A kind of preparation method of high-purity butylphthalide

Abstract

The present invention relates to a kind of preparation method of high-purity butylphthalide, comprising the following steps: (1) preparation of n-butylmagnesium bromide; (2) synthesis of 2-pentanoylbenzoic acid; (3) synthesis of butylphthalide (4) Refining of butylphthalide. The present invention has the following advantages due to the adoption of the above technical scheme: n-butylmagnesium bromide is used as the initiator in the step (1), the initiation condition is mild, and the safety performance is improved; and the initiation temperature is 38~42° C., and the reaction temperature is also Only 48 ~ 52 ℃, easy to achieve in the mass production process. Using 2-pentanoylbenzoic acid as the raw material, the carbonyl group is reduced by sodium borohydride aqueous solution, which avoids explosion easily caused by the solid feeding method, thereby ensuring the safety of production. The butylphthalide is refined by vacuum distillation, which is simple and easy, and the obtained high-purity butylphthalide has a purity of 100%. The synthesis process of the butylphthalide of the present invention is stable, the preparation process is mild and controllable, and is suitable for mass 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, which uses phthalic anhydride as raw material, and is characterized in that the intermediate of pht...

AI Technical Summary

Problems solved by technology

When preparing the Grignard reagent, iodine is added as an initiator, and new impurities are introduced. The purity of the obtained product reaches 97-98%, and the impurity content is 2-3%. It cannot be directly used in the preparation of injection-type medicines.

[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 insufficient product purity, 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, which is dissolved in ether 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 generation 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-closure reaction Dissolving hydroxyamyl benzoate potassium salt, dichloromethane is a second class solvent; (6) finally adopt rectification 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

Images