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Sitafloxacin fumarate crystal form a and its pharmaceutical use

A technology of sitafloxacin and fumarate, applied in the preparation of carboxylates, antibacterial drugs, pharmaceutical formulations, etc., can solve the problems of low stability and low dissolution rate of preparations, and achieve high and stable dissolution rate. The effect of high performance and simple preparation process

Active Publication Date: 2014-10-29
NANJING YOUKE BIOLOGICAL MEDICAL RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The active drug of the commercially available sitafloxacin tablets (Gracevit, 50 mg, Daiichi Pharmaceutical Sankyo Co., Ltd.) is sitafloxacin containing 1.5 crystal water. The researchers found that the sitafloxacin containing 1.5 crystal water It has the disadvantages of low stability and low dissolution rate of its preparation

Method used

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  • Sitafloxacin fumarate crystal form a and its pharmaceutical use
  • Sitafloxacin fumarate crystal form a and its pharmaceutical use
  • Sitafloxacin fumarate crystal form a and its pharmaceutical use

Examples

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Comparison scheme
Effect test

Embodiment 1

[0033] Embodiment 1 Preparation of sitafloxacin fumarate crystal form A

[0034] Take 4.0g of sitafloxacin free base (containing 1.5 crystalline water, commercially available, Beijing Zhongshuo Pharmaceutical Technology Development Co., Ltd.) into a 1L three-necked bottle, add 200ml of acetone, stir and heat up to 55-60°C under reflux under dark conditions, After the solution was clear, it was filtered while it was hot, and the filtrate was reheated to reflux.

[0035] Dissolve 1.27g of fumaric acid in 44ml of acetone, add it dropwise to the reaction flask under reflux, and react under reflux for 1h after dropping, add 300ml of n-heptane under the condition of heat preservation, and precipitate a light yellow solid, lower it to room temperature, stir and crystallize for 1h, After filtering, the filtrate was washed with a small amount of n-heptane, and dried under vacuum at 35-40°C to obtain 4.75 g of a light yellow solid.

Embodiment 2

[0036] Embodiment 2 Preparation of sitafloxacin fumarate crystal form A

[0037] Take 4.0g of sitafloxacin free base (containing 1.5 crystal water, commercially available, Beijing Zhongshuo Pharmaceutical Technology Development Co., Ltd.) into a 1L three-necked bottle, add 200ml of methyl ethyl ketone, stir and heat up to 55-60°C under dark conditions, dissolve After clearing, filter while hot, and reheat the filtrate to reflux.

[0038] Dissolve 1.27g of fumaric acid in 44ml of methyl ethyl ketone and add it dropwise to the reaction flask under reflux. After the dropwise reaction, reflux for 50min. Add 300ml of n-hexane under heat preservation conditions to precipitate a light yellow solid. Cool down to room temperature, stir and crystallize for 1h, and filter , The filtrate was washed with a small amount of n-heptane, and dried under vacuum at 35-40°C to obtain 4.69 g of a pale yellow solid.

Embodiment 3

[0039] Embodiment 3 Preparation of sitafloxacin fumarate crystal form A

[0040] Take 8.0g sitafloxacin free base (containing 1.5 crystal water, commercially available, Beijing Zhongshuo Pharmaceutical Technology Development Co., Ltd.) into a 1L three-necked bottle, add 200ml of dichloromethane and anhydrous methanol mixed solvent (dichloromethane and The volume ratio of anhydrous methanol is 1:1), stirring and raising the temperature to 40-45°C and reflux under the condition of avoiding light. After dissolving, filter while it is hot, and reheat the filtrate to reflux.

[0041]Dissolve 2.12g of fumaric acid in 44ml of a mixed solvent of dichloromethane and anhydrous methanol (the volume ratio of dichloromethane to anhydrous methanol is 1:1), and add it dropwise into the reaction flask under reflux, and react under reflux for 1h after dropping. Add 300ml of n-heptane under the condition of heat preservation, and a light yellow solid precipitates out. Cool down to room temper...

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Abstract

The invention mainly relates to trioxymethylene fumarate crystal form A. Cu-Ka radiation is adopted, and in an X-ray powder diffraction graph of the trioxymethylene fumarate crystal form A, diffraction peaks exist when the crystal plane is away from a value d by about 7.557 angstroms, 6.622 angstroms, 5.771 angstroms, 4.263 angstroms, 4.203 angstroms, 3.748 angstroms, 3.666 angstroms, 3.358 angstroms, 3.302 angstroms and 2.884 angstroms. The invention further relates to a preparation method and the pharmaceutical usage of the trioxymethylene fumarate crystal form A. The trioxymethylene fumarate crystal form A has the advantages of high stability, high dissolution rate after being made into preparation and simplicity in preparation process.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a new crystal form of sitafloxacin fumarate, a preparation method and a pharmaceutical application of the new crystal form. Background technique [0002] Sitafloxacin (sitafloxacin) is a broad-spectrum quinolone antibacterial drug developed by Daiichi Sankyo Co., Ltd., which has a relatively strong effect on Gram-negative bacteria, Gram-positive bacteria, anaerobic bacteria, mycoplasma and chlamydia, etc. Strong antibacterial activity, also has good bactericidal effect on many common clinical fluoroquinolone-resistant strains. [0003] Japan's Daiichi Pharmaceutical Co., Ltd. initially disclosed the chemical structure, pharmaceutical use and preparation method of sitafloxacin in JP2231475A, and its chemical name is 7-[4(S)-amino-6-azaspiro[2,4] Heptane-6-yl]-8-chloro-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroquinoline-3-carboxy Acid, Cas ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04C07C57/15C07C51/41A61K31/4709A61P31/04
Inventor 张峰徐晓霞史为龙车晓明包玉胜
Owner NANJING YOUKE BIOLOGICAL MEDICAL RES
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