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High selectivity method for synthesizing moxifloxacin

A technology of moxifloxacin and high selectivity, which is applied in the field of compound synthesis technology, can solve problems affecting product purity and yield, unsuitable for industrial production, and unfavorable for industrial production, so as to avoid difficult-to-separate impurities and high selectivity , the effect of mild reaction conditions

Active Publication Date: 2012-02-15
ZHEJIANG LEPU PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Fluoroboric acid is highly toxic and has a strong corrosive effect on enamel reactors, which is not conducive to industrial production
B(OPh) 3 Good performance, although it does not corrode equipment, but it is difficult to synthesize, which increases the production cost and is not suitable for industrial production
B(OAc) 3 The preparation method is simple and convenient, and the reaction conditions are mild, but there are still about 3-5% C in the reaction. 6 -F is replaced, which affects the purity and yield of the product

Method used

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  • High selectivity method for synthesizing moxifloxacin
  • High selectivity method for synthesizing moxifloxacin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] Add 69.0 g of boric anhydride and 630.0 g of trifluoroacetic anhydride in a 2000 ml three-necked flask, react at 35°C for 10 hours to obtain a thick slurry, directly add 161.1 g of 1-cyclopropyl -Ethyl 6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate (I), react at 110°C for 2 hours, cool to room temperature, add Ice water, precipitated solid, filtered with suction, washed the filter cake with water until neutral, dried to obtain white powder 1-ethyl-7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3 - Methyl carboxylate trifluoroacetic anhydride boride chelate (Ⅱ) 231.0g, yield 87.0%;

[0016] Add 500ml of acetone to a 2000ml three-necked flask, add 231.0g of 1-ethyl-7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid methyl trifluoroacetic anhydride Boronated chelate (Ⅱ); add 184.1 g (S,S)-2,8-diazabicyclo[4.3.0]nonane; react at 0°C for 10 hours to obtain 1-cyclopropyl-6 -Fluoro-7-([S,S]-2,8-diazabicyclo[4.3.0]nonan-8-methoxy-4-oxo-1,4-dihydro-...

Embodiment 2

[0022] Add 69.0 g of boric anhydride and 840.0 g of trifluoroacetic anhydride in a 2000 ml three-necked flask, react at 40°C for 5 hours to obtain a thick slurry, directly add 323.1 g of 1-cyclopropyl -Ethyl 6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate (I), reacted at 80°C for 3 hours, cooled to room temperature, added Ice water, precipitated solid, filtered with suction, washed the filter cake with water until neutral, dried to obtain white powder 1-ethyl-7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3 - Methyl carboxylate trifluoroacetic anhydride boride chelate (II) 500.5g, yield 94.3%;

[0023] In a 2000 ml three-necked flask, add 500ml of acetonitrile, add 500.5 g of 1-ethyl-7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid methyl trifluoroacetic anhydride Boronated chelate (Ⅱ); add 132.5 g (S,S)-2,8-diazabicyclo[4.3.0]nonane; react at -10°C for 24 hours to obtain 1-cyclopropyl- 6-fluoro-7-([S,S]-2,8-diazabicyclo[4.3.0]nonan-8-methoxy-4-o...

Embodiment 3

[0025] Add 69.0 g of boric anhydride and 700.0 g of trifluoroacetic anhydride in a 2000 ml three-necked flask, react at 40°C for 8 hours to obtain a thick slurry, directly add 300.0 g of 1-cyclopropane to the slurry Ethyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate (I), reacted at 90°C for 3 hours, cooled to room temperature, Add ice water, precipitate solid, filter with suction, wash the filter cake with water until neutral, and dry to obtain white powder 1-ethyl-7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline- 3-Carboxylate methyl trifluoroacetic anhydride boride chelate (Ⅱ) 473.5g, yield 96.1%;

[0026] Add 500ml N,N'-dimethylformamide to a 2000ml three-neck flask, add 473.5g1-ethyl-7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3 -Methyl carboxylate trifluoroacetic anhydride borate chelate (Ⅱ); add 251.0 g (S,S)-2,8-diazabicyclo[4.3.0]nonane; react at -10°C for 18 hours, 1-cyclopropyl-6-fluoro-7-([S,S]-2,8-diazabicyclo[4.3.0]nonan-8-methoxy-4-oxo-1, Ethy...

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Abstract

The invention discloses a high selectivity method for synthesizing moxifloxacin. The method comprises the following steps of: reacting boric anhydride with trifluoro acetic anhydride to obtain a chelant; reacting 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid ethyl ester with the chelant, cooling to room temperature, adding ice water, performing suction filtration, and washing a filter cake with water until neutrality to obtain a 1-ethyl-7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid methyl ester trifluoroacetic anhydride boronized chelate; and reacting the 1-ethyl-7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid methyl ester trifluoroacetic anhydride boronized chelate with (S,S)-2,8-diazabicyclo[4,3,0]nonane to obtain a 1-cyclopropyl-6-fluoro-7-([S,S]-2,8-diazabicyclo[4,3,0]nonane-8-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid ethyl ester trifluoroacetic anhydride boronized chelate, recycling a solvent under reduced pressure, adding alkali, refluxing, discoloring, filtering, freezing, performing suction filtration, and drying a filter cake. The method is simple, mild in conditions, and high in selectivity, avoids difficultly separated impurities, is high in reaction yield and product purity, and is suitable for industrial production.

Description

technical field [0001] The invention relates to a compound synthesis process, in particular to a method for synthesizing moxifloxacin with high selectivity. Background technique [0002] Moxifloxacin is a product launched by Bayer AG of Germany, which belongs to the fourth generation of quinolones and has broad-spectrum antibacterial activity. The chemical name is 1-cyclopropyl-6-fluoro-8-methoxy-7-([S,S]-2,8-diazabicyclo[4.3.0]non-8-yl)-4- Oxo-1,4-dihydro-3-quinoline carboxylic acid hydrochloride, the trade name is Avelox. The final step in the synthesis of moxifloxacin is the parent nucleus 1-ethyl-7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid methyl ester C 7 nucleophilic substitution reaction with branched chain (S,S)-2,8-diazabicyclo[4.3.0]nonane, in which C 7 -F and C 6 Competitive substitution of -F; in addition, the parent core C 8 The forced electronic effect of the methoxy group lowers the C 7 The leaving activity of -F makes it difficult for...

Claims

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Application Information

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IPC IPC(8): C07D471/04
Inventor 洪华斌颜剑波林义蒋成君
Owner ZHEJIANG LEPU PHARMA CO LTD
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