(4-Methoxyphenyl)methyl (6R,7R)-3-(chloromethyl)-8-oxo-7-[(2-phenylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

2000ml dioxane, Sodium bicarbonate 120 g (1.43 mol), 200 g of azobutanone sulfinic acid intermediate (0.336 mmol), After stirring at 10 to 15 ° C, 30 g (0.422 mol) of chlorine gas was slowly introduced, About 3 h, HPLC analysis, Raw material peak area of 0.5percent or less, Stop the chlorine gas, filter out sodium bicarbonate, vacuum recovery of dioxane, add 2000ml methanol dissolved, To maintain the temperature of 0 ~ 5 , add sodium methoxide 18g (0.34mol) and 900ml methanol solution of sodium methoxide solution, after adding 0 ~ 5 reaction 30 minutes, add 10percent hydrochloric acid to adjust the system pH 4 ~ 6, 0 ~ 5 , stirring 1h, filtration, Washed with water and methanol, dried to give GCLE125g, yield 76.3percentContent ≥94percentAdding NaI to a suspension of Compound 1 (4.86 g, 10 mmol) and acetone (110 mL)15 g, 100 mmol, 10 equivalents). Stir at room temperature for 2 hours, A substitution reaction takes place and the solvent is removed in vacuo. The crude mixture was partitioned between H 2 O (100 mL) and organic solvent (100 mL). The aqueous layer was extracted with the same organic solvent (2×100 ml), and then the combined organic layer was washed with 5% Nas.The organic layer was dried over a dry pad, filtered and concentrated in vacuo.The crude product was dissolved in acetonitrile (150 mL), 7-hydroxy coumarin (3.24 g, 20 mmol, 2 eq.) and potassium carbonate (5.52 g, 40 mmol, 4 eq.).A substitution reaction occurs. The reaction mixture was stirred at room temperature for 12 hours.The solvent was evaporated in vacuo to give the crude mixture in water (100 ml) and organic solvent (100 ml)Allocated. After separating the layers, the aqueous layer was extracted with the same organic solvent (2×100 ml).The combined organic layers were then washed with 5% aqueous Na 2 O 3 (2 100 mL) and brine (100 mL). The organic layer was dried over a dry pad, filtered and concentrated in vacuo.The crude product was purified by column chromatography ( petroleum ether / ethyl acetate, 1:1).Compound 2 (2.4 g, 39%) was obtained as a light brown solid.25 g of GCLE and 17.9 g of AE active ester were added to a mixed solvent of 400 ml of dichloromethane and 80 ml of ethanol.Stir and cool to -5 ° C, add 7.7 ml of triethylamine and 1.2 ml of pyridine.The completion temperature of the drop does not exceed 0 ° C, and the temperature is controlled.Stir until dissolved and continue to react for 2.5 h.Warming up to 18 ° C, Add 300ml of purified water and stir for 15min, let stand for 10min, and dispense.The aqueous phase was collected, and 180 ml of purified water was added to the organic phase, and the mixture was stirred for 15 minutes.Allow to stand for 10 min, separate the liquid, and combine the two aqueous phases.Add 15percent dilute hydrochloric acid to adjust the pH to 3.0 crystallization, and cool down to 5 °C.Filtration, ethanol elution and vacuum drying gave 22.5 g of Compound A in a yield of 81.42percent.

Molecular Weight:487.0
XLogP3:2.7
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:9
Exact Mass:486.1016207
Monoisotopic Mass:486.1016207
Topological Polar Surface Area:110
Heavy Atom Count:33
Complexity:777
Defined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes