4-Ethyl-2,3-dioxo-l-piperazinocarbonyl chloride

D-(-)-a-Amino-p-hydroxyphenylacetamido]-3-[5-(l-methyl-l,2,3,4-tetrazolyl)-thiomethyl]-8(3)-cephem-4-carboxylic acid 4-Ethyl-2,3-dioxo-l-piperazinocarbonyl chloride... 

To a suspension of 3.0 g of 7-[D-(-)-a-amino-p-hydroxyphenylacetamido]-3-[5-(l-methyl-l,2,3,4-tetrazolyl)thiomethyl]-A3-cephem-4-carboxylic acid in 29 ml of water was added 0.95 g of anhydrous potassium carbonate. After the solution was formed, 15 ml of ethyl acetate was added to the solution, and 1.35 g of 4-ethyl-2,3-dioxo-l-piperazinocarbonyl chloride was added to the resulting solution at 0°C to 5°C over a period of 15 minutes, and then the mixture was reacted at 0°C to 5°C for 30 minutes. After the reaction, an aqueous layer was separated off, 40 ml of ethyl acetate and 10 ml of acetone... 

To this acid was then added 1 g of 4-ethyl-2,3-dioxo-l-piperazinocarbonyl chloride (from the reaction of N-ethylethylenediamine and diethyl oxalate to give 2,3-dioxo-4-ethyl-piperazine which is then reacted with phosgene) and the resulting mixture was reacted at 15°C to 20°C for 2 hours. After the reaction, a deposited triethylamine hydrochloride was separated by filtration, and the filtrate was incorporated with 0.4 g of n-butanol to deposit crystals. The deposited crystals were collected by filtration to obtain 1.25 g of white crystals of 6-[D(-)a-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino) phenylacetamido]penicillanic acid. Into a solution of these crystals in 30 ml of tetrahydrofuran was dropped a solution of 0.38 g of a sodium salt of 2-ethyl-hexanoic acid in 10 ml of tetrahydrofuran, upon which white crystals were deposited. The deposited crystals were collected by filtration, sufficiently washed with tetrahydrofuran and then dried to obtain 1.25 g of sodium salt of 6-[D(-)-a-(4-ethyl-2,3-dioxo-l-piperazinocarbonylamino)phenylacetamido] penicillanic acid, melting point 183°C to 185°C (decomposition), yield 90%. 

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