Trifluoroacetic acid → HCID 89488642, compound

Participants

Reaction Steps

To a solution of 1-(((6R,7R)-2-((benzhydryloxy)carbonyl)-7-((Z)-2-((((S)-4-(tert-butoxy)-1-((4-methoxybenzyl)oxy)-1,4-dioxobutan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)-5-chlorothiazol-4-yl)acetamido)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl)-1-((5-chloro-1-ethyl-6,7-bis((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinolin-3-yl)methyl)pyrrolidin-1-ium (2.41 g, 1.018 mmol) in Dichloromethane (DCM) (15 mL) under N2 at 0° C. was added anisole (1.112 mL, 10.18 mmol), followed by TFA (5.0 mL, 64.9 mmol). The mixture was warmed up to rt and stirred at rt over night. LCMS indicated completion of the deprotection. The mixture was cooled to 0° C., Diisopropyl ether (50 mL) was then added. The mixture was stirred for 10 min and the solid was collected by filtration, and washed twice with diisopropyl ether (2×10 mL). The crude product was dissolved in a mixture of CH3CN (10 mL)/water (10 mL)/2M HCl (2.5 mL), HP20SS resin (10 g) was then added. The mixture was concentrated to dryness, and the resin was loaded in a pre-column containing HP20SS resin (15 g), and was then purified by reverse phase Combiflash using C18 column and eluting with 0-30% CH3CN/water to afford (6R,7R)-7-((Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(((S)-1,2-dicarboxyethoxy)imino)acetamido)-3-((1-((5-chloro-1-ethyl-6,7-dihydroxy-4-oxo-1,4-dihydroquinolin-3-yl)methyl)pyrrolidin-1-ium-1-yl)methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (0.504 g, 0.59 mmol, 43.3% yield) as a slightly brown solid. Portion of this product (0.283 g, 0.331 mmol) was suspended in pure water (HPLC grade, 20 mL) with the help of sonication, and cooled to 0° C. With vigorous stirring, aq NaOH (0.2 N, 1.655 mL, 0.331 mmol) was added slowly into the suspension from an Eppendorf Pipette. After the addition a small piece of dry ice was added to quench any extra NaOH. The mixture was then frozen and lyophilized to afford (6R,7R)-7-((Z)-2-(2-amino-5-chlorothiazol-4-yl)-2-(((S)-1,2-dicarboxyethoxy)imino)acetamido)-3-((1-((5-chloro-1-ethyl-6,7-dihydroxy-4-oxo-1,4-dihydroquinolin-3-yl)methyl)pyrrolidin-1-ium-1-yl)methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, Sodium salt (0.291 g, 0.315 mmol, 95.2% yield) as a slightly brown solid. LCMS: (M+H)+: 854.0. 1H NMR (400 MHz, DEUTERIUM OXIDE) ppm 1.30 (t, J=6.95 Hz, 3 H) 2.01 (br. s., 4 H) 2.69 (d, J=6.57 Hz, 2 H) 3.23-3.47 (m, 6 H) 3.83-3.92 (m, 1 H) 3.96-4.04 (m, 1 H) 4.07-4.17 (m, 2 H) 4.18-4.37 (m, 2 H) 4.86 (t, J=6.57 Hz, 1H) 5.27 (d, J=4.80 Hz, 1 H) 5.67-5.76 (m, 1 H) 6.83-6.91 (m, 1 H) 7.97-8.06 (m, 1 H)

Provenance & Evidence