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Butyl phthalide raw material drug product and preparation method thereof

A technology of butylphthalide and raw material medicine, which is applied in the field of medicine and can solve problems such as cumbersome operation, increased impurities, and low content purity

Active Publication Date: 2015-12-09
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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  • Butyl phthalide raw material drug product and preparation method thereof
  • Butyl phthalide raw material drug product and preparation method thereof
  • Butyl phthalide raw material drug product and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

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

[0082] (1) Preparation of butylene phthalide

[0083] 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 Drying, filtering off the desiccant, distilling off diethyl ether, silica gel column chromatography, elution with chloroform-petroleum ether, to obtain 45.0Kg butylene phthalide

[0084] (2) Preparation of butylphthalide

[0085] Dissolve 45.0Kg of 3-butenephthalide in ether, add 4.5Kg10%Pd / C, and use H 2 Gas replacement 6 times, filled with H 2 , stirred, rea...

preparation example 2

[0086] Preparation example 2: Butylphthalide, a prior art raw material drug product, according to the preparation method disclosed in Chinese patent CN101962374

[0087] (1) Preparation of Bromobutane Grignard Reagent

[0088] 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 hour to obtain the Grignard reagent of bromobutane

[0089] (2) Preparation of o-valerylbenzoic acid

[0090] 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...

Embodiment 1

[0099] Embodiment 1: Butylphthalide bulk drug product

[0100] A. Preparation of potassium hydroxyamylbenzoate (ring-opening reaction): Add 8.0Kg potassium hydroxide to 18L methanol (density 0.79), heat to reflux until dissolved, add 20.2Kg crude butylphthalide (content: 94.9 %), heated to 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, which was washed with 4.5L methyl tert-butyl ether 1 time, dried to obtain 19.6Kg of potassium salt of hydroxyamylbenzoate

[0101] B. Add 92.0g of potassium hydroxyamylbenzoate obtained in step A to a mixed solvent of 450ml of water 1 and 225ml of dichloromethane (density 1.34), control the temperature at 35~40°C, slowly add dilute hydrochloric acid dropwise, Control the pH to 2.1~2.3, stir and react for 4 hours, stand still and separate the phases, take the dichloromethane phase, wash the dichloromethane phase with 150ml saturated sodium bi...

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Abstract

The present invention provides a butyl phthalide raw material drug product with the butyl phthalide content not less than 99.0%; the raw material drug is stable in quality, and can ensure the clinical curative effect and drug safety of a butyl phthalide preparation.

Description

technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a raw material drug product 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 with no optical activity (racemization), and butylphthalide is Oily liquid with a strong celery fragrance, the chemical structural formula is as shown in formula 1: [0003] [0004] Butylphthalide increases cerebral vascular endothelial NO and PGI 2 Reduce the level of intracellular calcium, inhibit the release of...

Claims

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Application Information

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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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