4-Methylmorpholine → 4-O-tert-butyl 1-O-[(4-methoxyphenyl)methyl] (2S)-2-[(Z)-[2-[[(6R,7R)-2-benzhydryloxycarbonyl-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-yl]amino]-1-[5-chloro-2-[(2-methylpropan-2-yl)oxycarbonylamino]-1,3-thiazol-4-yl]-2-oxoethylidene]amino]oxybutanedioate

Participants

Reaction Steps

To a suspension of (S,Z)-2-(((4-(tert-butoxy)-1-((4-methoxybenzyl)oxy)-1,4-dioxobutan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)acetic acid (16.7 g, 27.2 mmol) and (6R,7R)-benzhydryl 7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, Hydrochloride (12.89 g, 28.6 mmol) in Dichloromethane (DCM) (210 mL) at −30° C. was added phenyl phosphorodichloridate (4.95 mL, 32.6 mmol), followed by dropwise N-methylmorpholine (8.97 mL, 82 mmol) over 15 mins. The mixture was stirred at the same temperature over 3 h. LCMS indicated completion of the reaction. The reaction was quenched by addition of 10% aq. citric acid (85 mL), the organic solution was separated and washed with 5% NaHCO3, brine, and dried (Na2SO4), filtered, and concentrated. The residue was purified by CombiFlash automated silica gel chromatography (330 g column, 0-50% EtOAc/Hexanes) to afford (S)-4-tert-butyl 1-(4-methoxybenzyl) 2-(((Z)-(2-(((6R,7R)-2-((benzhydryloxy)carbonyl)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-7-yl)amino)-1-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)-2-oxoethylidene)amino)oxy)succinate (26 g, 25.7 mmol, 95% yield) as a light yellow foaming solid. LCMS: (M+H)+: 1010.6

Provenance & Evidence