98106-17-3

Basic information

• Product Name: Difloxacin
• Synonyms: -1-piperazinyl)-4-oxo-;3-quinolinecarboxylicacid,1,4-dihydro-6-fluoro-1-(4-fluorophenyl)-7-(4-methyl;a56619;DIFLOXACIN;6-Fluoro-1-(4-fluorophenyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinecarboxylic Acid Hydrochloride Salt;Difloxacin Hydrochloride Salt;6-Fluoro-1-(4-fluorophenyl)-7-(4-methylpiperazin-1-yl)-4-oxoquinoline-3-carboxylic acid;DIFLOXACINHCL/MESYLATE
• CAS NO: 98106-17-3
• Molecular Formula: C₂₁H₁₉F₂N₃O₃
• Molecular Weight: 399.39
• Product Categories: Chiral Reagents;Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 98106-17-3.mol
• Article Data: 7

Chemical Properties

• Melting Point: 279-282 °C(Solv: chloroform (67-66-3); ethanol (64-17-5))
• Boiling Point: 595.5 °C at 760 mmHg
• Flash Point: 313.9 °C
• Appearance: whtie-cream to yellowish crystalline powder
• Density: 1.409 g/cm³
• Storage Temp.: 2-8°C
• Solubility: DMSO (Slightly), Methanol (Slightly), Water (Slightly)
• PKA: 6.17±0.41(Predicted)
• CAS DataBase Reference: Difloxacin(CAS DataBase Reference)
• NIST Chemistry Reference: Difloxacin(98106-17-3)
• EPA Substance Registry System: Difloxacin(98106-17-3)

Safety Data

• Hazardous Substances Data: 98106-17-3(Hazardous Substances Data)

Usage

Description

Difloxacin (INN) is a second-generation, synthetic fluoroquinolone antibiotic used in veterinary medicine,it has broad-spectrum, concentration dependent, bactericidal activity; however, its efficacy is not as good as enrofloxacin or pradofloxacin.

Mechanism of action

Difloxacin mainly acts on bacterial deoxyribonucleic acid (DNA) helicase, inhibiting DNA replication and transcription, thereby affecting the normal shape and function of DNA to achieve bactericidal purposes.

Physical properties

Whtie-Cream to Yellowish Crystalline Powder

Uses

Difloxacin is a fluoroquinolone antibacterial structurally related to norfloxacin.

Definition

ChEBI: A quinolone that is pefloxacin in which the ethyl group at position 1 of the quinolone has been replaced by a p-fluorophenyl group. A broad-spectrum antibiotic effective against both Gram-positive and Gram-negative bacteria, it is used (usuall as the monohydrochloride salt) for the treatment of bacterial infections in dogs.

InChI:InChI=1/C21H19F2N3O3/c1-24-6-8-25(9-7-24)19-11-18-15(10-17(19)23)20(27)16(21(28)29)12-26(18)14-4-2-13(22)3-5-14/h2-5,10-12H,6-9H2,1H3,(H,28,29)

Synthetic route

1-methyl-piperazine (109-01-3) + 7-Chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (98105-79-4) → difloxacin (98106-17-3)

Conditions	Yield
In various solvent(s) at 110℃; for 24h;	21.3 g

1-methyl-piperazine (109-01-3) + ethyl 2,4,5-trifluorobenzoylacetate (98349-24-7) + N,N-dimethyl-formamide dimethyl acetal (4637-24-5) + 4-fluoroaniline (371-40-4) → difloxacin (98106-17-3)

Conditions	Yield
Yield given. Multistep reaction;

1-methyl-piperazine (109-01-3) + 7-Chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (98105-79-4) → difloxacin (98106-17-3) + 7-Chloro-1-(4-fluoro-phenyl)-6-(4-methyl-piperazin-1-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid

Conditions	Yield
In dimethylsulfoxide-d6 at 120 - 130℃;	A 84 % Spectr. B 16 % Spectr.

1-methyl-piperazine (109-01-3) + C20H13BClF2NO7 → difloxacin (98106-17-3) + 7-Chloro-1-(4-fluoro-phenyl)-6-(4-methyl-piperazin-1-yl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid

Conditions	Yield
With sodium hydroxide 1.) DMSO, 110 deg C, 2 h; 2.) reflux, 1 h; Yield given. Yields of byproduct given. Title compound not separated from byproducts;

2,4-dichloro-5-fluoroacetophenone (704-10-9) → difloxacin (98106-17-3)

Conditions	Yield
Multi-step reaction with 6 steps 1: 80 percent / NaH / 1.5 h / 80 °C 2: Ac2O / 2 h / 130 °C 3: CH2Cl2 / 0.5 h / Ambient temperature 4: NaH / 1,2-dimethoxy-ethane / 3 h / 80 °C 5: aq. NaOH / tetrahydrofuran / 1.5 h / 80 °C 6: 21.3 g / various solvent(s) / 24 h / 110 °C View Scheme

ethyl 2,4-dichloro-5-fluoro-benzoyl-acetate (86483-51-4) → difloxacin (98106-17-3)

Conditions	Yield
Multi-step reaction with 5 steps 1: Ac2O / 2 h / 130 °C 2: CH2Cl2 / 0.5 h / Ambient temperature 3: NaH / 1,2-dimethoxy-ethane / 3 h / 80 °C 4: aq. NaOH / tetrahydrofuran / 1.5 h / 80 °C 5: 21.3 g / various solvent(s) / 24 h / 110 °C View Scheme

1-(4'-fluoro-phenyl)-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester (98105-80-7) → difloxacin (98106-17-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: aq. NaOH / tetrahydrofuran / 1.5 h / 80 °C 2: 21.3 g / various solvent(s) / 24 h / 110 °C View Scheme

ethyl 2,4-dichloro-5-fluoro-α-[[(4-fluorophenyl)amino]methylene]-β-oxobenzenepropanoate (98105-65-8) → difloxacin (98106-17-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: NaH / 1,2-dimethoxy-ethane / 3 h / 80 °C 2: aq. NaOH / tetrahydrofuran / 1.5 h / 80 °C 3: 21.3 g / various solvent(s) / 24 h / 110 °C View Scheme

2,4-dichloro-alpha(elhoxymethlene)-5-fluoro-beta-oxo-benzene propanoic acid ethyl ester (86483-52-5) → difloxacin (98106-17-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: CH2Cl2 / 0.5 h / Ambient temperature 2: NaH / 1,2-dimethoxy-ethane / 3 h / 80 °C 3: aq. NaOH / tetrahydrofuran / 1.5 h / 80 °C 4: 21.3 g / various solvent(s) / 24 h / 110 °C View Scheme

1-methyl-piperazine (109-01-3) + 6,7-difluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (103994-99-6) → difloxacin (98106-17-3)

Conditions	Yield
With triethylamine In acetonitrile Inert atmosphere; Reflux;

ethyl 2,4,5-trifluorobenzoylacetate (98349-24-7) → difloxacin (98106-17-3)

Conditions	Yield
Multi-step reaction with 5 steps 1: acetic anhydride / Heating 2: dichloromethane / Inert atmosphere 3: sodium hydride / tetrahydrofuran; mineral oil / Inert atmosphere; Heating 4: hydrogenchloride; water; acetic acid / Reflux 5: triethylamine / acetonitrile / Inert atmosphere; Reflux View Scheme

α-(ethoxymethylene)-2,4,5-trifluoro-β-oxobenzenepropanoic acid, ethyl ester (101799-75-1) → difloxacin (98106-17-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: dichloromethane / Inert atmosphere 2: sodium hydride / tetrahydrofuran; mineral oil / Inert atmosphere; Heating 3: hydrogenchloride; water; acetic acid / Reflux 4: triethylamine / acetonitrile / Inert atmosphere; Reflux View Scheme

1-(p-fluorophenyl)-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester (108138-16-5) → difloxacin (98106-17-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogenchloride; water; acetic acid / Reflux 2: triethylamine / acetonitrile / Inert atmosphere; Reflux View Scheme

ethyl 3-(4-fuoroanilino)-2-(2,4,5-trifuorobenzoyl)acrylate (108115-66-8) → difloxacin (98106-17-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium hydride / tetrahydrofuran; mineral oil / Inert atmosphere; Heating 2: hydrogenchloride; water; acetic acid / Reflux 3: triethylamine / acetonitrile / Inert atmosphere; Reflux View Scheme

Upstream product

• 109-01-3 1-methyl-piperazine 
• 98105-79-4 7-Chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid 
• 98349-24-7 ethyl 2,4,5-trifluorobenzoylacetate 
• 4637-24-5 N,N-dimethyl-formamide dimethyl acetal 
• 371-40-4 4-fluoroaniline 
• 103994-99-6 6,7-difluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid 
• 101799-75-1 α-(ethoxymethylene)-2,4,5-trifluoro-β-oxobenzenepropanoic acid, ethyl ester 
• 108138-16-5 1-(p-fluorophenyl)-6,7-difluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester 
• 108115-66-8 ethyl 3-(4-fuoroanilino)-2-(2,4,5-trifuorobenzoyl)acrylate 
• 704-10-9 2,4-dichloro-5-fluoroacetophenone 
• 86483-52-5 2,4-dichloro-alpha(elhoxymethlene)-5-fluoro-beta-oxo-benzene propanoic acid ethyl ester 
• 98105-65-8 ethyl 2,4-dichloro-5-fluoro-α-[[(4-fluorophenyl)amino]methylene]-β-oxobenzenepropanoate 
• 98105-80-7 1-(4'-fluoro-phenyl)-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid ethyl ester 
• 86483-51-4 ethyl 2,4-dichloro-5-fluoro-benzoyl-acetate 

Relevant articles and documents

A high-efficient environment friendly preparation method of quinolone ciprofloxacin drug (by machine translation)

The invention discloses a high-efficient environmental protection quinolone ciprofloxacin preparation method of drug, is fluorobenzene formyl ethyl acetate, the original carboxylic acid triethyl amine compound as a raw material, the three raw materials into the reactor at a temperature of 90 - 150 °C reaction under 20 - 30 H prepare get quinolone basic parent ring, then adding piperazine, to aminocapronitrile as the solvent, the temperature of the reflux reaction 20 - 28 of H, continue adding 50% sodium hydroxide solution is carboxyl ester hydrolysis to obtain the target compound. The invention is simple in raw material market can buy price is cheap; multi-step reaction link together a pan operation intermediate does not need to separate operation, the reaction process is efficient labor-saving; the whole process of transformation efficiency is high, the final product does not need chromatographic treatment is simple washing can get the pure compound; safety in the course of reaction, after-treatment does not need the eluent separation only needs to ethyl acetate, petroleum ether and methanol washing and can be recycled can be pollution prevention; green reaction process, only ethanol by-product, the atom economy is high; quinolone compounds and high utility value, is important trovafloxacins antibacterial drug composition structure. (by machine translation)

NOVEL METHOD OF SYNTHESIS OF FLUOROQUINOLONES

The invention relates to a method of preparation of fluoroquinolones of formula (I) from compounds of formula (II): in which R1, R2, R3, R4, R5, R6, R7, and X are as defined in Claim 1.

A solid phase approach to quinolones using the DIVERSOMER technology

The first example of a library of the quinolone antibacterial agents prepared by solid phase organic synthesis is described. Results of these studies and the parallel synthesis, isolation, purification and analysis of eight quinolones are discussed.