Triethylamine → Cefuroxime Sodium

Participants

Reaction Steps

Chlorosulphonyl isocyanate (39.0 ml) was added to a stirred solution of triethylamine (1.5 ml) in ethyl acetate (280 ml) pre-cooled to -10°, the temperature of the mixture rising to 0°. This mixture was recooled to -10°, and a suspension of (6R,7R)-3-hydroxymethyl-7-[Z-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylic acid (114.4 g) in ethyl acetate (350 ml), pre-cooled to -12°, was blown in by nitrogen pressure. Ethyl acetate (60 ml) was used to wash through the residual solid. The temperature of the reaction mixture rose to 0°. The mixture was stirred at 0° to 3° for 40 minutes to give a clear solution which was blown under nitrogen pressure over 21/2 minutes into a stirred mixture of water (180 ml) and acetone (300 ml) pre-cooled to 8°. Ethyl acetate (60 ml) was used as a line wash. The temperature of the mixture rose gradually to 25° and a granular off-white precipitate formed after ca 10 minutes. Stirring was continued for a total of 60 minutes before acetone (450 ml) was added followed by, over 5 minutes, a solution, pre-cooled to 5°, of sodium hydroxide (48 g) in water (300 ml). This gave a clear two-phase mixture at 29° with a pH of 2.2. The layers were separated and the upper, organic layer was washed with a solution of sodium chloride (90 g) in water (300 ml). The two aqueous layers were suquentially back extracted with the same portion of ethyl acetate (150 ml). The organic layers were combined and stirred with SS 110 charcoal (11.5 g) for 1 hour. The charcoal was removed by filtration on a bed of Hyflo Supercel which was washed with a mixture of acetone (150 ml) and ethyl acetate (150 ml) applied in two parts, the filtrate and wash being combined. Sodium 2-ethylhexanoate (54.9 g) was dissolved in a mixture of acetone (300 ml) and water (3 ml) and the solution was clarified by filtration through a bed of Hyflo Supercel which was washed with acetone (150 ml). The combined wash and filtrate was added over 25 minutes to the stirred cefuroxime solution to give a suspension with a pH of 6.3. The suspension was stirred for 10 minutes and filtered, and the cake was washed by displacement with acetone (4×150 ml), sucked dry for 10 minutes and dried in vacuo at 20° to give sodium cefuroxime (130.25 g); [α]D20 +60° (c 0.5; 0.1M pH 4.5 buffer); λmax (H2O) 273 nm, (E1 cm1% 382); impurities by hplc 1.8% m/m. Assay (hplc) 92% m/m; water (Karl Fischer) 2.6% m/m; solvents (g.l.c.) 0.75% m/m.

Provenance & Evidence