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3-(3'-hydroxyl)-butyl phthalide ester, and preparation thereof and uses

A technology of butylphthalide and hydroxyl, applied in the field of 3--butylphthalide derivatives, can solve the problems of limited application, insoluble in water, etc.

Active Publication Date: 2008-10-22
BEIJING YILING BIOENG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But because 3-(3'-hydroxyl) butylphthalide is insoluble in water, its application is limited

Method used

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  • 3-(3'-hydroxyl)-butyl phthalide ester, and preparation thereof and uses
  • 3-(3'-hydroxyl)-butyl phthalide ester, and preparation thereof and uses
  • 3-(3'-hydroxyl)-butyl phthalide ester, and preparation thereof and uses

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1: Preparation of 3'-hydroxybutylphthalide

[0032] In a 250ml three-necked round bottom flask, add 150ml of tetrahydrofuran and 2g of 60% sodium hydroxide, cool to -5℃ and stir, then add 13.4g (0.1mol) phthalide, keep the temperature at -5℃-0℃, and stir React for 30 minutes. The mixture was a light green solution. At this time, drop in a 50ml tetrahydrofuran solution containing 16.4g (0.1mol) of 3-hydroxybromo-n-butane. Control the dropping rate to keep the temperature at 0°C. Keep the reaction after the dropping, TLC The thin layer makes the raw material point of phthalide disappear. At this time, 8ml of distilled water was added dropwise, the mixture was added to 300ml of ethyl acetate, washed twice with 50ml of saturated sodium hydride solution, and then washed with 50ml of water twice, dried with anhydrous sodium sulfate for 2 hours, filtered, and the filtrate was concentrated to dryness to obtain a nearly white color. Crystalline solid. It was vacuum dried in ...

Embodiment 2

[0035] Example 2: Preparation of 3-(3'-phosphoric acid) butylphthalide and its sodium salt

[0036] In a 250ml three-necked flask, add 150ml of N,N-dimethylformamide and 20ml of pyridine, then cool to -10°C and drop 25ml of phosphorus oxychloride. After the drop is stirred for 20 minutes, add a total of 20.7g3 to it. '-Hydroxybutylphthalide, stir and react for 3 hours, after the thin-layer identification reaction is completed, pour the mixture into water, adjust the pH to 2-3 with dilute hydrochloric acid, extract twice with 200ml ethyl acetate, and wash the extract with water To neutral. Dry with anhydrous sodium sulfate and concentrate to dryness to obtain 3-(3'-phosphoric acid) butylphthalide. 3-(3'-phosphoric acid) butylphthalide was dissolved in 95% ethanol, 10.6g of sodium carbonate was added, and the reaction was stirred at 30°C for 1 hour. Then, it was added to 100ml of acetone to cool, and a white crystalline solid was precipitated, which was dried under vacuum. Obtained ...

Embodiment 3

[0040]Example 3: Preparation of 3-(3'-glycinate)butylphthalide and 3-(3'-glycinate)butylphthalide hydrochloride

[0041] In a 500ml three-necked flask, add 20.7g of 3'-hydroxybutylphthalide, 150ml of ethyl acetate, cool to 0°C, add 5ml of anhydrous pyridine and 1g of DMAP, add 6g of glycine while stirring, keep the temperature to 0-5°C, After the reaction is complete, pour the mixture into 50ml ice water, adjust the pH value to neutral with 0.1N hydrochloric acid, stand for separation, save the organic layer, extract the aqueous layer twice with 50ml ethyl acetate, combine the organic phases, wash twice with 50ml water Then, it was dried with anhydrous magnesium sulfate, filtered, and concentrated to dryness to obtain 16.7 g of 3-(3'-glycinate)butylphthalide with a yield of 58%.

[0042]

[0043] 1H-NMR (400MHz, CDCl3δppm): 1.14~1.17(3H, m, H4'), 1.45~1.70(1H, m, H2'), 1.86~2.24(1H, m, H1'), 3.64(2H, m ,H6')3.74--3.82(1H,m,H3'),5.46-5.50(1H,m,H2),7.42-7.44(1H,m,Ar-H6),7.48(1H,m,...

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PUM

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Abstract

The invention relates to an ester obtained by the reaction of 3-(3'-hydroxyl)-butylphthalide and acids, wherein, the acids can be acceptable inorganic acids or organic acids in pharmacy. Proved by testing, the efficacy of the ester is increased significantly. Part of the ester can go on reacting with the acids or alkalis to form salts in order to increase water solubility and prepare injection preparations; being proved by testing, the injection preparations have no muscle and vascular stimulation.

Description

Technical field: [0001] The invention belongs to the field of compound medicine, and specifically relates to 3-(3'-hydroxy)-butylphthalide derivatives, preparation methods and uses. Background technique: [0002] Butylphthalide is an active ingredient extracted from celery seeds. The Institute of Medicine of the Chinese Academy of Sciences first discovered its new use. It can improve the damage of the central nervous system of patients with acute ischemic stroke and can promote the recovery of patients' functions. According to the literature report (Wang Chunhua et al.: Research on the Metabolites of Butylphthalide in Rats Acta Pharmaceutical Sciences 1997, 32(9): 641-646), Butylphthalide is mainly transformed into two metabolites 3-(3′) in the body -Hydroxy)butylphthalide and 3-hydroxy-3-butylphthalide: [0003] [0004] 3-(3′-hydroxy)butylphthalide (Metabolite I, MI) [0005] [0006] 3-hydroxy-3-butylphthalide (Metabolite II, MII) [0007] The ratio of butylphthalide to me...

Claims

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Application Information

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IPC IPC(8): C07D307/88C07F9/655A61K31/365A61K31/665A61P9/10
Inventor 陈文展王伟
Owner BEIJING YILING BIOENG
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