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Preparation method of moxifloxacin hydrochloride

A technology for moxifloxacin hydrochloride and ethyl quinoline carboxylate, which is applied in the field of pharmaceutical production, can solve the problems that the quality of moxifloxacin hydrochloride cannot be guaranteed, is not suitable for industrial production, and is difficult to control the quality of crystallization finished products, and improves the preparation efficiency. And the quality of the finished product, improve the reaction speed and reaction efficiency, optimize the effect of the process flow

Inactive Publication Date: 2021-01-15
BEIJING FOUR RINGS BIOPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, in the prior art, moxifloxacin hydrochloride is prone to explosive crystallization in the process of crystal formation. Because the crystallization speed is too fast, it is difficult to control the quality of the finished product of crystallization, and the quality of the finished product moxifloxacin hydrochloride cannot be guaranteed. , secondly, the synthesis method is relatively simple, but the competitive substitution between C7-F and C6-F cannot be avoided during the reaction process, resulting in some C6-F substituted by-products mixed in the finished product, and the two are separated It needs to be separated and purified by silica gel column chromatography, which is not suitable for industrial production

Method used

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  • Preparation method of moxifloxacin hydrochloride
  • Preparation method of moxifloxacin hydrochloride
  • Preparation method of moxifloxacin hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0070] Group 1-1

[0071] A preparation method for moxifloxacin hydrochloride, comprising the following steps:

[0072] Under the protection of nitrogen, add to the reactor, 3.3g ethylene glycol, 0.8gMnCl 2 , 160mL ethanol and 16.2g 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxyl-4-oxo-3-quinolinecarboxylic acid ethyl ester, at a temperature of 40°C 274g of 2-bromobutane was added to the reaction kettle, sodium hydroxide was added, and the pH was adjusted to 8, and the reaction kettle was continued to be heated at 54°C for 4h; under the protection of nitrogen, Sodium hydroxide was added in the reaction kettle, and the pH was adjusted to be 8, and 160mL acetone and 6.3g (S, S)-2,8-diazabicyclo[4.3.0]nonane were added in the reaction kettle, at 80 Under the temperature of ℃, after reacting for 4h, add 2.8g of 30% hydrogen peroxide solution in the reactor, control the reaction temperature to be 70℃, and continue the heating reaction for 5h; after the reaction is completed, ex...

Embodiment 2

[0080] Group 2-1

[0081] A preparation method for moxifloxacin hydrochloride, comprising the following steps:

[0082] Under the protection of nitrogen, add to the reactor, 3.8g1,2-propanediol, 0.8gMnCl 2, 160mL ethanol and 16.2g 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxyl-4-oxo-3-quinolinecarboxylic acid ethyl ester, at a temperature of 40°C 274g of 2-bromobutane was added to the reaction kettle, sodium hydroxide was added, and the pH was adjusted to 8, and the reaction kettle was continued to be heated at 54°C for 4h; under the protection of nitrogen, Sodium hydroxide was added in the reaction kettle, and the pH was adjusted to be 8, and 160mL acetone and 6.3g (S, S)-2,8-diazabicyclo[4.3.0]nonane were added in the reaction kettle, at 80 Under the temperature of ℃, after reacting for 4h, add 2.8g of 30% hydrogen peroxide solution in the reactor, control the reaction temperature to be 70℃, and continue the heating reaction for 5h; after the reaction is completed, expo...

Embodiment 3

[0092] Group 3-1

[0093] Coordination reaction, under the protection of nitrogen, add 3.8g1,2-propanediol, 0.7gCoCl to the reaction kettle 2 , 160mL ethanol and 16.2g 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxyl-4-oxo-3-quinolinecarboxylic acid ethyl ester, at a temperature of 40°C , reacted for 5 h, and measured the content of 1,2-propanediol in the coordination reaction product by using HPLC, and calculated the coordination ratio of the coordination reaction according to the remaining amount of 1,2-propanediol.

[0094] Group 3-2

[0095] Coordination reaction, under the protection of nitrogen, add 3.8g1,2-propanediol, 1.4gCoCl to the reaction kettle 2 , 160mL ethanol and 16.2g 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxyl-4-oxo-3-quinolinecarboxylic acid ethyl ester, at a temperature of 40°C , reacted for 5 h, and measured the content of 1,2-propanediol in the coordination reaction product by using HPLC, and calculated the coordination ratio of the coordination...

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Abstract

The invention provides a preparation method of moxifloxacin hydrochloride. The preparation method of the moxifloxacin hydrochloride comprises the following steps of: carrying out coordination reaction, specifically, carrying out reaction on a catalyst, ethanol, polyol and 1-cyclopropyl-6, 7-difluoro-1, 4-dihydro-8-methoxy-4-oxo-3-quinoline carboxylic acid ethyl ester in a protective gas at 35-45 DEG C for 4.5-5.5 hours; carrying out a first substitution reaction, specifically, mixing a first substitute and sodium hydroxide, adjusting the pH value to 8-9, performing continuous heating, and performing heating at 50-58 DEG C for 3-5 hours; carrying out a second substitution reaction, specifically, introducing protective gas, adding sodium hydroxide, adjusting the pH value to 8-9, adding a second solvent and (S, S) 2, 8-diazabicyclo [4.3. 0] nonane into a reaction kettle, and carrying out a reaction for 8-10 h at a temperature of 75-85 DEG C; carrying out purifying and separating, specifically, leading out a product in the reaction kettle, carrying out hot filtration, cooling to room temperature, dropwise adding concentrated hydrochloric acid, adjusting the pH value to be 1-3, stirringfor 2-3 hours, cooling to -10 to -5 DEG C, carrying out crystallizing, suction filtration, washing with ethanol, and carrying out vacuum drying.

Description

technical field [0001] The invention relates to the technical field of medicine production, in particular to a preparation method of moxifloxacin hydrochloride. Background technique [0002] Moxifloxacin hydrochloride (moxifloxacin hydrochloride), a quinolone drug, has high performance, low toxicity and broad-spectrum antibacterial ability, and can be effectively used in the treatment of infections caused by most bacteria, and it is effective against Gram-positive bacteria, pneumonia It is excellent in inhibiting the activity of streptococcus and enterococcus. In particular, with the introduction of the difluoromethoxy group at the C-8 position of the quinolone core, the ability of the novel quinolone with a hydrogen atom at the C-6 position of the quinolone core to further strengthen the in vitro activity of Streptococcus pneumoniae. [0003] Moxifloxacin hydrochloride, its chemical name is 1-cyclopropyl-7-(S,S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-8-methanol Oxygen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04
CPCC07D471/04
Inventor 韩明娣薛霞
Owner BEIJING FOUR RINGS BIOPHARM
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