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A kind of preparation method of high-purity butylphthalide
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A butylphthalide, high-purity technology, applied in the field of butylphthalide refining, can solve the problems of unfavorable safety production, unfavorable energy consumption and cost control, cumbersome process, etc.
Active Publication Date: 2019-04-05
LIVZON PHARM GRP INC
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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
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Embodiment 1
[0021] Embodiment 1: the preparation of butylphthalide crude product:
[0022] Under the protection of nitrogen, add 90Kg of n-butylmagnesium chloride tetrahydrofuran solution into the reactor, add 10Kg of o-carboxybenzaldehyde and 50L of anhydrous tetrahydrofuran to make a solution, and add Grignard reagent dropwise. First add 100L saturated ammonium chloride to quench the reaction, then add 50L HCl (4M) solution to adjust the pH of the system to about 2.0, continue to stir and stand for stratification, the organic phase is distilled off under reduced pressure to remove the solvent, add 50L dichloromethane to dilute, and 50L saturated carbonic acid Wash with sodium hydrogen solution, let stand to separate layers, and concentrate the organic phase under reduced pressure to obtain 12.3Kg of crude racemic-3-n-butylphthalide.
Embodiment 2
[0023] Embodiment 2: the refining (potassium salt) of butylphthalide crude product:
[0024] A. Add 1.23Kg of racemic-3-n-butylphthalide crude product into the reaction flask connected with rectification and separation device, reduce the pressure to a system vacuum of 1-2mbar; raise the temperature to 150-160°C, collect the previous fraction, and finally Then the temperature was raised to 220° C., and the fraction at 130-140° C. was collected to obtain 0.99 kg of rac-3-n-butylphthalide fraction; the HPLC purity was 99.4%.
[0025] B. Add 0.99Kg of rac-3-n-butylphthalide fraction and 2.2L of methanol into a single-necked bottle, stir to dissolve, add 0.31Kg of potassium hydroxide and 1.33L of methanol in advance, and heat to 65°C for 1 hour. 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. Add 1.19Kg 1-hydroxypentyl-2-potassium benzoate and 2.4L water into the reaction...
Embodiment 3
[0027] Embodiment 3: Synthesis of 1-hydroxypentyl-2-sodium benzoate
[0028] Add 9g of rac-3-n-butylphthalide fraction and 25mL of methanol into a one-necked flask, stir to dissolve, add sodium hydroxide methanol solution (3.3g / 12mL), heat to 65°C for 1h, 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 refining 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 function in patients with acute ischemic stroke, and can promote the improvement of neurological deficit. Clinically, it is mainly used for 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 vacuum distillation, the highest purity can only reach about 98%, and the number of impurities de...
Claims
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