Effects of skeletal modifications of ciprofloxacin on ... - ResearchGate

JOURNAL <strong>of</strong> CHINESE CLINICAL MEDICINE VOLUME 2|NUMBER 4|April 2007
MATERIALS AND METHODS
Tabross Pharmaceuticals, Karachi, gifted cipr<strong>of</strong>loxacin
ydrochloride and the microorganisms for antimicrobial
activity were obtained from ESSA laboratory, Karachi
Pakistan.
IR spectra ( KBr) were recorded on a Bruker FT
-IR IFS48 spectrophotometer.EI mass spectra were
measured with various MAT 711 (70 eV ) spectrome唱
ters and data are tabulated as m /z.1H唱NMR spectra
were recorded in DMSO唱d6 using Bruker AC300 (300
MHz) spectrophotometer.Splitting patterns were as
follows: s, singlet; d, doublet; dd, double doublets; t,
triplet;m, multiplet.Chemical shifts are reported in δ
( ppm) and coupling constants are given in Hz.The
progress <strong>of</strong> all reactions was monitored by TLC, which
was performed on 2畅0 cm ×5.0 cm aluminum sheets
pre唱coated with silica gel 60F254 to a thickness <strong>of</strong>
0畅25 mm ( Merck).The chromatograms were visualized
under ultraviolet light ( 254 ~366 nm ) or iodine
vapours.Melting points were determined in glass capil唱
laries on a Büchi 434 melting point apparatus and are
uncorrected.The title compounds were synthesized and
characterized successfully and satisfactorily.
Regeneration<strong>of</strong> Free Cipr<strong>of</strong>loxacin
A solution <strong>of</strong> cipr<strong>of</strong>loxacin hydrochloride (10 g ) in
water (50 ml) was treated with an excess <strong>of</strong> 5% aque唱
ous sodium bicarbonate solution resulting in the forma唱
tion <strong>of</strong> white precipitates which were filtered through
suction filtration and left to dry as a neutral cipr<strong>of</strong>loxa唱
cin (1,8.3 g,83%) .
These precipitates were pure enough and used as
starting material for all the reactions without purifica唱
tion.
General Procedure for the Cipr<strong>of</strong>loxacin Deriva唱
tives
Cipr<strong>of</strong>loxacin(1)
Cipr<strong>of</strong>loxacin(1畅0 g,3.01 mmol) was dissolved in 30
ml <strong>of</strong> anhydrous THF.To this solution,triethylamine (1
molar equivalent,0畅629 ml) and one molar equivalent
<strong>of</strong> appropriate acid chloride was added and the result唱
ant mixture was refluxed until completion <strong>of</strong> the reac唱
tion ( TLC analysis).The resultant mixture was cooled
189
to room temperature, excess <strong>of</strong> solvent was removed in
vaccuo and the residue was suspended in brine and ex唱
tracted with dichloromethane (3 ×50).The organic
phase was dried over Na2 SO4 , filtered and evaporated
at reduced pressure to afford the solid product in pure
form.
7-(4-Acetyl唱1唱piperazinyl) -6唱fluoro -1 唱cyclo唱
propyl -4唱oxo -1,4唱dihydro唱3唱quinoline carboxylic
acid(2)
Yield:0畅48 g (73%);M.P.= 261℃ ~263 ℃;IR nmax
cm -1
: 3421 , 3046, 2921, 1711, 1627, 1470, 1337,
1217; 1
H唱NMR (300 MHz唱DMSO -d 6 ):d 15畅16 ( s,
1 H,H -14),8畅6 (s,1H,H -2) ,7畅8 (d,1H,J =7畅8
Hz,H -5),7畅5(d,1 H,J =4 .3 Hz, H -8 ) ,3畅8 (s,
1 H,H -11),3畅6 (s,4H,H -16,20),2畅4(s,4H,H
-17,19) ,2畅0 (s,3 H,H -2 ′),1畅3(d,2H,J =3 畅7
Hz,H -13) ,1畅1 (s,2 H,H -12);EIMS m /z (% rel.
abund.):373 (M +1
,18),329 (68 ),301 (6 ),257
(10),231 (8).
1 -Cyclopropyl -7 -[ 4 -( ethoxycarbonyl) -1唱
piperazinyl] -6唱fluoro唱4唱oxo唱1,4唱dihydro唱3唱quino唱
line carboxylic acid (3 )
Yield:0畅87 g (87%);M.P.=161℃ -163℃;IR nmax
cm -1
: 3453 , 3097, 2977, 2830, 1736, 1626, 1476,
1386,1342 ,1210 ,1098;1H唱NMR (300 MHz唱DMSO -
d 6 ):d 15畅2 (s,1H,H -14 ) ,8畅6(s,1H,H -2),7畅9
( d,1H,J =7.9 Hz,H -5) ,7畅5 (d,1 H,J =4畅4 Hz,
H -8),4畅15 ( s,1H, H -11),4畅14 ( d,2H,J =5 畅7
Hz,H -4′) ,4畅10 ( s,1H, H -1 ′),4畅0 (s,4 H,H -
16,20) ,3畅2 (s,4H, H -17,19 ),1畅8 (s,3H, H -
5′),1畅1(s,2H,H -13) ,1畅0 (s,2H,H -12 ) ; EIMS
m /z (% rel.abund.):417 (M +,25) ,373 (11) ,343
(100),299 (7),230 (6).
1 -Cyclopropyl -7 -[ 4 -( 2,2唱dichloroacetyl) -1唱
piperazinyl] -6唱fluoro唱4唱oxo唱1,4唱dihydro唱3唱quino唱
line carboxylic acid (4 )
Yield:0畅51 g (51%);M.P.=219℃ ~221℃ ( de唱
composed); IRnm ax cm -1
: 3424, 3013, 2958, 2926,
1719,1625, 1493, 1444, 1249, 805; 1
H -NMR (300
MHz -DMSO -d6 ):d 15畅2 (s,1 H,H -14),8畅6(s,
1 H,H -2) ,7畅7 (d,1H,J =9 .8 Hz,H -5),7畅5 (d,
1 H,J =5畅3 Hz,H -8),5畅7(s,1H,H -2 ′),4畅1(s,
2 H,H -11),3畅7 (s,4H,H -16,20),2畅4(s,4H,H
-17,19) ,1畅1 (d,2H,J =3畅7 Hz,H -13 ) ,0畅8 (s,