Preparation method of high-purity n-butylphthalide

A high-purity technology of n-butylphthalide, applied in the field of medicine, can solve problems such as cost increase, environmental pollution, and harsh operating conditions, and achieve the effects of less equipment occupation, short synthesis process, and high production efficiency

Active Publication Date: 2016-03-02
山东诚创蓝海医药科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is active hydrogen in o-toylbenzoic acid, which needs to consume an equimolar amount of Grignard reagent, resulting in an increase in cost; phthalic anhydride reacts with Grignard reagent, and the ring is opened to form a carbonyl group, which can be reacted with Grignard reagent again. Consuming part of the Grignard reagent to form by-products, resulting in incomplete reaction of phthalic anhydride, on the other hand, the formed by-products affect the purity of the product and increase the difficulty of purification
In the o-bromobenzaldehyde method, the second step reaction needs to use highly toxic cyanide, which causes great pollution to the environment. Moreover, these methods all use tetrahydrofuran as a solvent. Because tetrahydrofuran is miscible with water, the solvent is not easy to recycle, causing pollution. , also increases the water solubility of the product, resulting in product loss
In addition, there are also reports that phthalic anhydride and valeric anhydride were used to obtain butenylphthalide under the condition of anhydrous sodium acetate, and then hydrogenation reduction was used to obtain apigenin A, but the operating conditions of this method are harsh and the yield is very low

Method used

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  • Preparation method of high-purity n-butylphthalide
  • Preparation method of high-purity n-butylphthalide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Add 5.28g (0.22mol) magnesium strips into a 250ml four-necked bottle, add a grain of elemental iodine and 25ml ether, stir, add about 1g of n-butyl bromide, and slowly add the remaining n-butyl bromide dropwise after the reaction is initiated. A total of 30.14 g (0.22 mol) of butyl bromide was added, and 100 ml of isopropyl ether was added at the same time. The addition was completed dropwise in about 1 hour, and then refluxed for another 1 hour, cooled, and set aside.

[0027] 2. Crude product preparation

[0028] Add 29.20g (0.2mol) of o-cyanobenzaldehyde into a 500ml four-necked bottle, add it into 150ml of isopropyl ether, stir, add 0.5g of cuprous iodide, cool down to -25°C, and drop the temperature at -25±2°C Add the above-mentioned Grignard reagent, drop it for about 1 hour, keep stirring at -20±2°C for 2 hours, add 10% hydrochloric acid dropwise, adjust the pH to 2~3, after dropping, heat and reflux for 2 hours, separate the water layer, and organic The layer w...

Embodiment 2

[0034] 1. Preparation of Grignard reagent

[0035] Add 11.04g (0.46mol) magnesium strips into a 500ml four-necked bottle, add a grain of elemental iodine and 50ml ether, stir, add about 2g of n-butyl bromide, and slowly add the remaining n-butyl bromide dropwise after the reaction is triggered, and the normal A total of 63.02 g (0.46 mol) of butyl bromide was added, and 200 ml of isopropyl ether was added at the same time. The addition was completed dropwise in about 1 hour, and then refluxed for 1 hour, cooled, and set aside.

[0036] 2. Crude product preparation

[0037] Add 58.40g (0.4mol) of o-cyanobenzaldehyde into a 1000ml four-necked bottle, add 300ml of isopropyl ether, stir, add 1.0g of cuprous iodide, cool down to -25°C, control the temperature at -25±2°C and drop Add the above-mentioned Grignard reagent, drop it for about 1 hour, keep stirring at -20±2°C for 2 hours, add 10% hydrochloric acid dropwise, adjust the pH to 2~3, after dropping, heat and reflux for 2 hou...

Embodiment 3

[0041] 1. Preparation of Grignard reagent

[0042] Add 10.08g (0.42mol) magnesium bars into a 500ml four-necked bottle, add a grain of elemental iodine and 50ml ether, stir, add about 2g of n-butyl bromide, and slowly add the remaining n-butyl bromide dropwise after the reaction is triggered, and the normal A total of 57.54 g (0.42 mol) of butyl bromide was added, and 200 ml of isopropyl ether was added at the same time. The addition was completed dropwise in about 1 hour, and then refluxed for 1 hour, cooled, and set aside.

[0043] 2. Crude product preparation

[0044]Add 58.40g (0.4mol) of o-cyanobenzaldehyde into a 1000ml four-necked bottle, add 300ml of isopropyl ether, stir, add 1.0g of cuprous iodide, cool down to -25°C, and drop the temperature at -25±2°C Add the above-mentioned Grignard reagent, drop it for about 1 hour, keep stirring at -20±2°C for 2 hours, add 10% hydrochloric acid dropwise, adjust the pH to 2~3, after dropping, heat and reflux for 2 hours, separat...

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Abstract

The invention belongs to the technical field of medicine, and relates to a method for easily and efficiently synthesizing n-butylphthalide. The method particularly comprises the following steps that in the presence of a copper iodide catalyst, o-cyanobenzaldehyde is reacted with a Grignard reagent of n-butyl bromide in solvent; hydrochloric acid is added for a reaction after the reaction in the first step is completed, standing layering is conducted, and an organic phase is obtained; the organic phase is washed through an aqueous hydrochloric acid solution, a sodium hydroxide aqueous solution is added, reflux is conducted through heating, standing layering is conducted after reflux is completed, and an aqueous phase is obtained; pH of the aqueous phase is adjusted to 3-4, a reaction is conducted through heating, solvent extraction is conducted after the reaction is completed, concentration and vacuum distillation are conducted on an obtained oil phase, and a finished product is obtained. According to the method for easily and efficiently synthesizing the n-butylphthalide, the raw materials are easy to obtain, the yield is high, the cost is low, industrialization is easy, the n-butylphthalide with the content of any individual impurity smaller than 0.1 percent can be obtained, and the purity is larger than 99.7 percent.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a method for synthesizing high-purity n-butylphthalide simply and efficiently. Background technique [0002] N-butylphthalide (n-butylphthalide, NBP) is called butylphthalide for short, and its chemical name is 3-butyl-1(3H)-isobenzofuranone (3-Butyl-1(3H)-isobenzofuranone), and its molecular formula is C 12 h 14 o 2 , molecular weight is 190.24, structural formula: [0003] [0004] Butylphthalide, commonly known as apigenin A, is the main component of celery volatile oil. At the same time, it is also widely found in other plants of Umbelliferae and Compositae. Apigenin A has strong anti-convulsant, anti-asthma, and inhibition of prostaglandin F 2x Proliferation, increasing blood flow, anti-tumor and antihypertensive and other pharmacological activities indicate that it has broad application prospects in clinic. In addition, apigenin A has a natural banana f...

Claims

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Application Information

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IPC IPC(8): C07D307/88
CPCC07D307/88
Inventor 王素兰张伟王寅陈红相谭光明
Owner 山东诚创蓝海医药科技有限公司
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