4-Methylmorpholine → N-({4-[(2R,3R)-1-(4-Fluorophenyl)-3-({2-hydroxy-2-[4-(methylthio)phenyl]ethyl}thio)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycyl-D-valine

Participants

Reaction Steps

A solution of {4-[(2R,3R)-1-(4-fluorophenyl)-3-({2-hydroxy-2-[4-(methylthio)phenyl]ethyl}thio)-4-oxoazetidin-2-yl]phenoxy}acetic acid (0.015 g, 0.029 mmol), tert-butyl glycyl-D-valinate hydrochloride (0.009 g, 0.034 mmol) and N-Methylmorpholine (0.013 ml, 0.118 mmol) in DCM (3 ml) was stirred at RT for 10 min, after which TBTU (0.014 g, 0.044 mmol) was added. After 17 h the conversion to the intermediate (m/z: 724.7, M+1) was completed. The solution was diluted with TFA (2 ml) and the mixture was allowed to stir for 2 h. The resulting acid (m/z: 668.6, M+1) was concentrated and the residue was dissolved in MeOH (3 ml). To this solution was added NaBH4 (80 mg, 2.11 mmol) in portions until the reduction of the ketone was completed (LC/MS). The reaction was quenched by the addition of a 0.1M ammonium acetate buffer (3 ml) before most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC, using a gradient of 20-50% MeCN in a 0.1M ammonium acetate buffer as eluent. Freeze-drying of the pure fractions gave the desired product (0.014 g, 70%) as a white solid.

Provenance & Evidence