Method for splitting antipode of 3-butylbenzene phthalein

A technology of n-butylphthalide and enantiomers, which is applied in the production field of optically active 3-n-butylphthalide, can solve the problem of unsatisfactory optical purity of optically active products, tedious and time-consuming separation process, and narrow scope of application of the method, etc. problem, to achieve the effect of reliable measurement results, good splitting effect and wide application range

Inactive Publication Date: 2004-10-27
萍乡分水科技有限公司
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  • Abstract
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AI Technical Summary

Problems solved by technology

It has been reported that Comparison of Different Di-tert-butyldimethyl-Silylated Cyclodextrins as Chiral Stationary Phases in Capillary Gas Chromatography (T.Beck, J-M.Liepe, J.Nandzik et al; J.HighResol.Chromatogr.; 2000, 23(10), 569:575) using cyclodextrin derivatives as chiral stationary phases, using capillary gas chromatography to directly resolve 3-n-butylphthalide enantiomers, the method has a narrow scope of application, and the analysis and determination process must be carried out at 150 ° C. Easy to change the enantiomeric configuration, and not suitable for preparative separation
Yang Jinghua, Zhang Yingxin, Feng Yipu, the method for preparing optically active 3-n-butylphthalide (patent application number 99109673.8), using optically pure chiral amine as a resolution reagent, and using chemical resolution to indirectly resolve 3-n-butylphthalide Enantiomers; the specific process is: first ring-opening racemic n-butylphthalide under alkaline conditions, then acidifying, separating and forming a diastereomeric salt mixture with an optically active amine, and then separating the above diastereoisomeric The optically active amine salts of the single enantiomers are respectively prepared by the crystallization method from the mixture of constitutive salts, and then the above-mentioned amine salts are dissociated and re-cyclized to obtain optically active n-butylphthalide with a yield of 45.4%-53.3%. Purity≤95%; its disadvantages are: the resolution process is cumbersome and time-consuming, the yield is not high, and the optical purity of the optically active product obtained is not satisfactory

Method used

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  • Method for splitting antipode of 3-butylbenzene phthalein
  • Method for splitting antipode of 3-butylbenzene phthalein

Examples

Experimental program
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Effect test

Embodiment 1

[0022] 1) Preparation of chiral stationary phase:

[0023] ① Prepare γ-aminopropyl silica gel according to conventional methods;

[0024] ② Synthesis of cellulose-tris(3,5-dimethylphenylcarbamate) derivatives: Take 1.0 g of dry cellulose in a three-necked flask, add 50 mL of dry pyridine, heat to reflux for 24 hours, then add 5 mL of 3, 5-Dimethylphenylisocyanate, electromagnetic stirring reflux 24; cooling, slowly add a large amount of methanol, there is solid precipitation, filter, the solid product is washed with methanol, vacuum-dried, the final product is a white solid; yield 85 %;

[0025] ③ Dissolve 0.5g of cellulose-tris(3,5-dimethylphenylcarbamate) derivative in 25ml of tetrahydrofuran, add the above solution into 2.0g of aminopropyl silica gel, stir and evaporate until tetrahydrofuran evaporates to dryness , to finally obtain a cellulose-tri(3,5-dimethylphenylcarbamate) chiral stationary phase with a coating amount of 20% (mass fraction);

[0026] 2) Chiral column...

Embodiment 2

[0029] 1) Preparation of chiral stationary phase:

[0030] ① Prepare γ-aminopropyl silica gel according to conventional methods;

[0031] ②Synthetic starch (amylose or amylopectin) phenyl carbamate derivatives: Take 1.0 g of dry starch in a three-neck flask, add 50 mL of dry pyridine, heat and reflux for 24 hours, then add 5 mL of phenyl isocyanate, and stir with electromagnetic Reflux for 24°C; cool down, slowly add a large amount of methanol, then a solid precipitates, filter, wash the solid product with methanol, and dry it in vacuum, the final product is a white solid; the yield is 85%.

[0032] ③Dissolve 0.5g of starch phenylcarbamate derivatives in 25ml of chloroform, add the above solution into 2.0g of aminopropyl silica gel, stir and evaporate until tetrahydrofuran volatilizes to dryness, and finally obtain a coating amount of 20% (mass fraction ) starch phenyl carbamate chiral stationary phase;

[0033] 2) Chiral column packing: take 2.0 g of starch phenylcarbamate ...

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Abstract

A process for splitting 3-n-butylphenyl phthaleine antipode features that the phenylamino formate or benzoate of polyose compound is used as chiral fixed phase, and the liquid-phase chromatography is directly used for said splitting. Its advantages are high speed and effect, high stability and long service life.

Description

technical field [0001] The invention relates to the production of optically active 3-n-butylphthalide, in particular to a method for separating the enantiomers of 3-n-butylphthalide. Background technique [0002] 3-n-Butylphthalide is a national first-class new drug developed by my country with independent intellectual property rights. Pharmacodynamic studies have shown that it has good anti-ischemic activity and can increase the levels of ATP and PCr in the ischemic brain. Recent studies have shown that the two isomers of the drug have significantly different therapeutic effects on stroke. Since no suitable method for asymmetric synthesis and chiral resolution to prepare optically active 3-n-butylphthalide has been found, the drug is temporarily listed as a racemate. It has been reported that Comparison of Different Di-tert-butyldimethyl-Silylated Cyclodextrins as Chiral Stationary Phases in Capillary Gas Chromatography (T.Beck, J-M.Liepe, J.Nandzik et al; J.HighResol.Chro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/88
Inventor 邹汉法刘月启陈小明孔亮
Owner 萍乡分水科技有限公司
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