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N-3-aramid-5-cyclopropane spiro hydantoin derivative, preparation method and application thereof

A spirohydantoin and cyclopropane technology, applied in the field of N-3-arylamide-5-cyclopropane spirohydantoin derivatives and their preparation and application, can solve cognitive dysfunction, serious Allergic reactions, adverse reactions and other problems, to achieve the effect of simple preparation method and high yield

Inactive Publication Date: 2012-02-15
SYNCOM CHINA CO LTD WUHAN
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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-aramid-5-cyclopropane spiro hydantoin derivative, preparation method and application thereof
  • N-3-aramid-5-cyclopropane spiro hydantoin derivative, preparation method and application thereof
  • N-3-aramid-5-cyclopropane spiro hydantoin derivative, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Embodiment 1: 1-isocyanate-2, the synthesis of ethyl 2-dimethylcyclopropanecarboxylate

[0023] Dissolve ethyl 1-carboxy-2,2-dimethylcyclopropanecarboxylate (10mmol) in anhydrous tetrahydrofuran (30mL), cool in an ice-salt bath to about -15°C, and then add ethyl chloroformate (10mmol ) and N-methylpyrrolidone (NMM), immediately produced a white precipitate. At this temperature, after stirring the mixture for 20 minutes, the NaN 3 (10 mmol) in 5 mL of aqueous solution was added to the reaction solution, and stirring was continued for 1 hour. 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 (2×10mL), washed with anhydrous Na 2 SO 4 Let dry overnight. After filtration, the solvent was evaporated 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 tra...

Embodiment 2

[0026] Embodiment 2: 1-isocyanate-2, the synthesis of ethyl 2-dimethylcyclopropanecarboxylate

[0027] 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. After stirring the mixture for 30 minutes at this temperature, the NaN 3 (40 mmol) in 5 mL of aqueous solution was added to the reaction solution, and stirring was continued for 1 hour. 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 (2×10mL), washed with anhydrous Na 2 SO 4 Let dry overnight. After filtration, the solvent was evaporated 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 trans...

Embodiment 20

[0044] Example 20: Synthesis of 1,1-dimethyl-6-benzamide-4,6-diazaspiro[2.4]heptane-5,7-dione

[0045] Dissolve ethyl 2,2-dimethyl-1-benzohydrazide carboxamide cyclopropanecarboxylate (1 mmol) obtained in Example 1 in absolute ethanol (10 mL), then add metal Na, react at 5°C, TLC monitoring, after the completion of the reaction, 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. Filtrate, evaporate the solvent under reduced pressure, and separate by silica gel column chromatography to obtain the compound 1,1-dimethyl-6-benzamide-4,6-diazaspiro[2.4]heptane-5,7-dione.

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Abstract

The invention relates to an N-3-aramid-5-cyclopropane spiro hydantoin derivative which has a structural formula described in the specification, wherein R1 is phenyl, substituted phenyl and heterocycle aryl. A preparation method comprises the steps of: reacting 1-carboxyl-2,2-dimethylcyclopropane carboxylic ethyl ester with ethyl chloroformate to generate 1-acid azide-2,2-dimethylcyclopropane carboxylic ethyl ester under the action of NaN3; carrying out Curtius rearrangement on the 1-acid azide-2,2-dimethylcyclopropane carboxylic ethyl ester to generate isocyanate, reacting the isocyanate witharylacethydrazide to obtain N'-aramid substituted carbamido cyclopropane; and then carrying out cyclization on the N'-aramid substituted carbamido cyclopropane under the alkaling condition to generate the N-3-aramid-5-cyclopropane spiro hydantoin derivative. The compound has relatively good convulsions resisting activity, simple preparation method and higher yield.

Description

technical field [0001] The invention relates to a hydantoin derivative, 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 application abroad are: zonisamide, oxcarbazepine, lamotrigine, felbam...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/12C07D409/12A61K31/4184A61K31/4439C07D235/02A61P25/08C07D401/12
Inventor 胡先明贺贤然
Owner SYNCOM CHINA CO LTD WUHAN
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