Ethyl Acetate → (6R,7R)-3-[[5-amino-1-methyl-4-[[(3S)-pyrrolidin-3-yl]carbamoylamino]pyrazol-2-ium-2-yl]methyl]-7-[[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(2-carboxypropan-2-yloxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

Participants

Reaction Steps

To a solution of benzhydryl 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-tert-butoxycarbonyl-1-methylethoxyimino)acetamido]-3-iodomethyl-3-cephem-4-carboxylate (820 mg) in N,N-dimethylformamide (2.4 ml) was added N-(trimethylsilyl)acetamide (656 mg), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added tert-butyl (3S)-3-[({[1-methyl-5-(tritylamino)-1H-pyrazol-4-yl]amino}carbonyl)amino]-1-pyrrolidinecarboxylate (680 mg). The whole mixture was stirred at room temperature for 3 hours. To the resulting reaction mixture were added ethyl acetate (80 ml) and water (50 ml). The aqueous layer was separated, and the organic layer was washed successively with 10% aqueous sodium trifluoroacetate solution, 10% aqueous sodium thiosulfate solution and brine, dried over sodium sulfate and filtered. The filtrate was concentrated to about 5 ml in vacuo. The concentrate was poured into diisopropyl ether (120 ml), and the resulting precipitate was collected by filtration and dried in vacuo. To a solution of the resulting solid in methylene chloride (3.0 ml) were added anisole (1.0 ml) and trifluoroacetic acid (2.0 ml), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into diisopropyl ether (100 ml), and the resulting precipitate was collected by filtration and dried in vacuo to give a crude product (870 mg), which was purified by preparative HPLC utilizing ODS column. The eluate containing a desired product was concentrated to about 30 ml in vacuo. The concentrate was adjusted to about pH 3 with concentrated hydrochloric acid and chromatographed on Diaion® HP-20 (Mitsubishi Chemical Corporation) eluting with 30% aqueous 2-propanol. The eluate was concentrated to about 30 ml in vacuo and lyophilized to give 3-{[3-amino-2-methyl-4-({[(3S)-3-pyrrolidinylamino]carbonyl}amino)-1-pyrazolio]methyl}-7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(1-carboxy-1-methylethoxyimino)acetamido]-3-cephem-4-carboxylate (68 mg) as an amorphous solid.

Provenance & Evidence