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Preparation method of high-purity butylphthalide

A kind of butylphthalide, high-purity technology, applied in the refining field of butylphthalide, can solve the problems of long reaction time, degradation, unfavorable energy consumption and cost control and the like

Active Publication Date: 2016-08-17
LIVZON PHARM GRP INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But this method still has the following deficiencies: 1) the product is darker in color and is yellow to dark yellow oily liquid; 2) the rectification step at high temperature is used as the last step, and the product has the risk of degradation; 3) the reaction process uses a large amount of Flammable and explosive solvents ether and methyl isobutyl ether are not conducive to safe production; 4) The reaction takes a long time and the process is cumbersome, which is not conducive to energy consumption and cost control in production; 5) In some cases, two or even three times are required Vacuum distillation to meet the purity requirements

Method used

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  • Preparation method of high-purity butylphthalide

Examples

Experimental program
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Effect test

Embodiment 1

[0021] Embodiment 1: the preparation of butylphthalide crude product:

[0022] Under nitrogen protection, 90Kg of n-butylmagnesium chloride tetrahydrofuran solution was added to the reactor, 10Kg of o-carboxybenzaldehyde was added to 50L of anhydrous tetrahydrofuran to make a solution, and the Grignard reagent was added dropwise, and the temperature was controlled not to exceed 55 °C. First add 100L of saturated ammonium chloride to quench the reaction, then add 50L of HCl (4M) solution to adjust the pH of the system to about 2.0, continue to stir and let stand for stratification, the organic phase is depressurized to remove the solvent, add 50L of dichloromethane to dilute, 50L of saturated carbonic acid The solution was washed with sodium hydrogen solution, left to stand for layers, and the organic phase was concentrated under reduced pressure to obtain 12.3Kg of a crude product of racemic-3-n-butylphthalide.

Embodiment 2

[0023] Example 2: Refinement of crude butylphthalide (potassium salt):

[0024] A. 1.23Kg of racemic-3-n-butylphthalide crude product was added to the reaction flask connected with the rectification separation device, and the pressure was reduced to a vacuum degree of 1-2mbar; Then the temperature was raised to 220° C., and the fractions at 130-140° C. were collected to obtain 0.99 kg of racemic-3-n-butylphthalide fraction; the HPLC purity was 99.4%.

[0025] B. Add 0.99Kg of racemic-3-n-butylphthalide fraction and 2.2L of methanol into a single-necked flask, stir to dissolve, add a solution prepared in advance of 0.31Kg of potassium hydroxide and 1.33L of methanol, heat to 65°C and react for 1h, Concentrate to remove methanol, add 25L of dichloromethane, stir to precipitate a large amount of solid, filter, and dry to obtain 1.19Kg of solid.

[0026] C. 1.19Kg 1-hydroxypentyl-2-potassium benzoate and 2.4L water were added to the reaction flask, stirred and dissolved, then the...

Embodiment 3

[0027] Example 3: Synthesis of sodium 1-hydroxypentyl-2-benzoate

[0028] Add 9 g of racemic-3-n-butylphthalide fraction and 25 mL of methanol into a single-neck flask, stir to dissolve, add sodium hydroxide methanol solution (3.3 g / 12 mL), heat to 65 °C for 1 h, heat and evaporate to dryness to obtain a white solid.

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Abstract

The invention provides a preparation method of high-purity butylphthalide. The preparation method comprises the following steps: A. adding a crude product of rac-3-n-butylphthalide to a reaction flask and reducing the pressure until the system vacuum degree is 1-2mbar; raising the temperature and collecting a 130-140 DEG C fraction, thus obtaining a rac-3-n-butylphthalide fraction; B. adding the rac-3-n-butylphthalide fraction and methanol to the reaction flask, stirring to dissolve the materials, adding a methanol solution of inorganic base, heating till reflux reaction, carrying out filtration, removing methanol through concentration, adding dichloromethane, stirring the materials to precipitate solids, and carrying out filtration and drying, thus obtaining 1-hydroxypentyl-2-benzoate; and C. adding 1-hydroxypentyl-2-benzoate to water, stirring to dissolve 1-hydroxypentyl-2-benzoate, then adding the solution to a reaction flask with a hydrochloric acid solution, stirring to react at a temperature of 35-45 DEG C, standing for layering, washing an oil phase with a sodium bicarbonate solution and water in sequence, and carrying out drying and filtration, thus obtaining the pure product of rac-3-n-butylphthalide.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a method for purifying butylphthalide. Background technique [0002] Butylphthalide is a synthetic racemic n-butylphthalide, which has the same structure as natural L-apigenin A. Clinical research results show that butylphthalide can improve the damage of central nervous system in patients with acute ischemic stroke, and can promote the improvement of neurological deficits. Clinically, it is mainly used to treat the improvement of neurological deficit in patients with acute ischemic stroke. [0003] Since butylphthalide is a liquid volatile oil, it cannot be purified by conventional recrystallization methods. The existing butylphthalide preparation method is mainly to prepare the crude butylphthalide through various synthetic routes, and then obtain the finished product through rectification under reduced pressure. Poor color. Alternatively, the butylphthalide crude product...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/88
CPCC07D307/88
Inventor 王涛陆文岐杨登科倪俊赵梨陈斌王伟徐朋陈亭亭
Owner LIVZON PHARM GRP INC
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