissolved in methylene chloride (0.5 ml). TBTU (14 mg, 0.0436 mmol) was added and the mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was dissolved in formic acid (1 ml). The mixture was stirred at 45-50° C. for 4 h and was then evaporated under reduced pressure. Methanol (10 ml) was added and evaporated. The residue was dissolved in methanol (2 ml). Three drops of TEA were added and the mixture was stirred overnight at room temperature. The solvent was evaporated and the residue was purified by preparative HPLC using acetonitrile/ammonium acetate buffer (40:60) as eluent. After freeze-drying 15 mg (54%) of the title compound was obtained. 1H-NMR, 300 MHz, DMSO): 1.60-2.00 (m, 4H), 2.69-3.0 (m, 4H), 4.09-4.18 (m, 1H), 4.22-4.35 (m, 3H), 4.49 (s, 2H), 4.65-4.78 (m, 1H), 4.97-5.08 (m, 1H), 6.56 (d, 2H), 6.70 (s, 1H), 6.86-7.40 (m, 18H), 7.77-7.91 (m, 1H), 8.12 (d, 1H), 9.10 (bs, 1H).

Provenance & Evidence