42835-25-6

Basic information

• Product Name: Flumequine
• Synonyms: 9-Fluoro-6,7-dihydro-5-methyl-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid;FLUMEQUIN;FLUMEQUINE;Fluoromethylquinoline;Flumequine solution;FLUMEQUINE STANDARD SOLUTION;FLUMEQUINE PESTANAL, 250 MG;Fluoromethyl
• CAS NO: 42835-25-6
• Molecular Formula: C₁₄H₁₂FNO₃
• Molecular Weight: 261.25
• EINECS: 255-962-6
• Product Categories: Aromatics Compounds;Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Quinolones and Fluoroquinolones;A - KAntibiotics;Antibacterial;Antibiotics A to;Antibiotics A-FAntibiotics;Chemical Structure Class;Inhibits an EnzymeAntibiotics;Interferes with DNA SynthesisAntibiotics;Mechanism of Action;Spectrum of Activity;API's;Pharmaceutical raw material;FLUGERAL
• Mol File: 42835-25-6.mol

Chemical Properties

• Melting Point: 253-255°C
• Boiling Point: 439.7 °C at 760 mmHg
• Flash Point: >110°(230°F)
• Appearance: white to off-white/
• Density: 1.45 g/cm³
• Vapor Pressure: 1.66E-08mmHg at 25°C
• Refractive Index: 1.645
• Storage Temp.: 0-6°C
• Solubility: 1 M NH4OH: soluble50mg/mL
• PKA: pKa 6.42(H2O t=25.0 I=0.025)(Approximate)
• Water Solubility: Soluble in DMSO and dilute alkali hydroxides. Insoluble in water
• Stability: Stable. Incompatible with strong oxidizing agents.
• Merck: 14,4137
• BRN: 490724
• CAS DataBase Reference: Flumequine(CAS DataBase Reference)
• NIST Chemistry Reference: Flumequine(42835-25-6)
• EPA Substance Registry System: Flumequine(42835-25-6)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 22-24/25-36/37/39-27-26
• WGK Germany: 3
• RTECS: DK1672000
• F: 10
• Hazardous Substances Data: 42835-25-6(Hazardous Substances Data)

Usage

Uses

Used in Veterinary Medicine:
Flumequine is used as an antimicrobial agent for the treatment of enteric infections in food animals such as bovine, ovine, chicken, rabbits, goats, and horses. It is particularly effective in treating bacterial infections in farmed fish, including salmonidae.
Used in Aquaculture:
Flumequine is used as a replacement for oxolinic acid in aquaculture due to its more appropriate pharmacokinetic profile and lower effective doses. It helps in the treatment and prevention of bacterial infections in farmed fish, contributing to the overall health and productivity of the aquaculture industry.
Used in Human Medicine (Limited):
Flumequine has limited use in humans for the treatment of urinary tract infections, providing an alternative option for patients requiring antibacterial therapy.

Originator

Apurone,Riker,France,1977

Preparation

Synthesis: Condensation of 5-fluoro-2-methyltetrahydroquinoline with diethyl ethoxy-methylenemalonate followed by thermal cycli- zation gives ethyl 6,7-dihydro-9-fluoro-5-meth-yl-1-oxo-1H,5H-benzo[i,j]quinolizine-2-car-boxylate,which is saponified with sodium hydroxide to give flumequine.

Manufacturing Process

6-Fluoro-2-methyltetrahydroquinoline (32.2 g, 0.2 mol) is mixed with diethyl ethoxymethylenemalonate, and the mixture is heated at 125°C to 130°C for 3 hours. Polyphosphoric acid (200 g) is added, and the solution is gradually heated to 115°C to 120°C in an oil bath with occasional stirring. The temperature is maintained for 1 hour, then the mixture is poured into 600 ml of water and neutralized with 40% sodium hydroxide solution. The product ester which precipitates is separated by filtration, washed with water and suspended in 2 liters of 10% sodium hydroxide solution. The mixture is heated on the steam bath for 1 hour, treated with decolorizing charcoal, filtered, then neutralized with concentrated hydrochloric acid. The solid product is isolated by filtration of the hot solution, washed with water and recrystallized from dimethylformamide.

Therapeutic Function

Antibacterial

Pharmaceutical Applications

A tricyclic fluorinated 4-quinolone, with activity similar to that of nalidixic acid in vitro, although it is somewhat more active against some Enterobacteriaceae. Following escalating oral doses of 400, 800 or 1200 mg, mean peak plasma levels reached at 2 h are 13.5, 23.8 and 31.9 mg/L, respectively. The apparent elimination half-life is about 7 h. The main metabolite, hydroxyflumequine, is much more rapidly eliminated. About 60% of a dose appears in the urine, mostly in the form of conjugates. Urinary concentrations following an 800 mg dose are 10–35 mg/L, with a peak of 105 mg/L. It has no effect on the pharmacokinetics of theophylline.Flumequine is generally well tolerated, side effects being mainly mild gastrointestinal tract disturbances, rashes, dizziness and confusion.It is principally used in uncomplicated urinary tract infections.

InChI:InChI=1/C14H12FNO3/c1-7-2-3-8-4-9(15)5-10-12(8)16(7)6-11(13(10)17)14(18)19/h4-7H,2-3H2,1H3,(H,18,19)

Synthetic route

9-fluoro-5-methyl-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid ethyl ester (42835-47-2) → flumequine (42835-25-6)

Conditions	Yield
With water at 100℃; for 3h;	70.8%
With sodium hydroxide at 80℃; for 2h;	304.5 mg

6-fluoro-1,2,3,4-tetrahydro-2-methylquinoline (42835-89-2) → flumequine (42835-25-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: 97 percent / 2.5 h / 125 °C 2: 69.1 percent / polyphosphoric acid / toluene / 6 h / 110 °C 3: 70.8 percent / H2O / 3 h / 100 °C View Scheme
Multi-step reaction with 3 steps 1: 2.5 h / 125 °C 2: polyphosphoricacid / water / Heating 3: sodium hydroxide / 2 h / 80 °C View Scheme

Diethyl (2-methyl-6-fluorotetrahydro-quinolin-1-yl)methylenemalonate (105450-09-7) → flumequine (42835-25-6)

Conditions	Yield
Multi-step reaction with 2 steps 1: 69.1 percent / polyphosphoric acid / toluene / 6 h / 110 °C 2: 70.8 percent / H2O / 3 h / 100 °C View Scheme

6-fluoro-1,2,3,4-tetrahydro-2-methylquinoline (42835-89-2) + diethyl 2-ethoxymethylenemalonate (87-13-8) → flumequine (42835-25-6)

Conditions	Yield
With PPA In water; toluene
In sodium hydroxide; toluene
With PPA In water; toluene
In sodium hydroxide; toluene

5-methoxymethylene-2,2-dimethyl-1,3-dioxane-4,6-dione (15568-85-1) + 6-fluoro-1,2,3,4-tetrahydro-2-methylquinoline (42835-89-2) → 5-[1-(6-fluoro-2-methyl-1,2,3,4-tetrahydroquinolyl)]-methylene-2,2-dimethyl-1,3-dioxan-4,6-dione (123400-74-8) + flumequine (42835-25-6)

Conditions	Yield
In tetrahydrofuran

5-[1-(6-fluoro-2-methyl-1,2,3,4-tetrahydroquinolyl)]-methylene-2,2-dimethyl-1,3-dioxan-4,6-dione (123400-74-8) → flumequine (42835-25-6)

Conditions	Yield
With sodium hydroxide; PPA In 5,5-dimethyl-1,3-cyclohexadiene

6-fluoro-2-methyl-quinoline (1128-61-6) → flumequine (42835-25-6)

Conditions	Yield
Multi-step reaction with 4 steps 1: hydrogen / toluene / 24 h / 120 °C / 3750.38 Torr / Autoclave 2: 2.5 h / 125 °C 3: polyphosphoricacid / water / Heating 4: sodium hydroxide / 2 h / 80 °C View Scheme

1,2,3-Benzotriazole (95-14-7) + flumequine (42835-25-6) → 2-(1H-benzo[d][1,2,3]triazole-1-carbonyl)-9-fluoro-5-methyl-6,7-dihydropyrido[3,2,1-ij]quinolin-1(5H)-one (1173208-75-7)

Conditions	Yield
Stage #1: 1,2,3-Benzotriazole With thionyl chloride In dichloromethane at 25℃; for 0.5h; Stage #2: flumequine In dichloromethane at 25℃; for 2h;	90%

flumequine (42835-25-6) + zinc(II) chloride (7646-85-7) → [Zn(flmq)2(H2O)2] (1268236-43-6)

Conditions	Yield
Stage #1: flumequine With potassium hydroxide In methanol for 0.333333h; Stage #2: zinc(II) chloride In methanol for 0.5h;	75%

di(pyridin-2-yl)amine (1202-34-2) + cobalt(II) chloride hexahydrate + flumequine (42835-25-6) → C38H31CoF2N5O6*H2O

Conditions	Yield
Stage #1: flumequine With potassium hydroxide In methanol for 0.5h; Stage #2: di(pyridin-2-yl)amine; cobalt(II) chloride hexahydrate In methanol for 0.5h;	70%

flumequine (42835-25-6) → 9-fluoro-5-methyl-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carbonitrile

Conditions	Yield
Stage #1: flumequine With polyphosphate ester; ammonia In chloroform at 119 - 123℃; for 45h; Stage #2: With polyphosphate ester at 120℃; for 1.5h;	65%

[2,2]bipyridinyl (366-18-7) + flumequine (42835-25-6) + zinc(II) chloride (7646-85-7) → [(2,2'-bipyridine)chlorido(flumequinato-k2O,O')zinc(II)]

Conditions	Yield
Stage #1: flumequine With potassium hydroxide In methanol for 0.333333h; Stage #2: [2,2]bipyridinyl; zinc(II) chloride In methanol for 1h;	65%

methanol (67-56-1) + 1,10-Phenanthroline (66-71-7) + flumequine (42835-25-6) + zinc(II) chloride (7646-85-7) → [Zn(flmq)(phen)Cl]*0.5MeOH

Conditions	Yield
Stage #1: flumequine With potassium hydroxide In methanol at 20℃; for 0.333333h; Stage #2: methanol; 1,10-Phenanthroline; zinc(II) chloride	65%

[2,2]bipyridinyl (366-18-7) + cobalt(II) chloride hexahydrate + flumequine (42835-25-6) → C38H30CoF2N4O6*H2O

Conditions	Yield
Stage #1: flumequine With potassium hydroxide In methanol for 0.5h; Stage #2: [2,2]bipyridinyl; cobalt(II) chloride hexahydrate In methanol for 0.5h;	65%

methanol (67-56-1) + 1,10-Phenanthroline (66-71-7) + manganese(II) chloride tetrahydrate + flumequine (42835-25-6) → [Mn(flmq)2(1,10-phenanthroline)]*2MeOH

Conditions	Yield
Stage #1: methanol; flumequine With potassium hydroxide for 0.5h; Stage #2: 1,10-Phenanthroline; manganese(II) chloride tetrahydrate for 0.25h;	65%

zinc nitrate tetrahydrate + flumequine (42835-25-6) → [Zn(II)(7-fluoro-12-methyl-4-oxo-1-azatricyclo[7.3.1.0(5,13)]trideca-2,5,7,9(13)-tetraene-3-carboxylate)2(H2O)2]*H2O (1268154-95-5)

Conditions	Yield
With KOH In ethanol; water soln. of Zn salt in distd. H2O added dropwise to soln. of basified (KOH)flumequine in EtOH-H2O; stirred at room temp. overnight; ppt. isolated after filtration; elem. anal.;	64%

[2,2]bipyridinyl (366-18-7) + flumequine (42835-25-6) + potassium hydroxide + zinc(II) chloride (7646-85-7) → [(2,2'-bipyridine)di(9-fluoro-5-methyl-1-oxo-1,5,6,7-tetrahydropyrido[3,2,1-ij]quinoline-2-carboxylato-k2O,O')zinc(II)] dihydrate

Conditions	Yield
Stage #1: flumequine; potassium hydroxide In methanol Stage #2: [2,2]bipyridinyl; zinc(II) chloride In methanol for 1h;	60%

methanol (67-56-1) + 1,10-Phenanthroline (66-71-7) + flumequine (42835-25-6) + zinc(II) chloride (7646-85-7) → [Zn(flmq)2(phen)]*2MeOH

Conditions	Yield
With potassium hydroxide	60%

1,10-Phenanthroline (66-71-7) + cobalt(II) chloride hexahydrate + flumequine (42835-25-6) → C40H30CoF2N4O6*1.6CH4O*0.4H2O

Conditions	Yield
Stage #1: flumequine With potassium hydroxide In methanol for 0.5h; Stage #2: 1,10-Phenanthroline; cobalt(II) chloride hexahydrate In methanol for 0.5h;	60%

methanol (67-56-1) + cobalt(II) chloride hexahydrate + flumequine (42835-25-6) → Co(2+)*2CH4O*2C14H11FNO3(1-)

Conditions	Yield
Stage #1: methanol; flumequine With potassium hydroxide for 0.5h; Stage #2: cobalt(II) chloride hexahydrate In methanol	60%

methanol (67-56-1) + manganese(II) chloride tetrahydrate + flumequine (42835-25-6) → C30H30F2MnN2O8

Conditions	Yield
Stage #1: methanol; flumequine With potassium hydroxide for 0.5h; Stage #2: manganese(II) chloride tetrahydrate for 0.5h;	60%

di(pyridin-2-yl)amine (1202-34-2) + manganese(II) chloride tetrahydrate + flumequine (42835-25-6) → Mn(flmq)2(2,2′-bipyridylamine)

Conditions	Yield
Stage #1: flumequine With potassium hydroxide In methanol for 0.5h; Stage #2: di(pyridin-2-yl)amine; manganese(II) chloride tetrahydrate In methanol for 0.25h;	60%

copper(II) nitrate trihydrate + flumequine (42835-25-6) → Cu(II)(7-fluoro-12-methyl-4-oxo-1-azatricyclo[7.3.1.0(5,13)]trideca-2,5,7,9(13)-tetraene-3-carboxylate)2(H2O)2 (1268154-93-3)

Conditions	Yield
With KOH In ethanol; water soln. of Cu salt in distd. H2O added dropwise to soln. of basified (KOH)flumequine in EtOH-H2O; stirred at room temp. for 2 h; solvent removed; washed with distd. H2O and EtOH; dried under vac.; elem. anal.;	51%

zinc acetate hydrate + terephthalic acid (100-21-0) + water (7732-18-5) + flumequine (42835-25-6) → [Zn2(flmq)2(bdc)(H2O)2]

Conditions	Yield
With potassium hydroxide at 150℃; for 72h; Autoclave; High pressure;	48%

Isopropenyl chloroformate (57933-83-2) + flumequine (42835-25-6) → C18H16FNO5

Conditions	Yield
With triethylamine In dichloromethane

flumequine (42835-25-6) → 9-fluoro-6,7-dihydro-5-methyl-N-[2-(4-pyridyl)ethyl]-1-oxo-1H,5H-benzo-[i,j]quinolizine-2-carboxamide

Conditions	Yield
Multi-step reaction with 2 steps 1: Et3N / CH2Cl2 View Scheme

formic acid (64-18-6) + flumequine (42835-25-6) → 9-({2-[(2-hydroxyethyl)oxy]ethyl}amino)-5-methyl-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid formate (887262-12-6)

Conditions	Yield
Stage #1: flumequine; 2-(2-Aminoethoxy)ethanol In 1-methyl-pyrrolidin-2-one at 220℃; for 1h; Microwave irradiation; Stage #2: formic acid In water; acetonitrile

formic acid (64-18-6) + flumequine (42835-25-6) → 9-({2-[(2-aminoethyl)oxy]ethyl}amino)-5-methyl-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid formate (887262-13-7)

Conditions	Yield
Stage #1: 2,2'-diaminodiethyl ether; flumequine In 1-methyl-pyrrolidin-2-one at 200℃; for 1h; Microwave irradiation; Stage #2: formic acid In water; acetonitrile

formic acid (64-18-6) + flumequine (42835-25-6) → 9-[(2-aminoethyl)amino]-5-methyl-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid formate (887262-24-0)

Conditions	Yield
Stage #1: flumequine; ethylenediamine In 1-methyl-pyrrolidin-2-one at 180℃; for 1.5h; Microwave irradiation; Stage #2: formic acid In water; acetonitrile

flumequine (42835-25-6) + ethyl iodide (75-03-6) → 9-fluoro-5-methyl-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid ethyl ester (42835-47-2)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 4h;
With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 4h;

4-(aminomethyl)pyridine (3731-53-1) + Isopropenyl chloroformate (57933-83-2) + flumequine (42835-25-6) → 9-fluoro-6,7-dihydro-5-methyl-N-[(4-pyridyl)methyl]-1-oxo-1H,5H-benzo-[i,j]quinolizine-2-carboxamide (195191-84-5)

Conditions	Yield
With triethylamine In dichloromethane

4-(2-Aminoethyl)pyridine (13258-63-4) + Isopropenyl chloroformate (57933-83-2) + flumequine (42835-25-6) → 9-fluoro-6,7-dihydro-5-methyl-N-[2-(4-pyridyl)ethyl]-1-oxo-1H,5H-benzo-[i,j]quinolizine-2-carboxamide

Conditions	Yield
In dichloromethane

flumequine (42835-25-6) + ethylenediamine (107-15-3) → 9-[(2-aminoethyl)amino]-5-(R,S)-methyl-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid (885696-98-0)

Conditions	Yield
In 1-methyl-pyrrolidin-2-one at 200℃; for 0.5h; Microwave irradiation;

Upstream product

• 42835-47-2 9-fluoro-5-methyl-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid ethyl ester 
• 42835-89-2 6-fluoro-1,2,3,4-tetrahydro-2-methylquinoline 
• 87-13-8 diethyl 2-ethoxymethylenemalonate 
• 15568-85-1 5-methoxymethylene-2,2-dimethyl-1,3-dioxane-4,6-dione 
• 123400-74-8 5-[1-(6-fluoro-2-methyl-1,2,3,4-tetrahydroquinolyl)]-methylene-2,2-dimethyl-1,3-dioxan-4,6-dione 
• 1128-61-6 6-fluoro-2-methyl-quinoline 
• 105450-09-7 Diethyl (2-methyl-6-fluorotetrahydro-quinolin-1-yl)methylenemalonate 

Downstream Products

• 42835-47-2 9-fluoro-5-methyl-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid ethyl ester 
• 215178-95-3 R-(+)-flumequine 
• 202349-45-9 S-(-)-flumequine 

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Synthesis, absolute configuration and intermediates of 9-fluoro- 6,7- dihydro-5-methyl-1-oxo-1H,5H-benzo[i.j]quinolizine-2-carboxylic acid (flumequine)

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Process for the synthesis of a benzo [ij] quinolizine-2-carboxylic acid derivative

Process for preparing 6,7-dihydro-9-fluoro-5-methyl--1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid (flumequine, I) wherein, 6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline (II) is reacted in the presence of a catalyst with an alkyl ortho-formate (IX), wherein R3 represents a C1-C4 alkyl, and with a 2,2-disubstituted 1,3-dioxan-4,6-dione, wherein each R1 and R2, which can be the same or different, represents a hydrogen atom, a branched- or straight-chain C1-C6 alkyl or phenyl, or R1 and R2 together represent a polymethylene group -(CH2)n-, n= 4 or 5, so as to form a 2,2-disubstituted 5- [1-(6-fluoro-2-methyl--1,2,3,4-tetrahydroquinolyl)] methylene-1,3-dioxan--4,6-dione of formula (VII): and then said compound of formula (VII) is reacted in the presence of polyphosphoric acid and ethyl polyphosphate, whereby the desired compound (I) is directly obtained and isolated according to conventional methods.

Process for 6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo(ij)quinolizine-2-carboxylic acid

An improved process for preparing the antimicrobial compound flumequine is disclosed. The first step of the process comprises reacting 4-fluoroaniline with crotonaldehyde under acidic conditions at a temperature between 50° and 60° C. In the second step, the product of the first step is slowly added to a refluxing solvent which forms a binary azeotrope with water and has a boiling point between 90° and 120° C. to provide a mixture of 6-fluoroquinaldine and 6-fluorotetrahydroquinaldine. This mixture is then treated with base in the presence of weak acid followed by reducing to provide 6-fluorotetrahydroquinaldine. This compound is then treated according to known procedures to form flumequine.

Process for 6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo(ij)quinolizine-2-carboxylic acid

An improved process for preparing the antimicrobial compound flumequine is disclosed. The first step of the process comprises reacting 4-fluoroaniline with crotonaldehyde under acidic conditions at a temperature between 50° and 60° C. In the second step, the product of the first step is treated to provide a mixture of 6-fluoroquinaldine and 6-fluorotetrahydroquinaldine. This mixture is then treated with base in the presence of weak acid followed by reducing to provide 6-fluorotetrahydroquinaldine. This compound is then treated according to known procedures to form flumequine.

Intermediates for 6,7-dihydro-9-fluoro-5-methyl-1-oxo-1H,5H-benzo(ij)quinolizine-2-carboxylic acid

Intermediates in a process for preparing the antimicrobial compound flumequine are disclosed. The intermediates have the following formula STR1 wherein R is hydrogen or alkyl having 1-3 carbon atoms and acid addition salts thereof.