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A kind of butylphthalide crude drug product and preparation method thereof

A technology of butylphthalide and raw material medicine, which is applied in the field of medicine, can solve problems such as production process, raw material medicine products that cannot be directly used in preparation research, hidden safety hazards, etc., and achieve the effects of stable quality, clinical efficacy and drug safety

Active Publication Date: 2018-11-23
SHIJIAZHUANG PHARMA GRP NBP PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The product content, impurities and other indicators of the butylphthalide bulk drug prepared by the above method have been improved, such as the butylphthalide content increased to about 97%, the impurity content Reduced to about 3.0%, but the stability of the bulk drug product is still poor. During the placement process, the content of the bulk drug product is significantly reduced, and the impurities are significantly increased. Therefore, the bulk drug product cannot be directly used in the research of preparations, especially It cannot be applied to injections that directly enter the blood; (2) At the same time, this method uses formatted reagents in the production process. Formatted reagents need to be stored in an anhydrous and oxygen-free sealed environment. Suitable for industrial production
[0013] In view of the low content (or purity) of the above API products, during the storage process, the quality is unstable and uncontrollable, and cannot be used as a drug, so it is still required Improve the existing technology, reduce the content of various impurities in butylphthalide, obtain butylphthalide bulk drug products with stable quality, and use the stable quality butylphthalide bulk drug products to prepare pharmaceutical preparations to ensure the clinical efficacy of the preparations and drug safety

Method used

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  • A kind of butylphthalide crude drug product and preparation method thereof
  • A kind of butylphthalide crude drug product and preparation method thereof
  • A kind of butylphthalide crude drug product and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0081] Preparation Example 1: Butylphthalide, the prior art bulk drug product, prepared according to the preparation method disclosed by Li Shaobai et al in "Synthesis of (±) Apigenin A"

[0082] (1) Preparation of butene phthalide

[0083] 148.0Kg of phthalic anhydride, 82.0Kg of anhydrous sodium acetate and 300.0L of n-valeric anhydride were heated to reflux at 300°C for 4h, the low boiling point fractions were distilled off (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 Dry, filter off the desiccant, evaporate the ether, perform silica gel column chromatography, eluted with chloroform-petroleum ether to obtain 45.0Kg of butylene phthalide

[0084] (2) Preparation of butylphthalide

[0085] 45.0Kg of 3-butenephthalide was dissolved in ether, 4.5Kg of 10% Pd / C was added, and H 2 Gas replacement 6 times, filled with H 2 , stirred, reacted at roo...

preparation example 2

[0086] Preparation Example 2: Butylphthalide, the prior art bulk drug product, according to the preparation method disclosed in Chinese Patent CN101962374

[0087] (1) Preparation of bromobutane Grignard reagent

[0088] Under nitrogen protection, 200L of tetrahydrofuran, 6.0Kg of magnesium flakes and 0.1Kg of iodine were added to a reaction tank equipped with stirring, a thermometer and a reflux condensing device, the temperature was raised to 50°C, and 31.50Kg of bromobutane dissolved in 40L of tetrahydrofuran was added dropwise. alkane, control the temperature not to exceed 70 ℃, after the dropwise addition, continue to stir for 1h to obtain the Grignard reagent of bromobutane

[0089] (2) Preparation of o-valeryl benzoic acid

[0090] Under nitrogen protection, add 300L of tetrahydrofuran, 30Kg of phthalic anhydride and 2.5Kg of copper iodide, cool to -10°C, and dropwise add the Grignard reagent of bromobutane obtained in step (1) for about 1 hour. After the dropwise add...

Embodiment 1

[0099] Example 1: Butylphthalide bulk drug product

[0100] A. Preparation of potassium hydroxyamyl benzoate (ring-opening reaction): add 8.0Kg potassium hydroxide to 18L methanol (density is 0.79), heat under reflux to dissolve, add 20.2Kg crude butylphthalide (content: 94.9 %), heated under reflux for 1.5 hours; cooled to 26°C, slowly added 145L methyl tert-butyl ether (density 0.74), stirred for 2 hours, filtered to obtain a filter cake, and the filter cake was washed with 4.5L methyl tert-butyl ether 1 time, dried to obtain hydroxyamyl benzoate potassium salt 19.6Kg

[0101] B. the 92.0g hydroxyamyl benzoate potassium salt that step A obtains is joined in the mixed solvent of 450ml water 1 and 225ml methylene dichloride (density is 1.34), control temperature 35~40 ℃, slowly drip dilute hydrochloric acid, Control the pH to be 2.1~2.3, stir and react for 4 hours, stand for phase separation, take the dichloromethane phase, wash the dichloromethane phase once with 150ml of sa...

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Abstract

The invention provides a butylphthalide bulk drug product, the butylphthalide content of which is not less than 99.0%. The bulk drug has stable quality and can ensure the clinical curative effect and medication safety of the butylphthalide preparation.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a crude drug product comprising 3-butyl-1(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; patented in China CN1100097 discloses the application of apigenin A in the preparation of medicines for the prevention and treatment of diseases caused by cerebral ischemia in mammals or humans, apigenin A is butylphthalide without optical activity (racemic), and butylphthalide is An oily liquid with a strong celery fragrance, the chemical structure is shown in formula 1: [0003] [0004] Butylphthalide increases cerebral vascular endothelial NO and PGI 2 The level of intracellular calcium, inhibiting the release of glutamate, reducing the cont...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D307/88A61K31/365A61P9/10A61P25/00
CPCA61K31/365C07D307/88
Inventor 牛锋齐军彩赵楠焦魁良韩春景
Owner SHIJIAZHUANG PHARMA GRP NBP PHARMA CO LTD
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