Preparation method of moxifloxacin hydrochloride and intermediate of moxifloxacin hydrochloride

A technology for moxifloxacin hydrochloride and moxifloxacin ethyl ester is applied in the field of preparation of moxifloxacin hydrochloride and its intermediates, which can solve the problems of many synthesis steps, low product purity, narrow supply of raw materials and the like, and achieves high atom economy. , environmental friendliness, raw material price and cost reduction effect

Inactive Publication Date: 2019-09-03
ZHEJIANG GUOBANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0027] In view of this, the application firstly provides a preparation method of moxifloxacin hydrochloride to overcome the low product purity, narrow supply of raw materials, high price, low yield, many synthesis steps and high cost in the existing preparation method. question

Method used

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  • Preparation method of moxifloxacin hydrochloride and intermediate of moxifloxacin hydrochloride
  • Preparation method of moxifloxacin hydrochloride and intermediate of moxifloxacin hydrochloride
  • Preparation method of moxifloxacin hydrochloride and intermediate of moxifloxacin hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] Embodiment 1: the preparation of moxifloxacin ethyl ester tartrate

[0045] In a 2L four-neck flask, add 100g (0.309mol) of ticycline ester, 40.5g (0.321mol) of (S,S)-2,8-diazabicyclo[4,3,0]nonane, acetonitrile 1000ml, stirred, put in 32.5g (0.321mol) of triethylamine, AlCl 3 2.05g (0.015mol), heat up to 60°C, keep warm for about 3 hours, the system is basically clear, take a sample, TLC (developing agent is methanol: acetone: ammonia water = 15:5:3) detection and tracking basically no reaction raw material (gaticycline ester) spots, cooled to room temperature, filtered, the filtrate continued to heat up to 50°C, added 27.84g (0.185mol) of L-(+)-tartaric acid, stirred and kept for about 2h, the system precipitated in large quantities, cooled to 0-5°C, filtered After the filter cake was washed with acetonitrile slurry, the filter cake was collected, vacuum-dried to constant weight at 50-80° C., and powdered to obtain 142 g of moxifloxacin ethyl ester tartrate, with a mo...

Embodiment 2

[0046] Embodiment 2: the preparation of moxifloxacin ethyl ester tartrate

[0047] In a 2L four-necked flask, add 100g (0.309mol) of ticycline ester, 40.8g (0.323mol) of (S,S)-2,8-diazabicyclo[4,3,0]nonane, and 1000ml of DMF , stirred, put in DBU50.2g (0.323mol), AlCl 3 2.05g, heat up to 55°C, keep warm for about 3 hours, the system is basically clear, take a sample, TLC (eluent: methanol: acetone: ammonia water = 15:5:3) detect and track basically no reaction raw material (gaticyclate) spots , add 28.1g (0.187mol) of L-(+)-tartaric acid, stir and keep warm for about 2 hours, the system precipitates in large quantities, cool down to 0-5°C, filter, wash the filter cake with cooled DMF and collect the filter cake, 50-80°C Under vacuum drying to constant weight, collect powder, obtain moxifloxacin ethyl ester tartrate 140.7g, molar yield 90.2% (according to moxifloxacin ethyl ester and tartaric acid salify ratio is 2: 1 calculation), related substance purity 99.85% , Optical is...

Embodiment 3

[0048] Embodiment 3: the preparation of moxifloxacin ethyl ester tartrate

[0049] In a 2L four-necked flask, add 100g of ticycline ester, 41.0g (0.325mol) of (S,S)-2,8-diazabicyclo[4,3,0]nonane, 1000ml of DMF, stir, and put Triethylamine 32.9g (0.325mol), ZnCl 2 4.2g (0.031mol), heat up to 75°C, keep warm for about 3 hours, the system is basically clear, take a sample, TLC (developing agent is methanol: acetone: ammonia water = 15:5:3) detection and tracking basically no reaction raw material (gaticycline Ester) spots, cooled to room temperature, filtered, the filtrate continued to heat up to 60°C, added 50.4g (0.335mol) of L-(+)-tartaric acid, stirred and kept for about 2h, the system precipitated in large quantities, cooled to 0-5°C, filtered, After the filter cake is washed with cooled DMF slurry, the filter cake is collected, vacuum-dried to constant weight at 50-80° C., and powdered to obtain 158.8 g of moxifloxacin ethyl ester tartrate, with a molar yield of 88.6% (by ...

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Abstract

The invention provides a preparation method of moxifloxacin hydrochloride and an intermediate of moxifloxacin hydrochloride, and belongs to the technical field of heterocyclic compound. The preparation method comprises following steps: gatifloxacin intermediate, (S, S)-2, 8-diazabicyclo[4, 3, 0]nonane, a reaction solvent, an organic base, and a Lewis acid are mixed, are reacted fully at a preset temperature, and are subjected to cooling filtering, an obtained filtrate is heated, L-(+)-tartaric acid is added, thermal insulation crystallization is carried out, cooling is carried out, centrifugation filtration, washing, and drying are carried out so as to obtain moxifloxacin ethyl ester tartrate; moxifloxacin ethyl ester tartrate is added into a hydrogen chloride containing solution, heatingis carried out, thermal insulation full reaction is carried out, crystallization is carried out, after cooling, centrifugation filtration, beating, and baking are carried out so as to obtain finishedproducts. According to the preparation method, one-pot reaction is realized, the selectivity and conversion rate are higher than those of disclosed methods, energy is saved, post-treatment is convenient, the preparation method is suitable for industrialized production, and HPLC>99.9%.

Description

technical field [0001] The application relates to a preparation method of moxifloxacin hydrochloride and an intermediate thereof, belonging to the technical field of heterocyclic compounds. Background technique [0002] Moxifloxacin hydrochloride was launched by Bayer in December 1999 in the FDA of the United States. In 2002, Moxifloxacin hydrochloride tablets were approved by SFDA for import and listed in China. Currently, it is available in more than 90 countries and regions including the United States, Germany and other EU countries. Listed in the region, product name: Moxifloxacin Hydrochloride Sodium Chloride Injection was launched in the United States in 2001 and in China in 2004 with a dosage of 400mg (moxifloxacin) / 250ml. Listed by region. [0003] At present, in the prescription drug market used by hospitals in my country, anti-infective drugs are the most used category, and play a pivotal role in the increasingly expanding pharmaceutical market. According to th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07C51/41C07C59/255
CPCC07B2200/07C07C51/412C07D471/04C07C59/255
Inventor 朱庆国张幸钟胡德行詹绪琴方露露周建斌黄健张斌王兆刚邱家军
Owner ZHEJIANG GUOBANG PHARMA
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