Grepafloxacin


Grepafloxacin was an oral broad-spectrum fluoroquinolone antibacterial agent used to treat bacterial infections. Grepafloxacin was withdrawn worldwide from markets in 1999, due to its side effect of lengthening the QT interval on the electrocardiogram, leading to cardiac events and sudden death.

Clinical uses

Grepafloxacin was used for treating exacerbations of chronic bronchitis caused by susceptible bacteria, community-acquired pneumonia gonorrhea and non-gonococcal urethritis and cervicitis.

Synthesis

The preparation of quinolones bearing a substituent at position 5 is complicated by the greater electrophilic character of the 8 position. One scheme for resolving the problem consists in blocking access to position 8 by first adding a readily removable group to that center.
The scheme starts with the conversion of the carboxylic acid in to its dimethyloxazoline derivative by reaction with the aminomethyl propanol. Lithium diisopropylamide then removes a proton from the 8 position; treatment of that anion with trimethylsilyl iodide leads to the silylated intermediate. A second round of LDA then generates a carbanion at the only open position; reaction with methyl iodide leads to the corresponding 5 methyl derivative. Treatment of that product with cesium fluoride breaks the carbon–silicon bond, removing the silyl group; aqueous acid then hydrolyzes the oxazoline to afford the free acid. This last intermediate is then taken on to the quinolone by essentially the same scheme as that used to prepare difloxacin, with the difference that the chain elongation is by means of Grignard reagent of ethyl bromoacetate. Treatment of with 2-methylpiperazine proceeds by reaction at the less hindered of the two amino groups; saponification then affords grepafloxacin.

Stereochemistry

Grepafloxacin contains a stereocenter and consists of two enantiomers. This is a racemate, ie a 1: 1 mixture of - and the -forms: