Grepafloxacin

Grepafloxacin (trade name Raxar, Glaxo Wellcome) was an oral broad-spectrum fluoroquinolone antibacterial agent used to treat bacterial infections. Grepafloxacin was withdrawn worldwide from markets in 1999,^[1][2] due to the drug's potential to cause a potentially fatal cardiac arrhythmia.^[3]

Grepafloxacin

Clinical data
AHFS/Drugs.com	Multum Consumer Information
ATC code	J01MA11 (WHO)
Pharmacokinetic data
Protein binding	50%
Identifiers
IUPAC name (RS)-1-Cyclopropyl-6-fluoro-5-methyl-7-(3-methylpiperazin-1-yl)-4-oxo-quinoline-3-carboxylic acid
CAS Number	119914-60-2 Y
PubChem CID	72474
DrugBank	DB00365 Y
ChemSpider	65391 Y
UNII	L1M1U2HC31
KEGG	C11368 Y
ChEMBL	ChEMBL583 Y
CompTox Dashboard (EPA)	DTXSID2048321
ECHA InfoCard	100.159.692
Chemical and physical data
Formula	C19H22FN3O3
Molar mass	359.401 g·mol−1
3D model (JSmol)	Interactive image
Chirality	Racemic mixture
SMILES O=C(O)\C2=C\N(c1cc(c(F)c(c1C2=O)C)N3CC(NCC3)C)C4CC4
InChI InChI=1S/C19H22FN3O3/c1-10-8-22(6-5-21-10)15-7-14-16(11(2)17(15)20)18(24)13(19(25)26)9-23(14)12-3-4-12/h7,9-10,12,21H,3-6,8H2,1-2H3,(H,25,26) Y Key:AIJTTZAVMXIJGM-UHFFFAOYSA-N Y
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Clinical uses

Grepafloxacin was used for treating exacerbations of chronic bronchitis caused by susceptible bacteria (e.g. Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis),^[4][5][6] community-acquired pneumonia (including those, in addition to the above germs, caused by Mycoplasma pneumoniae)^[7][8] gonorrhea and non-gonococcal urethritis and cervicitis (for example caused by Chlamydia trachomatis or Ureaplasma urealyticum).^[9][10]

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.

Grepafloxacin synthesis:^[11][12]

The scheme starts with the conversion of the carboxylic acid in (1) to its dimethyloxazoline derivative (3) by reaction with the aminomethyl propanol (2). Lithium diisopropylamide (LDA) then removes a proton from the 8 position; treatment of that anion with trimethylsilyl iodide leads to the silylated intermediate (4). 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 (5). 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 (6). This last intermediate is then taken on to the quinolone (9) ^[13] 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 (9) with 2-methylpiperazine proceeds by reaction at the less hindered of the two amino groups; saponification then affords grepafloxacin (10).

Stereochemistry

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

Enantiomers of grepafloxacin
(R)-grepafloxacin CAS number: 146761-68-4	(S)-grepafloxacin CAS number: 146761-69-5

See also

• Quinolone antibiotics