CN103664570B - The recoverying and utilizing method of divalproex sodium crystallization mother liquor - Google Patents
The recoverying and utilizing method of divalproex sodium crystallization mother liquor Download PDFInfo
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Abstract
The invention provides a kind of recoverying and utilizing method of divalproex sodium crystallization mother liquor.The method comprises: 1) divalproex sodium crystallization mother liquor concentrated, thus obtains the solid mixt containing Sodium hydrogen divalproate; 2) solid mixt that step 1) obtains is mixed with alkaline solution, described solid mixt is dissolved, thus obtains mixing solutions; 3) by step 2) mixing solutions that obtains mixes with inorganic salt, to produce valproate precipitation, is separated, and obtains described valproate precipitation; And 4) valproate that step 3) obtained precipitation mixes with acid solution, obtain organic layer, described organic layer is carried out fractionation, thus obtains valproic acid.The valproic acid yield that method of the present invention obtains can up to 93%, and purity is not less than 99.6%, can fulfilling medicinal requirements, and method of the present invention is simple, and reaction process is easy to control, and reduces real cost of production, meets the requirement of industrialized production.
Description
Technical field
The invention belongs to chemical field, in particular to a kind of recoverying and utilizing method of divalproex sodium crystallization mother liquor.
Background technology
Sodium hydrogen divalproate is a kind of anticonvulsion and medicine of being emotionally stable, and is mainly used in treatment epilepsy and bipolar affective disorder, also may be used for migraine and schizoid treatment.Sodium hydrogen divalproate is used for controlling the petit mal of epileptic, grand mal (grand mal), complex partial seizures, the outbreak relevant to Lennox-Gastaut syndrome.Sodium hydrogen divalproate combines and suppresses GABA transaminase.It is dissociated into valproate ion at gi tract and works.The gastrointestinal side effect of Sodium hydrogen divalproate is little, drug interaction is less, therefore has the physiological property being parity with or superiority over valproic acid or Sodium Valproate, is widely used clinically.
The report of the synthesis technique about Sodium hydrogen divalproate in currently available technology comprises:
American documentation literature US6,077, what adopt in 542 is condition of no solvent, is dissolved in valproic acid reacts by Sodium Valproate.The shortcoming of this method is: the partial concn of valproic acid and Sodium Valproate is uneven, and likely have several ratio to mix in the product therefore obtained, the purity drop of product, quality is wayward.
Adopt in Chinese patent literature CN101003476A: make solvent with alcohol, by valproic acid and the polymerization of Sodium Valproate equimolar ratio, reaction solvent is under reduced pressure distilled dry.The shortcoming of this method is: this technique has higher requirement to equipment, and general production is difficult to meet, and in drying process, easily cause product to lump, and affect product and use, quality is wayward.
American documentation literature US4,988,731 and US5,212, use acetone as solvent in 326, valproic acid and the polymerization of Sodium Valproate equimolar ratio, then subcooling crystallization, after filtration, drying under reduced pressure obtains product.The advantage of aforesaid method is good product quality, being most widely used therefore in current actual production.
But at above-mentioned patent documentation, particularly US4,988,731 and US5,212, in the technique described in 326, by the impact of cooling performance, in divalproex sodium crystallization mother liquor, at least also have the Sodium hydrogen divalproate of 10%-15% not separate out.In addition, also 2 methyl valeric acid and other impurity is contained in divalproex sodium crystallization mother liquor.Therefore, need to be further processed this crystalline mother solution, to meet environmental requirement increasingly strict at present.
For the recycling of divalproex sodium crystallization mother liquor, method conventional in currently available technology is: use recrystallization technology recovery Sodium hydrogen divalproate wherein, namely repeated multiple times condensing crystal is to reclaim Sodium hydrogen divalproate in crystalline mother solution.But the method operation is loaded down with trivial details, and the rate of recovery is low, and the Sodium hydrogen divalproate reclaimed is off quality or purity is not high, both effectively cannot utilize, and also increase real cost of production.
Summary of the invention
For solving above-mentioned problems of the prior art, the invention provides a kind of recoverying and utilizing method of divalproex sodium crystallization mother liquor.
Specifically, the invention provides:
(1) recoverying and utilizing method for divalproex sodium crystallization mother liquor, it comprises:
1) divalproex sodium crystallization mother liquor is concentrated, thus obtain the solid mixt containing Sodium hydrogen divalproate;
2) solid mixt that step 1) obtains is mixed with alkaline solution, described solid mixt is dissolved, thus obtains mixing solutions;
3) by step 2) mixing solutions that obtains mixes with inorganic salt, to produce valproate precipitation, is separated, and obtains described valproate precipitation; And
4) valproate precipitation step 3) obtained mixes with acid solution, obtains organic layer, described organic layer is carried out fractionation, thus obtains valproic acid.
(2) method Gen Ju (1), wherein, the solvent in described divalproex sodium crystallization mother liquor is acetone, butanone, ethanol or butanols, is more preferably acetone.
(3) method Gen Ju (1), wherein, step 2) pH of mixing solutions that obtains is 7.5-9.5, is more preferably 8.0.
(4) method Gen Ju (1), wherein, described alkaline solution is sodium hydroxide solution.
(5) method Gen Ju (4), wherein, the concentration of described sodium hydroxide solution is 10-30%(w/v), be more preferably 25%(w/v).
(6) method Gen Ju (1), wherein, step 2) also comprise: in described mixing solutions, add gac carry out desolventing technology.
(7) method Gen Ju (1), wherein, the inorganic salt in step 3) are magnesium chloride or calcium chloride.
(8) method Gen Ju (1), wherein, described acid solution is hydrochloric acid soln.
(9) method Gen Ju (8), wherein, the concentration of described hydrochloric acid soln is 1-10mol/L, is more preferably 2mol/L.
(10) method Gen Ju (1), wherein, in step 4), carries out vacuum fractionation by described organic layer, and the temperature of described vacuum fractionation is 112-114 DEG C, and pressure is 7-8mmHg.
Method of the present invention compared with prior art has the following advantages and positively effect:
1. method of the present invention is by being converted into valproic acid by the Sodium hydrogen divalproate in divalproex sodium crystallization mother liquor, achieves the recycling effectively to divalproex sodium crystallization mother liquor.The valproic acid purity obtained is high, is not less than 99.6%, and single contaminant content is less than 0.1%, and the total content of impurity is less than 0.5%, can fulfilling medicinal requirements.Prepare Sodium hydrogen divalproate therefore, it is possible to be directly used in, thus make the production technique of Sodium hydrogen divalproate achieve recycle, reduce real cost of production, really achieve economical environment-protective.
2. valproic acid yield obtained in method of the present invention can up to 93%, and such as, yield can up to 98% in a preferred embodiment of the invention.
3. method of the present invention is simple, and reaction process is easy to control, and without the need to the specific equipment of complexity, meets the requirement of industrialized production.
Embodiment
Below by way of the description of embodiment, the invention will be further described, but this is not limitation of the present invention, those skilled in the art are according to basic thought of the present invention, various amendment or improvement can be made, but only otherwise depart from basic thought of the present invention, all within the scope of the present invention.
In Sodium hydrogen divalproate synthesis technique, usually by Sodium Valproate and valproic acid with equimolar ratio reacting by heating in organic solvent, then crystallization, separation is carried out, thus obtain Sodium hydrogen divalproate crystal (can see (such as) american documentation literature US4,988,731 and US5,212,326), and remaining solution is described divalproex sodium crystallization mother liquor herein, the Sodium hydrogen divalproate wherein also containing the non-crystallization of part and organic solvent etc.
Herein " %(w/v) " refer to weight/volume percent, that is: (solute weight (g)/liquor capacity (mL)) × 100%.
Sodium hydrogen divalproate described is herein also referred to as valproate semisodium, valproic acid half sodium salt, International Nonproprietary Name (INN) is: Valproatesemisodium, CAS:76584-70-8, United States Adopted Names (USAN) is: divalproexsodium, molecular formula: C
16h
31o
4na, molecular weight: 310.40.Shown in the following chemical structural formula I of chemical structural formula, the low-molecular(weight)polymer that it is made up of equimolar valproic acid and Sodium Valproate.
Chemical structural formula I
Valproic acid described herein, also referred to as valproic acid, its molecular formula is C
8h
16o
2, molecular weight is 144.21, is at room temperature liquid.Valproic acid is slightly soluble in water; And Sodium Valproate is white crystalline powder or particle, slightly valproic acid is smelly, draws moist extremely strong, soluble in water, is soluble in ethanol, is dissolved in acetone hardly.
Valproate precipitation described herein refers to water insoluble or is slightly soluble in the salt of valproic acid of water, such as, Magnesium Valproate or valproic acid calcium etc., but the present invention is not limited thereto, the salt of other kind that those skilled in the art can learn according to general knowledge known in this field water insoluble or the valproic acid that is slightly soluble in water is also applicable.
The object of the present invention is to provide a kind of recoverying and utilizing method of divalproex sodium crystallization mother liquor.
The present inventor have been surprisingly found that by experiment: in the recycling process of divalproex sodium crystallization mother liquor, relative to the prior art of Sodium hydrogen divalproate being carried out recrystallization, Sodium hydrogen divalproate in divalproex sodium crystallization mother liquor is converted into valproic acid, purity, product that yield is higher can be obtained, and the product obtained can reach medicinal rank by valproic acid, can be recycled.On the basis that this finds, the present inventor obtains embodiment of the present invention further.
Specifically, the invention provides a kind of recoverying and utilizing method of divalproex sodium crystallization mother liquor, it comprises:
1) divalproex sodium crystallization mother liquor is concentrated, thus obtain the solid mixt containing Sodium hydrogen divalproate;
2) solid mixt that step 1) obtains is mixed with alkaline solution, described solid mixt is dissolved, thus obtains mixing solutions;
3) by step 2) mixing solutions that obtains mixes with inorganic salt, to produce valproate precipitation, is separated, and obtains described valproate precipitation; And
4) valproate precipitation step 3) obtained mixes with acid solution, obtains organic layer, described organic layer is carried out fractionation, thus obtains valproic acid.
Preferably, the solvent in described divalproex sodium crystallization mother liquor is acetone, butanone, ethanol or butanols, is more preferably acetone.
Preferably, step 2) pH of mixing solutions that obtains is 7.5-9.5, is preferably 8.0.
Preferably, described alkaline solution is alkali hydroxide soln, such as sodium hydroxide solution, potassium hydroxide solution etc.
It is further preferred that when using sodium hydroxide solution, the concentration of sodium hydroxide solution is 10-30%(w/v), be more preferably 25%(w/v).
Preferably, step 2) also comprise: in described mixing solutions, add gac carry out desolventing technology.
Preferably, the inorganic salt in step 3) are magnesium chloride or calcium chloride.
Preferably, described acid solution can be inorganic acid solution, such as hydrochloric acid soln, sulphuric acid soln etc.It is further preferred that when using hydrochloric acid soln, the concentration of hydrochloric acid soln is 1-10mol/L, is more preferably 2mol/L.
Preferably, in step 4), described organic layer is carried out vacuum fractionation, the temperature of described vacuum fractionation is 112-114 DEG C, and pressure is 7-8mmHg.
A kind of preferred embodiment of the present invention is:
A recoverying and utilizing method for divalproex sodium crystallization mother liquor, it comprises:
1) divalproex sodium crystallization mother liquor is concentrated, thus obtain the solid mixt containing Sodium hydrogen divalproate;
2) solid mixt that step 1) obtains is added in sodium hydroxide solution, thus obtains mixing solutions;
3) to step 2) add inorganic salt in the mixing solutions that obtains, filter, thus obtain the metal salt precipitate of valproic acid; And
4) valproate precipitation step 3) obtained is added in hydrochloric acid soln, the organic layer obtained is carried out fractionation, thus obtain valproic acid after reaction.
Another preferred embodiment of the present invention is:
1) Sodium hydrogen divalproate reaction mother liquor is concentrated into dry;
2) 10-30%(w/v is added) sodium hydroxide of concentration is entirely molten to mother liquor residue;
3) pH value controls 8.0;
4) add activated carbon decolorizing to filter;
5) add inorganic salt solution, separate out valproate white solid, filter, washing and drying;
6) valproate is added in dilute hydrochloric acid, separate valproic acid layer; And
7) fraction collecting 112-114 DEG C/7 ~ 8mm mercury column is collected in decompression.
Mode by the following examples further explains and describes content of the present invention, but these embodiments are not to be construed as limiting the scope of the invention.
In the examples below, the measuring method of the purity of valproic acid is vapor-phase chromatography.Concrete gas chromatography can measure part see Chinese Pharmacopoeia (the 3rd edition) Sodium Valproate.
In the examples below, the calculation formula of the yield of valproic acid is: (valproic acid weight/Sodium hydrogen divalproate residue weight) × 1.0764 × 100%.
In the examples below, divalproex sodium crystallization mother liquor is according to american documentation literature US4, and 988,731 and US5,212,326 methods recorded obtain, but the present invention is not limited thereto, and also can use the divalproex sodium crystallization mother liquor that other method obtains.
Embodiment 1
In there-necked flask, add Sodium hydrogen divalproate acetone reaction mother liquor 1700ml, acetone is reclaimed in air distillation, and complete to distillating when 60 DEG C, concentrated residue weighs about 75 grams.Add 25%(w/v) sodium hydroxide solution be about 39ml, stirring and adjusting pH to 8.0, in bottle, residue all dissolves, add gac 20 grams, stir filtration in 10 minutes, in filtrate, add the aqueous solution 54ml be made into by 27 grams of calcium chloride, stir and separate out a large amount of white solid, cooling, suction filtration, washing, dries to obtain white valproic acid calcium solid 74.9 grams, yield about 95%, content is greater than 99.1%.
The valproic acid calcium of gained is added in the hydrochloric acid 200ml of 2mol/L, stirs layering, upper organic layer underpressure distillation, collect the overhead product of 112-114 DEG C/7 ~ 8mm mercury column, obtain valproic acid transparent liquid 64.8 grams, it is 99.8% that vapor-phase chromatography records purity, and yield is 98%.
Embodiment 2
In there-necked flask, add Sodium hydrogen divalproate acetone reaction mother liquor 1700ml, acetone is reclaimed in air distillation, complete to distillating when 60 DEG C, concentrated residue weighs about 75 grams, adds 25%(w/v) sodium hydroxide solution be about 39ml, stirring and adjusting pH to 9.5, in bottle, residue all dissolves, and adds gac 20 grams, stirs filtration in 10 minutes, the aqueous solution 34ml be made into by 23 grams of magnesium chlorides is added in filtrate, stir and separate out a large amount of white solid, cooling, suction filtration, washing, dry to obtain white Magnesium Valproate solid 71.6 grams, yield about 95.2%, content is greater than 99.1%.
Added by the Magnesium Valproate of gained in the hydrochloric acid 200ml of 2mol/L, stir layering, upper organic layer underpressure distillation, collect the overhead product of 112-114 DEG C/7 ~ 8mm mercury column, obtain valproic acid transparent liquid 65 grams, it is 99.8% that vapor-phase chromatography records purity, and yield is 98%.
Claims (14)
1. a recoverying and utilizing method for divalproex sodium crystallization mother liquor, it comprises:
1) divalproex sodium crystallization mother liquor is concentrated, thus obtain the solid mixt containing Sodium hydrogen divalproate;
2) by step 1) solid mixt that obtains mixes with alkaline solution, described solid mixt dissolved, thus obtains mixing solutions;
3) by step 2) mixing solutions that obtains mixes with inorganic salt, to produce valproate precipitation, is separated, and obtains described valproate precipitation; And
4) by step 3) valproate that obtains precipitation mixes with acid solution, obtains organic layer, described organic layer is carried out fractionation, thus obtains valproic acid.
2. method according to claim 1, wherein, the solvent in described divalproex sodium crystallization mother liquor is acetone, butanone, ethanol or butanols.
3. method according to claim 1, wherein, the solvent in described divalproex sodium crystallization mother liquor is acetone.
4. method according to claim 1, wherein, step 2) pH of mixing solutions that obtains is 7.5-9.5.
5. method according to claim 1, wherein, step 2) pH of mixing solutions that obtains is 8.0.
6. method according to claim 1, wherein, described alkaline solution is sodium hydroxide solution.
7. method according to claim 6, wherein, the concentration of described sodium hydroxide solution is 10-30% (w/v).
8. method according to claim 6, wherein, the concentration of described sodium hydroxide solution is 25% (w/v).
9. method according to claim 1, wherein, step 2) also comprise: in described mixing solutions, add gac carry out desolventing technology.
10. method according to claim 1, wherein, step 3) in inorganic salt be magnesium chloride or calcium chloride.
11. methods according to claim 1, wherein, described acid solution is hydrochloric acid soln.
12. methods according to claim 11, wherein, the concentration of described hydrochloric acid soln is 1-10mol/L.
13. methods according to claim 11, wherein, the concentration of described hydrochloric acid soln is 2mol/L.
14. methods according to claim 1, wherein, in step 4) in, described organic layer is carried out vacuum fractionation, and the temperature of described vacuum fractionation is 112-114 DEG C, and pressure is 7-8mmHg.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5212326A (en) * | 1979-08-20 | 1993-05-18 | Abbott Laboratories | Sodium hydrogen divalproate oligomer |
| CN101643400A (en) * | 2009-06-26 | 2010-02-10 | 安徽丰原发酵技术工程研究有限公司 | Method for extracting succinic acid from fermentation liquor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5212326A (en) * | 1979-08-20 | 1993-05-18 | Abbott Laboratories | Sodium hydrogen divalproate oligomer |
| CN101643400A (en) * | 2009-06-26 | 2010-02-10 | 安徽丰原发酵技术工程研究有限公司 | Method for extracting succinic acid from fermentation liquor |
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