4-Methylmorpholine → benzhydryl (6R,7R)-3-(chloromethyl)-7-[[(2Z)-2-[5-chloro-2-[(2-methylpropan-2-yl)oxycarbonylamino]-1,3-thiazol-4-yl]-2-[2-methyl-1-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]oxyiminoacetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

Participants

Reaction Steps

To a suspension of (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)acetic acid (20 g, 39.2 mmol) and (6R,7R)-benzhydryl 7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, Hydrochloride (18.59 g, 41.2 mmol) in Dichloromethane (DCM) (300 mL) at −30° C. was added phenyl phosphorodichloridate (7.15 mL, 47.1 mmol), followed by dropwise 4-methylmorpholine (12.94 mL, 118 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 (120 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, 0-45% EtOAc/Hexanes) to afford (6R,7R)-benzhydryl 7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)acetamido)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (29.9 g, 34.7 mmol, 89% yield) as a light yellow foaming solid. LCMS: (M+H)+: 860.3

Provenance & Evidence