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Pyridone carboxylic acid derivative, preparation method and composition thereof

A composition and hydrate technology, applied in organic chemistry methods, pharmaceutical formulations, medical preparations containing active ingredients, etc., can solve the problems of unstable crystal form, excessive solvent residue, poor stability of sitafloxacin derivatives, etc. , to achieve the effect of stable humidity and good stability

Pending Publication Date: 2020-02-14
NANJING YOUKE BIOLOGICAL MEDICAL RES +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The patent also discloses the stability experiment. The crystal form of sitafloxacin 1.5 hydrate A changes under the conditions of high temperature 60°C and high humidity RH75%. The crystal form is stable, and the crystal form does not change in 5 days under the condition of high humidity RH75%, which is improved compared with the stability of sitafloxacin free base, but the crystal form changes in 10 days under the condition of high humidity RH75%, if it is made If the drug is placed for a long time, its crystal form is still unstable, and there are hidden dangers in the safety and stability of the drug
[0009] Therefore, in the process of drug development, the poor stability of sitafloxacin derivatives and excessive solvent residues are technical problems that need to be solved

Method used

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  • Pyridone carboxylic acid derivative, preparation method and composition thereof
  • Pyridone carboxylic acid derivative, preparation method and composition thereof
  • Pyridone carboxylic acid derivative, preparation method and composition thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0050] Embodiment 1 recrystallization solvent screening

[0051] In ethanol / ethyl acetate / water, ethanol / acetone / water, methanol / water, ethanol / water, isopropanol / water, acetone / water solvent system, add fumaric acid and sitafloxacin 1.5 hydrate The reaction was heated to make the system basically clear, and then the reaction was stirred for 1 to 2 hours, the temperature was lowered and the crystallization was stirred, the solid was collected by suction filtration, washed with n-heptane, dried in vacuum, and the obtained solid was tested. The results are shown in Table 1.

[0052] Table 1 Screening of recrystallization solvent

[0053]

[0054]

[0055] As can be seen from Table 1, the mixed solvent system of ethanol and water can obtain a single crystal form (alpha crystal form), and the remaining solvent systems can obtain amorphous or mixed crystals. Therefore, it is determined that the mixed solvent of ethanol and water is the recrystallization solvent. The sample o...

Embodiment 2

[0080] Add 10g of sitafloxacin 1.5 hydrate (0.0229mol), 3.2g of fumaric acid (0.0275mol, 1.2equal), 100mL of ethanol and 200mL of water into a 500mL reaction bottle, heat to above 40°C, and stir for 1 to 2 hours , cooled in an ice-water bath, stirred and crystallized for 2 to 5 hours, filtered and washed, and dried in vacuum at 40 to 60°C for 4 to 6 hours to obtain 11.3 g of off-white powdery solid with a yield of 91% and a HPLC purity of 99.95%.

[0081] According to X-ray powder diffraction, X-ray single crystal diffraction, differential thermal analysis and thermogravimetric analysis, the obtained hydrate and crystal form are consistent with the α crystal form in Example 1.

Embodiment 3

[0083] Add 20g of sitafloxacin 1.5 hydrate (0.0458mol), 6.9g of fumaric acid (0.0595mol, 1.3equal), 100mL of ethanol and 500mL of water into a 1L reaction flask, heat to above 40°C, and stir for 1 to 2 hours , cooled in an ice-water bath, stirred and crystallized for 2 to 5 hours, filtered and washed, and dried in vacuum at 40 to 60° C. for 4 to 6 hours to obtain 20.9 g of off-white powdery solid with a yield of 84% and an HPLC purity of 99.96%.

[0084] According to X-ray powder diffraction, X-ray single crystal diffraction, differential thermal analysis and thermogravimetric analysis, the obtained hydrate and crystal form are consistent with the α crystal form in Example 1.

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Abstract

The invention discloses a pyridone carboxylic acid derivative and a preparation method thereof. According to the present invention, a stable hydrate is obtained by screening a recrystallization solvent, wherein the hydrate is stable under a RH 95% condition, the weight change is not large through dynamic analysis of water adsorption, the solvent residue is less than 0.5%, and the drug quality requirement is met. The present invention further provides a composition containing the hydrate, wherein the structure formula of the pyridone carboxylic acid derivative is represented by a formula I.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and specifically relates to pyridone carboxylic acid derivatives, a preparation method and a composition thereof. Background technique [0002] Daiichi Pharmaceutical Sankyo Co., Ltd.'s spectral antibacterial drug sitafloxacin hydrate 50mg tablet and 10% fine granules approved by the Japanese Ministry of Health and Welfare are used to treat severe and refractory bacterial infections. The form of the listed raw material is sitafloxacin free state. Contains 1.5 crystal water. Because its structure contains a cis-fluorocyclopropylamine group, it has good pharmacokinetic properties and can reduce adverse reactions, and its antibacterial activity in vitro is significantly enhanced compared with most similar drugs. Sitafloxacin has a broad-spectrum antibacterial effect, not only has antibacterial activity against Gram-negative bacteria, but also against Gram-positive bacteria (methicillin-resistant ...

Claims

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Application Information

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IPC IPC(8): C07D401/04A61K31/4709A61P31/04
CPCC07D401/04A61P31/04C07B2200/13
Inventor 张峰车晓明朱素华薛峪泉刘春猛
Owner NANJING YOUKE BIOLOGICAL MEDICAL RES
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