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Preparation method of gatifloxacin cyclization ester

A technology of gatifloxacin cyclization ester and cyclization reaction, applied in the field of medicine and chemical industry, can solve the problems of inability to recycle, increase the recovery process, low product yield and the like, achieve simplified operation, high atom economy, and by-products high purity effect

Active Publication Date: 2022-07-08
内蒙古源宏精细化工有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The use of acid and alkali will increase the recovery process. The use of strong alkali in the cyclization process will damage the material, resulting in low yield and more impurities. The use of potassium fluoride will produce other by-products that cannot be recycled, and the cost is high.
In addition, in the prior art, organic bases such as DBU and triethylamine are also used as catalysts in the cyclization process of the quinolone main ring, but there are also problems such as large amount of base used, low product yield, and difficulty in recycling.

Method used

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  • Preparation method of gatifloxacin cyclization ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] 1. Coupling reaction

[0043] Put 2,4,5-trifluoro-3-methoxybenzoyl chloride 45g (0.2004mol, 1 times the amount), N,N-dimethylamino ethyl acrylate: 29g (0.2024mol, 1.01 times the amount) into the reaction kettle amount), 150ml of toluene, 0.5g of cuprous iodide, control the vacuum degree to 0.06-0.07Mpa, control the temperature to 35-40℃, keep under reduced pressure for 3h, control the raw material point of the reaction to be ≤0.5%, the reaction is complete, and there are The absorption device absorbs hydrogen chloride with water to obtain by-product hydrochloric acid for the next step of solvent toluene recovery.

[0044] After the reaction was completed, the vacuum was broken with nitrogen, the temperature was lowered to 5-10° C., and 11.44 g (0.2004 mol, 1 times the amount) of cyclopropylamine was added dropwise, and the dropwise addition took 1 h. After the dropwise addition, the temperature was kept at 25-30° C. for 2 hours, and the reaction raw material point was co...

Embodiment 2

[0049] 1. Coupling reaction

[0050] Put 2,4,5-trifluoro-3-methoxybenzoyl chloride 45g (0.2004mol, 1 times the amount), N,N-dimethylamino ethyl acrylate: 29g (0.2024mol, 1.01 times the amount) into the reaction kettle amount), 150ml of toluene, 0.3g of cuprous iodide, the control vacuum degree is 0.06-0.07Mpa, the control temperature is 35-40℃, the vacuum is kept for 3h, the reaction raw material point is controlled to ≤0.5%, the reaction is complete, and there are The absorption device absorbs hydrogen chloride with water to obtain by-product hydrochloric acid for the next step of solvent toluene recovery.

[0051] After the reaction was completed, the vacuum was broken with nitrogen, the temperature was lowered to 5-10° C., and 11.44 g (0.2004 mol, 1 times the amount) of cyclopropylamine was added dropwise, and the dropwise addition took 1 h. After the dropwise addition, the temperature was kept at 25-30° C. for 2 hours, and the reaction raw material point was controlled to...

Embodiment 3

[0056] 1. Coupling reaction

[0057] Put 2,4,5-trifluoro-3-methoxybenzoyl chloride 45g (0.2004mol, 1 times the amount), N,N-dimethylamino ethyl acrylate: 29g (0.2024mol, 1.01 times the amount) into the reaction kettle amount), 150ml of toluene, 0.75g of cuprous iodide, the control vacuum degree is 0.06-0.07Mpa, the control temperature is 35-40℃, the vacuum is kept for 3h, the reaction raw material point is controlled ≤0.5%, the reaction is complete, and there are The absorption device absorbs hydrogen chloride with water to obtain by-product hydrochloric acid for the next step of solvent toluene recovery.

[0058] After the reaction was completed, the vacuum was broken with nitrogen, the temperature was lowered to 5-10° C., and cyclopropylamine 11.44 (0.2004 mol, 1 times the amount) was added dropwise, and the dropwise addition took 1 h. After the dropwise addition, the temperature was kept at 25-30° C. for 2 hours, and the reaction raw material point was controlled to be les...

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Abstract

The invention provides a preparation method of gatifloxacin cyclization ester. According to the preparation method, coupling reaction of 2, 4, 5-trifluoro-3-methoxybenzoyl chloride and N, N-dimethylamino ethyl acrylate is carried out in a negative pressure state, a cuprous halide catalyst is used, hydrogen chloride is timely exported, the reaction speed and the conversion rate are high, and few three wastes are generated; in the cyclization reaction, tri-n-propylamine is used as alkali, so that the catalytic efficiency is high, the dosage is small, impurities are few, and recovery is easy; in addition, the method disclosed by the invention can be carried out by a one-pot method, and is simple and convenient to operate and lower in cost. Therefore, the preparation method is a production process which is efficient, energy-saving, green, environment-friendly, simple to operate, simple in post-treatment, high in product yield and purity and good in atom economy, has extremely high economic and practical values, and is more suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, and in particular, the invention relates to a preparation method of gatifloxacin cyclic ester. Background technique [0002] Gatifloxacin (gatifloxacin, AM-1155, 1-cyclopropyl-6-fluoro-7-(3-methylpiperazin-1-yl)-8-methoxy-1,4-dihydro-4 -Oxo-quinoline-3-carboxylic acid) is a fourth-generation quinolone antibacterial drug, developed by Japan Xinglin Pharmaceutical Co., Ltd., which makes up for the third-generation quinolone drugs such as ciprofloxacin and ofloxacin, which can only be used against The disadvantage of Gram-negative bacteria is that it also has good antibacterial effect on Gram-positive bacteria, anaerobic bacteria, mycoplasma, chlamydia and mycobacteria, and has almost no potential photosensitivity side reactions, which is a safe Effective antibacterial drugs, with good development and application prospects. [0003] The synthesis of gatifloxacin was first applied for ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/56
CPCC07D215/56Y02P20/584
Inventor 王兵波张森王伟张晓弟宋立雪
Owner 内蒙古源宏精细化工有限公司
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