Pyridine → Cephalexin

Participants

Reaction Steps

To a stirred suspension of 7β-amino-3-methylceph-3-em-4-carboxylic acid (21.4 g, 0.1 mole) in N,N-dimethylformamide (300 ml) at room temperature were added triethylamine (20.5 g, 0.2 mole) and trimethylchorosilane (21.7 g, 0.2 mole). The mixture was stirred without external heating or cooling for 25 minutes and then for a further 5 minutes following the addition of quinoline 1.25 hydrochloride (2.8 g, 0.016 mole containing 0.02 mole hydrogen chloride). The mixture was cooled to -40° and pyridine (8.4 g, 0.106 mole) was added, followed immediately by D(-)α-phenylglycyl chloride hydrochloride (23.2 g, 94% pure, 1.06 molar equivalents) in one charge. The reaction temperature was allowed to rise to -30° where it was maintained for 15 minutes. Dry industrial methylated spirit (IMS-6ml) was added and the mixture was allowed to warm to 0° and was then filtered. The filter bed was washed with N,N-dimethylformamide (50 ml) and the filtrate and wash were combined and diluted with water (60 ml). The solution was mixed well and was adjusted from pH 2.4 to 5.2 using 0.880 ammonia solution. After stirring for 30 minutes with periodic additions of ammonia solution to maintain pH, the mixture was adjusted to pH 6.0. After a further 30 minutes at this pH, the mixture was brought to pH 6.9 where it was stirred at 0° for 15 minutes and the precipitated solid filtered off. The bed was slurry washed with a mixture of N,N-dimethylformamide (100 ml) and water (10 ml) and then with ethyl acetate (100 ml) and ether (100 ml) before being dried in vacuo to constant weight to give cephalexin bis-N,N-dimethylformamide solvate as a white solid (45.8 g, 93% theory); [α]D + 103.6°; E1 cm1% (262 nm) 154.

Provenance & Evidence