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Preparation method of moxifloxacin hydrochloride

A technology of moxifloxacin hydrochloride and carboxylic acid, which is applied in the field of preparation of moxifloxacin hydrochloride, can solve the problems of high cost, high impurity content of moxifloxacin hydrochloride, expensive reagents, etc.

Active Publication Date: 2013-03-06
SICHUAN GOWELL PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Chinese patent CN1192440A discloses the use of 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-di Hydrogen-3-quinolinic acid and (S,S)-2,8-diazabicyclo[4.3.0]nonane as raw materials, catalytic reaction in 1,4-diazabicyclo[4.3.0]octane Next, after reacting in acetonitrile and dimethylformamide, react with concentrated hydrochloric acid, and prepare the preparation method of moxifloxacin hydrochloride with ethanol post-treatment, but the moxifloxacin hydrochloride prepared by this method has more impurities. Chromatographic column purification, although the prepared moxifloxacin hydrochloride has a high purity, the yield of the reaction is only 40%
[0011] The yields of the preparation methods of moxifloxacin hydrochloride in the prior art are all low, and some experimental methods have expensive reagents, high toxicity and need for chiral resolution and other high cost problems, so it is very important to seek a method for the preparation of moxifloxacin hydrochloride that is simple in process, low in cost, high in yield and high in purity, and is more suitable for industrialized production.

Method used

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  • Preparation method of moxifloxacin hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Dissolve 248.6g of ethyl borate chelate and 81.6g (S,S)-2,8-diazabicyclo[4.3.0]nonane (molar ratio 1:1.1) in 994.4mL acetonitrile (248.6* 4) React with 90.2mL triethylamine (molar ratio 1:1.1) at 60°C, check the progress of the reaction by TLC, and determine the end of the reaction. After the reaction is complete, cool to 25°C, add hydrochloric acid, adjust the pH to 6, stir and crystallize for 20 minutes, slowly add hydrochloric acid dropwise to adjust the pH to 2. Cool to 15°C, stir and crystallize for 1 hour. Filter with suction, drain, and wash with cold ethanol. The product was dried to obtain 237.3g, the yield was 92.2%, and the total impurities were 2.5‰.

Embodiment 2

[0057] 497.2g of ethyl borate chelate and 163.1g (S,S)-2,8-diazabicyclo[4.3.0]nonane (molar ratio 1:1.1) were dissolved in 1988.8mL acetonitrile (497.2* 4) React with 180.4ml triethylamine (molar ratio 1:1.1) at 65°C, check the progress of the reaction by TLC, and determine the end of the reaction. After the reaction is complete, cool to 35°C, add hydrochloric acid, adjust the pH to 4, stir and crystallize for 30 minutes, slowly add hydrochloric acid dropwise to adjust the pH to 0.5. The temperature was lowered to 10°C, and the mixture was stirred and crystallized for 3 hours. Filter with suction, drain, and wash with cold ethanol. The dried product is 489.5 g, the yield is 95.1%, and the total impurities are 2.7‰.

Embodiment 3

[0059] Dissolve 248.6g of ethyl borate chelate and 81.6g (S,S)-2,8-diazabicyclo[4.3.0]nonane (molar ratio 1:1.1) in 994.4mL acetonitrile (248.6* 4) React with 90.2mL triethylamine (molar ratio 1:1.1) at 62°C, check the progress of the reaction by TLC, and determine the end of the reaction. After the reaction is complete, cool to 30°C, add hydrochloric acid, adjust the pH to 5, stir and crystallize for 25 minutes, slowly add hydrochloric acid dropwise to adjust the pH to 1. The temperature was reduced to 12°C, and the mixture was stirred and crystallized for 2 hours. Filter with suction, drain, and wash with cold ethanol. The dried product was 241.4g, the yield was 93.8%, and the total impurities were 2.3‰.

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Abstract

The invention relates to a preparation method of moxifloxacin hydrochloride, which comprises the steps of: making 1-cyclopropyl-6,7-difluoro-8-methoxyl-1,4-dihydro-4-oxoquinoline-3-carboxylate-03,04-broron ester acetate and (S,S)-2,8-diazabicyclo[4.3.0] nonane as raw materials completely react in a solvent, then cooling, adding hydrochloric acid, regulating the pH value to 4-6, stirring and crystallizing for more than 10 minutes, then adding the hydrochloric acid, regulating pH value to 0.5-2, cooling to 0-40 DEG C, crystallizing, leaching, washing, and drying to prepare the moxifloxacin hydrochloride. The preparation method has the advantages of simple process, low cost, high yield and high purity, and is more suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of moxifloxacin hydrochloride. [0002] Background technique [0003] Moxifloxacin hydrochloride, 1-cyclopropyl-7-(S,S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-8-methoxy Base-4-oxo-1,4-dihydro-3-quinoline carboxylic acid hydrochloride) is the fourth generation of fluoroquinolone antibiotics, because of its broad antibacterial spectrum, low drug resistance, strong antibacterial effect and long half-life , low phototoxicity and other advantages, it has become a very effective anti-infective agent. Its structural formula is as follows: [0004] [0005] The original manufacturer of moxifloxacin hydrochloride is German Bayer Company. Moxifloxacin tablets were first launched in Germany in June 1996 under the trade name: Avelox; in December of the same year, it was approved by the US FDA for marketing. In November 2001, Moxifloxacin Hydroch...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
Inventor 张俊国郭礼新
Owner SICHUAN GOWELL PHARMA
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