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Method for preparing high-purity butyphthalide

A butylphthalide, high-purity technology, applied in the field of drug synthesis, can solve the problems of poor stability of format reagents, long reaction routes, cumbersome operations, etc., and achieve the effects of easy industrial production, stable batch supply, and simple process

Inactive Publication Date: 2019-07-12
SHIJIANGZHUANG ZHIHENG PHARMACY TECH CO LTD
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  • Abstract
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  • Application Information

AI Technical Summary

Problems solved by technology

[0013] In the method of condensing phthalic anhydride and valeric anhydride at high temperature, hydrogenation reduction, and acidic ring closure to prepare butylphthalide, the advantage is that the starting materials phthalic anhydride and valeric anhydride are cheap and easy to obtain; the disadvantage is that the condensation process High temperature is required, the synthesis process requires hydrogenation to reduce double bonds, the reaction route is long, purification is difficult, the yield is low, and the color grade of the product is not good
[0014] The addition of o-formylbenzoic acid and butylmagnesium chloride, acidic ring-closing method for preparing butylphthalide, has the advantages of short reaction route, good product color, and high yield compared with the high-temperature method; the disadvantages are: 1. The format reagent needs to be used immediately Now-made, the preparation requires not only absolute anhydrous conditions, but also cumbersome operation, the activation of magnesium powder is also crucial, and the preparation of formatted reagents takes a long time to activate, and there are also disadvantages such as large differences in the preparation of formatted reagents between batches; 2. If the purchased format reagent is used, due to the poor stability of the format reagent and strict storage conditions, if the purchased reagent is placed for a long time, solids will be precipitated, resulting in the inability to accurately measure the feeding ratio, resulting in large differences between batches of butylphthalide obtained, etc. Defects; 3. The Grignard reagent is used to prepare butylphthalide. When post-processing the quenching reaction, it must be carried out under acidic conditions, so that the impurity content in the crude product is higher, and the number of times of refining butylphthalide is increased; at the same time, the obtained butylphthalide crude product A certain amount of magnesium salt will remain, which will bring great trouble to post-processing
[0015] Aiming at avoiding the shortcomings of high temperature reaction of phthalic anhydride method, poor product color, difficult purification, low yield and low temperature addition of phthalic acid method, harsh operating conditions and poor reproducibility, the process is studied

Method used

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  • Method for preparing high-purity butyphthalide
  • Method for preparing high-purity butyphthalide
  • Method for preparing high-purity butyphthalide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053] The microchannel reactor was cooled to -30°C for pre-cooling, 100 g (0.666 mol) of o-formylbenzoic acid was dissolved in 600 mL of tetrahydrofuran, and 606 mL of n-butyllithium in n-hexane (2.2 mol / L). Put the THF solution of o-formylbenzoic acid into the first piece of the microchannel; inject the n-butyllithium n-hexane solution into the second piece of the microchannel, and mix in the third piece of the microchannel, with a total flow rate of 30mL / min. After the reaction was complete, 3N hydrochloric acid aqueous solution was added, stirred for 30 minutes, allowed to stand for liquid separation, and the lower aqueous phase (pH=2) was extracted twice with 300 mL of dichloromethane. The organic phases were combined, dried and concentrated to obtain 126 g of a yellow oil.

[0054] Take 143g of crude product, add methanol 715mL, sodium hydroxide 26.6g, heat to reflux for 1hrs, and the reaction is complete; concentrate to remove methanol, add 430mL of dichloromethane, wate...

Embodiment 2

[0057] The microchannel reactor was cooled to -30°C for pre-cooling, 100 g (0.666 mol) of o-formylbenzoic acid was dissolved in 600 mL of tetrahydrofuran, and 606 mL of n-butyllithium in n-hexane (2.2 mol / L). Put the THF solution of o-formylbenzoic acid into the first piece of the microchannel; inject the n-butyllithium n-hexane solution into the second piece of the microchannel, and mix in the third piece of the microchannel, with a total flow rate of 50mL / min. Add 10% sodium hydroxide aqueous solution to the microchannel effluent, stir for 30 minutes, let stand to separate the liquid, discard the organic phase, adjust the pH to 2 with 55 mL of concentrated hydrochloric acid in the aqueous phase, precipitate solid, stir for 30 minutes, and suction filter to obtain shallow yellow solid.

[0058] Add the solid to the reaction flask, add 300 mL of dichloromethane, 100 mL of water, and 50 mL of concentrated hydrochloric acid, and heat to reflux for 1 hrs. The feed liquid is cool...

Embodiment 3

[0061] The microchannel reactor was cooled to -30°C for pre-cooling, 100 g (0.666 mol) of o-formylbenzoic acid was dissolved in 600 mL of tetrahydrofuran, and 606 mL of n-butyllithium in n-hexane (2.2 mol / L). Put the THF solution of o-formylbenzoic acid into the first piece of the microchannel; 300mL of n-butyllithium n-hexane solution into the second piece of the microchannel, after mixing in the third piece of the microchannel reactor, in the fourth Pour the remaining 306 mL of tetrahydrofuran solution of n-butyllithium into the main pipeline of the microchannel with a total flow rate of 100 mL / min. Add 10% sodium hydroxide aqueous solution to the microchannel effluent, stir for 30 minutes, let stand to separate the liquid, discard the organic phase, adjust the pH to 2 with 55 mL of concentrated hydrochloric acid in the aqueous phase, precipitate solid, stir for 30 minutes, and suction filter to obtain shallow yellow solid.

[0062] Add the solid to the reaction flask, add ...

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Abstract

The invention relates to a method for preparing high-purity butyphthalide. The method comprises the following steps: dissolving phthalaldehydic acid in an organic solvent, reacting with n-butyllithiumin a micro-channel reactor to generate a butyphthalide crude product, and carrying out aftertreatment to obtain the high-purity butyphthalide. The method overcomes the disadvantages that the yield for preparing the butyphthalide is low, the reaction temperature is high and the product color grade is high in existing phthalic acid method and valeric anhydride reaction; and moreover, the technicalproblems that magnesium ions are difficult to remove through aftertreatment and the high-purity butyphthalide is difficult for industrial production when the butyphthalide is prepared in the reactionof o-formoxyl benzoic acid and butyl magnesium bromide. The method is high in yield, the raw materials are easily obtained, and the prepared butyphthalide is high in purity and is applicable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a method for preparing high-purity colorless butylphthalide. Background technique [0002] n-butylphthalide (n-butylphthalise, NBP), referred to as butylphthalide, chemical name is 3-n-butyl-1(3H)-isobenzofuranone. Butylphthalide Soft Capsules is listed on the domestic market by CSPC Enbipu Pharmaceutical Co., Ltd. with the product name "Enbipu". A chemical drug with "ischemic stroke treatment" as its main indication. In addition, it has various pharmacological activities such as anticonvulsant, antitumor, hypotensive and antiasthmatic, and has broad application prospects. Its structural formula is as follows: [0003] [0004] At present, many documents have reported the synthetic method of butylphthalide, mainly for two reaction routes that take phthalic anhydride and o-formylbenzoic acid as starting raw materials: [0005] Route 1: Starting from p...

Claims

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Application Information

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IPC IPC(8): C07D307/88B01J19/00
CPCB01J19/0093C07D307/88
Inventor 陈金萍赵军旭付德才刘叶杨晨亮周芳杨华
Owner SHIJIANGZHUANG ZHIHENG PHARMACY TECH CO LTD
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