Novel torasemide impurity and preparation method thereof

A technology of torasemide and impurities, which is applied in the field of new impurities of torasemide and its preparation, and can solve problems such as the difficulty of complete removal of impurities, the influence of drug safety and effectiveness, etc.

Pending Publication Date: 2021-11-09
南京恒正药物研究院有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0016] The synthesis of torasemide raw material medicine will produce various side reaction impurities during the multi-step chemical reaction process. Some impurities are easy to produce and are not easy to completely remove in the existing production process. The

Method used

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  • Novel torasemide impurity and preparation method thereof
  • Novel torasemide impurity and preparation method thereof
  • Novel torasemide impurity and preparation method thereof

Examples

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Effect test

Embodiment 1

[0029] Embodiment 1: Preparation of TL-Imp07 intermediate

[0030] Condensation reaction of 4-chloro-3-pyridine sulfonamide with 4-chloro-3-pyridine sulfonyl chloride and ammoniation reaction with m-toluidine to obtain crude product separated by column chromatography to obtain pure impurity product

[0031] Add 4-chloro-3-pyridinesulfonamide (20g), 4-chloro-3-pyridinesulfonyl chloride hydrochloride (28g) and dichloromethane (200ml) into a 500ml round bottom flask and start stirring, then add potassium carbonate (30g), continue to stir at room temperature for about 4~5h, filter, add 100ml of water to the filtrate, separate the liquid, extract the organic phase with water twice, dry with anhydrous sodium sulfate and concentrate to dryness to obtain the TL-Imp07 intermediate.

Embodiment 2

[0032] Embodiment 2: Preparation of TL-Imp07

[0033] Add the TL-Imp07 intermediate obtained above, m-toluidine (30g) and N,N-dimethylformamide (200ml) into a 500ml round bottom flask, start stirring, add potassium carbonate (40g) and heat to 80°C Then continue to react for about 24h, cool down to room temperature and concentrate to dryness. The obtained crude product is dissolved in methanol (30ml) and added with silica gel (20g) and then concentrated to dryness. TL-Imp07 (9.65 g, HPLC purity 97.1%) was obtained by analysis.

Embodiment 3

[0034] Embodiment 3: the preparation of TL-Imp07 intermediate

[0035] Condensation reaction of 4-chloro-3-pyridine sulfonamide with 4-chloro-3-pyridine sulfonyl chloride and ammoniation reaction with m-toluidine to obtain crude product separated by column chromatography to obtain pure impurity product

[0036] Add 4-chloro-3-pyridinesulfonamide (20g), 4-chloro-3-pyridinesulfonyl chloride hydrochloride (28g) and dichloromethane (200ml) into a 500ml round bottom flask and start stirring, then add triethyl Amine (20ml), continue to stir at room temperature for about 4~5h, filter, add 100ml of water to the filtrate, separate the liquid, extract the organic phase with water twice, dry with anhydrous sodium sulfate and concentrate to dryness to obtain the TL-Imp07 intermediate.

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Abstract

The invention relates to a novel torasemide impurity and a preparation method thereof. The invention relates to a novel torasemide impurity, namely TL-Imp07: 4-m-toluene amino-N-[(4-m-toluene aminopyridine-3-yl) sulfonyl] pyridine-3-sulfonamide. The preparation method of the TL-Imp07 comprises the steps of carrying out condensation and ammoniation reactions on 4-chloro-3-pyridine sulfonamide. The impurity is novel in structure, is reported for the first time and has great significance on quality control of torasemide crude drugs and preparations. Meanwhile, the preparation method has the advantages of being simple, convenient to operate, high in product purity and the like and can be applied to research of impurity reference substances of torasemide.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a new torasemide impurity and a preparation method thereof. Background technique [0002] Torsemide is a new generation of high-efficiency loop diuretics, which was launched in Germany in 1993 and in the United States in the following year. More than 20 years of clinical application have proved that torasemide has a wide range of indications, rapid, powerful and long-lasting diuretic effect, low incidence of adverse reactions, and more in line with the requirements of pharmacoeconomics. It is a class of high-efficiency diuretics worth promoting in clinical practice. [0003] The structural formula of torasemide is as follows: [0004] [0005] The relevant impurities of torasemide reported in current literature and data mainly include: EP impurities A~E, and their structural formulas are as follows: [0006] EP impurity A, chemical name: 4-(3-methylphenyl)-2H-p...

Claims

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Application Information

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IPC IPC(8): C07D213/74
CPCC07D213/74
Inventor 杨鑫徐卓业
Owner 南京恒正药物研究院有限公司
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