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Synthesis method of high-purity moxifloxacin hydrochloride

A technology of moxifloxacin hydrochloride and its synthesis method, which is applied in the field of synthesis of quinolone broad-spectrum antibacterial drugs, can solve the problems of unreported synthesis method of anhydrous moxifloxacin hydrochloride, low purity and large loss of moxifloxacin hydrochloride, and achieve Human drug safety, mild conditions, good reproducible effect

Inactive Publication Date: 2013-06-26
天津康鸿医药科技发展有限公司
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Problems solved by technology

[0005] (1) Cheng Qingfang, Wang Qifa, etc., Synthesis of Moxifloxacin, China Journal of Pharmaceutical Industry, 2010.1(8): 561-563 reported the following method: from 1-cyclopropyl-6,7,8-trifluoro-1 , 4-dihydro-4-oxo-3-quinolinecarboxylic acid ethyl ester was hydrolyzed, condensed and methoxylated to obtain moxifloxacin, but the synthesis method of anhydrous moxifloxacin hydrochloride was not reported;
[0006] (2) Liu Mingliang, Wei Yonggang, etc., Synthesis of Moxifloxacin, China Journal of Pharmaceutical Industry, 2004.35(3): 129-131 reported the synthesis of 1-cyclopropyl-6,7-difluoro-8-methoxy-4 Synthesis of moxifloxacin from ethyl oxo-1,4-dihydro-3-quinolinecarboxylate and (S,S)-2,8-diazabicyclo[4.3.0]nonane, not reported The synthetic method of moxifloxacin hydrochloride anhydrous;
[0007] Zhai Hong, Chang Yu, etc., Synthesis of Moxifloxacin, Chemical Production and Technology, 2007.16(4): 15-18 reported the same synthetic method, and did not report the synthetic method of anhydrous moxifloxacin hydrochloride;
[0008] (3) Chinese patent CN101817820 discloses a method for preparing moxifloxacin hydrochloride with Boc-protected side chain (S, S)-2,8-diazabicyclo[4.3.0]nonane, in which the obtained The crude product of moxifloxacin was added dilute hydrochloric acid to stir and crystallize, filtered, and washed with a large amount of ice water to obtain moxifloxacin hydrochloride, but the purity of moxifloxacin hydrochloride prepared by this method was relatively low, and the loss in water was relatively large, and the yield was relatively low. Low

Method used

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  • Synthesis method of high-purity moxifloxacin hydrochloride
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  • Synthesis method of high-purity moxifloxacin hydrochloride

Examples

Experimental program
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Effect test

Embodiment 1

[0039] Dissolve 50 g of crude moxifloxacin hydrochloride in aqueous sodium hydroxide solution with a concentration of 5 mol / L. At this time, the pH is 14, then extract three times with 60 ml of ethyl acetate, remove the organic phase, and add concentrated hydrochloric acid to the water phase to adjust the pH to 1. , then crystallize and filter to obtain a filter cake, and then use 300ml of methanol aqueous solution with a volume percentage of 90% to recrystallize the filter cake. Specifically, add the obtained filter cake and methanol aqueous solution to the reaction flask, and reflux for 15 to 30 minutes under stirring conditions. Filtrate while hot, then distill to recover the solvent, crystallize at 0-5°C, and finally filter and dry under reduced pressure at 40°C for 36 hours to obtain 48g of moxifloxacin hydrochloride with a yield of 96%.

[0040]Adopt Agilent 1100 type high performance liquid chromatography (HPLC) to analyze the purity of moxifloxacin hydrochloride product...

Embodiment 2

[0043] Dissolve 50g of moxifloxacin hydrochloride crude product with an aqueous potassium hydroxide solution with a concentration of 2mol / L. At this time, the pH is 13, then extract three times with 60ml of dichloromethane, remove the organic phase, and add concentrated hydrochloric acid to the water phase to adjust the pH to 2 , then crystallize and filter to obtain a filter cake, and then use 250ml of 85% methanol aqueous solution to recrystallize the filter cake, specifically, add the obtained filter cake and ethanol aqueous solution to the reaction flask, and reflux for 30 to 40 minutes under stirring conditions, Filtrate while hot, then distill to recover the solvent, crystallize at 5-10°C, finally filter, and dry under reduced pressure at 60°C for 28 hours to obtain 44g of moxifloxacin hydrochloride with a yield of 88%, of which, the water content is 0.8%, and the HPLC purity is is 99.97%.

Embodiment 3

[0045] Dissolve 50g of crude moxifloxacin hydrochloride in ammonia water with a concentration of 3mol / L. At this time, the pH is 11, then extract it three times with 60ml of methyl tert-butyl ether, remove the organic phase, and add concentrated hydrochloric acid to the water phase to adjust the pH to 3. , filter, then crystallize and filter to obtain a filter cake, and then use 500ml of 95% ethanol aqueous solution to recrystallize the filter cake, specifically, add the obtained filter cake and methanol aqueous solution to the reaction flask, and reflux for 40 to 60 minutes under stirring , filtered while it was hot, then distilled to recover the solvent, crystallized at 0-5°C, finally filtered, and dried under reduced pressure at 90°C for 16 hours to obtain 47g of moxifloxacin hydrochloride with a yield of 94%, of which the water content was 0.8%, HPLC The purity is 99.96%.

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Abstract

The invention provides a synthesis method of high-purity moxifloxacin hydrochloride, which comprises the following steps: protecting carbonyl of ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinolyl-3-carboxylate by using ethyl borate; performing condensation with (S,S)-2,8-diazabicyclo[4.3.0]nonane; deprotecting with hydrochloric acid to obtain a moxifloxacin hydrochloride crude product; dissolving the obtained moxifloxacin hydrochloride crude product with an alkali water solution, extracting with organic solvent, removing the organic phase, and adding hydrochloric acid into the water phase to regulate the pH value to acidity; crystallizing, filtering to obtain a filter cake, and recrystallizing the obtained filter cake with water-containing organic solvent; and finally, filtering, and drying to obtain the high-purity moxifloxacin hydrochloride. The product prepared by the method has the advantages of high purity, high yield and favorable reproducibility, and has very high industrial operation feasibility.

Description

technical field [0001] The invention relates to a synthesis method of quinolone broad-spectrum antibacterial drugs, which belongs to the field of medicinal chemistry, in particular to a synthesis method of high-purity moxifloxacin hydrochloride. Background technique [0002] Moxifloxacin hydrochloride (Moxifloxacin hydrochloride), as shown in formula (V), chemical name is 1-cyclopropyl-7-(S, S-2,8-diazabicyclo[4.3.0]nonane- 8-yl)-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinoline carboxylate hydrochloride is the fourth generation quinolone broad-spectrum antibacterial drug. Moxifloxacin hydrochloride has broad-spectrum antibacterial activity against Gram-positive bacteria, Gram-negative bacteria, anaerobic bacteria, acid-fast bacteria, and atypical microorganisms (such as mycoplasma, chlamydia, etc.) in vitro. Moxifloxacin hydrochloride was first launched in Germany in 1999, and in the United States in December of the same year. The dosage forms currently on the market in my ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
Inventor 邹美香郭建锋段桂运孙歆慧蒋庆峰雷勇胜
Owner 天津康鸿医药科技发展有限公司
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