7-{(3S,4S)-3-[(cyclopropylamino)methyl]-4-fluoropyrrolidine-1-yl}-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid crystal

A technology of cyclopropylamino and fluoropyrrolidine, which is applied in the direction of organic active ingredients, organic chemistry, organic chemical methods, etc., can solve the problem that antibacterial agents are not very effective, and achieve the effect of improving solubility

Active Publication Date: 2014-07-16
KYORIN PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] Known compound (1) is not only safe and has strong antibacterial effect, but also shows strong antibacterial activity against Gram-positive bacteria, especial

Method used

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  • 7-{(3S,4S)-3-[(cyclopropylamino)methyl]-4-fluoropyrrolidine-1-yl}-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid crystal
  • 7-{(3S,4S)-3-[(cyclopropylamino)methyl]-4-fluoropyrrolidine-1-yl}-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid crystal
  • 7-{(3S,4S)-3-[(cyclopropylamino)methyl]-4-fluoropyrrolidine-1-yl}-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid crystal

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preparation example Construction

[0088] According to the method for preparing crystals A and B exemplified in the embodiments of the present invention, crystals A and B can be selectively prepared in an efficient manner. Therefore, these methods also contribute to the provision of crystals of salts of compound (1) useful as active pharmaceutical ingredients of medicaments.

[0089] Next, the present invention will be described in more detail by way of examples, but the present invention is not limited to these examples.

[0090] Melting points were measured using a Yanagimoto micro melting point apparatus MP-500D. The IR spectrum was measured using a Nicolet 6700 infrared spectrometer manufactured by Thermo Fisher Scientific K.K. The NMR spectrum was measured using a JNM-EX400 nuclear magnetic resonance apparatus manufactured by JEOL Ltd., using tetramethylsilane (TMS) as an internal standard. MS spectra were measured using JMS-T100LP and JMS-SX102A mass spectrometers manufactured by JEOL Ltd. Elemental an...

Embodiment 2

[0099] 7-{(3S,4S)-3-[(cyclopropylamino)methyl]-4-fluoropyrrolidin-1-yl}-6-fluoro-1-(2-fluoroethyl)-8-methyl Oxy-4-oxo-1,4-dihydroquinoline-3-carboxylate hydrochloride hydrate (crystal C)

[0100] Add 0.3 mL of hot water at 70°C to 0.02 g (0.04 mmol) of 7-{(3S,4S)-3-[(cyclopropylamino)methyl]-4-fluoropyrrolidine obtained in Example 1 -1-yl}-6-fluoro-1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid hydrochloride to dissolve Hydrochloride. The solution was cooled to room temperature and left overnight at 5°C. The precipitated crystals were filtered and dried under reduced pressure to give 7-{(3S,4S)-3-[(cyclopropylamino)methyl]-4-fluoropyrrolidin-1-yl}-6-fluoro - White powder of 1-(2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate hydrochloride hydrate (crystal C).

[0101] (Refer to Example 3)

[0102] 7-{(3S,4S)-3-[(cyclopropylamino)methyl]-4-fluoropyrrolidin-1-yl}-6-fluoro-1-(2-fluoroethyl)-8-methyl Oxy-4-oxo-1,4-dihydroquinoline-3...

Embodiment 1

[0123] 7-{(3S,4S)-3-[(cyclopropylamino)methyl]-4-fluoropyrrolidin-1-yl}-6-fluoro-1-(2-fluoroethyl)-8-methyl Oxy-4-oxo-1,4-dihydroquinoline-3-carboxylate hydrochloride (crystal A)

[0124] 9.57 kg of the crude 7-{(3S,4S)-3-[(cyclopropylamino)methyl]-4-fluoropyrrolidin-1-yl}-6-fluoro-1 obtained in Reference Example 1 -(2-Fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate hydrochloride was added to a solvent mixture of 60 L of ethanol and 10.8 L of purified water, and The mixture was heated to dissolve. The solution was filtered through a filter and washed with a solvent mixture of 24.0 L of ethanol and 1.20 L of purified water. After confirming the dissolution, 96.0 L of heated ethanol (99.5) was added to the solution at 71.2 to 72.6°C. After that, the resulting solution was cooled (warm water temperature setting: 60.0° C.). After the appearance of crystallization was observed (crystallization temperature: 61.5°C), the mixture was stirred at 59.4-61.5°C for 30 m...

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Abstract

The purpose of the present invention is to provide a hydrochloride crystal, a hydrochloride hydrate crystal, and a methanesulfonate crystal of the compound represented by formula (1). These crystals are less susceptible to decomposition caused by the effects of light, and also have high preservation stability and high water solubility compared to a free crystal of the compound (1).

Description

technical field [0001] The present invention relates to 7-{(3S,4S)-3-[(cyclopropylamino)methyl]-4-fluoropyrrolidin-1-yl}-6-fluoro-1-( Crystals of salt of 2-fluoroethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (hereinafter may be referred to as compound (1)) and methods for producing these crystals method. [0002] [chemical formula 1] [0003] Background technique [0004] Generally speaking, the requirements for pharmaceutical products include safety, quality, etc., as well as the curative effect on diseases. Therefore, compounds that are active ingredients of pharmaceutical products need to have high storage stability under various conditions (light, temperature, moderate, etc. have an influence on the compound). When the drug product is in the form of an oral formulation or an injection, it is preferred that the active ingredient contained in the drug product has a high solubility in water. [0005] Known compound (1) is not only safe and has strong ...

Claims

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Application Information

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IPC IPC(8): C07D401/04A61K31/4709A61P31/04
CPCC07D401/04A61K31/4709A61P31/04C07B2200/13
Inventor 荒谷一郎后藤晃范皆川渡船田惠子长尾宗树
Owner KYORIN PHARMA CO LTD
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