100986-85-4 Usage
Description
Levofloxacin, the optically active S-isomer of the fluoroquinolone antibiotic ofloxacin,
is two to four times more potent than ofloxacin with reportedly less side effects in treating
infections of the lower respiratory and urinary tract, prostate infections and sexually
transmitted diseases. It has broad and potent antibacterial activity over common Grampositive
and -negative aerobic pathogens and obligate anaerobes. Different from the cephem
antibiotics, levofloxacin is unique in its marked selectivity against members of the family
Enterobacteriaceae and its negligible effect on predominant anaerobes. Levofloxacin also
exhibits satisfactory antimicrobial effects in surgical infections and it may be used for
treatment of gastrointestinal infections such as traveler’s diarrhea associated with the
pathogenic Enterobacteriaceae.
Chemical Properties
Slight yellow powder
Originator
Daiichi (Japan)
Uses
Different sources of media describe the Uses of 100986-85-4 differently. You can refer to the following data:
1. Levofloxacin is a broad-spectrum antibiotic used in pharmacokinetic?, antibiotic resistance?, and resistance prevention?studies. Levofloxacin is active against Gram-positive and Gram-negative bacteria. It inhibits DNA gyrase (type II topoisomerase) and topoisomerase IV, thereby inhibiting cell division.
2. Antibacterial.
Manufacturing Process
()-3-Acetoxymethyl-7,8-difluoro-2,3-dihydro-4H-[1,4]benzoxazine (m.p. 73-
74°C) was synthesized by hydrogenation of a compound prepared from 2,3-
difluoro-6-nitrophenol, 1-acetoxy-3-chloro-2-propane and potassium iodide.
The hydrogenation was carried out on Raney nickel. The resulting compound
was dissolved in THF, and 3,5-dinitrobenzoyl chloride and pyridine were added
thereto, followed by heating at 60°C for 3 hours. The mixture was
concentrated, and the concentrate was dissolved in ethyl acetate, washed
successively with diluted hydrochloric acid, an aqueous solution of sodium
bicarbonate and water, dried over anhydrous sodium sulfate and concentrated.
Addition of n-hexane to the concentrate caused precipitation of yellow crystals
of a racemate. The yield of 3,5-dinitrobenzoyl derivative of the ()-3-
acetoxymethyl-7,8-difluoro-2,3-dihydro-4H-[1,4]benzoxazine 3.93 g.To 2.0 ml of Amberlite XAD 7 was added 2.0 ml of a 0.05 M phosphoric acid
buffer (pH 7.0) having dissolved therein 20 mg of lipoprotein lipase, and the
system was allowed to stand at room temperature for 18 hours to thereby
adsorb the enzyme onto the resin. The resin was filtered. A solution of 250
mg of 3,5-dinitrobenzoyl derivative of ()-3-acetoxymethyl-7,8-difluoro-2,3-
dihydro-4H-[1,4]benzoxazine as a substrate in 25 ml of a mixed solvent of
benzene and n-hexane (4:1 by volume) was added to the resin, followed byallowing to react at 37°C for 4 hours. It was obtained 117 mg of a 3,5-
dinitrobenzoyl derivative of the (-)-3-acetoxymethyl-7,8-difluoro-2,3-dihydro-
4H-[1,4]benzoxazine and 65 mg of a derivative of the (-)-3-acetoxymethyl-
7,8-difluoro-2,3-dihydro-4H-[1,4]benzoxazine.In 135 ml THF was dissolved 3.03 g of a 3,5-dinitrobenzoyl derivative of (-)-
3-acetoxymethyl-7,8-difluoro-2,3-dihydro-4H-[1,4]benzoxazine, and 135 ml of
ethanol and 30 ml of 1.0 N potassium hydroxide were added to the solution.
After 30 min 3 ml of acetic acid was added thereto for neutralization. The
mixture was concentrated. The solid was subjected to column chromatography
using 40 g of silica gel and eluted with chloroform/methanol to obtain 1.17 g
of (-)-7,8-difluoro-2,3-dihydro-3-hydroxymethyl-4H-[1,4]benzoxazine; [α]D22
= -14.1° (c = 1.80, CHCl3).To 1.17 g of (-)-7,8-difluoro-2,3-dihydro-3-hydroxymethyl-4H-[1,4]
benzoxazine was added 2.77 g of thionyl chloride in pyridine. The reaction
mixture was concentrated and the concentrate was subjected to column
chromatography using 40 g of silica gel and eluted with chloroform to obtain
1.18 g of the reaction product as a colorless oily product. This product was
dissolved in 30 ml of dimethyl sulfoxide, and 0.41 g of sodium borohydride
was added thereto, followed by heating at 80-90°C for 1 hour. The reaction
mixture was dissolved in 500 ml of benzene, washed with water to remove
the dimethyl sulfoxide, dried over anhydrous sodium sulfate and concentrated
under reduced pressure. The concentrate was subjected to column
chromatography using 40 g of silica gel and eluted with benzene to obtain
0.80 g of (-)-7,8-difluoro-2,3-dihydro-3-methyl-4H-[1,4]benzoxazine as a
colorless oily product; [α]D25 = -9.6° (c = 2.17, CHCl3). Optical Purity: >99%
e.e.To 1.13 g of (-)-7,8-difluoro-2,3-dihydro-3-methyl-4H-[1,4]benzoxazine was
added 1.58 g of diethyl ethoxymethylenemalonate, and the mixture was
stirred at 130-140°C for 70 min. The reaction mixture was subjected to
column chromatography using 50 g of silica gel and eluted with chloroform to
obtain 2.47 g of diethyl [(-)-7,8-difluoro-3-methyl-2,3-dihydro-4H-[1,4]
benzoxazin-4-yl]methylenemalonate. This product was dissolved in 5 ml of
acetic anhydride, and 10 ml of a mixture of acetic anhydride and concentrated
sulfuric acid (2/1 by volume) with stirring under ice-cooling, followed by
stirring at 50-60°C for 40 min. To the reaction mixture were added ice and an
aqueous solution of sodium bicarbonate, and the product was extracted three
times with 150 ml portions of chloroform. The combined extract was washed
with water, dried over anhydrous sodium sulfate and concentrated. The
precipitate was washed with a small amount of diethyl ether to yield 1.32 g of
(-)-ethyl 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]
benzoxazine-6-carboxylate.In 12 ml of acetic acid was dissolved 1.20 g of the resulting compound, and
25 ml of concentrated hydrochloric acid was added, followed by refluxing at
120-130°C for 90 min. Upon allowing the reaction mixture to stand at room
temperature, colorless crystals were precipitated, which were collected by
filtration and washed successively with a small amount of water, ethanol and
diethyl ether to obtain 0.96 g of (-)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-
7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid.In 30 ml of diethyl ether was suspended 324 mg of the resulting compound,and a large excess of boron trifluoride ethyl etherate was added thereto,
followed by stirring at room temperature for 30 min to form a chelate
compound. The product was collected by filtration and washed with a small
amount of diethyl ether to obtain 373 mg of a powder. The powder was
dissolved in 7 ml of dimethyl sulfoxide, and 136 mg of N-methylpiperazine
and 228 mg of triethylamine were added thereto, followed by stirring at room
temperature for 17 hours. The reaction mixture was concentrated to dryness
under reduced pressure, and to the solid were added 15 ml of 95% methanol
and 0.31 ml of triethylamine. The resulting mixture was refluxed for 3 hours.
The reaction mixture was concentrated under reduced pressure, and the
residue was filtered and washed successively with a small amount of ethanol
and diethyl ether to obtain 350 mg of a white powder. Recrystallization from a
mixed solvent of ethanol and thick aqueous ammonia gave 230 mg of S-(-)-
ofloxacin (Levofloxacin).Melting Point: 225-227°C (with decomposition); [α]D23 = -76.9° (c = 0.39,
0.05 N NaOH).
Brand name
Iquix (Sanofi Winthrop); Levaquin
(Ortho-McNeil); Quixin (Sanofi Winthrop);Cravit.
Therapeutic Function
Antibacterial
Antimicrobial activity
Levofloxacin is the active component of ofloxacin; d-ofloxacin is without significant antibacterial activity. It exhibits good activity in vitro against Gram-positive cocci (including Str. pneumoniae), Enterobacteriaceae, some fastidious Gram-negative bacilli and Ps. aeruginosa as well as chlamydiae, Mycoplasma pneumoniae, L. pneumophila and M. tuberculosis. MICs for Acinetobacter spp. and Sten. maltophilia are 0.06–0.25 and 0.5–2.0 mg/L, respectively. Activity against anaerobes is moderate to low.
General Description
Chemical structure: quinolone
Pharmaceutical Applications
For molecular weight and structure, see ofloxacin . Levofloxacin is the l-isomer of ofloxacin.
Pharmacokinetics
Oral absorption: >95% Cmax 500 mg oral: c. 5 mg/L after 1.5–2 h 750 mg oral: c. 8 mg/L after 1.5–2 h 500 mg intravenous (90-min infusion): c. 6 mg/L end infusion 750 mg intravenous (90-min infusion) ：c. 12 mg/L end infusion Plasma half-life ：6–8 h Volume of distribution：0.6–0.8 L/kg Plasma protein binding： <25%Co-administration with antacids, calcium, sucralfate and heavy metals decreases bioavailability and AUC. No interactions with warfarin or theophylline have been observed. Co-administration of a non-steroidal anti-inflammatory drug may increase the risk of convulsions. It undergoes limited metabolism and is primarily eliminated unchanged in urine by both glomerular filtration and tubular secretion. The free AUC:MIC ratio for Str. pneumoniae increases from about 55 to 70 when the daily dosage is raised from 500 mg to 750 mg.It is stable in plasma and does not revert to d-ofloxacin. It undergoes limited metabolism and is primarily eliminated unchanged in the urine. Renal clearance in excess of the glomerular filtration rate suggests that tubular secretion also occurs. Concomitant administration of either cimetidine or probenecid reduces renal clearance by approximately onethird. Clearance is reduced and half-life is prolonged in patients with impaired renal function (creatinine clearance <50 mL/min) requiring dosage adjustment in such patients.
Clinical Use
Acute bacterial sinusitis Acute bacterial exacerbations of chronic bronchitis, community-acquired pneumonia Uncomplicated and complicated skin and skin structure infections Uncomplicated and complicated urinary infections including acute pyelonephritis Chronic bacterial prostatitis
Side effects
Side effects have been reported in 6–7% of patients and include fever, rash and other events common to the group. Elderly patients are at increased risk of developing severe tendon disorders including rupture, a risk increased by concomitant corticosteroid therapy.
Drug interactions
Potentially hazardous interactions with other drugs
Aminophylline and theophylline: possibly increased
risk of convulsions.
Analgesics: possibly increased risk of convulsions
with NSAIDs.
Anti-arrhythmics: increased risk of ventricular
arrhythmias with amiodarone - avoid.
Anticoagulants: anticoagulant effect of coumarins
and phenindione enhanced.
Antimalarials: manufacturer advises avoid
concomitant use with artemether and lumefantrine.
Ciclosporin: half-life of ciclosporin increased by 33%;
increased risk of nephrotoxicity.
Cytotoxics: increased risk of ventricular arrhythmias
with arsenic trioxide.
Tacrolimus: may increase tacrolimus concentration.
Metabolism
Levofloxacin is metabolised to a very small extent, the
metabolites being desmethyl-levofloxacin and levofloxacin
N-oxide.
These metabolites account for <5% of the dose and are
excreted in urine. Excretion is primarily by the renal route
Check Digit Verification of cas no
The CAS Registry Mumber 100986-85-4 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,0,0,9,8 and 6 respectively; the second part has 2 digits, 8 and 5 respectively.
Calculate Digit Verification of CAS Registry Number 100986-85:
(8*1)+(7*0)+(6*0)+(5*9)+(4*8)+(3*6)+(2*8)+(1*5)=124
124 % 10 = 4
So 100986-85-4 is a valid CAS Registry Number.
InChI:InChI=1/C18H20FN3O4/c1-10-9-26-17-14-11(16(23)12(18(24)25)8-22(10)14)7-13(19)15(17)21-5-3-20(2)4-6-21/h7-8,10H,3-6,9H2,1-2H3,(H,24,25)/t10-/m0/s1
100986-85-4Relevant articles and documents
Experimental and computational study on the enantioseparation of four chiral fluoroquinolones by capillary electrophoresis with sulfated-β-cyclodextrin as chiral selector
Ma, Qianyun,Cong, Wei,Liu, Ye,Geng, Zikai,Lin, Ying,Wang, Zhaokun
, p. 549 - 557 (2021)
In this work, enantioseparation of four chiral fluoroquinolones (FQs), namely, ofloxacin, gemifloxacin, lomefloxacin, and gatifloxacin, was achieved by capillary electrophoresis with sulfated-β-cyclodextrin (S-β-CD) as chiral selector. Factors affecting the enantiomeric resolution, such as the concentrations of S-β-CD, BGE pH conditions, and the buffer types and concentrations, were optimized and discussed. A BGE consisting of 30 g/L S-β-CD and 30-mM phosphate at pH?4.0 was found fit for enantiomeric resolution of ofloxacin and gemifloxacin, while the same BGE at pH?3.0 was suitable for enantioseparation of lomefloxacin and gatifloxacin. The pH-dependent experiments showed that separation resolutions of four FQs enantiomers were significantly affected by BGE pH, which was thought to be related with the varying electrostatic attraction between the enantiomers and chiral selector. To verify this speculation, molecular docking studies were used for further investigation of the enantiomeric recognition mechanism of S-β-CD. Molecular model indicated that hydrophobic effect and hydrogen bond were involved in host-guest inclusion, but the electrostatic attraction enhanced the chiral discrimination by increasing the difference in binding energy between individual enantiomers and S-β-CD. This work provided a further insight into the chiral recognition mechanisms of CD derivatives.
Equilibrium and structural characterization of ofloxacin-cyclodextrin complexation
Toth, Gergo,Mohacsi, Reka,Racz, Akos,Rusu, Aura,Horvath, Peter,Szente, Lajos,Beni, Szabolcs,Noszal, Bela
, p. 291 - 300 (2013)
The enantiomer-specific characterization of ofloxacin-cyclodextrin complexes was carried out by a set of complementary analytical techniques. The apparent stability constants of the ofloxacin enantiomers with 20 different cyclodextrins at two different pH values were determined to achieve good resolution capillary electrophoresis enantioseparation either to establish enantioselective drug analysis assay, or to interpret and design improved host-guest interactions at the molecular level. The cyclodextrins studied differed in the nature of substituents, degree of substitution (DS), charge and purity, allowing a systematic test of these properties on the complexation. The seven-membered beta-cyclodextrin and its derivatives were found to be the most suitable hosts. Highest stability and best enantioseparation were observed for the carboxymethylated-beta-cyclodextrin (DS 3.5). The effect of substitution pattern (SP) was investigated by molecular modeling, verifying that SP greatly affects the complex stability. Induced circular dichroism was observed and found especially significant on carboxymethylated-beta- cyclodextrin. The complex stoichiometry and the geometry of the inclusion complexes were determined by 1H NMR spectroscopy, including 2D ROESY techniques. Irrespective of the kind of cyclodextrin, the complexation ratio was found to be 1:1. The alfa-cyclodextrin cavity can accommodate the oxazine ring only, whereas the whole tricyclic moiety can enter the beta- and gamma-cyclodextrin cavities. These equilibrium and structural information offer molecular basis for improved drug formulation. Springer Science+Business Media B.V. 2012.
Enantioselective separation of chiral ofloxacin using functional Cu(ii)-coordinated G-rich oligonucleotides
Fu, Yan,Duan, Xiaoli,Chen, Xiongfei,Zhang, Jinli,Li, Wei
, p. 1329 - 1333 (2014)
The DNA-based selector for discriminating chiral ofloxacin with high enantioselectivity and affinity is constructed through Cu(ii)-coordination with G-rich duplex containing successive guanines. Using this chiral selector, R- and S-ofloxacin can be direct
Conventional and microwave-assisted synthesis of quinolone carboxylic acid derivatives
Mirzaie,Lari,Vahedi,Hakimi
, p. 2865 - 2869 (2016)
Various antibacterial fluoroquinolone compounds are synthesized by the direct amination of 7-halo-6-fluoroquinolone-3-carboxylic acids with a variety of piperazine derivatives and (4aR,7aR)-octahydro-1H-pyrrolo[3,4-b]pyridine using microwave under different reaction conditions. Solvent free high yield microwave synthesis of antibacterial fluoroquinolone compounds is convenient, rapid and environmentally friendly method.
Intrinsic enantioselectivity of natural polynucleotides modulated by copper ions
Fu, Yan,Chen, Xiongfei,Zhang, Jinli,Li, Wei
, p. 306 - 313 (2015)
Natural polynucleotides including Micrococcus lysodeikticus and calf thymus DNA exhibit enantioselective recognition to S-ofloxacin regulated by Cu2+. This is the first report that ofloxacin and Cu2+ have cooperative effects on the local distortions of polynucleotides. At the [Cu2+]/[base] ratio of 0.1, S-ofloxacin is more liable to induce the locally distorted structures of polynucleotides, of which the association constant of S-ofloxacin toward DNA-Cu(II) is three times higher than that of the R-enantiomer. The apparent increase of adsorption capability and cooperativity, as well as the change of adsorption mechanism were detected in the adsorption of ofloxacin enantiomers on polynucleotides upon Cu(II)-coordination. This study not only discloses the effect of the chiral drug on the structural transition of long double-stranded DNA, but provides fundamental data to develop a novel enantioseparation method based on natural polynucleotides.
Determination of levofloxacin in human urine with capillary electrophoresis and fluorescence detector
Tsai, Yu-Hsien,Bair, Ming-Jong,Hu, Cho-Chun
, p. 991 - 995 (2007)
In this study, we developed an analytical method for the enantioseparation of ofloxacin, using capillary electrophoresis with fluorescence detection. The optimum background electrolyte was obtained to be 60 mM hydroxylpropyl-β- cyclodextrin (HP-β-CD) in 50 mM phosphate buffer at pH 2.30. Under these conditions, the (+) and (-) ofloxacin were completely separated, with the detection limit of 10 nM when the sample was prepared in deionized water. The linear ranges of levofloxacin in deionized water and untreated urine were 10-7 to 5 × 10-3 M with R2 = 0.9989 and 5 × 10-6 to 5 × 10-3 M with R2 = 0.9943, respectively. We also applied this method to investigate the purity of a commercial drug. The results revealed that the ratio between (+)-ofloxacin and (-)-ofloxacin (levofloxacin) was 99.9:0.1, and there is about 93 mg levofloxacin per tablet (200 mg). The concentration of levofloxacin in patient's urine was founded to be 7.9 × 10-4 M, and the ratio between the two optical isomers was 99.3:0.7.
Structure-retention relationship for enantioseparation of selected fluoroquinolones
Hassan, Rasha M.,Yehia, Ali M.,Saleh, Ola A.,El-Azzouny, Aida A.,Aboul-Enein, Hassan Y.
, p. 828 - 836 (2018)
Fluoroquinolones are popular class of antibiotics with distinct chemical functionality. Most of them are ampholytes with one chiral center. Stereogeneic center is located either in the side ring of Gatifloxacin (GFLX) or in the quinolone core of Ofloxacin (OFLX). These two amphoteric fluoroquinolones have terminal amino groups in common. The unusual Nadifloxacin (NFLX) is an acidic fluoroquinolone with a core chiral center. Owing to chirality and functionality differences among GFLX, OFLX, and NFLX, we mapped these enantiomers onto structure-retention relationship. Amount of acetic acid modifier was studied in screened mobile phase and cellulose tris(3-chloro-4-methyl phenyl carbamate) (Lux cellulose-2) stationary phase. Experimental design of acetic acid% along with column temperature have been applied. Resolution and enantioselectivity have been related to structural features of the studied enantiomers. High amount of acid (0.4%) was optimum for the separation of either side chirality with a proximate amino group (GFLX) or core chirality without basic functionality (NFLX), while low amount (0.2%) is optimum for core chiral center with distal amino group (OFLX). Temperature has no significant effect on resolution and retention of enantiomers except for OFLX. Enantio-retention explains possible chiral selective and nonselective interactions. The proposed methods have been validated for pharmaceutical analyses.
Preparation method of levofloxacin and intermediates thereof
-
, (2021/03/30)
The invention relates to a preparation method of levofloxacin and intermediates thereof, and belongs to the field of medicinal chemistry. The preparation method comprises the following steps of: carrying out amino substitution and ring closing reaction on an intermediate substrate to integrate a plurality of intermediates into a one-pot reaction, and hydrolyzing under an acidic condition to obtainlevofloxacin. According to the method provided by the invention, the intermediates do not need to be separated, the reaction operation is simplified, the production period is greatly shortened, multiple times of after-treatment are not needed, emission of three wastes is reduced, the method is more environmentally friendly, the reaction yield is increased compared with the prior art, and the method is suitable for industrial amplification.
Novel marking method of levofloxacin
-
Paragraph 0019-0030, (2021/01/30)
The invention provides a synthetic method of levofloxacin, which uses formaldehyde and formic acid to methylate N-demethylated levofloxacin to obtain levofloxacin, and the method has the characteristics of high yield and high purity, and is suitable for labeling levofloxacin and isotopes thereof.
