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1-hydroxy-2-ketopyrrolidine compound and preparation method and application thereof

A pyrrolidone and compound technology, applied in the field of medicinal chemistry, can solve the problems that calcium antagonistic activity has not been reported yet

Inactive Publication Date: 2012-06-13
THE KEY LAB OF CHEM FOR NATURAL PROD OF GUIZHOU PROVINCE & CHINESE ACADEMY OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, 1-hydroxy-2-pyrrolidones are different from 2-pyrrolidones, and the calcium antagonistic activity of these compounds has not been reported

Method used

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  • 1-hydroxy-2-ketopyrrolidine compound and preparation method and application thereof
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  • 1-hydroxy-2-ketopyrrolidine compound and preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0047] Embodiment 1: the synthesis of compound DL-41

[0048] Take 57mg (0.322mmol) of nickel chloride and dissolve it in a round bottom flask with methanol, add an ice bath, and slowly add 6mg (0.161mmol) of NaBH under magnetic stirring 4 , stirred at room temperature for 30 min, and added 54 mg (0.161 mmol) of γ-8 (trans) and 312 μL (6.5 mmol) of hydrazine hydrate. Reaction at room temperature for 3h (TLC detection of reaction progress). After the reaction was completed, the methanol was distilled off under reduced pressure, the residue was dispersed with water, extracted with ethyl acetate under acidic conditions, and the organic layer was washed with anhydrous MgSO 4 Dry, filter, and concentrate under reduced pressure, and the residue is subjected to silica gel column chromatography (10:1 → 5:1 chloroform-ethanol elution) to obtain 45mg DL-41 (trans 1-hydroxyl-4-p-chlorophenyl- 5-o-chlorobenzyl-2-pyrrolidone) (yield 83.4%).

[0049]

[0050] DL-41: Light red powder, ...

Embodiment 2

[0051] Embodiment 2: the synthesis of compound DL-42

[0052] Take 53mg (0.224mmol) of nickel chloride and dissolve it in a round bottom flask with methanol, add an ice bath, and slowly add 6mg (0.149mmol) of NaBH under magnetic stirring 4 , stirred at room temperature for 30 min, and added 57 mg (0.149 mmol) of γ-8 (cis) and 289 μL (5.9 mmol) of hydrazine hydrate. Reaction at room temperature for 3h (TLC detection of reaction progress). After the reaction was completed, the methanol was distilled off under reduced pressure, the residue was dispersed with water, extracted with ethyl acetate under acidic conditions, and the organic layer was washed with anhydrous MgSO 4 Dry, filter, and concentrate under reduced pressure, and the residue is subjected to silica gel column chromatography (10:1 → 5:1 chloroform-ethanol elution) to obtain 40 mg DL-42 (cis-1-hydroxyl-4-p-chlorophenyl- 5-o-chlorobenzyl-2-pyrrolidone) (yield 70.2%).

[0053]

[0054] DL-42: Light red powder, mp6...

Embodiment 3

[0055] Embodiment 3: the synthesis of compound W-41

[0056] Take 258mg (1.088mmol) of nickel chloride and dissolve it in a round bottom flask with methanol, add an ice bath, and slowly add 24mg (0.725mmol) of NaBH under magnetic stirring 4 , stirred at room temperature for 30 min, and added 227 mg (0.725 mmol) of γ-9 (trans) and 1405 μL (29.0 mmol) of hydrazine hydrate. Reaction at room temperature for 3h (TLC detection of reaction progress). After the reaction was completed, the methanol was distilled off under reduced pressure, the residue was dispersed with water, extracted with ethyl acetate under acidic conditions, and the organic layer was washed with anhydrous MgSO 4 Dry, filter, and concentrate under reduced pressure, and the residue is subjected to silica gel column chromatography (10:1 → 5:1 chloroform-ethanol elution) to obtain 200 mg of W-41 (trans 1-hydroxyl-4-phenyl-5- benzyl-2-pyrrolidone) (yield 88.2%).

[0057]

[0058] W-41: Light red powder, mp120~124...

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Abstract

The invention discloses a 1-hydroxy-2-ketopyrrolidine compound with a novel structure, i.e., 1-hydroxy-4-substituted phenyl-5-substited phenmethyl-2-ketopyrrolidine. The general formula of the compound is shown in a structural formula I, wherein X and Y are selected from hydrogen, ortho-position, meta-position and contraposition mono-substituted or multi-substituted fluorine and / or chlorine and / or bromine, and ortho-position, meta-position and contraposition mono-substituted or multi-substituted methoxyl and / or ethyoxyl and / or methyl; and X and Y are the same or different. The compound provided by the invention has calcium antagonistic activity, particularly has high selectivity calcium antagonistic activity to nerve cells, can be applied to preparation of a medicament with a calcium antagonistic action, and can be expected to be taken as a brain protecting agent for treating brain dysfunction, senile dementia, presenile dementia, vascular dementia or low learning and memory capabilities; and the preparation method provided by the invention has the advantages of quick reaction, easiness, easiness for operating, suitability for large-scale preparation and easiness for realizing industrial production. The structural I is shown in the description.

Description

technical field [0001] The invention relates to 1-hydroxy-2-pyrrolidone compounds and their preparation method and application, belonging to the technical field of medicinal chemistry. Background technique [0002] Calcium antagonists selectively block Ca 2+ Enter the cell through the voltage-dependent calcium channel on the cell and reduce intracellular Ca 2+ Concentration and utilization rate, drugs that inhibit the activity of ATPase, thereby affecting cell function, some can still slow down Ca 2+ Channel restoration allows intracellular Ca 2+ The decrease of the level will change the cardiovascular function and protect the heart and cerebrovascular. Calcium antagonists are mainly used clinically to treat hypertension, angina pectoris, arrhythmia, congestive cardiomyopathy and ischemic heart disease, etc., and are a class of widely used cardiovascular drugs (Zhang WG. Can we use calcium antagonist better in antihypertensive therapy? Pharmacol Res, 1996, 34(5 / 6): 187)....

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/46A61K31/4015A61P25/28
Inventor 杨小生宋磊郝小江汪冶付慧晓
Owner THE KEY LAB OF CHEM FOR NATURAL PROD OF GUIZHOU PROVINCE & CHINESE ACADEMY OF SCI
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