Cefroxadine

Description

Cefroxadine was synthesized by Ciba-Geigy in 1972. A methoxyl group replaced the methyl group of cephradine at the 3 position of the cephem nucleus. Cefroxadine shows stronger activities than cephalexin, especially bactericidal and bacteriolytic activities, and it has better oral absorption that is less affected by a recent meal. Cefroxadine shows less renal toxicity than cephalexin in toxicological studies using animals.

Originator

Oraspor,Ciba Geigy,Switz.,1981

The Uses of Cefroxadine

Antibacterial.

Definition

ChEBI: Cefroxadine is a first-generation cephalosporin antibiotic having methoxy and [(2R)-2-amino-2-(cyclohexa-1,4-dien-1-yl)acetyl]amino side groups located at positions 3 and 7 respectively.

Manufacturing Process

A suspension of 30.64 g (0.2 mol) of D-α-amino-α-(1,4-cyclohexadienyl)- acetic acid in 600 ml of methylene chloride is cooled under a stream of argon to 6°C, whereupon hydrogen chloride is passed in for about 30 minutes until the mixture is saturated. Phosphorpentachloride (62.4 g, 0.3 mol) is added in two portions. The mixture is stirred for 2 hours at 6°C to 8°C. The colorless precipitate is filtered off under nitrogen and exclusion of moisture, washed with methylene chloride and dried for 18 hours at 0.05 mm Hg at room temperature to give D-α-amino-α-(1,4-cyclohexadienyl)-acetylchloride hydrochloride in form of colorless crystals.
A suspension of 37.3 g (0.1 mol) of 7β-amino-3-methoxy-3-cephem-4- carboxylic acid hydrochloride dioxanate in 500 ml methylene chloride is stirred for 15 minutes at room temparature under an argon atmosphere and treated with 57.2 ml (0.23 mol) of bis-(trimethylsilyl)acetamide. After 45 minutes the faintly yellow slightly turbid solution is cooled to 0°C and treated within 10 minutes with 31.29 (0.15 mol) of D-α-amino-α-(1,4-cyclohexadienyl)-acetyl chloride hydrochloride. Thirty minutes thereafter 15 ml (about 0.21 mol) of propylene oxide is added and the mixture is further stirred for 1 hour at 0°C: A cooled mixture of 20 ml of absolute methanol in 200 ml of methylene chloride is added within 30 minutes, after another 30 minutes the precipitate is filtered off under exclusion of moisture, washed with methylene chloride and dried under reduced pressure at room temperature. The obtained hygroscopic crystals of the hydrochloride of 7β-[D-α-(1,4-cyclohexadienyl)- acetylamino]-3-methoxy-3-cephem-4-carboxylic acid are stirred into 200 ml of ice water and the milky solution treated with about 66 ml of cold 2 N sodium hydroxide solution until pH 3.5 is reached. The solution is clarified by filtration through diatomaceous earth, washed with ice water, cooled to 0°C and treated with 20 ml of 2 N sodium hydroxide solution until pH 5.7 is reached. A second filtration through a glass filter frit results in a clear solution which is treated with acetone (800 ml) at 0°C. The crystals are filtered washed with acetone:water (2:1), acetone and diethyl ether and dried for 20 hours at room temperature and 0.05 mm Hg to give the 7β-[D-α-amino-α-(1,4- cyclohexadienyl)-acetylamino]-3-methoxy-3-cephem-4-carboxylic acid dihydrate.

Therapeutic Function

Antibacterial

Antimicrobial activity

Cefroxadine is closely related to cefradine, the structure differing only by the presence of a methoxy group replacing methyl at the C-3 position. The antimicrobial spectrum is identical to that of cefradine and cefalexin. A dose of 1 g as film-coated tablets produced mean peak plasma levels of 25 mg/L at 1 h. Absorption is depressed and delayed by administration with food. The plasma elimination half-life is 0.8 h, rising to 40 h in end-stage renal failure and falling to 3.4 h during hemodialysis. Around 85% of an oral dose is excreted unchanged in the urine. It is available in Japan.