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A kind of flumazenil compound and its preparation method

A flumazenil and compound technology, applied in the field of flumazenil compounds and preparation methods thereof, can solve problems such as difficulty in obtaining high-purity and high-yield flumazenil compounds, reduce toxic and side effects, improve product quality, improve reaction simple steps

Inactive Publication Date: 2011-12-07
HAINAN MEILAN SMITH KLINE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] On the basis of a large number of existing documents, the applicant, through a large number of screening experiments, found that the above-mentioned documents and general purification and separation methods such as crystallization are difficult to obtain the flumazenil compound with high purity and high yield. The inventor has worked hard for a long time Research, surprisingly found a kind of preparation method of flumazenil compound, thus completed the present invention

Method used

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  • A kind of flumazenil compound and its preparation method
  • A kind of flumazenil compound and its preparation method
  • A kind of flumazenil compound and its preparation method

Examples

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Embodiment 1

[0035] The purification of embodiment 1 flumazenil

[0036] (1) Disperse 100g of flumazenil crude product with a purity of 98.24% in 500ml of water, add 200ml of sodium hydroxide solution with a mass percentage of about 6% as a catalyst, heat to 45°C, stir and react for 2 hours, and adjust the pH to 5.5, extracted with 500ml of diethyl ether, dried with a solid desiccant, filtered, added 0.5g of activated carbon, kept at 40°C for 30 minutes, stirred and adsorbed, decarburized by filtration, distilled off under reduced pressure to remove diethyl ether to obtain 83.15g of intermediate (II);

[0037] (2) Add 16.8g of ethanol to the intermediate (II), then add 2.6g of copper chloride (CuCl 2 2H 2 O) as catalyzer, 26ml hexanaphthene is used as water-carrying agent, under stirring heating reflux, stop reaction when no water comes out in water separator, filter out insoluble matter, filtrate is dried with activated alumina again, removes diethyl ether by distillation under reduced p...

Embodiment 2

[0038] The purification of embodiment 2 flumazenil

[0039] (1) Disperse 100g of flumazenil crude product with a purity of 98.24% in 500ml of water, add 200ml of sodium hydroxide solution with a mass percentage of about 6% as a catalyst, heat to 55°C, stir and react for 2 hours, and adjust the pH to 6.0, extracted with 500ml of diethyl ether, dried with a solid desiccant, filtered, added 2.5g of activated carbon, kept at 45°C for 30 minutes, stirred and adsorbed, decarburized by filtration, distilled off under reduced pressure to obtain 83.24g of intermediate (II);

[0040](2) Add 18.8g of ethanol to the intermediate (II), then add 3.9g of copper chloride (CuCl 2 2H 2 O) as catalyzer, 29ml hexanaphthene is used as water-carrying agent, under stirring heating reflux, stop reaction when no water comes out in water trap, filter out insoluble matter, filtrate is dried with activated alumina again, diethyl ether is removed by distillation under reduced pressure, After vacuum dryi...

Embodiment 3

[0041] The purification of embodiment 3 flumazenil

[0042] (1) Disperse 100g of flumazenil crude product with a purity of 98.24% in 500ml of water, add 200ml of sodium hydroxide solution with a mass percentage of about 6% as a catalyst, heat to 60°C, stir and react for 2.5 hours, and adjust the pH to 6.5, extracted with 500ml of diethyl ether, dried with solid desiccant, filtered, added 1g of activated carbon, kept at 50°C for 30 minutes, stirred and adsorbed, decarburized by filtration, and the organic solvent was distilled off under reduced pressure to obtain 81.68g of intermediate (II);

[0043] (2) Add 20.5g ethanol to intermediate (II), then add 5.1g copper chloride (CuCl 2 2H 2 O) as catalyzer, 32ml hexanaphthene is as water-carrying agent, reflux under heating under agitation, stop reaction when anhydrous goes out in water separator, filter out insoluble matter, filtrate is dried with activated alumina again, diethyl ether is removed by distillation under reduced pres...

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Abstract

The invention provides a preparation method of a flumazenil compound, and the preparation method comprises the following steps of: carrying out hydrolysis reaction to obtain a flumazenil precursor intermediate, purifying the flumazenil precursor intermediate by activated carbon adsorption, and then carrying out esterification reaction to obtain flumazenil. The preparation method provided by the invention has the advantages of simple reaction steps, high product yield, high product purity and low cost, and is suitable for industrial mass production; and the quality of a preparation product prepared by the method is improved, and the toxic and side effects of the flumazenil compound used as benzodiazepine selective antagonist drugs can be reduced.

Description

technical field [0001] The invention relates to a flumazenil compound and a preparation method thereof, belonging to the technical field of medicine. Background technique [0002] Flumazenil, chemical name: 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazole (1,5-α)(1,4)benzo Ethyl diaza-3-carboxylate, molecular formula: C 15 h 14 FN 3 o 3 , molecular weight: 303.29, structural formula: [0003] [0004] Flumazenil is a selective antagonist of benzodiazepines (BDZ), which can act on brain BDZ receptors and block receptors without producing the effect of BDZ drugs. Pharmacological experiments show that flumazenil can reverse the effects of BDZ and non-BDZ drugs with affinity to the central nervous system BDZ receptor, and can also antagonize the anticonvulsant effect of sodium valproate. Antipsychotic drugs can often increase the level of prolactin in the body, while BDZ tranquilizers can reduce it, and flumazenil can antagonize this effect of reducing prolactin, which ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04A61P25/28A61K49/00
Inventor 杨明贵
Owner HAINAN MEILAN SMITH KLINE PHARMA
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