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Preparation method of tosufloxacin tosylate monohydrate

A technology of tosufloxacin tosylate and monohydrate, which is applied in the field of drug synthesis, can solve the problems of large amount of waste water and liquid, poor product quality, and low yield, so as to reduce the discharge of "three wastes" and shorten the production cycle , the effect of improving the purity

Active Publication Date: 2019-07-23
HINYE PHARM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] The technical problem to be solved in the present invention is to provide a "one-pot method" method for preparing tosufloxacin tosylate monohydrate, so as to overcome the cumbersome preparation process and low yield of tosufloxacin tosylate in the prior art , the amount of waste water and liquid produced is relatively large, which is not conducive to environmental protection and large-scale production, as well as problems such as poor product quality

Method used

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  • Preparation method of tosufloxacin tosylate monohydrate
  • Preparation method of tosufloxacin tosylate monohydrate
  • Preparation method of tosufloxacin tosylate monohydrate

Examples

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Embodiment 1

[0033] A preparation method of tosufloxacin tosylate monohydrate, adding 2000ml of acetone and 2500.0ml of water into a 10L reaction kettle for mixing, and then sequentially adding 500g of 7-(3-aminopyrrolidin-1-yl) -1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester (formula Ⅱ), p Toluenesulfonic acid monohydrate 901.83g, mechanically stirred and heated, the temperature of the system was controlled at 65~70°C, stirred and reacted for 6 hours, the residual amount of raw materials was detected by sampling HPLC ≤ 0.5%, 50g of activated carbon was added to the system, and continued at 65~70°C Stir for 0.5h, filter while hot, stir and cool the filtrate to 0-5°C, keep stirring and crystallize for 7 hours. Filter and wash the filter cake with 1000ml of purified water; dry the filter cake at 55~65°C for 8~18 hours to obtain 611.9g of off-white tosufloxacin tosylate monohydrate (Formula Ⅰ), with a yield of 89.0% , 99.90% purity.

[003...

Embodiment 2

[0042] Add 101.3ml of ethanol and 100.0ml of water into the reaction flask for mixing, then add 20.0 g of 7-(3-aminopyrrolidin-1-yl)-1-(2,4-difluorophenyl)-6- Fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester (Formula II) and p-toluenesulfonic acid monohydrate 36.0g, stirred and heated, the system temperature was controlled at 65 ~85°C, keep stirring and reflux for 7 hours, sample HPLC to detect the residual amount of raw materials is ≤0.5%, add 2.0g of activated carbon to the system, continue stirring for 0.5 hours at 65~70°C, filter while hot, and cool the filtrate to 0~5 ℃, heat preservation and crystallization for 4h. Filter and wash the filter cake with 40.0ml of purified water; dry the filter cake at 55-65°C for 8-18 hours to obtain 25.1 g of off-white tosufloxacin tosylate monohydrate (Formula Ⅰ), with a yield of 91.2 %, purity 99.42%

Embodiment 3

[0044] Add 126.6ml methanol and 100.0ml water into the reaction flask for mixing, then add 20.0 g of 7-(3-aminopyrrolidin-1-yl)-1-(2,4-difluorophenyl)-6- Add ethyl fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylate (Formula II) and p-toluenesulfonic acid monohydrate 36.0g into the reaction flask in turn, stir and heat , the temperature of the system is controlled at 65~70°C, heat-preserved, stirred and refluxed for 7 hours. Sampling HPLC detects that the residual amount of raw materials is ≤0.5%. Add 2.0g of activated carbon to the system, continue to stir at 65~70°C for 0.5h, filter while it is hot, and stir the filtrate Cool down to 20~25°C, keep warm and crystallize for 4h. Filter and wash the filter cake with 40.0ml of purified water; dry the filter cake at 55~65°C for 8~18 hours to obtain 24.9g of off-white tosufloxacin tosylate monohydrate (Formula Ⅰ), with a yield of 90.5 %, purity 99.47%.

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Abstract

The invention provides a preparation method of tosufloxacin tosylate monohydrate, the method uses 7-(3-aminopyrrolidine-1-yl)-1-(2,4-difluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-[1,8] naphthyridine-3-carboxylic acid ethyl ester as a tosufloxacin tosylate synthesizing key intermediate to directly react with p-toluenesulfonic acid monohydrate in a mixed solvent of organic solvent and water to preparethe tosufloxacin tosylate monohydrate. By adopting the preparation method of the invention, the yield of the prepared tosufloxacin tosylate monohydrate is about 90%, and the purity is more than 99%. Compared with the prior art, the production cycle is greatly shortened, the discharge amount of ''three wastes'' is reduced, and the method is suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of tosufloxacin tosylate monohydrate. [0002] technical background [0003] The chemical name of tosufloxacin tosylate is 7-[3-amino-1-(pyrrolidinyl)]-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro- 4-oxo-1,8-naphthyridine-3-carboxylic acid p-toluenesulfonate monohydrate, its chemical formula is as shown in formula I below: [0004] [0005] Formula I. [0006] Tosufloxacin tosylate is a fluoroquinolone antibacterial drug. Its antibacterial activity in vitro shows that this product has greater antibacterial activity against Gram-negative bacteria than ofloxacin (2-4 times greater than ofloxacin) , Ciprofloxacin, Sparfloxacin. The antibacterial activity of this product against Gram-positive bacteria is the strongest among all quinolones currently on the market in the international market, and its antibacterial activity against Staphylococcus aureus...

Claims

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Application Information

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IPC IPC(8): C07D471/04C07C309/30C07C303/32
CPCC07C303/32C07C309/30C07D471/04
Inventor 曾伟强贺境杰栗涛高玉贺王衡新程雪清
Owner HINYE PHARM CO LTD
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