A kind of butylphthalide pharmaceutical active composition and preparation method thereof

A technology of drug activity and butylphthalide, applied in the field of medicine, can solve problems such as poor product stability, inability to be used as medicine, and potential safety hazards, and achieve the effects of stable quality, clinical efficacy and drug safety

Active Publication Date: 2017-10-24
CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0015] Indexes such as the butylphthalide product content that adopts said method to prepare, impurity improve to some extent, as butylphthalide content improves to about 97%, and impurity content reduces to about 3.0%, but this product stability is still relatively poor, after placing During the process, the content of the product is significantly reduced, and the impurities are significantly increased, so the product cannot be used as a medicine; (2) At the same time, this method uses formatted reagents in the production process, which need to be stored in an anhydrous and oxygen-free sealed environment. It is made now, the operation is cumbersome, and there are safety hazards in the production process, so it is not suitable for industrial production
[0016] In view of the low content (or purity) of the above products, during the storage process, the quality is unstable, uncontrollable, and cannot be used as a medicine. Therefore, it is still necessary to improve the existing technology to reduce the content of various impurities in butylphthalide , obtain butylphthalide products with stable quality, and use the butylphthalide products with stable quality to prepare pharmaceutical preparations to ensure the clinical efficacy and drug safety of the preparations

Method used

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  • A kind of butylphthalide pharmaceutical active composition and preparation method thereof
  • A kind of butylphthalide pharmaceutical active composition and preparation method thereof
  • A kind of butylphthalide pharmaceutical active composition and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0070] Preparation Example 1: Butylphthalide, a prior art product, prepared according to the preparation method disclosed by Li Shaobai et al. in "(±) Synthesis of Apigenin A"

[0071] (1) Preparation of butylene phthalide

[0072] 148.0Kg of phthalic anhydride, 82.0Kg of anhydrous sodium acetate and 300.0L of n-valeric anhydride were heated and refluxed at 300°C for 4 hours, and the low-boiling point fraction was evaporated (controlled below 150°C), the residue was dissolved in hot water, and then NaHCO 3 Neutralize to pH=6~7, extract with 7×500L ether, combine organic layers, anhydrous Na 2 SO 4 After drying, the desiccant was filtered off, diethyl ether was distilled off, and silica gel column chromatography was eluted with chloroform-petroleum ether to obtain 45.0 Kg of butylenephthalide.

[0073] (2) Preparation of butylphthalide

[0074] Dissolve 45.0Kg of 3-butenephthalide in ether, add 4.5Kg of 10% Pd / C, and use H 2 Gas replacement 6 times, filled with H 2 , stirr...

preparation example 2

[0075] Preparation example 2: Butylphthalide, a prior art product, according to the preparation method disclosed in Chinese patent CN101962374

[0076] (1) Preparation of Bromobutane Grignard Reagent

[0077] Under the protection of nitrogen, add 200L of tetrahydrofuran, 6.0Kg of magnesium flakes and 0.1Kg of iodine in a reaction tank equipped with stirring, thermometer and reflux condensing device, raise the temperature to 50°C, and add 31.50Kg of bromobutyl dissolved in 40L of tetrahydrofuran dropwise Alkanes, the temperature is controlled not to exceed 70 ° C, after the dropwise addition, continue to stir for 1 h to obtain the Grignard reagent of bromobutane.

[0078] (2) Preparation of o-valerylbenzoic acid

[0079] Under the protection of nitrogen, add 300L tetrahydrofuran, 30Kg phthalic anhydride and 2.5Kg copper iodide, cool to -10°C, add the Grignard reagent of bromobutane obtained in step (1) dropwise for about 1 hour Complete; after the dropwise addition, continue ...

Embodiment 1

[0088] Embodiment 1: Butylphthalide pharmaceutically active composition

[0089] Crude butylphthalide: butylphthalide prepared in Preparation Example 1

[0090] A. butylphthalide crude product 3.0Kg is joined in the rectifying tower;

[0091] B. Control the vacuum degree to 5mmHg, heat up to about 130°C, collect the fraction at this temperature, and discard it; continue to heat up to 154°C, control the reflux ratio to 3:1, and collect the fraction at this temperature;

[0092] C. re-add the collected fractions into the rectification tower, repeat step B2 times, and obtain 2.7Kg of butylphthalide.

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PUM

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Abstract

The invention provides a butylphthalide pharmaceutical active composition, comprising the following components: component I: butylphthalide content ≥ 98.0%; component II: selected from methylenephthalide, vinylphthalide, propylenephthalide, butylphthalide One or more of enphthalide, pentylenephthalide, phthalide, toluene, ethylphthalide, propylphthalide, and pentylenephthalide, and the content of component II > 0 and ≤ 2.0%; when the component When any one of methylenephthalide, vinylphthalide, propylenephthalide, butylenephthalide, and amylenephthalide is contained in II, the maximum content of any one of the ingredients contained therein shall not exceed 0.5%. When component II contains When any one of phthalide, methylphthalide, ethylphthalide, propylphthalide, and pentaphthalide is used, the maximum content of any one of the ingredients contained in it shall not exceed 1.0%. The pharmaceutical active composition has stable quality and can guarantee the clinical curative effect and drug safety of the butylphthalide preparation.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a pharmaceutically active composition containing 3-butyl-l(H)-isobenzofuranone (butylphthalide) and a preparation method thereof. Background technique [0002] Butylphthalide, whose chemical name is 3-butyl-l(H)-isobenzofuranone, also known as apigenin A, is a racemate extracted from celery seeds and can also be synthesized artificially; it is patented in China In CN1100097, the application of apigenin A in the preparation of medicines for preventing and treating diseases caused by cerebral ischemia in mammals or humans is disclosed. Apigenin A is butylphthalide without optical activity, and butylphthalide is an oily liquid with Strong celery fragrance, the chemical structural formula is shown in Formula 1: [0003] . [0004] 1 [0005] Butylphthalide increases cerebral vascular endothelial NO and PGI 2 Reduce the level of intracellular calcium, inhibit the re...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/365A61P9/10C07D307/88
CPCA61K31/365C07D307/88
Inventor 申东民杨汉煜牛锋马玉秀齐军彩郭海波
Owner CSPC ZHONGQI PHARM TECH (SHIJIAZHUANG) CO LTD
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