Stable isotope labeled norfloxacin and synthesis method thereof

Abstract

The invention discloses stable isotope labeled norfloxacin and a synthesis method thereof. Stable isotope labeled bromoethane used as a stable isotope labeling source reacts with 6, 7-difluoro-4-hydroxyquinoline-3-carboxylic acid ethyl ester to obtain stable isotope labeled 6, 7-difluoro-1-ethyl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid ethyl ester, hydrolysis reaction is carried out to obtainstable isotope labeled 6, 7-difluoro-1-ethyl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acid, and finally the stable isotope labeled 6, 7-difluoro-1-ethyl-1, 4-dihydro-4-oxoquinoline-3-carboxylic acidreacts with piperazine under an alkaline condition to obtain a stable isotope labeled norfloxacin product. The stable isotope labeling raw material used in the method is cheap and easy to obtain, thesynthesis process is simple, the product is easy to separate and purify, the chemical purity and isotope abundance of the obtained product both reach 99% or above, and the requirement for serving as astandard reagent for quantitative detection of norfloxacin is met; and the use value is high, and good economy is achieved.

Description

technical field [0001] The invention relates to the field of isotope labeling, in particular to a stable isotope-labeled norfloxacin and a synthesis method thereof. Background technique [0002] Norfloxacin (Norfloxacin, also known as Noroxin, Fulgram), aliases: Ribolol, Norfloxacin, Linbuxing. Its chemical name is 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid. This product is a third-generation quinolone antibacterial drug with broad-spectrum antibacterial effect, especially high antibacterial activity against aerobic Gram-negative bacilli. Therefore, it has been developing rapidly since its inception, and has become the first choice for clinical combination drugs due to its advantages of broad antibacterial spectrum, strong antibacterial activity, convenient administration, small adverse reactions, and no cross-resistance with other antibiotics. Norfloxacin also has antibacterial activity against multidrug-resistant bacteria in vitro, an...

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Problems solved by technology

[0005] The advantage of the former route is that there is no need to use ethoxymethylene malonate diethyl ester, and the reaction raw materials are easy to get, but the problem that exists is that the reaction raw materials are boiled in one pot, there are many side reactions, and the yield is not ideal enough. Roughly 30-40%

In a word, compared with the above two routes, each has its own advantages, but its common disadvantages are high reaction temperature, long reaction time, low overall yield, difficult post-processing, and certain inconvenience for industrial production.

Although norfloxacin is a classic broad-spectrum antibiotic drug, there are generally disadvantages such as long steps, low yield, and large amount of three wastes in its synthetic method. Therefore, people have been looking for simpler operation and higher yield. Unremitting efforts for higher and more environmentally friendly synthetic methods

[0006] At present, there are almost no public documents about the synthetic route of stable isotope labeling norfloxacin

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