CN102942467B - Preparation method of divalproex sodium - Google Patents
Preparation method of divalproex sodium Download PDFInfo
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- CN102942467B CN102942467B CN 201210393735 CN201210393735A CN102942467B CN 102942467 B CN102942467 B CN 102942467B CN 201210393735 CN201210393735 CN 201210393735 CN 201210393735 A CN201210393735 A CN 201210393735A CN 102942467 B CN102942467 B CN 102942467B
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Abstract
The invention relates to a preparation method of divalproex sodium. The method comprises the following steps of firstly dissolving valproic acid and sodium valproate in an organic solvent, heating to a temperature of 30-60 DEG C, reacting for 1-5 hours with stirring, then cooling to a temperature of -10 DEG C-20 DEG C, standing, and crystallizing to obtain the divalproex sodium. The preparation method employs a low temperature crystallization process, so that the obtained product has good product quality and high purity, and fits medicinal standard without further purification. Besides, the preparation method is simple in operations and mild in reaction conditions, has no toxic and side product generated, and is easy for industrialized production.
Description
Technical field
The present invention relates to technical field of medicine synthesis, specifically, relate to a kind of preparation method of Sodium hydrogen divalproate.
Background technology
Sodium hydrogen divalproate is a kind of epilepsy, bipolar affective disorder and migrainous medicine of being used for the treatment of, and its chemical name is two-(valproic acid) hydrogen sodium, and molecular formula is C
16H
31NaO
4, molecular weight is 310.37.
The oligomer that Sodium hydrogen divalproate is comprised of valproic acid and the Sodium Valproate of equimolar ratio, this material not only has the curative properties identical with valproic acid and Sodium Valproate, and overcome the shortcoming that valproic acid and Sodium Valproate have as classical antiepileptic drug: valproic acid is liquid at normal temperatures, is difficult for making the solid preparation of convenient oral; Sodium Valproate is the moisture absorption very easily, the poor stability of the pharmaceutical preparation of making.
At present, by U.S. Abbott (ABBOTT) development and production, its commodity are called Depakote to Sodium hydrogen divalproate, and successively go on the market on the U.S., Canada, Germany, Philippines, France, Britain and India and other places.
In the synthetic method of bibliographical information Sodium hydrogen divalproate, all be take Sodium Valproate or valproic acid as starting raw material, through different synthetic routes, final sintetics Sodium hydrogen divalproate.
Such as Abbott at its U.S. Patent application US4,988,731, US5,212, a kind of preparation method of Sodium Valproate oligopolymer is disclosed in 326, be that 166g Sodium Valproate and 144g valproic acid are reacted in acetone, temperature of reaction is 50 ℃, reacts complete, mixture is cooled to 0 ℃, filtration, crystallization obtain the Sodium Valproate oligopolymer, and yield is about 90%.The shortcoming of this technology is that reactant filters and crystallization at 0 ℃, causes its purity low, brings hidden danger to drug safety.
Procos SpA company is at its U.S. Patent application US6, discloses a kind of preparation method of Sodium hydrogen divalproate in 667,420, be that 81.8g sodium methylate and 437g valproic acid are reacted in heptane, then azeotropic is removed methyl alcohol, and 60-70 ℃ of filtration, get Sodium hydrogen divalproate, yield is 88.3%.The shortcoming of this technology is; need to use sodium methylate in the reaction process; sodium methylate is met water, damp atmosphere, acids, naked light etc. can cause burning, and its steam has strong impulse and corrodibility to respiratory tract, after the suction; can cause that maincenter suppresses; eye is produced intense stimulus, can cause blindly, skin contact can cause and burn; to having relatively high expectations of labour protection, therefore be unfavorable for industrialized production.In addition, the purity of the product that obtains of this technology is also lower.
Liu Junhong, the people such as Qiu Longhui disclose a kind of preparation technology of Sodium hydrogen divalproate in Chinese invention patent CN101003476, under 55 ℃-90 ℃, valproic acid and the Sodium Valproate of equimolar ratio are dissolved in the suitable solvent, underpressure distillation after the reaction, until solvent-free steaming collected white solid, obtain Sodium hydrogen divalproate.The shortcoming of this technology is, the product purification process adopts reduced pressure distillation process, and the purity of the Sodium hydrogen divalproate that obtains still is not improved significantly, so still there is hidden danger in drug safety.
Summary of the invention
For the deficiencies in the prior art, the purpose of this invention is to provide a kind of preparation method of Sodium hydrogen divalproate, the method is simple, is easy to suitability for industrialized production, and the Sodium hydrogen divalproate purity of preparation is high, needn't do further to make with extra care, and can meet medicinal standard.
For achieving the above object, the invention provides following technical scheme:
A kind of preparation method of Sodium hydrogen divalproate comprises the steps: at first valproic acid and Sodium Valproate to be dissolved in the organic solvent, is heated to 30～60 ℃, stirring reaction 1～5 hour; Then be cooled to-10～-20 ℃, leave standstill, crystallization gets Sodium hydrogen divalproate.
Preferably, the mol ratio of described valproic acid and Sodium Valproate is 1:1.2～1.2:1.
Preferably, the mol ratio of described valproic acid and Sodium Valproate is 1:1.
Preferably, describedly leave standstill, time of crystallization is 1～3 hour.
Preferably, treat that temperature reduces-15 ℃, crystallization, the Sodium hydrogen divalproate purity that obtains is the highest.
Should be noted that, organic solvent of the present invention can be selected the known any organic solvent of those skilled in the art, such as alcoholic solvent ethanol, ethylene glycol, Virahol, n-propyl alcohol, glycerol, propyl carbinol etc., ketones solvent acetone, butanone, pentanone, pimelinketone etc., varsol hexane, heptane, octane, nonane, decane, hexanaphthene, toluene, dimethylbenzene, methylene dichloride, trichloromethane etc.Preferably, described organic solvent is acetone.
Beneficial effect of the present invention:
(1) because after preparation method of the present invention adopted low temperature crystallization technique, the products obtained therefrom quality was good, and purity is high, needn't do further refiningly, namely meet medicinal standard;
(2) preparation method of the present invention is simple to operate, and reaction conditions is gentle, generates without other toxic byproduct, is easy to suitability for industrialized production.
Embodiment
Below further describe the present invention by embodiment.Because preferred following embodiment has described the present invention according to the present invention, some is modified and equivalent variations is apparent for those of ordinary skill in the art and comprises within the scope of the invention.
Embodiment 1
In reaction flask, add the 144g valproic acid, acetone 1000ml, heating in water bath to 30 ℃ adds Sodium Valproate 199.2g, be dissolved as colourless solution, stirring reaction 1 hour, filtrate was left standstill 1 hour under-10 ℃ of conditions, crystallization, filter, then wash in right amount with acetone, 50 ℃ of oven dry get the product Sodium hydrogen divalproate.
Embodiment 2
In reaction flask, add the 172.8g valproic acid, butanols 1000ml, heating in water bath to 60 ℃ adds Sodium Valproate 166g, be dissolved as colourless solution, stirring reaction 5 hours, filtrate was left standstill 3 hours under-20 ℃ of conditions, crystallization, filter, wash in right amount with butanols, 45 ℃ of oven dry get the product Sodium hydrogen divalproate.
Embodiment 3
In reaction flask, add the 144g valproic acid, hexane 1000ml, heating in water bath to 40 ℃ adds Sodium Valproate 166g, be dissolved as colourless solution, stirring reaction 2 hours, filtrate was left standstill 2 hours under-13 ℃ of conditions, crystallization, filter, wash in right amount with hexane, 40 ℃ of oven dry get the product Sodium hydrogen divalproate.
Embodiment 4
In reaction flask, add the 158.4g valproic acid, toluene 1000ml, heating in water bath to 50 ℃ adds Sodium Valproate 166g, be dissolved as colourless solution, stirring reaction 3 hours, filtrate left standstill under-16 ℃ of conditions 1 hour 30 minutes, crystallization, filter, wash in right amount with toluene, 50 ℃ of oven dry get the product Sodium hydrogen divalproate.
Embodiment 5
In reaction flask, add the 144g valproic acid, trichloromethane 1000ml, heating in water bath to 50 ℃ adds Sodium Valproate 182.6g, be dissolved as colourless solution, stirring reaction 4 hours, filtrate left standstill under-18 ℃ of conditions 2 hours 30 minutes, crystallization, filter, trichloromethane washes in right amount, and 60 ℃ of oven dry get the product Sodium hydrogen divalproate.
Embodiment 6
In reaction flask, add the 144.2g valproic acid, acetone 1000ml, heating in water bath to 30 ℃ adds Sodium Valproate 166.2g, be dissolved as colourless solution, stirring reaction 1 hour, filtrate was left standstill 1 hour under-15 ℃ of conditions, crystallization, filter, then wash in right amount with acetone, 50 ℃ of oven dry get the product Sodium hydrogen divalproate.
The comparative example 1
In reaction flask, add the 144.2g valproic acid, acetone 1000ml, heating in water bath to 50 ℃ adds Sodium Valproate 166.2g, be dissolved as colourless solution, stirring reaction 1 hour, filtrate was left standstill 1 hour under 0 ℃ of condition, crystallization, filter, then wash in right amount with acetone, 50 ℃ of oven dry get the product Sodium hydrogen divalproate.
The comparative example 2
In reaction flask, add the 144.2g valproic acid, propyl carbinol 1000ml, heating in water bath to 60 ℃ adds Sodium Valproate 166.2g, stirring reaction is opened underpressure distillation simultaneously, and pressure is remained on 300Pa, underpressure distillation gets Sodium hydrogen divalproate until till no longer including solvent and steaming, collect white solid.
Get the Sodium hydrogen divalproate of embodiment 1-5 and comparative example 1-2 preparation, measure respectively its purity according to the relevant regulations of American Pharmacopeia USP35-NF30 S1.
Concrete condition determination is as follows:
Chromatographic column: Agela XBP-phenyl, 4.6 * 150mm, 5 μ m 100
Moving phase: A:B:C=35:35:30, phosphoric acid is transferred pH to 3.0
A:0.5g citric acid+0.4g SODIUM PHOSPHATE, MONOBASIC is dissolved in the 1000ml water
B:6.8g potassium primary phosphate+1.7g sodium hydroxide is dissolved in 900ml water, and constant volume is transferred pH=7.4 to 1000ml with phosphoric acid
C: acetonitrile
Detect wavelength: 210nm
Flow velocity: 1.2 mL/min
Sampling volume: the dissolving of 20 μ L(moving phases)
Measurement result sees Table 1.
Table 1
Can be found out by result shown in the table 1, compared with prior art, the purity of the Sodium hydrogen divalproate that obtains according to preparation method of the present invention is significantly improved.
Claims (2)
1. the preparation method of a Sodium hydrogen divalproate is characterized in that, comprises the steps:
(1) at first valproic acid and Sodium Valproate are dissolved in the organic solvent, are heated to 30～60 ℃, stirring reaction 1～5 hour; (2) then be cooled to-10～-20 ℃, leave standstill, crystallization gets Sodium hydrogen divalproate, and the mol ratio of described valproic acid and Sodium Valproate is 1:1, describedly leaves standstill, time of crystallization is 1～3 hour.
2. the preparation method of a kind of Sodium hydrogen divalproate according to claim 1 is characterized in that, described organic solvent is acetone.
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| CN 201210393735 CN102942467B (en) | 2012-10-17 | 2012-10-17 | Preparation method of divalproex sodium |
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| CN114354803B (en) * | 2021-12-31 | 2023-11-14 | 成都倍特得诺药业有限公司 | Method for detecting related substances of sodium valproate oral solution |
| CN114853595B (en) * | 2022-06-01 | 2024-04-26 | 广州茂丰药业有限公司 | Preparation method of sodium valproate and valproic acid eutectic and product thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4988731A (en) * | 1979-08-20 | 1991-01-29 | Abbott Laboratories | Sodium hydrogen divalproate oligomer |
| WO2007004238A2 (en) * | 2005-07-06 | 2007-01-11 | Morepen Laboratories Limited | A process for the manufacture of divalproex sodium |
-
2012
- 2012-10-17 CN CN 201210393735 patent/CN102942467B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4988731A (en) * | 1979-08-20 | 1991-01-29 | Abbott Laboratories | Sodium hydrogen divalproate oligomer |
| WO2007004238A2 (en) * | 2005-07-06 | 2007-01-11 | Morepen Laboratories Limited | A process for the manufacture of divalproex sodium |
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