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5-cyclopropane toroid hydantoin derivatives as well as preparation method and uses thereof

A technology of spirohydantoin and cyclopropane, which is applied in the field of 5-cyclopropane spirohydantoin derivatives and their preparation and application, can solve the problems of large side effects, gingival hyperplasia, etc., and achieve simple preparation method, The effect of high yield

Inactive Publication Date: 2008-09-03
SYNCOM CHINA CO LTD WUHAN
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it has been clinically found that long-term use of phenytoin sodium can cause gingival hyperplasia, with large side effects.

Method used

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  • 5-cyclopropane toroid hydantoin derivatives as well as preparation method and uses thereof
  • 5-cyclopropane toroid hydantoin derivatives as well as preparation method and uses thereof
  • 5-cyclopropane toroid hydantoin derivatives as well as preparation method and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

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

[0023] Dissolve ethyl 1-carboxy-2,2-dimethylcyclopropanecarboxylate 1 (10mmol) in anhydrous tetrahydrofuran (30mL), cool in an ice-salt bath to below 0°C to -20°C, and then add chloroformic acid in sequence Ethyl ester and triethylamine or N-methylpyrrolidone (NMM), immediately produced a white precipitate. At this temperature, after stirring the mixture for 20 minutes, the NaN 3 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 t...

Embodiment 2

[0024] Example 2: Synthesis of 2,2-dimethyl-1-ureidocyclopropanecarboxylic acid ethyl ester (compound 3a)

[0025] At room temperature, all the colorless thick liquid (compound 2) obtained in Example 1 was dissolved in tetrahydrofuran (30 mL), 28%-30% ammonia water (about 8 mmol) was dissolved in a small amount of tetrahydrofuran, and then added to the above compound 2 in tetrahydrofuran solution, reacted for 15 minutes, evaporated the solvent under reduced pressure, and performed column chromatography immediately to obtain compound 3a. The product is a white solid; Yield: 52%; Melting point: 127-129°C; IR(KBr): 3355(N-H), 1704(C=O), 1658(C=O), 1534, 1365, 1318cm -1 ; 1 H NMR (300MHz, CDCl 3 ): δ0.98(d, 1H, J=4.6Hz, Cpr-H), 1.20(s, 3H, -CH 3 ), 1.27(t, 3H, J=7.2Hz, -CH 3 ), 1.29 (s, 3H, -CH 3 ), 1.72(d, 1H, J=4.6Hz, Cpr-H), 4.19(q, 2H, J=7.2Hz, CH 2 ), 4.97-5.01 (m, 2H, NH), 5.62 (br s, 1H, NH); MS (m / z): 223[M+Na]; Anal.Calcd.forC 9 h 16 N 2 o 3 : C, 53.98; H, 8.05;...

Embodiment 3

[0026] Example 3: Synthesis of ethyl 2,2-dimethyl-1-[3-(4-methoxycarbonylphenyl)ureido)cyclopropanecarboxylate (compound 31)

[0027] At room temperature, all the colorless thick liquid (compound 2) obtained in Example 2 was dissolved in tetrahydrofuran (30 mL), p-methoxycarbonylaniline (8 mmol) was dissolved in tetrahydrofuran, and then added to the THF solution of the above compound 2 , reacted for 30 minutes, evaporated the solvent under reduced pressure, and immediately column chromatographed to obtain compound 31. White solid; Yield: 45%; Melting point: 159-161°C; IR(KBr): 3391(N-H), 1712(C=O), 1687(C=O), 1608, 1589, 1525, 1438, 1384cm -1 ; 1 H NMR (300MHz, DMSO-d 6 ): δ1.04(d, 1H, J=5.1Hz, Cpr-H), 1.23(s, 3H, -CH 3 ), 1.27 (s, 3H, -CH 3 ), 1.26(s, 3H, -CH 3 ), 1.83(d, 1H, J=5.1Hz, Cpr-H), 3.86(s, 3H, CH 3 ), 4.18-4.25 (m, 2H, CH 2 ), 7.36(d, 2H, Ar-H), 7.85(d, 2H, Ar-H); 13 C NMR (150MHz, DMSO-d 6 ): δ14.94, 20.27, 22.67, 27.28, 29.11, 42.86, 52.43, 61.13, 117.4...

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Abstract

The invention relates to 5-cyclopropane spirocyclic hydantoin derivates with a structural formula, whereinR1 in the formula represents hydrogen, alkyl group, benz or substituted benz. The preparation method comprises: reacting 1-carboxyl-2, 2-dimethyl carbethoxycyclopropane with ethyl chloroformate, generating 1-acid azide-2, 2- dimethyl carbethoxycyclopropane under the action of NaN3; generating corresponding isocyanate by curtius rearing 1-acid azide-2, 2- dimethyl carbethoxycyclopropane, wherein the isocyanate is reacted with primary amine, secondary amine or ammonia water to obtain N-substituted ureido cyclopropane which closes loop to generate 5-cyclopropane spirocyclic hydantoin derivates. The preparation method of the invention is simple, the yield is high, and 5-cyclopropane spirocyclic hydantoin derivates can be easy to prepare. The compounds of the invention have good anticonvulsant activity.

Description

technical field [0001] The invention relates to a 5-cyclopropane spirohydantoin derivative, a preparation method and application thereof, and an intermediate N'-substituted ureido cyclopropane of the 5-cyclopropane spirohydantoin derivative. Background technique [0002] Hydantoin, also known as hydantoin, ureidohydantoin, chemical name 2,4-imidazole dione, is a five-membered heterocyclic compound containing urea unit. 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. Contents of the invention [0003] The problem to be solved by the present invention is to provide 5-cyclopropane...

Claims

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Application Information

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IPC IPC(8): C07D233/74C07C275/16A61K31/4184A61P25/08
Inventor 胡先明朱齐凤
Owner SYNCOM CHINA CO LTD WUHAN
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