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

Participants

Reaction Conditions

Reaction Steps

To a solution of (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (30.5 g, 71.0 mmol) and (6R,7R)-benzhydryl 7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, hydrochloride (32.1 g, 71.0 mmol) in dichloromethane (500 mL), stirred under nitrogen at −30° C., was added neat phenyl phosphorodichloridate (12.93 mL, 85 mmol). The reaction mixture was cooled to −40° C. and N-methylmorpholine (23.42 mL, 213 mmol) was added dropwise over 30 min, and stirred for an additional 2 hours at −40° C. The reaction was then quenched by addition of 150 mL of a 10% aq. solution of citric acid, and the phases were separated. The organic phase was concentrated and the residue was then dissolved in 500 mL of ethyl acetate. The organic solution was washed with 100 mL of a 5% aq. sodium bicarbonate, 100 mL of brine, dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified on a 330 g silica gel column eluting with 0-80% ethyl acetate in 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)thiazol-4-yl)acetamido)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (42 g, 50.8 mmol, 71.6% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42 (s, 9 H) 1.55 (s, 9 H) 1.63 (s, 3 H) 1.66 (s, 3 H) 3.52 (d, J=18.19 Hz, 1 H) 3.66 (d, J=18.19 Hz, 1 H) 4.43 (d, J=4.29 Hz, 2 H) 5.12 (d, J=5.05 Hz, 1 H) 6.08 (dd. J=8.84, 5.05 Hz, 1 H) 6.99 (s, 1 H) 7.30-7.49 (m, 12 H) 8.25 (d, J=8.84 Hz, 1 H). LCMS: (M+H)+: 826.5.

Provenance & Evidence