Preparation method of zabofloxacin intermediate

A technology for zabfloxacin and intermediates, which is applied in the field of preparation of zabfloxacin intermediates, can solve the problems of unsuitability for industrial production, low yield and high synthesis cost, and achieves simplified operation, improved product quality and huge profit margins. Effect

Inactive Publication Date: 2018-10-09
沈阳林特制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] The synthesis route of side chain dimesylate has a relatively stable reaction and is easier to control. Most raw materials are cheap and easy to obtain, and the structure of mesylate is stable. However, the synthesis cost of this reaction route is high and the yield is low. About 2,000 yuan per kilogram, not suitable for industrial production

Method used

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  • Preparation method of zabofloxacin intermediate
  • Preparation method of zabofloxacin intermediate
  • Preparation method of zabofloxacin intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Example 1 Preparation of tert-butyl 3-cyano-4-oxo-pyrrolidine-1-carboxylate (intermediate III)

[0046] The reaction equation is as follows:

[0047]

[0048] Feeding ratio:

[0049]

[0050] crafting process:

[0051] At room temperature, add 500g of glycine ethyl ester hydrochloride, 172.8g of NaOH and 1000g of methanol into the reaction flask and stir for 1 hour, cool the reaction solution to below 10°C, and add 257.4g of acrylonitrile dropwise to the reaction system under temperature control below 10°C 500g of methanol solution, drop it in about 2h, raise the temperature of the reaction solution to room temperature and continue to stir for 1h, then raise the temperature of the reaction solution to 65°C, reflux and stir for 5h, and monitor the completion of the reaction by thin-layer chromatography (ninhydrin baking plate method ), the reaction solution was cooled to below 40°C, the temperature was controlled below 40°C and the methanol was concentrated under...

Embodiment 1-1

[0054] Example 1-1 Preparation of tert-butyl 3-cyano-4-oxo-pyrrolidine-1-carboxylate (intermediate III) Feed ratio:

[0055]

[0056]

[0057] crafting process:

[0058] At room temperature, add 500g of glycine ethyl ester hydrochloride, 158.4g of NaOH and 1000g of methanol into the reaction flask and stir for 1h, cool the reaction solution to 5°C, and add 248g of acrylonitrile and 500g of Methanol solution, after about 2 hours of dripping, the temperature of the reaction solution was raised to room temperature and continued stirring for 1 hour, and then the temperature of the reaction solution was raised to 70°C, and stirred at reflux for 5 hours, and the reaction was monitored by thin-layer chromatography (ninhydrin baking plate method). The temperature of the reaction solution was lowered to below 40°C, the temperature was controlled below 40°C, and the methanol was concentrated under reduced pressure to obtain 570 g of crude intermediate I as a light yellow oil. The ...

Embodiment 1-2

[0061] Example 1-2 Preparation of tert-butyl 3-cyano-4-oxo-pyrrolidine-1-carboxylate (intermediate III)

[0062] Feeding ratio:

[0063]

[0064]

[0065] crafting process:

[0066] At room temperature, add 500g of glycine ethyl ester hydrochloride, 187.2g of NaOH and 1200g of methanol into the reaction flask and stir for 1h. After about 2 hours of dripping, the reaction solution was raised to room temperature and continued to stir for 0.5 hours, then the reaction solution was raised to 68°C, refluxed and stirred for 5 hours, and the reaction was monitored by thin-layer chromatography (ninhydrin baking plate method) , the temperature of the reaction solution was lowered to below 40°C, the temperature was controlled below 40°C, and the methanol was concentrated under reduced pressure until it was purified to obtain 575g of crude intermediate I as a light yellow oil.

[0067] Cool the oil obtained in the previous step to 2°C, add 1020.2g of Boc anhydride, after the addit...

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Abstract

The invention provides a preparation method of a zabofloxacin intermediate. The method comprises: reacting ethyl glycinate hydrochloride with acrylonitrile under catalysis of a base to form an intermediate I; then reacting the intermediate I with Boc anhydride under the function of a strong base to generate an intermediate III; reacting the intermediate III, the methoxyamine hydrochloride and formaldehyde to generate an intermediate IV; and then preparing the zabofloxacin intermediate by reacting the intermediate IV with methanesulfonyl chloride, performing reduction with sodium borohydride, and other steps. The zabofloxacin intermediate is prepared through nine steps with a high yield and high quality by the method, the material adding amount reaches the level of hundreds of grams, and the method is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of synthesis of antibacterial drugs, in particular to a preparation method of a zabofloxacin intermediate. Background technique [0002] Quinolones are a class of synthetic antibacterial drugs with quinoline or naphthyridine structures in their molecules. The common feature of this class of drugs is that they block DNA replication by inhibiting DNA gyrase to produce antibacterial effects, and have high selectivity for bacteria. , the safety of people is great, so the discovery and development of quinolones has created a new era of synthetic antibacterial drugs. [0003] Norfloxacin was successfully synthesized in 1979. The structural feature of this type of drug is that there is a fluorine atom at the -6 position of the quinolone mother nucleus. Subsequently, a series of new quinolone drugs containing fluorine were synthesized, collectively called fluoroquinolones. It has broad spectrum, strong antibacterial effect a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/10
CPCC07D487/10
Inventor 何镭权奇哲林虎徐明黄荣涛李军业
Owner 沈阳林特制药有限公司
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