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Novel sitafloxacin crystal form and preparation method thereof

A sitafloxacin and crystal form technology, which is applied in the field of pharmaceutical inventions, can solve the problems of complex desolvation and high solvent residue, and achieve the effects of simple operation, safety and drug quality

Inactive Publication Date: 2014-01-29
SHENZHEN SALUBRIS PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Patent ZL94116197.8 discloses that sitafloxacin 1 / 2 hydrate, 1 hydrate and 3 / 2 hydrate are obtained by recrystallization in a mixed solvent containing ammonia and water-containing ethanol, and the desolvation process after crystallization is better than using a single solvent Desolvation of crystallization is more complex with higher residual solvent

Method used

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  • Novel sitafloxacin crystal form and preparation method thereof
  • Novel sitafloxacin crystal form and preparation method thereof
  • Novel sitafloxacin crystal form and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Embodiment 1 Preparation of sitafloxacin raw material

[0035] The sitafloxacin raw material is prepared according to the method disclosed in the literature [J.Med.Chem.1994, 37, 3344-3352], that is, 5.6 g of ethyl 3-chloro-2,4,5-trifluoro-benzoylacetate , condensed with 15g triethyl orthoformate to generate 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)ethyl acrylate, and the solvent was evaporated under reduced pressure for direct use in the following One step, then react with 2.25g (1R,2S)-2-fluoro-cyclopropylamine hydrochloride to synthesize 8-chloro-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl ]-4-oxo-1,4-dihydroxyquinoline-3-carboxylic acid ethyl ester 5.5g, two-step yield 75%, take 3.65g of the solid from the previous step and then cyclize to generate 8-chloro-6,7 -Difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-4-oxo-1,4-dihydroxyquinoline-3-carboxylic acid 3.2g, yield 92.5%, and then passed Hydrochloric acid hydrolysis gives 7-[7-(s)-tert-butoxycarbonyl-5-azaspiro[2,4]...

Embodiment 2

[0036] Example 2 Preparation of new crystal form of sitafloxacin

[0037] Take 0.5 g of the crude anhydrous sitafloxacin prepared in Example 1, dissolve it in 25 ml of methanol solution, heat to dissolve at 50° C., place the solution at room temperature, slowly evaporate the solvent, and crystallize to obtain 0.35 g of needle-like crystals. The X-ray powder diffraction spectrum of gained new crystal form product, differential scanning calorimetry (DSC) collection of illustrative plates and the molecular space three-dimensional structure figure obtained by single crystal diffraction are respectively as follows figure 1 , figure 2 , image 3As shown, the single crystal diffractometer uses Mo-kα as the radiation source to measure, and the results of crystallographic parameters are as follows:

[0038]

[0039]

Embodiment 3

[0040] Example 3 Preparation of new crystal form of sitafloxacin

[0041] Take 0.4 g of the anhydrous sitafloxacin crude product prepared in Example 1, dissolve it in 35 ml of methanol solution, heat to dissolve at 40° C., place the solution at room temperature, slowly evaporate the solvent, and crystallize to obtain 0.27 g of needle-like crystals.

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Abstract

The invention discloses a novel sitafloxacin crystal form and a preparation method thereof. Peaks appear in an X-ray powder diffraction spectrum of the novel crystal form when the angle 2theta is at 10. 6 degrees, 11.4 degrees, 21.7 degrees and 24.6 degrees; and in a differential thermal analysis spectrum of the novel crystal form, the endothermic peak appears at 126.2 DEG C and the exothermic peak of the novel crystal form is at 152.9 DEG C. The novel crystal form disclosed by the invention is used for solving the problem that the absolute configuration of sitafloxacin medicinal hydrate is difficult to determine in the prior art. The preparation method of the novel sitafloxacin crystal form is simple to operate, and the crystal form prepared by the method is stable, and residue solvent risk is avoided; therefore, the preparation method is very suitable for large-scale industrial production.

Description

technical field [0001] The invention belongs to the field of medical inventions, and in particular relates to a new crystal form of sitafloxacin and a preparation method thereof. Background technique [0002] Sitafloxacin (sitafloxacin), the chemical name is 7-[(7S)-amino-5-azaspiro[2.4]hept-5-yl]-8-chloro-6-fluoro-1-[(1R,2S )-cis-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid is a fluoroquinolone antibacterial drug developed by Japan’s Daiichi Pharmaceutical Company, which is clinically used 3 / 2 hydrate. Sitafloxacin is a new oral N-1-fluorocyclopropyl new quinolone antibacterial drug with broad-spectrum antibacterial activity, which is effective against aerobic or anaerobic Gram-positive bacteria and Gram-negative bacteria, and Chlamydia have broad-spectrum antibacterial effect. [0003] In the biological world, the importance of stereochemistry has been elucidated in many ways. After a chiral drug enters the organism, its pharmacological effects ar...

Claims

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Application Information

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IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 许文杰邱雪辉华怀杰谭颂德郑加林肖尚志
Owner SHENZHEN SALUBRIS PHARMA CO LTD
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