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N-3-arylamine-5-cyclopropane spirohydantoin and preparation method and application thereof

A spirohydantoin, N-3- technology, applied in pharmaceutical formulations, medical preparations containing active ingredients, organic active ingredients, etc., can solve cognitive dysfunction, severe allergic reactions, adverse reactions, etc. problem, to achieve the effect of a simple preparation method

Inactive Publication Date: 2013-09-18
JIANGHAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the new antiepileptic drugs have partially improved the shortcomings of some antiepileptic drugs, most of the new drugs can still be accompanied by some special adverse reactions, such as cognitive dysfunction, acute eye symptoms, severe allergic reactions, etc.

Method used

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  • N-3-arylamine-5-cyclopropane spirohydantoin and preparation method and application thereof
  • N-3-arylamine-5-cyclopropane spirohydantoin and preparation method and application thereof
  • N-3-arylamine-5-cyclopropane spirohydantoin and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] Embodiment 1: Synthesis of ethyl 1-isocyanate-2,2-dimethylcyclopropanecarboxylate

[0033] Dissolve ethyl 1-carboxy-2,2-dimethylcyclopropanecarboxylate (10mmol) in anhydrous tetrahydrofuran (30mL), cool in an ice-salt bath to about -10°C, and then add ethyl chloroformate (10mmol ) and N-methylpyrrolidone (NMM), immediately produced a white precipitate. At this temperature, after the mixture continued to stir for 20 min, the NaN 3 (10mmol) of 5mL aqueous solution was added to the reaction solution, and stirring was continued for 1h. After the reaction was completed, a small amount of water was added to dissolve the insoluble matter, extracted with ethyl acetate, washed with saturated brine (3×10mL), washed with anhydrous Na 2 SO 4 Let dry overnight. Filter and distill off the solvent under reduced pressure to obtain a light yellow liquid (note: compounds containing azide are explosive and cannot be evaporated to dryness). This crude product is transferred on the sil...

Embodiment 2

[0036] Embodiment 2: Synthesis of ethyl 1-isocyanate-2,2-dimethylcyclopropanecarboxylate

[0037] Dissolve ethyl 1-carboxy-2,2-dimethylcyclopropanecarboxylate (10mmol) in anhydrous tetrahydrofuran (30mL), cool in an ice-salt bath to about -5°C, and then add ethyl chloroformate (30mmol ) and N-methylpyrrolidone (NMM), immediately produced a white precipitate. At this temperature, after the mixture was stirred for 30 min, the NaN 3 (40mmol) of 5mL aqueous solution was added to the reaction solution, and stirring was continued for 1h. After the reaction was completed, a small amount of water was added to dissolve the insoluble matter, extracted with ethyl acetate, washed with saturated brine (3×10mL), washed with anhydrous Na 2 SO 4 Let dry overnight. Filter and distill off the solvent under reduced pressure to obtain a light yellow liquid (note: compounds containing azide are explosive and cannot be evaporated to dryness). This crude product is transferred on the silica gel...

Embodiment 15

[0055] Example 15: Synthesis of 1,1-dimethyl-6-aniline-4,6-diazaspiro[2.4]heptane-5,7-dione

[0056] Dissolve ethyl 2,2-dimethyl-1-phenylhydrazine carboxamide cyclopropanecarboxylate (1mmol) obtained in Example 1 in absolute ethanol (10mL), then add metal Na, react at 5°C, and monitor by TLC , after the reaction was completed, the ethanol was evaporated under reduced pressure, the residue was added a small amount of water, extracted with ethyl acetate (3×20mL), the organic layer was collected, washed with saturated brine, anhydrous Na 2 SO 4 Let dry overnight. After filtration, the solvent was evaporated under reduced pressure and separated by silica gel column chromatography to obtain the compound 1,1-dimethyl-6-aniline-4,6-diazaspiro[2.4]heptane-5,7-dione.

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Abstract

The invention discloses N-3-arylamine-5-cyclopropane spirohydantoin and a preparation method and application thereof. The structural general formula of the N-3-arylamine substituent-5-cyclopropane spirohydantoin is shown in the specification, wherein R1 is phenyl, substituted phenyl and heterocyclic arene. The preparation method comprises the following steps of: performing a reaction between 1-carboxyl-2,2-dimethylcyclopropane ethyl carboxylate and ethyl chloroformate to generate 1-acyl azide-2,2-dimethylcyclopropane ethyl carboxylate under the effect of NaN3; performing Curtius rearrangement on the 1-acyl azide-2,2-dimethylcyclopropane ethyl carboxylate to generate corresponding isocyanate; performing a reaction between the isocyanate and hydrazine to obtain N'-arylamine substituent ureidocyclopropane; and generating N-3-arylamine substituent-5-cyclopropane spirohydantoin from the N'-arylamine substituent ureidocyclopropane. The preparation method disclosed by the invention is simple, has higher yield, and can be used for easily preparing the N-3-arylamine substituent-5-cyclopropane spirohydantoin.

Description

technical field [0001] The invention relates to a 5-substituted hydantoin, specifically an N-3-arylamine-5-cyclopropane spirohydantoin and a preparation method and application thereof. Background technique [0002] Hydantoin, also known as hydantoin, has attracted widespread attention since its discovery in 1861. Some hydantoin derivatives have unique pharmacological activities and are widely used in medicine. Among them, a representative one is phenytoin sodium, chemical name 5-ethyl-5-phenylhydantoin, which is a common drug for treating epilepsy. However, it has been clinically found that long-term use of phenytoin sodium can cause gingival hyperplasia, with large side effects. [0003] Since the 1980s, with the in-depth study of the pathogenesis of epilepsy, the mechanism of action of antiepileptic drugs has been clarified, and some new antiepileptic drugs have been designed on this basis. At present, the new antiepileptic drugs that have been approved for clinical app...

Claims

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Application Information

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IPC IPC(8): C07D235/02C07D409/12C07D405/12A61K31/4184A61P25/08
Inventor 贺贤然钟敏
Owner JIANGHAN UNIVERSITY
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