Synthesis method of gatifloxacin cyclic ester

A gatifloxacin cyclization ester and synthesis method technology, applied in the direction of organic chemistry, can solve the problems of long synthesis route steps, lower raw material utilization rate, poor atom economy, etc., achieve convenient post-processing and reduce tar-like substances The effect of production and short synthetic route

Inactive Publication Date: 2019-10-22
内蒙古源宏精细化工有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In the above-mentioned reactions, there are many by-products during decarboxylation and Grignard reaction, difficult product separation, large discharge of three wastes, need to use raw materials with great safety hazards such as triethyl orthoformate, and use 2,4,5-tetrafluoro-3-formazol Oxybenzoyl chloride is used as a starting material, which increases the cost of synthesis
[0006] In addition, 3,4,5,6-tetrafluorophthalic acid can als

Method used

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  • Synthesis method of gatifloxacin cyclic ester
  • Synthesis method of gatifloxacin cyclic ester

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Embodiment 1

[0040] A kind of synthetic method of gatifloxacin cyclic ester, comprising:

[0041] (1) Add 100mL of 30% sodium hydroxide solution to a 500mL reactor, and mix 100g of 3,4,5,6-tetrafluoro-N-methylphthalimide and sodium hydroxide evenly , heated and refluxed for 10 hours, and reacted to obtain 2,4,5-trifluoro-3-hydroxyphthalate sodium; then the temperature was controlled below 70°C, Add sulfuric acid to sodium diformate, carry out decarboxylation reaction and acidify to pH 3.05; after that, adjust the temperature to 105°C, keep the temperature for 8 hours, and cool down to 25°C to obtain 2,4,5-trifluoro-3-hydroxybenzoic acid ;

[0042](2) Transfer the obtained 2,4,5-trifluoro-3-hydroxybenzoic acid into the methylation device, add alkali to adjust the pH to 9.07, control the temperature to be less than 35°C, add dimethyl sulfate, and at the same time, pass Add lye to control the pH to 8.55. After the addition of dimethyl sulfate, raise the temperature to 80°C, adjust the pH to...

Embodiment 2

[0046] A kind of synthetic method of gatifloxacin cyclic ester, comprising:

[0047] (1) Add 100mL of 30% sodium hydroxide solution to a 500mL reactor, and mix 100g of 3,4,5,6-tetrafluoro-N-methylphthalimide and sodium hydroxide evenly , heated up and refluxed for 8 hours, and reacted to obtain 2,4,5-trifluoro-3-hydroxyphthalate sodium; then the temperature was controlled below 70°C, Add sulfuric acid or hydrochloric acid to sodium diformate for decarboxylation and acidification to pH 0.87; after that, adjust the temperature to 100°C, keep the temperature for 6 hours, and cool down to 20°C to obtain 2,4,5-trifluoro-3-hydroxyl benzoic acid;

[0048] (2) Transfer the obtained 2,4,5-trifluoro-3-hydroxybenzoic acid into the methylation device, add alkali to adjust the pH to 9.49, control the temperature to be less than 35°C, add dimethyl sulfate, and simultaneously add Control the pH of the lye to 8.51. After the addition of dimethyl sulfate, raise the temperature to 75°C, adjus...

Embodiment 3

[0052] A kind of synthetic method of gatifloxacin cyclic ester, comprising:

[0053] (1) Add 100mL of 30% sodium hydroxide solution to a 500mL reactor, and mix 100g of 3,4,5,6-tetrafluoro-N-methylphthalimide and sodium hydroxide evenly , heated up and refluxed for 12 hours, and reacted to obtain 2,4,5-trifluoro-3-hydroxyphthalate sodium; then the temperature was controlled below 70°C, Add sulfuric acid or hydrochloric acid to sodium diformate, decarboxylate and acidify to pH 3.98; after that, adjust the temperature to 110°C, keep the temperature for 10 hours, and cool down to 30°C to obtain 2,4,5-trifluoro-3-hydroxyl benzoic acid;

[0054] (2) Transfer the obtained 2,4,5-trifluoro-3-hydroxybenzoic acid into the methylation device, add alkali to adjust the pH to 9.53, control the temperature to be less than 35°C, add dimethyl sulfate, and simultaneously add Control the pH of the lye to 9.47. After the addition of dimethyl sulfate, raise the temperature to 85°C, adjust the pH ...

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Abstract

The invention belongs to a production process of a pharmaceutical intermediate, and particularly discloses a synthesis method of gatifloxacin cyclic ester. The synthesis method comprises the followingsteps: performing hydrolysis, decarboxylation and methylation on 3, 4, 5, 6-tetrafluoro-N-methylphthalimide serving as a starting material to obtain 2,4,5-trifluoro-3-methoxybenzoyl chloride, coupling the 2,4,5-trifluoro-3-methoxybenzoyl chloride with N,N-ethyl dimethylaminoacrylate, then replacing with cyclopropylamine, and finally performing cyclization to produce the gatifloxacin cyclic esterunder the action of DMF and potassium fluoride. The reaction route is short, the raw materials are wide in source; furthermore, the reaction conditions are mild and easy to operate and control, whichreduces the consumption of the raw materials, facilitates the post-treatment and reduces the cost; potassium fluoride used instead of potassium carbonate in the reaction can not only reduce productionof exhaust gas, but also make the used potassium fluoride used continuously through adjustment by potassium hydroxide, and the cost is further reduced.

Description

technical field [0001] The invention belongs to the production process of pharmaceutical intermediates, in particular to a synthesis method of gatifloxacin cycloester. Background technique [0002] Quinolones, also known as pyruvate or pyridone, target the deoxyribonucleic acid of bacteria and have a broad antibacterial spectrum. Quinolones have developed rapidly since their inception, and have been written as one of the main drugs against bacterial infections. They are widely used to treat various infections, and have played an important role in improving the cure rate of infections caused by sensitive bacteria and reducing the fatality rate of critical infections. [0003] Gatifloxacin, whose English name is gatifloxacin, is a new 6-fluoro-8-methoxyquinolone compound created by Japan Kyorin Pharmaceutical Co., Ltd., which is effective against Gram-negative bacteria, Gram-positive bacteria, anaerobic bacteria, mycoplasma, and chlamydia Both mycobacteria and mycobacteria ha...

Claims

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Application Information

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IPC IPC(8): C07D217/26
CPCC07D217/26
Inventor 王兵波张森王伟张晓弟
Owner 内蒙古源宏精细化工有限公司
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