Preparation method of high-purity butylphthalide

Abstract

The invention relates to a preparation method of high-purity butylphthalide. The preparation method comprises the following steps: (1) preparing n-butyl magnesium bromide; (2) synthesizing 2-valerylbenzoic acid; (3) synthesizing butylphthalide; and (4) refining the butylphthalide. Due to the adoption of the technical scheme, the preparation method has the advantages that the n-butyl magnesium bromide is used as an initiator in the step (1), so that the initiation condition is mild, and the safety performance is improved; and the initiation temperature is 38-42 DEG C, and the reaction temperature is only 48-52 DEG C, so that the temperature is easy to implement in the mass production process; the 2-valerylbenzoic acid is used as the raw material, and carbonyl is reduced in a sodium borohydride aqueous solution mode, so that explosion easily caused by a solid feeding mode is avoided, and production safety is guaranteed; and the butylphthalide is refined in a reduced pressure distillationmode, so that the method is simple and easy to implement, and the purity of the obtained high-purity butylphthalide reaches 100%. The synthesis process of butylphthalide is stable, the preparation process is mild and controllable, and the method is suitable for batch production.

Description

technical field [0001] The invention belongs to the field of chemical industry and pharmacy, and in particular relates to a preparation method of butylphthalide. Background technique [0002] The chemical name of butylphthalide is 3-n-butylphthalide, also known as apigenin A. Butylphthalide is a racemate extracted from celery seed, which is artificially synthesized. Butylphthalide has anti-cerebral ischemia Pharmacological effect, it is a drug with independent intellectual property rights in my country. Butylphthalide can reduce the infarction after focal cerebral ischemia, increase cerebral blood flow in ischemic area and improve microcirculation in cerebral ischemic area, protect mitochondrial function, relieve The degree of neurological damage, improve the functional metabolism after global cerebral ischemia. [0003] CN 101962374A discloses a preparation method of apigenin, using phthalic anhydride as raw material, characterized in that the intermediate of phthalic anhydr...

AI Technical Summary

Problems solved by technology

It adds iodine as initiator when preparing Grignard reagent, introduces new impurity, the purity of gained product reaches 97~98%, impurity content 2~3%, can not be directly used in the preparation of injection medicine

[0004] CN 105130934 A A butylphthalide raw material drug product and its preparation method are based on Li Shaobai's method for preparing butylphthalide. Due to the lack of purity of the product, some related impurities are controlled through a refining process. The main defects of the reaction are: (1) Li Shaobai’s method for preparing butylphthalide is to use phthalic anhydride as the starting material, and reflux with anhydrous sodium acetate and valeric anhydride at 300°C to obtain the butylenephthalide intermediate. Catalytic hydrogenation with 10% Pd / C to obtain crude butylphthalide

The use of ether solvent and high temperature conditions are not suitable for large-scale industrial production; (2) the reflux time is too long (1.5 hours) in the ring-opening reaction of the refining process, which affects the production progress; (3) the temperature is higher in the ring-closing reaction (35 ~ 40 ℃), is conducive to the formation of by-products; (4) in the recrystallization process of potassium hydroxyamylbenzoate, the use of water and ether system is not conducive to industrial production; (5) the use of dichloromethane and water system in the ring-closing reaction Dissolve hydroxyamyl benzoate potassium salt, dichloromethane is the second class solvent; (6) finally adopt the rectification method to refine butylphthalide, which consumes manpower and material resources, and the maintenance cost is high, which is not conducive to large-scale production

[0005] CN 105859670 A discloses a method for preparing high-purity butylphthalide. The purity of butylphthalide prepared by this method is increased to more than 99.0%, but the method has the following disadvantages: (1) The synthesis process is only suitable for small batch processes, For example, use column chromatography and rectification equipment; in the scale-up production, the separation and purification of column chromatography is difficult, and the cost and maintenance cost of rectification equipment are relatively uneconomical, so it should be more reasonable and safe to use in large-scale production , efficient way to carry out

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