100986-85-4

Basic information

• Product Name: Levofloxacin hydrochloride
• Synonyms: (s)-ofloxacin;7h-pyrido(1,2,3-de)-1,4-benzoxazine-6-carboxylicacid,2,3-dihydro-9-fluoro-3-m;dr3355;hemihydrate,(s)-ethyl-10-(4-methyl-1-piperazinyl)-7-oxo;LEVOFLOXACIN HCL;LEVOFLOXACIN HEMIHYDRATE;(3s)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7h-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid monohydrochloride;Levofloxacin base
• CAS NO: 100986-85-4
• Molecular Formula: C₁₈H₂₀FN₃O₄
• Molecular Weight: 361.37
• EINECS: 1533716-785-6
• Product Categories: Pharmaceutical material and intermeidates;Active Pharmaceutical Ingredients;Anti-Infective;Antibiotics for Research and Experimental Use;Biochemistry;Quinolones (Antibiotics for Research and Experimental Use);Peptide Synthesis/Antibiotics;Pharmaceutical intermediate;Antimicrobial;API;Pharmaceutical intermediates;Inhibitors
• Mol File: 100986-85-4.mol

Chemical Properties

• Melting Point: 218°C
• Boiling Point: 572℃
• Flash Point: >110°(230°F)
• Appearance: white to faint yellow/
• Density: 1.48 g/cm³
• Vapor Pressure: 6.7E-14mmHg at 25°C
• Refractive Index: 1.669
• Storage Temp.: Store at 0-5°C
• Solubility: chloroform: soluble10mg/mL
• PKA: 5.19±0.40(Predicted)
• Water Solubility: Slightly soluble in water or methanol. Soluble in glacial acetic acid or dichloromethane
• Sensitive: Light Sensitive
• Merck: 14,6771
• BRN: 7327015
• CAS DataBase Reference: Levofloxacin hydrochloride(CAS DataBase Reference)
• NIST Chemistry Reference: Levofloxacin hydrochloride(100986-85-4)
• EPA Substance Registry System: Levofloxacin hydrochloride(100986-85-4)

Safety Data

• Hazard Codes: Xn
• Statements: 22-42/43-68-20/21/22-64-63
• Safety Statements: 26-36/37/39-36
• RIDADR: UN 1648 3 / PGII
• WGK Germany: 3
• RTECS: UU8815550
• Hazardous Substances Data: 100986-85-4(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Levofloxacin hydrochloride is used as an antibiotic for the treatment of various bacterial infections. It is particularly effective against infections of the lower respiratory and urinary tract, prostate infections, and sexually transmitted diseases. Its broad and potent antibacterial activity covers common Gram-positive and -negative aerobic pathogens and obligate anaerobes.
Used in Pharmacokinetic Studies:
Levofloxacin hydrochloride is utilized in pharmacokinetic research to understand the absorption, distribution, metabolism, and excretion of the drug in the body. This helps in optimizing the drug's dosage and administration for maximum efficacy and minimal side effects.
Used in Antibiotic Resistance Studies:
The antibiotic is employed in studies aimed at understanding and combating antibiotic resistance. By examining the mechanisms of resistance and the effectiveness of levofloxacin against resistant strains, researchers can develop strategies to preserve the drug's efficacy and address the growing concern of antibiotic resistance.
Used in Resistance Prevention:
Levofloxacin hydrochloride is also used in efforts to prevent the development of antibiotic resistance. By promoting the responsible use of antibiotics and understanding the factors that contribute to resistance, the spread of resistant bacteria can be minimized, ensuring the continued effectiveness of levofloxacin and other antibiotics.
Used in Surgical Infections Treatment:
Levofloxacin hydrochloride exhibits satisfactory antimicrobial effects in the treatment of surgical infections, making it a valuable option for postoperative care and infection prevention.
Used in Gastrointestinal Infections Treatment:
The antibiotic is also used for the treatment of gastrointestinal infections, such as traveler's diarrhea associated with pathogenic Enterobacteriaceae, providing relief and reducing the risk of complications.

Originator

Daiichi (Japan)

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).

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.

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

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

Synthetic route

1-methyl-piperazine (109-01-3) + levofloxacin Q-acid (100986-89-8) → levofloxacin (100986-85-4)

Conditions	Yield
With potassium hydroxide In water at 55℃; for 24h; Reagent/catalyst; Time; Temperature; Solvent;	97.1%
With nano iron oxide on ZrO2 coated sulfonic acid In water for 0.366667h; Reflux;	96%
at 150℃; Microwave irradiation;	89%

N-methylpiperazine dihydrochloride (50398-09-9, 51545-09-6, 34352-59-5) + levofloxacin Q-acid (100986-89-8) → levofloxacin (100986-85-4)

Conditions	Yield
Stage #1: N-methylpiperazine dihydrochloride; levofloxacin Q-acid With boron trifluoride-tetrahydrofuran complex; triethylamine In acetonitrile at 20℃; for 24.5h; Stage #2: With methanol for 24h; Reflux; Stage #3: In ethanol at 20℃; for 16h;	92%

1-methyl-piperazine (109-01-3) + ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8) → levofloxacin (100986-85-4)

Conditions	Yield
With acetic acid In water; N,N-dimethyl-formamide at 70 - 105℃; for 10h; Temperature; Solvent; Reagent/catalyst;	85.7%

(S)-ethyl 6,8-difluoro-1-(1-hydroxypropan-2-yl)-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (177472-29-6) → levofloxacin (100986-85-4)

Conditions	Yield
Stage #1: (S)-ethyl 6,8-difluoro-1-(1-hydroxypropan-2-yl)-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate With potassium hydroxide; ethanol; water at 20℃; for 2.5h; Heating / reflux; Stage #2: With acetic acid In ethanol at 0 - 20℃; for 2h; pH=7; Product distribution / selectivity;	78%

C20H24FN3O4 → levofloxacin (100986-85-4)

Conditions	Yield
With hydrogenchloride In ethanol; water at 83℃; for 36h;	77.9%
With hydrogenchloride In ethanol; water at 83℃; for 36h;	75.3%

(S)-6,8-difluoro-1-(1-hydroxypropan-2-yl)-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (1036016-10-0) → levofloxacin (100986-85-4)

Conditions	Yield
Stage #1: (S)-6,8-difluoro-1-(1-hydroxypropan-2-yl)-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid With potassium hydroxide In ethanol; water for 3h; Heating / reflux; Stage #2: With acetic acid In ethanol; water at 0 - 20℃; Product distribution / selectivity;	76%

G of N-methylpiperazine + levofloxacin Q-acid (100986-89-8) → levofloxacin (100986-85-4)

Conditions	Yield
In pyridine; diethyl ether	74.3%

formaldehyd (50-00-0) + S-(-)-9-fluoro-2,3-dihydro-3-methyl-10-(1-piperazinyl)-7-oxo-7H-pyrido-<1,2,3-de><1,4>benzoxazine-6-carboxylic acid (117707-40-1) → levofloxacin (100986-85-4)

Conditions	Yield
With formic acid In water at 90℃; for 10h; Temperature;	74.3%

1-methyl-piperazine (109-01-3) + (-)-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido<1,2,3-de><1,4>benzoxazine-6-carboxylic acid BF2-chelate (129306-33-8) → levofloxacin (100986-85-4)

Conditions	Yield
In dimethyl sulfoxide for 17h; Ambient temperature;	52%

ofloxacin (82419-36-1) → levofloxacin (100986-85-4) + (R)-ofloxacin (100986-86-5)

Conditions	Yield
With Bis(2-ethylhexyl)phosphoric acid; sodium dodecyl-sulfate; O,O'-dibenzoyl-L-tartaric acid In octanol; water at 20℃; for 4h; pH=7; Reflux; Resolution of racemate; optical yield given as %ee; enantioselective reaction;	A 8.54% B 34.23%
With (2-hydroxypropyl)-α-cyclodextrin In phosphate buffer pH=2.3; capillary electrophoresis;
With Bis(2-ethylhexyl)phosphoric acid; Di-p-toluoyl-L-tartaric acid; O,O'-dibenzoyl-L-tartaric acid In octanol; water at 25℃; for 0.5h; pH=6.86; Resolution of racemate; aq. phosphate buffer; enantioselective reaction;

ethyl 3-(2,3,4,5-tetrafkuorophenyl)-3-oxopropanoate (94695-50-8) → levofloxacin (100986-85-4)

Conditions	Yield
Multi-step reaction with 5 steps 1: acetic anhydride / 2 h / 110 °C 2: CH2Cl2 / 0.5 h / Ambient temperature 3: 59 percent / 50percent NaH / dimethylsulfoxide / 3 h / Ambient temperature 4: 70 percent / 10percent aq. KOH / tetrahydrofuran / 2 h / 65 - 70 °C 5: 83 percent / pyridine / 12 h / 120 °C View Scheme

3-(2,3,4,5-tetrafluorophenyl)-3-oxo-2-(ethoxymethylene)-propanoic acid ethyl ester (103995-33-1) → levofloxacin (100986-85-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: CH2Cl2 / 0.5 h / Ambient temperature 2: 59 percent / 50percent NaH / dimethylsulfoxide / 3 h / Ambient temperature 3: 70 percent / 10percent aq. KOH / tetrahydrofuran / 2 h / 65 - 70 °C 4: 83 percent / pyridine / 12 h / 120 °C View Scheme

(+)-ethyl 2-<<<(S)-1-hydroxyprop-2-yl>amino>methylene>-3-oxo-3-(2,3,4,5-tetrafluorophenyl)propionate (110548-02-2) → levofloxacin (100986-85-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: 59 percent / 50percent NaH / dimethylsulfoxide / 3 h / Ambient temperature 2: 70 percent / 10percent aq. KOH / tetrahydrofuran / 2 h / 65 - 70 °C 3: 83 percent / pyridine / 12 h / 120 °C View Scheme

(-)-ethyl 1,4-dihydro-1-<1(S)-(hydroxymethyl)ethyl>-4-oxo-6,7,8-trifluoroquinoline-3-carboxylate (110548-03-3) → levofloxacin (100986-85-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: 70 percent / 10percent aq. KOH / tetrahydrofuran / 2 h / 65 - 70 °C 2: 83 percent / pyridine / 12 h / 120 °C View Scheme

1-methyl-piperazine (109-01-3) + (3S)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid-boron difluoride chelate complex → levofloxacin (100986-85-4)

Conditions	Yield
Stage #1: 1-methyl-piperazine; (3S)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid-boron difluoride chelate complex With triethylamine In dimethyl sulfoxide at 20℃; for 17h; Stage #2: With triethylamine In ethanol for 8h; Heating / reflux; Stage #3: With hydrogenchloride In water

(-) potassium N-(1-hydroxy-propy-2(S)-yl)-6-fluoro-7-(N-methylpiperazinyl)-8-nitro-quinol-4-one-3-carboxylate → levofloxacin (100986-85-4)

Conditions	Yield
Stage #1: (-) potassium N-(1-hydroxy-propy-2(S)-yl)-6-fluoro-7-(N-methylpiperazinyl)-8-nitro-quinol-4-one-3-carboxylate With potassium hydroxide In methanol for 2.5h; Heating / reflux; Stage #2: With acetic acid In methanol

levofloxacin Q-acid (100986-89-8) + ascorbic acid (50-81-7) → levofloxacin (100986-85-4)

Conditions	Yield
In dimethyl sulfoxide	5.63 g (87.6%)

sodium metabisulfite + levofloxacin Q-acid (100986-89-8) → levofloxacin (100986-85-4)

Conditions	Yield
In dimethyl sulfoxide	11.8 g (92.4%)

1-methyl-piperazine (109-01-3) + 1-methoxy-2-propanol (107-98-2) + n-heptane (142-82-5) + levofloxacin Q-acid (100986-89-8) → levofloxacin (100986-85-4)

Conditions	Yield
	2.98 g (77.3%)

levofloxacin Q-acid (100986-89-8) → levofloxacin (100986-85-4)

Conditions	Yield
In 1-methyl-piperazine; n-heptane

1-methyl-piperazine (109-01-3) + trifluoroborane diethyl ether (109-63-7) + levofloxacin Q-acid (100986-89-8) → levofloxacin (100986-85-4)

Conditions	Yield
With triethylamine In hydrogenchloride; methanol; diethyl ether; dimethyl sulfoxide

1-methyl-piperazine (109-01-3) + chloroform-methanol-water + levofloxacin Q-acid (100986-89-8) → levofloxacin (100986-85-4)

Conditions	Yield
In ethanol; dimethyl sulfoxide

ofloxacin (82419-36-1) + Cu(II)-coordinated G-rich oligonucleotides → levofloxacin (100986-85-4) + (R)-ofloxacin (100986-86-5)

Conditions	Yield
pH=7; Reagent/catalyst; Resolution of racemate;

ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate (106939-34-8) → levofloxacin (100986-85-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: acetic acid; sulfuric acid / water / 4 h / Reflux 2: triethylamine / dimethyl sulfoxide / 8 h / 90 °C View Scheme
Multi-step reaction with 2 steps 1: sulfuric acid; acetic acid / N,N-dimethyl-formamide / 1 h / Reflux; Green chemistry 2: water / 10.5 h / 110 °C / Green chemistry View Scheme
Multi-step reaction with 2 steps 1: sulfuric acid; acetic acid / water / 3 h / 20 °C / Reflux 2: water / 15.5 h / 120 °C View Scheme
Multi-step reaction with 2 steps 1: sulfuric acid; acetic acid / N,N-dimethyl-formamide / 1 h / Reflux 2: water / 10.5 h / 110 °C View Scheme

(+)-ethyl 3-[(1-hydroxyprop-2(S)-yl)amino]acrylate → levofloxacin (100986-85-4)

Conditions	Yield
Multi-step reaction with 6 steps 1: ammonia / toluene / 4 h / 50 °C 2: toluene / 50 - 100 °C / pH < 7 3: hydrogenchloride / toluene; water / pH < 7 4: potassium fluoride / N,N-dimethyl-formamide / Reflux 5: acetic acid; sulfuric acid / water / 4 h / Reflux 6: triethylamine / dimethyl sulfoxide / 8 h / 90 °C View Scheme

C14H31NO3Si2 → levofloxacin (100986-85-4)

Conditions	Yield
Multi-step reaction with 5 steps 1: toluene / 50 - 100 °C / pH < 7 2: hydrogenchloride / toluene; water / pH < 7 3: potassium fluoride / N,N-dimethyl-formamide / Reflux 4: acetic acid; sulfuric acid / water / 4 h / Reflux 5: triethylamine / dimethyl sulfoxide / 8 h / 90 °C View Scheme

C21H31F4NO4Si2 → levofloxacin (100986-85-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: hydrogenchloride / toluene; water / pH < 7 2: potassium fluoride / N,N-dimethyl-formamide / Reflux 3: acetic acid; sulfuric acid / water / 4 h / Reflux 4: triethylamine / dimethyl sulfoxide / 8 h / 90 °C View Scheme

3-(2-hydroxy-1-methylethylamino)-2-(2,3,4,5-tetrafluorobenzoyl)acrylic acid ethyl ester → levofloxacin (100986-85-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium fluoride / N,N-dimethyl-formamide / Reflux 2: acetic acid; sulfuric acid / water / 4 h / Reflux 3: triethylamine / dimethyl sulfoxide / 8 h / 90 °C View Scheme
Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 4 h / 100 °C / Green chemistry 2: sulfuric acid; acetic acid / N,N-dimethyl-formamide / 1 h / Reflux; Green chemistry 3: water / 10.5 h / 110 °C / Green chemistry View Scheme
Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 8 h / 150 °C 2: sulfuric acid; acetic acid / water / 3 h / 20 °C / Reflux 3: water / 15.5 h / 120 °C View Scheme
Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 4 h / 100 °C 2: sulfuric acid; acetic acid / N,N-dimethyl-formamide / 1 h / Reflux 3: water / 10.5 h / 110 °C View Scheme
Multi-step reaction with 3 steps 1: 24 h / 120 °C 2: potassium carbonate / 16 h / 140 °C 3: hydrogenchloride / ethanol; water / 36 h / 83 °C View Scheme

C20H24FN3O4S → levofloxacin (100986-85-4)

Conditions	Yield
With GLUTATHIONE In methanol at 23℃; pH=6.5; Kinetics;

LACTIC ACID (849585-22-4) + levofloxacin (100986-85-4) → levofloxacin lactate

Conditions	Yield
In ethanol at 80℃; for 1h; Temperature;	94.3%

cerium(IV) sulphate + water (7732-18-5) + levofloxacin (100986-85-4) → [Ce(levofloxacin)2(H2O)2]SO4*5H2O

Conditions	Yield
With sodium hydroxide In methanol; acetone at 20℃; for 24h;	94%

levofloxacin (100986-85-4) + Propargylamine (2450-71-7) → (S)-9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-N-(prop-2-yn-1-yl)-3,7-dihydro-2H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxamide

Conditions	Yield
Stage #1: levofloxacin With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; Inert atmosphere; Stage #2: Propargylamine With potassium carbonate In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 1h; Inert atmosphere;	90.7%

levofloxacin (100986-85-4) → (-)-9-fluoro-3-methyl-10(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de]-1,4-benzoxazine-6-carboxylic acid hemihydrate

Conditions	Yield
In water; ethyl acetate for 1h; Purification / work up; Heating / reflux;	90%
In 2,8-dimethylnonan-5-one; water for 1h; Purification / work up; Heating / reflux;	89.6%
In acetic acid methyl ester; water for 1h; Purification / work up; Heating / reflux;	85.6%

di(pyridin-2-yl)amine (1202-34-2) + copper(II) choride dihydrate + levofloxacin (100986-85-4) → C28H28ClCuFN6O4*ClH

Conditions	Yield
Stage #1: copper(II) choride dihydrate; levofloxacin With potassium hydroxide In methanol at 20℃; for 0.5h; Stage #2: di(pyridin-2-yl)amine In methanol at 60℃; for 2h;	83%

4-amino-N-(diaminomethylene) benzenesulfonamide (57-67-0) + levofloxacin (100986-85-4) → (S)−7-((4-(N-carbamimidoylsulfamoyl)phenyl)imino)−9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)−2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid

Conditions	Yield
With acetic acid In methanol for 2h; Microwave irradiation; Reflux;	82.94%

uranyl nirate hexahydrate + levofloxacin (100986-85-4) → [UO2(levofloxacin)2(H2O)2]*2H2O

Conditions	Yield
With sodium hydroxide In methanol; acetone at 20℃; for 24h;	81.4%

octadecanoic acid chloromethyl ester (77878-01-4) + levofloxacin (100986-85-4) → C37H72O4 (121819-05-4) + (3S)-6-[(octadecanoyloxy)methyl] 9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate (1261134-66-0)

Conditions	Yield
Stage #1: levofloxacin With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 0.333333h; Stage #2: octadecanoic acid chloromethyl ester In N,N-dimethyl-formamide at 90℃; for 1h;	A n/a B 81%
Stage #1: levofloxacin With potassium carbonate In acetonitrile for 8h; Reflux; Stage #2: octadecanoic acid chloromethyl ester With tetra-(n-butyl)ammonium iodide In acetonitrile for 168h; Reflux;

isoniazid (54-85-3) + levofloxacin (100986-85-4) → 2-[3(1-cyclopropyl-6-fluoro-8-methoxy)-7-(3-methylpiperazin-1-yl)-4-oxo-1H quinolinyl]-5-(pyridin-4-yl)-1,3,4-oxadiazole

Conditions	Yield
With trichlorophosphate Reflux;	81%

gold(III) tetrachloride trihydrate + levofloxacin (100986-85-4) → [AuCl2(levofloxacin)]Cl.2H2O

Conditions	Yield
In methanol at 20℃; for 24h;	80%

sulfanilamide (63-74-1) + levofloxacin (100986-85-4) → (S)−9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)−7-((4-sulfamoylphenyl)imino)−2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid

Conditions	Yield
With acetic acid In methanol for 2h; Microwave irradiation; Reflux;	80%

chloromethyl n-dodecanoate (61413-67-0) + levofloxacin (100986-85-4) → C25H48O4 (1261134-88-6) + (3S)-6-[(dodecanoyloxy)methyl] 9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate (1261134-60-4)

Conditions	Yield
Stage #1: levofloxacin With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 0.333333h; Stage #2: chloromethyl n-dodecanoate In N,N-dimethyl-formamide at 90℃; for 1h;	A n/a B 79%
Stage #1: levofloxacin With potassium carbonate In acetonitrile for 8h; Reflux; Stage #2: chloromethyl n-dodecanoate With tetra-(n-butyl)ammonium iodide In acetonitrile for 168h; Reflux;

levofloxacin (100986-85-4) + chloromethyl n-hexadecanoate (61413-69-2) → C33H64O4 (91360-29-1) + (3S)-6-[(hexadecanoyloxy)methyl] 9-fluoro-3,7-dihydro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2H-[1,4]oxazino-[2,3,4-ij]quinoline-6-carboxylate (1261134-64-8)

Conditions	Yield
Stage #1: levofloxacin With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 0.333333h; Stage #2: chloromethyl n-hexadecanoate In N,N-dimethyl-formamide at 90℃; for 1h;	A n/a B 79%
Stage #1: levofloxacin With potassium carbonate In acetonitrile for 8h; Reflux; Stage #2: chloromethyl n-hexadecanoate With tetra-(n-butyl)ammonium iodide In acetonitrile for 168h; Reflux;

levofloxacin (100986-85-4) + decanoyloxymethyl chloride (67317-62-8) → (3S)-6-[(decanoyloxy)methyl] 9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylate (1261134-58-0) + Methylendidecanoat (76068-80-9)

Conditions	Yield
Stage #1: levofloxacin With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 0.333333h; Stage #2: decanoyloxymethyl chloride In N,N-dimethyl-formamide at 90℃; for 1h;	A 79% B n/a

1,2,3-Benzotriazole (95-14-7) + levofloxacin (100986-85-4) → (S)-6-(1H-benzo[d][1,2,3]triazole-1-carbonyl)-9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-2H-[1,4]oxazino[2,3,4-ij]quinolin-7(3H)-one (1381763-83-2)

Conditions	Yield
With thionyl chloride In dichloromethane at 20℃;	79%

dimethyltin dichloride (753-73-1) + levofloxacin (100986-85-4) → C38H44F2N6O8Sn

Conditions	Yield
Stage #1: levofloxacin With sodium hydrogencarbonate In water at 25℃; for 0.5h; Stage #2: dimethyltin dichloride In toluene Reflux;	79%

copper(II) choride dihydrate + bathophenanthroline (1662-01-7) + levofloxacin (100986-85-4) → C42H35ClCuFN5O4

Conditions	Yield
Stage #1: copper(II) choride dihydrate; levofloxacin With potassium hydroxide In methanol at 20℃; for 0.5h; Stage #2: bathophenanthroline In methanol at 60℃; for 2h;	79%

sulfamerazina (127-79-7) + levofloxacin (100986-85-4) → (S)−9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)−7-((4-(N-(4-methylpyrimidin-2-yl)sulfamoyl)phenyl)imino)−2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid

Conditions	Yield
With acetic acid In methanol for 2h; Microwave irradiation; Reflux;	78.91%

zirconyl chloride octahydrate + levofloxacin (100986-85-4) → [ZrO(levofloxacin)2(H2O)]*6H2O

Conditions	Yield
With sodium hydroxide In methanol; acetone at 20℃; for 24h;	78.6%

Upstream product

• 109-01-3 1-methyl-piperazine 
• 100986-89-8 levofloxacin Q-acid 
• 82419-36-1 ofloxacin 
• 110548-02-2 (+)-ethyl 2-<<<(S)-1-hydroxyprop-2-yl>amino>methylene>-3-oxo-3-(2,3,4,5-tetrafluorophenyl)propionate 
• 110548-03-3 (-)-ethyl 1,4-dihydro-1-<1(S)-(hydroxymethyl)ethyl>-4-oxo-6,7,8-trifluoroquinoline-3-carboxylate 
• 50-81-7 ascorbic acid 
• 107-98-2 1-methoxy-2-propanol 
• 142-82-5 n-heptane 
• 109-63-7 trifluoroborane diethyl ether 
• 94695-48-4 2,3,4,5-tetrafluorobenzoyl chloride 
• 138998-47-7 ethyl α<(N,N-dimethylamino)methylene>-2,3,4,5-tetrafluoro-β-oxobenzenepropanoate 
• 106939-34-8 ethyl (S)-(-)-9,10-Difluoro-3-Methyl-7-Oxo-2,3-Dihydro-7H-Pyrido[1,2,3-de]-[1,4]Benzoxazine-6-Carboxylate 
• 50-00-0 formaldehyd 
• 117707-40-1 S-(-)-9-fluoro-2,3-dihydro-3-methyl-10-(1-piperazinyl)-7-oxo-7H-pyrido-<1,2,3-de><1,4>benzoxazine-6-carboxylic acid 

Downstream Products

• 151250-76-9 S-(-)-9-fluoro-2,3-dihydro-3-methyl-10-(1,4-diazapentyl)-7-oxo-7H-pyrido-<1,2,3-de><1,4>benzoxazine-6-carboxylic acid 
• 117707-40-1 S-(-)-9-fluoro-2,3-dihydro-3-methyl-10-(1-piperazinyl)-7-oxo-7H-pyrido-<1,2,3-de><1,4>benzoxazine-6-carboxylic acid 
• 151377-74-1 S-(-)-9-fluoro-2,3-dihydro-3-methyl-10-(1,4-diformyl-1,4-diazapentyl)-7-oxo-7H-pyrido-<1,2,3-de><1,4>benzoxazine-6-carboxylic acid 
• 124-38-9 carbon dioxide 

Relevant articles and documents

Experimental and computational study on the enantioseparation of four chiral fluoroquinolones by capillary electrophoresis with sulfated-β-cyclodextrin as chiral selector

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.

Enantioseparation of racemic mixtures based on solvent sublation

A method of solvent sublation was developed for the enantioseparation of racemic ofloxacin (rac Oflx) and racemic tryptophan (rac Trp). In this method, dibenzoyl-L-tartaric acid (L-DBTA) and di-(2-ethylhexyl) phosphoric acid (D2EHPA) and sodium lauryl sulfate (SDS) were used as chiral coextractants and foamer, respectively. Several important parameters influencing the separation performances, such as pH in aqueous phase, concentrations of rac mixtures, L-DBTA, D2EHPA, and SDS, were investigated. Under the optimal operation conditions, the enantiomeric excess and enantioselectivity were 60.08% and 5.58 for Oflx and 65.09% and 6.31 for Trp, respectively. The yields of D-enantiomer and L-enantiomer were 34.23% and 8.54% for Oflx and 18.59% and 3.93% for Trp, respectively. The results suggest that the enantioselectivities have been enhanced compared with the traditional chiral extraction. This technique is an efficient chiral separation method, with many advantages such as low expenditures of organic solvent, low consumption of chiral extractant, and easy realization of multistage operation. Chirality 24:661-667, 2012. 2012 Wiley Periodicals, Inc. Copyright

Equilibrium and structural characterization of ofloxacin-cyclodextrin complexation

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.

GSH Induced Controlled Release of Levofloxacin from a Purpose-Built Prodrug: Luminescence Response for Probing the Drug Release in Escherichia coli and Staphylococcus aureus

Fluoroquinolones are third-generation broad spectrum bactericidal antibiotics and work against both Gram-positive and Gram-negative bacteria. Levofloxacin (L), a fluoroquinolone, is widely used in anti-infective chemotherapy and treatment of urinary tract infection and pneumonia. The main pathogen for urinary tract infections is Escherichia coli, and Streptococcus pneumoniae is responsible for pneumonia, predominantly a lower respiratory tract infection. Poor permeability of L leads to the use of higher dose of this drug and excess drug in the outer cellular fluid leads to central nervous system (CNS) abnormality. One way to counter this is to improve the lipophilicity of the drug molecule, and accordingly, we have synthesized two new Levofloxacin derivatives, which participated in the spatiotemporal release of drug via disulfide bond cleavage induced by glutathione (GSH). Recent studies with Streptococcus mutants suggest that it is localized in epithelial lining fluid (ELF) of the normal lower respiratory tract and the effective [GSH] in ELF is ～430 μM. E. coli typically cause urinary tract infections and the concentration of GSH in porcine bladder epithelium is reported as 0.6 mM for a healthy human. Thus, for the present study we have chosen two important bacteria (Gram + ve and Gram - ve), which are operational in regions having high extracellular GSH concentration. Interestingly, this supports our design of new lipophilic Levofloxacin based prodrugs, which released effective drug on reaction with GSH. Higher lipophilicity favored improved uptake of the prodrugs. Site specific release of the drug (L) could be achieved following a glutathione mediated biochemical transformation process through cleavage of a disulfide bond of these purpose-built prodrugs. Further, appropriate design helped us to demonstrate that it is possible also to control the kinetics of the drug release from respective prodrugs. Associated luminescence enhancement helps in probing the release of the drug from the prodrug in bacteria and helps in elucidating the mechanistic pathway of the transformation. Such an example is scarce in the contemporary literature.

Enantioselective separation of chiral ofloxacin using functional Cu(ii)-coordinated G-rich oligonucleotides

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

Preparation of polar group derivative β-cyclodextrin bonded hydride silica chiral stationary phases and their chromatography separation performances

Three novel β-cyclodextrin compounds derived with piperidine which is flexible, L-proline containing a chiral center, ionic liquid with 3,5-diamino-1,2,4-triazole as the cation were designed and synthesized as chiral selectors for enantiomer separation, whose name were (mono-6-deoxy-6-(piperidine)-β-cyclodextrin, mono-6-deoxy-6-(L-proline)-β-cyclodextrin, mono-6-deoxy-6-(3,5-diamino-1,2,4-triazole)-β-cyclodextrin, multi-substituted 3,5-diamino-1,2,4- triazole-(p-toluenesulfonic)-β-cyclodextrin), respectively. In addition, to enhance the polarity of chiral stationary phases, hydrosilylation and silylation reactions were implemented to derive ordinary silica, the common used selector carrier, to hydride silica, whose surface is covered with proton. 31 pyrrolidine compounds and some chiral drugs were tested in both polar organic mobile phase mode and normal mobile phase mode. 6-Deoxy-6-L-proline-β-cyclodextrin-CSP showed satisfactory separations in polar organic mobile phase mode and exihibited a strong separation capability in different pH values; multi-substituted 3,5-diamino-1,2,4-triazole-(p-toluenesulfonic)-β-cyclodextrin-CSP can separate pyrrolidine compounds in both mobile phase modes with high resolutions and separation efficiency compared to commercially available CSPs, making it to be the most valuable object to study. The composition of mobile phase, type of stationary phase as well as the peak problem of chromatograms was discussed deeply.

Conventional and microwave-assisted synthesis of quinolone carboxylic acid derivatives

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.

Nano-Fe3 O4@ZrO2-SO3 H as highly efficient recyclable catalyst for the green synthesis of fluoroquinolones

Nano-Fe3 O4 @ZrO2-SO3 H (n-FZSA), was utilized as a magnetic catalyst for the synthesis of various fluoroquinolone compounds. These compounds were prepared by the direct amination of 7-halo-6-fluoroquinolone-3-carboxylic acids with piperazine derivatives and (4aR,7aR)-octahydro-1H-pyrrolo[3,4-b] pyridine in water. The results showed that n-FZSA exhibited high catalytic activity towards the synthesis of fluoroquinolone derivatives, giving the desired products in high yields. Furthermore, the catalyst was recyclable and could be used at least seven times without any discernible loss in its catalytic activity. Overall, this new catalytic method for the synthesis of fluoroquinolone derivatives provides rapid access to the desired compounds in refluxing water following a simple work-up procedure, and avoids the use of organic solvents.

Intrinsic enantioselectivity of natural polynucleotides modulated by copper ions

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.

Chiral separation and modeling of quinolones on teicoplanin macrocyclic glycopeptide antibiotics CSP

New chiral high-performance liquid chromatography (HPLC) method for the enantiomeric resolution of quinolones is developed and described. The column used was Chirobiotic T (150?×?4.6?mm, 5.0?μm). Three mobile phases used were MeOH:ACN:Water:TEA (70:10:20:0.1%), (60:30:10:0.1%), and (50:30:20:0.1%). The flow rate of the mobile phases was 1.0?mL/min with UV detection at different wavelengths. The values of retention, resolution, and separation factors ranged from 1.5 to 6.0, 1.80 to 2.25, and 2.86 to 6.0, respectively. The limit of detection and quantification ranged from 4.0 to 12?ng and 40 to 52?ng, respectively. The modeling studies indicated strong interactions of R-enantiomers with teicoplanin chiral selector than S-enantiomers. The supra molecular mechanism of the chiral recognition was established by modeling and chromatographic studies. It was observed that hydrogen bondings and π-π interactions are the major forces for chiral separation. The present chiral HPLC method may be used for enantiomeric resolution of quinolones in any matrices.