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Nitroimidazole derivative, preparation method and application thereof

A technology of nitroimidazoles and nitroimidazoles, which is applied in the field of nitroimidazole derivatives and their preparation, and can solve the problems of increased degree of degradation, unsafety, and high toxicity of degradation products 2-methyl-5-nitroimidazole , to extend the validity period

Pending Publication Date: 2021-05-11
HC SYNTHETIC PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Levo-ornidazole is the left-handed isomer of ornidazole. Chinese patents CN200510068478.9 and CN200510083517.2 describe its poor water solubility and low melting point. It requires strong acidity when made into infusion preparations, and patients are prone to phlebitis when taking medicine. ; and the toxic degradation product 2-methyl-5-nitroimidazole is higher during high-temperature sterilization of infusion, which brings great unsafeness to clinical medication
[0005] The prior art discloses levonidazole phosphate and its pharmaceutical salts, which greatly increase water solubility, but impurities will be produced during the placement process, and the degree of degradation will increase as the temperature increases, and the toxicity of the degraded impurities is unknown. Great impact in clinical use

Method used

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  • Nitroimidazole derivative, preparation method and application thereof
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  • Nitroimidazole derivative, preparation method and application thereof

Examples

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Embodiment 1

[0040] Embodiment 1: the preparation of nitroimidazole compound II

[0041] Add 139.4g of formic acid and 13.3g of concentrated sulfuric acid into the reaction flask, start stirring, then add 40.0g of 2-methyl-5-nitroimidazole. The temperature of the reaction solution was controlled at 0°C to 5°C, and 89.8 g of S-(+)-epichlorohydrin was added dropwise. After the dropwise addition was completed, the temperature was raised to 5° C. to 10° C. and the reaction was stirred for 35 hours, and then the reaction was stopped. Raise the temperature to 85°C-95°C and concentrate under reduced pressure until no liquid flows out from the reflux tube, then stop the concentration. Add 190 g of purified water to the concentrated residue, lower the temperature to 0° C. to 5° C., and then add ammonia water dropwise to adjust the pH to 3 to 4. After the pH is stable, continue stirring for 2 hours. Shake the filter, discard the filter cake, and pump the filtrate into a 100mL reaction flask. The ...

Embodiment 2

[0043] Embodiment 2: the preparation of nitroimidazole compound II

[0044] Add 100ml of acetonitrile, 17g of phosphorus oxychloride and 50g of levonidazole into the reaction flask. Start stirring, heat up to reflux for 4-8 hours, after the reaction, concentrate under reduced pressure until there is no drop, put the residue in a chromatography column, and use dichloromethane:methanol (2:1) for elution, and the elution ends Afterwards, the target eluate was concentrated to 1 / 3 of the total volume, cooled to -5°C to 0°C, and crystallized for 8 to 12 hours. Filtrate, put the filter cake in a blast drying oven, control the temperature at 20°C to 30°C, and dry for 2 to 4 hours to obtain 40.3g of nitroimidazole compound II with a yield of 80.6%.

Embodiment 3

[0045] Embodiment 3: Preparation of nitroimidazole compound II racemate

[0046] Add 100ml of acetonitrile, 17g of phosphorus oxychloride and 50g of ornidazole into the reaction flask. Start stirring, heat up to reflux for 4-8 hours, after the reaction, concentrate under reduced pressure until there is no drop, put the residue in a chromatography column, and use dichloromethane:methanol (2:1) for elution, and the elution ends Afterwards, the target eluate was concentrated to 1 / 3 of the total volume, cooled to -5°C to 0°C, and crystallized for 8 to 12 hours. Filtrate, put the filter cake in a blast drying oven, control the temperature at 20°C to 30°C, and dry for 2 to 4 hours to obtain 43.5 g of racemate of nitroimidazole compound II, with a yield of 87.0%.

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Abstract

The invention provides a nitroimidazole derivative as shown in a general formula I or a pharmaceutically acceptable salt, a solvent compound, a hydrate, a polymorphic substance, a deuterated substance and an isomer thereof. The invention also provides a pharmaceutical composition containing the compound and application of the pharmaceutical composition. The nitroimidazole derivative provided by the invention has excellent pharmacokinetic properties, and also has excellent antibacterial activity.

Description

Technical field: [0001] The invention relates to a nitroimidazole derivative and its preparation method and application, and further relates to a nitroimidazole derivative for resisting anaerobic bacteria and antiprotozoal infection, its preparation method and application. [0002] technical background: [0003] Ornidazole is a nitroimidazole derivative, which is a powerful anti-anaerobic bacteria and anti-protozoal infection drug. Wide third-generation nitroimidazole derivatives. The antimicrobial effect of ornidazole is through the reduction of the nitro group in its molecular formula to an amino group in an oxygen-free environment or through the interaction with cell components in the form of free radicals, resulting in the death of microorganisms. [0004] Levo-ornidazole is the left-handed isomer of ornidazole. Chinese patents CN200510068478.9 and CN200510083517.2 describe its poor water solubility and low melting point. It requires strong acidity when made into infusio...

Claims

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Application Information

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IPC IPC(8): C07F9/6506A61K31/675A61P31/04A61P33/02
CPCC07F9/6506A61P31/04A61P33/02
Inventor 杨成刘晓鹏张起愿
Owner HC SYNTHETIC PHARMA CO LTD
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