Marbofloxacin Liquid

In addition to type II topoisomerase, mapofloxacin also has an inhibitory effect on type IV topoisomerase in bacterial cells. Type IV topoisomerase also plays an important role in bacterial DNA metabolism, and the inhibition of it by mapofloxacin further interferes with the normal physiological functions of bacterial DNA, enhancing its antibacterial effect. This inhibitory effect on multiple topoisomerases makes the antibacterial activity of mapofloxacin more comprehensive and effective against bacteria.

 

3. Antibacterial spectrum and differences from other antibacterial drugs

Mabofloxacin has a broad antibacterial spectrum and is effective against broad-spectrum Gram positive bacteria (especially Staphylococcus), Gram negative bacteria (such as Escherichia coli, Salmonella typhimurium, Campylobacter jejuni, Citrobacter freundii, Enterobacter cloacae, Serratia marcescens, Morgan Stanley, Proteus mirabilis, Shigella spp., Actinobacillus pleuropneumoniae, Bordetella bronchiseptica, Pasteurella multocida, Klebsiella spp., Haemophilus spp., etc.) and mycoplasma.

Compared with other antibacterial drugs, the antibacterial mechanism of mapofloxacin is different, so the possibility of cross resistance is very small, especially with non fluoroquinolone antibiotics. For example, some pathogenic bacteria that have developed partial resistance to erythromycin, lincomycin, chloramphenicol, doxycycline, and sulfonamide drugs, such as Staphylococcus aureus, are still sensitive to ciprofloxacin. This is because the unique antibacterial mechanism of mapofloxacin allows it to effectively exert its antibacterial effects without being affected by the resistance mechanisms of these drugs.

4. Manifestation of antibacterial effect

Mabofloxacin can rapidly kill bacteria through the above antibacterial mechanism. Sensitive bacteria can cause death within 20-30 minutes after exposure. In clinical application, marbofloxacin can be used to treat a variety of animal infectious diseases caused by sensitive bacteria, such as deep and superficial skin infections, urinary tract infections in dogs, skin and soft tissue infections in cats, acute upper respiratory tract infections, bovine and sheep mastitis, and porcine mastitis uteritis no milk syndrome.

Method 1: Synthesis route using 2,3-difluoro-6-nitrophenol as raw material

1. Overview of synthesis steps
Starting from 2,3-difluoro-6-nitrophenol, it was first subjected to catalytic hydrogenation reduction, and then reacted with diethyl ethoxymethylmalonate (EMME) to obtain N - (2-hydroxy-3,4-difluorophenyl) azomethylenebropane diethyl ester. This product did not require purification and was subjected to Gould Jacobs cyclization reaction and hydroxyl protection to obtain ethyl 6,7-difluoro-4-hydroxy-8benzyloxy-3-quinolinecarboxylate. Then, under the action of amine reagent O - (2,4-dinitrophenyl) hydroxylamine, it is nitrogenated at position 1, followed by amino protection, hydrogenation benzyl hydrolysis, and deprotection to obtain intermediate 6. Intermediate 6 is cyclized with polyformaldehyde to obtain Intermediate 7, which can be prepared in two ways: firstly, Intermediate 7 can be directly condensed with N-methylpiperazine to obtain Mabofloxacin; Secondly, 7 first reacts with tributylboronic acid ester to form a chelate, and then condenses with methyl piperazine to obtain mapofloxacin.

2. Characteristics of synthesis methods
This route has multiple steps, low overall yield, and the amination reagent O - (2,4-dinitrophenyl) hydroxylamine is prone to explosion, making it only suitable for small-scale preparation in the laboratory and has no industrial value. In laboratory research, this route can be used to explore and study the mechanism of the synthesis process of mapofloxacin, but due to its safety and yield issues, it is difficult to meet the needs of large-scale production.

Method 2: Synthesis route using 2,3,4,5-tetrafluorobenzoic acid as raw material

1. Overview of synthesis steps
Acyl chlorination reaction: Starting from 2,3,4,5-tetrafluorobenzoic acid, intermediate product 9 is obtained through acyl chlorination.
Subsequent reaction pathway one: Intermediate product 9 can react with 3-dialkylaminoethyl acrylate and then undergo amine exchange to obtain intermediate product 10; Intermediate product 10 can also be obtained by condensation with 3- (N-methylhydrazide) acrylic acid ethyl ester (17) in ethanol magnesium/ethyl acetate solution. Intermediate product 9 can also be acylated with diethyl malonate and decarboxylated with p-toluenesulfonic acid using conventional methods. It can be condensed with triethyl orthoformate in the presence of acetic anhydride to obtain ethoxy α - substituted benzoyl ethyl acrylate (11), which is then exchanged with amine to obtain intermediate product 10. Intermediate product 10 undergoes intramolecular nucleophilic substitution reaction and cyclization to obtain intermediate product 12. Intermediate product 12 is condensed with N-methylpiperazine and hydrolyzed in concentrated KOH solution for 72 hours to obtain intermediate product 13. Intermediate product 13 undergoes cyclization in formaldehyde/formic acid solution to form a salt, which is then neutralized with ammonia water to obtain mapoxloxacin.

Subsequent reaction pathway 2: Intermediate product 14 is obtained by cyclization of intermediate product 11 through amine exchange under the action of NaF; Alternatively, intermediate product 14 can be obtained by removing the aldehyde group from intermediate product 12. Intermediate product 14 can also be prepared by two methods: firstly, intermediate product 15 is obtained by N-hydroxymethylation reaction, and then condensed and cyclized into intermediate product 7 in tetrahydrofuran/tetrabutylammonium fluoride solution, and finally substituted with N-methylpiperazine to obtain mapofloxacin; The second method is to first piperazine and then react with sodium hydride/benzyl alcohol to obtain intermediate product 16, which is hydrolyzed and then cyclized with formaldehyde to obtain mapofloxacin.

2. Characteristics of synthesis methods
The literature reports that the total yield from intermediate product 5 to intermediate product 9, and then to intermediate products 11, 10, 12, 13, and 1 can reach 32%, which has industrial value. This route can effectively synthesize mapofloxacin through a series of chemical reactions with relatively high yields, making it suitable for large-scale production. In actual production, suitable subsequent reaction pathways can be selected to prepare mapofloxacin according to specific production conditions and requirements.

3. Improved synthesis process
Overview of synthesis steps
Starting from ethyl 6,7,8-trifluoro-1,4-dihydro-1- (N-methylformamide) -4-oxo-3-quinolinecarboxylate, crude mapofloxacin was prepared by coupling, dealdehydation, and Eschweiler Clarke methylation cyclization, and finally refined to obtain mapofloxacin. During the synthesis process, N-methylpiperazine coupling and dealdehyde reaction are carried out simultaneously, resulting in a one-step reaction synthesis without the need for intermediate steps for separation and purification.

4. Characteristics of synthesis methods
This process route has low raw material costs, safe and environmentally friendly processes, and produces products with excellent quality and performance compared to similar products. It has a large market demand and strong competitiveness. This improved synthesis process simplifies the production process, reduces production costs, and improves product quality and market competitiveness, which is of great significance for the large-scale production and application of mapofloxacin.

Method 3: Another synthetic route starting from tetrafluorobenzoic acid

1. Overview of synthesis steps
Intermediate synthesis: Starting from tetrafluorobenzoic acid, the intermediate 3- (methylbenzylamino) -2- (2,3,4,5-tetrafluorobenzoyl) acrylic acid ethyl ester is obtained through acylation, Michael addition, and nucleophilic substitution reactions; Then amine exchange and a cyclization reaction occur to generate the intermediate 6,7,8-trifluoro-1,4-dihydro-1- (N-methylformamide) -4-oxo-3-quinolinecarboxylic acid ethyl ester.
Synthesis of Mabofloxacin: The intermediate is substituted with N-methylpiperazine to obtain ethyl 6,8-difluoro-1,4-dihydro-1- (N-methylformamide) -7- (4-methyl-1-piperazine) -4-oxo-3-quinolinate, which is then hydrolyzed and cyclized to obtain the product Mabofloxacin.

2. Characteristics of synthesis method:
This paper conducted a detailed exploration and study of each step of the reaction, and obtained the optimal reaction conditions, laying a solid foundation for the industrial production of mapofloxacin. The synthesized product, marboxoxacin, and its main intermediates were characterized by FT-IR, DSC, and 1H-NMR, respectively. At the same time, marbofloxacin liquid was tested according to the requirements of the European Pharmacopoeia, proving that the product quality of marboxoxacin meets the requirements of the European Pharmacopoeia. This synthetic route ensures the synthesis quality and feasibility of industrial production of mapofloxacin through detailed reaction condition research and quality testing.