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Certain crystalline hydrates,pharmaceutical compositions thereof and methods for preparation and use thereof

A technology of crystalline hydrates and hydrates, which is applied in the direction of drug combinations, pharmaceutical formulations, antibacterial drugs, etc., and can solve problems such as unpredictable properties and no discovery

Active Publication Date: 2011-11-23
深圳沃克锂科技有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it is very challenging to develop a method for the preparation, screening and characterization of salts suitable for clinical application.
For example, (S)-N-3-(3'-fluoro-4'-(4"-phenylpiperazinyl))phenyl-2-oxo-5-oxazolidinyl]methyl Conditions for the salt formation of acetamide or its crystalline hydrate, and its properties after salt formation are also unpredictable

Method used

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  • Certain crystalline hydrates,pharmaceutical compositions thereof and methods for preparation and use thereof
  • Certain crystalline hydrates,pharmaceutical compositions thereof and methods for preparation and use thereof
  • Certain crystalline hydrates,pharmaceutical compositions thereof and methods for preparation and use thereof

Examples

Experimental program
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preparation example Construction

[0093] In some embodiments, (S)-[N-3-(3'-fluoro-4'-(4"-phenylpiperazinyl))phenyl-2-oxo-5-oxazolidinyl] The preparation method of methyl acetamide 1 / 2 crystalline hydrate comprises:

[0094] - (S)-[N-3-(3'-fluoro-4'-(4"-phenylpiperazinyl))phenyl-2-oxo-5-oxazolidinyl]methylacetamide Dissolved in an acidic solvent with a pH value≤5 or in a mixed solvent comprising at least one non-acidic organic solvent and at least one acidic solvent with a pH value≤5 to form (S)-[N-3-(3'-fluoro-4 '-(4"-phenylpiperazinyl))phenyl-2-oxo-5-oxazolidinyl]methylacetamide solution;

[0095] Wherein at least one acidic solvent and at least one non-acidic organic solvent are mixed in an appropriate volume ratio, such as 1:9 to 9:1, further such as 2:8 to 8:2 or 3:7 to 7:3 by volume than mixed;

[0096] - Stir the solution at an appropriate temperature, such as 35°C to 80°C, further such as 35°C to 70°C, further such as 35°C to 60°C, for a certain period of time, such as stirring for at least 1 hour, s...

example 1

[0174] Example 1: (S)-[N-3-(3′-fluoro-4′-(4″-phenylpiperazinyl))phenyl-2-oxo-5-oxazolidinyl]methylethyl Preparation of amides (crude)

[0175] (S)-[N-3-(3′-fluoro-4′-(4″-phenylpiperazinyl))phenyl-2-oxo-5-oxazolidinyl]methylacetamide (crude ) can generally be synthesized by the method disclosed in CN1355165A.

[0176] (1) Preparation of 3-fluoro-4-(4'-phenylpiperazinyl)nitrobenzene

[0177] Add 50ml of ethyl acetate, 13.5ml of 4-phenylpiperazine and 15.30ml of diisopropylethylamine into a 250ml three-necked flask. With magnetic stirring at room temperature, 9.0 ml of 3,4-difluoronitrobenzene was added. After reacting for 105 hours, the reaction solution was poured into water, extracted 3 times with ethyl acetate (150ml×3), the extract was washed 3 times with saturated sodium chloride solution (150ml×3), and anhydrous magnesium sulfate (MgSO 4 ) was dried and evaporated to dryness. An orange-yellow solid was obtained. Acetone:water (volume ratio 9:1) was recrystallized to ...

example 2

[0195] Example 2: (S)-[N-3-(3′-fluoro-4′-(4″-phenylpiperazinyl))phenyl-2-oxo-5-oxazolidinyl]methylethyl Preparation of Amide 1 / 2 Hydrate

[0196] (S)-[N-3-(3'-fluoro-4'-(4"-phenylpiperazinyl))phenyl-2-oxo-5-oxazolidine prepared by the method described in Example 1 Base] methyl acetamide crude product 1g joins in the 6wt% hydrochloric acid of 2ml.Add a small amount of gac, heat and stir at 50 ℃ for 2 hours, filter.Filtrate is placed crystallization at room temperature, and gained crystal is vacuum-dried at 40 ℃ for 5 hours. Content measured by HPLC: 99.0%.Melting point: 210-215°C (capillary measurement).

[0197] Figure 7-13 For the obtained (S)-[N-3-(3'-fluoro-4'-(4"-phenylpiperazinyl))phenyl-2-oxo-5-oxazolidinyl]methylacetamide Hydrate X-ray diffraction pattern, TGA, 1 H-NMR, 13 C-NMR, IR and DSC thermal analysis spectra.

[0198] X-ray powder diffraction measurement conditions are: CuKa rays, 1.54 monochromator, tube voltage 40KV, tube current 25mA. In the X-ray powd...

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Abstract

Provided is at least one crystalline hydrate of (S)-[N-3-(3'-fluoro-4'-(4''-phenyl piperazinyl)) phenyl-2-oxo-5-oxazolidinyl] methyl acetamide, such as those with the following formula, wherein y is a number ranging from 1 / 12 to 1. Also provided are methods for the preparation of such crystalline hydrates, pharmaceutical compositions comprising such crystalline hydrates, and methods for their uses.

Description

[0001] This application claims priority to US Provisional Patent Application Serial No. 61 / 257,924, filed November 4, 2009, entitled "Crystalline Hemihydrate, Pharmaceutical Compositions and Methods of Preparation and Use Thereof." technical field [0002] The present invention provides crystals of [N-3-(3'-fluoro-4'-(4"-phenylpiperazinyl))phenyl-2-oxo-5-oxazolidinyl]methylacetamide Hydrates, especially (S)-[N-3-(3′-fluoro-4′-(4″-phenylpiperazinyl))phenyl-2-oxo-5-oxazolidinyl]methanol Crystalline hydrate of acetamide, pharmaceutical composition, preparation method and use thereof. Background technique [0003] Currently, finding an effective treatment for infections caused by multidrug-resistant Gram-positive bacteria is extremely challenging due to the limited number of effective antimicrobial agents. In addition, the drug resistance mechanism of pathogenic bacteria is also constantly evolving, which increases the difficulty of clinical treatment. Therefore, there is a cl...

Claims

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Application Information

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IPC IPC(8): C07D263/22A61K31/21A61P31/00A61P31/04
CPCA61K31/496C07D263/22A61P31/00A61P31/04A61K31/497C07D413/10
Inventor 阙峰王莹
Owner 深圳沃克锂科技有限责任公司
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