CN103664570A - Recycling method of divalproex sodium crystallization mother liquor - Google Patents
Recycling method of divalproex sodium crystallization mother liquor Download PDFInfo
- Publication number
- CN103664570A CN103664570A CN201210339737.7A CN201210339737A CN103664570A CN 103664570 A CN103664570 A CN 103664570A CN 201210339737 A CN201210339737 A CN 201210339737A CN 103664570 A CN103664570 A CN 103664570A
- Authority
- CN
- China
- Prior art keywords
- sodium hydrogen
- solution
- valproate
- hydrogen divalproate
- valproic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/02—Preparation of carboxylic acids or their salts, halides or anhydrides from salts of carboxylic acids
Abstract
The invention provides a recycling method of divalproex sodium crystallization mother liquor. The method comprises the following steps: 1) concentrating the divalproex sodium crystallization mother liquor to obtain a solid-state mixture containing divalproex sodium; 2) mixing the solid-state mixture obtained in the step 1) with an alkaline solution to dissolve the solid-state mixture to further obtain a mixed solution; 3) mixing the mixed solution obtained in the step 2) with an inorganic salt to produce a valproate precipitate, and separating to obtain the valproate precipitate; 4) mixing the valproate precipitate obtained in the step 3) with an acid solution to obtain an organic layer, and performing fractionation on the organic layer to obtain valproic acid. Through the method provided by the invention, the yield of obtained valproic acid can be as high as 93%, the purity is not lower than 99.6%, and valproic acid can meet medicinal requirements; the method provided by the invention has the advantages of simplicity, easiness in operation, easiness in control of reaction process and effect of reducing actual production cost, and is in line with requirements of industrial mass production.
Description
Technical field
The invention belongs to chemical field, in particular to a kind of recoverying and utilizing method of Sodium hydrogen divalproate crystalline mother solution.
Background technology
Sodium hydrogen divalproate is a kind of anticonvulsion and medicine of being emotionally stable, and is mainly used in treating epilepsy and bipolar affective disorder, also can be for migraine and schizoid treatment.Sodium hydrogen divalproate is used for controlling epileptic's petit mal, grand mal (grand mal), complex partial seizures, the outbreak relevant to Lennox-Gastaut syndrome.Sodium hydrogen divalproate combination also suppresses GABA transaminase.It is dissociated into valproate ion and works at gi tract.The gastrointestinal side effect of Sodium hydrogen divalproate is little, drug interaction is less, therefore has the physiological property that is parity with or superiority over valproic acid or Sodium Valproate, is widely used clinically.
Report about the synthesis technique of Sodium hydrogen divalproate in currently available technology comprises:
American documentation literature US6, what adopt in 077,542 is condition of no solvent, is about to Sodium Valproate and is dissolved in valproic acid and reacts.The shortcoming of this method is: the partial concn of valproic acid and Sodium Valproate is inhomogeneous, likely has several ratios to mix in the product therefore obtaining, the purity drop of product, and quality is wayward.
In Chinese patent literature CN101003476A, adopt: with alcohol, make solvent, 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, is difficult to meet, and in drying process, easily causes product caking on general production, affects product and uses, and quality is wayward.
American documentation literature US4, is used acetone to make solvent in 988,731 and US5,212,326, 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, therefore being most widely used in current actual production.
But at above-mentioned patent documentation, particularly US4,988,731 and US5, in the technique described in 212,326, be subject to the impact of cooling performance, in Sodium hydrogen divalproate crystalline mother solution, at least also have the Sodium hydrogen divalproate of 10%-15% not separate out.In addition, in Sodium hydrogen divalproate crystalline mother solution, also contain 2 methyl valeric acid and other impurity.Therefore, need to be further processed this crystalline mother solution, to meet increasingly strict environmental requirement at present.
For the recycling of Sodium hydrogen divalproate crystalline mother solution, method conventional in currently available technology is: use recrystallization technology to reclaim Sodium hydrogen divalproate wherein, 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 reclaiming is off quality or purity is not high, both cannot effectively utilize, and has also increased 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 Sodium hydrogen divalproate crystalline mother solution.
Particularly, the invention provides:
(1) recoverying and utilizing method for Sodium hydrogen divalproate crystalline mother solution, it comprises:
1) Sodium hydrogen divalproate crystalline mother solution is concentrated, thereby obtain the solid mixt that contains Sodium hydrogen divalproate;
2) solid mixt step 1) being obtained mixes with alkaline solution, described solid mixt is dissolved, thereby obtain mixing solutions;
3) by step 2) mixing solutions that obtains mixes with inorganic salt, and to produce valproate precipitation, separation, obtains described valproate precipitation; And
4) valproate precipitation step 3) being obtained is mixed with acid solution, obtains organic layer, described organic layer is carried out to fractionation, thereby obtain valproic acid.
(2) according to the method (1) described, wherein, the solvent in described Sodium hydrogen divalproate crystalline mother solution is acetone, butanone, ethanol or butanols, more preferably acetone.
(3) pH of the mixing solutions method according to (1), wherein, step 2) obtaining is 7.5-9.5, more preferably 8.0.
(4) according to the method (1) described, wherein, described alkaline solution is sodium hydroxide solution.
(5) method according to (4), wherein, the concentration of described sodium hydroxide solution is 10-30%(w/v), 25%(w/v more preferably).
(6) method according to (1), wherein, step 2) also comprise: to adding the gac processing of decolouring in described mixing solutions.
(7) according to the method (1) described, wherein, the inorganic salt in step 3) are magnesium chloride or calcium chloride.
(8) according to the method (1) described, wherein, described acid solution is hydrochloric acid soln.
(9) according to the method (8) described, wherein, the concentration of described hydrochloric acid soln is 1-10mol/L, more preferably 2mol/L.
(10) according to the method (1) described, wherein, in step 4), described organic layer is carried out to vacuum fractionation, the temperature of described vacuum fractionation is 112-114 ℃, 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, by the Sodium hydrogen divalproate in Sodium hydrogen divalproate crystalline mother solution is converted into valproic acid, has realized the recycling effectively to Sodium hydrogen divalproate crystalline mother solution.Resulting valproic acid purity 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.Therefore can be directly used in and prepare Sodium hydrogen divalproate, thereby make the production technique of Sodium hydrogen divalproate realize recycle, reduce real cost of production, really realize economical environment-protective.
2. in method of the present invention, prepared valproic acid yield can be up to 93%, and for example, yield can be 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 complicated specific equipment, meets the requirement of industrialized production.
Embodiment
Below the invention will be further described for the description by embodiment, but this is not limitation of the present invention, those skilled in the art are according to basic thought of the present invention, can make various modifications or improvement, 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, conventionally by Sodium Valproate and valproic acid with equimolar ratio reacting by heating in organic solvent, then carry out crystallization, separation, thereby obtain Sodium hydrogen divalproate crystal (can for example, referring to () american documentation literature US4,988,731 and US5,212,326), and remaining solution is described Sodium hydrogen divalproate crystalline mother solution herein, wherein also contains the part not Sodium hydrogen divalproate of crystallization and organic solvent etc.
Described " %(w/v) " refers to weight/volume percent, that is: (solute weight (g)/liquor capacity (mL)) * 100% herein.
Described Sodium hydrogen divalproate is also referred to as valproate semisodium, valproic acid half sodium salt herein, International Nonproprietary Name (INN) is: Valproate semisodium, CAS:76584-70-8, United States Adopted Names (USAN) is: divalproex sodium, 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 comprised of equimolar valproic acid and Sodium Valproate.
Chemical structural formula I
Valproic acid 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 strongly, soluble in water, is soluble in ethanol, is dissolved in hardly acetone.
Described valproate precipitation refers to water insoluble or is slightly soluble in the salt of the valproic acid of water herein, for example, Magnesium Valproate or valproic acid calcium etc., but the invention is not restricted to this, other kind that those skilled in the art can learn according to general knowledge known in this field water insoluble or to be slightly soluble in the salt of valproic acid of water also applicable.
The object of the present invention is to provide a kind of recoverying and utilizing method of Sodium hydrogen divalproate crystalline mother solution.
The inventor have been surprisingly found that by experiment: in the recycling process of Sodium hydrogen divalproate crystalline mother solution, with respect to Sodium hydrogen divalproate being carried out to the prior art of recrystallization, Sodium hydrogen divalproate in Sodium hydrogen divalproate crystalline mother solution is converted into valproic acid, can access purity, product that yield is higher, and the product obtaining can reach medicinal rank by valproic acid, can be recycled.On the basis of this discovery, the inventor has further obtained embodiment of the present invention.
Particularly, the invention provides a kind of recoverying and utilizing method of Sodium hydrogen divalproate crystalline mother solution, it comprises:
1) Sodium hydrogen divalproate crystalline mother solution is concentrated, thereby obtain the solid mixt that contains Sodium hydrogen divalproate;
2) solid mixt step 1) being obtained mixes with alkaline solution, described solid mixt is dissolved, thereby obtain mixing solutions;
3) by step 2) mixing solutions that obtains mixes with inorganic salt, and to produce valproate precipitation, separation, obtains described valproate precipitation; And
4) valproate precipitation step 3) being obtained is mixed with acid solution, obtains organic layer, described organic layer is carried out to fractionation, thereby obtain valproic acid.
Preferably, the solvent in described Sodium hydrogen divalproate crystalline mother solution is acetone, butanone, ethanol or butanols, more preferably acetone.
The pH of the mixing solutions preferably, step 2) obtaining 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.
More preferably, when using sodium hydroxide solution, the concentration of sodium hydroxide solution is 10-30%(w/v), 25%(w/v more preferably).
Preferably, step 2) also comprise: to adding the gac processing of decolouring in described mixing solutions.
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.More preferably, when using hydrochloric acid soln, the concentration of hydrochloric acid soln is 1-10mol/L, more preferably 2mol/L.
Preferably, in step 4), described organic layer is carried out to vacuum fractionation, the temperature of described vacuum fractionation is 112-114 ℃, and pressure is 7-8mmHg.
A kind of preferred embodiment of the present invention is:
A recoverying and utilizing method for Sodium hydrogen divalproate crystalline mother solution, it comprises:
1) Sodium hydrogen divalproate crystalline mother solution is concentrated, thereby obtain the solid mixt that contains Sodium hydrogen divalproate;
2) solid mixt step 1) being obtained is added in sodium hydroxide solution, thereby obtains mixing solutions;
3) to step 2) add inorganic salt in the mixing solutions that obtains, filter, thereby obtain the metal salt precipitate of valproic acid; And
4) valproate precipitation step 3) being obtained is added in hydrochloric acid soln, the organic layer obtaining is carried out to fractionation, thereby 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) adding 10-30%(w/v) sodium hydroxide of concentration is entirely molten to mother liquor residue;
3) pH value is controlled at 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 of collecting 112-114 ℃/7 ~ 8mm mercury column is collected in decompression.
Mode by the following examples further explains and describes content of the present invention, but these embodiment are not to be construed as limiting the scope of the invention.
In following examples, the measuring method of the purity of valproic acid is vapor-phase chromatography.Concrete gas chromatography can be measured part referring to Chinese Pharmacopoeia (the 3rd edition) Sodium Valproate.
In following examples, the calculation formula of the yield of valproic acid is: (valproic acid weight/Sodium hydrogen divalproate residue weight) * 1.0764 * 100%.
In following examples, Sodium hydrogen divalproate crystalline mother solution is according to american documentation literature US4, and 988,731 and US5,212,326 methods of recording are resulting, but the invention is not restricted to this, the Sodium hydrogen divalproate crystalline mother solution that also can use other method to obtain.
Embodiment 1
In there-necked flask, add Sodium hydrogen divalproate acetone reaction mother liquor 1700ml, acetone is reclaimed in air distillation, distillates completely during to 60 ℃, and concentrated residue is weighed approximately 75 grams.Add 25%(w/v) the about 39ml of sodium hydroxide solution, stirring and adjusting pH to 8.0, bottle in a residue all dissolve, add 20 grams of gacs, stir filtration in 10 minutes, in filtrate, add the aqueous solution 54ml being made into by 27 grams of calcium chloride, stir and separate out a large amount of white solids, cooling, suction filtration, washing, dries to obtain 74.9 grams of white valproic acid calcium solids, yield approximately 95%, content is greater than 99.1%.
The valproic acid calcium of gained is added in the hydrochloric acid 200ml of 2mol/L, stir layering, upper strata organic layer underpressure distillation, collect the overhead product of 112-114 ℃/7 ~ 8mm mercury column, obtain 64.8 grams of valproic acid transparent liquids, 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, during to 60 ℃, distillate completely, concentrated residue is weighed approximately 75 grams, adds 25%(w/v) the about 39ml of sodium hydroxide solution, stirring and adjusting pH to 9.5, in bottle, residue all dissolves, and adds 20 grams of gacs, stirs filtration in 10 minutes, in filtrate, add the aqueous solution 34ml being made into by 23 grams of magnesium chlorides, a large amount of white solids are separated out in stirring, cooling, suction filtration, washing, dry to obtain 71.6 grams of white Magnesium Valproate solids, yield approximately 95.2%, content is greater than 99.1%.
The Magnesium Valproate of gained is added in the hydrochloric acid 200ml of 2mol/L, stir layering, upper strata organic layer underpressure distillation, the overhead product of 112-114 ℃/7 ~ 8mm of collection mercury column, obtains 65 grams of valproic acid transparent liquids, and it is 99.8% that vapor-phase chromatography records purity, and yield is 98%.
Claims (10)
1. a recoverying and utilizing method for Sodium hydrogen divalproate crystalline mother solution, it comprises:
1) Sodium hydrogen divalproate crystalline mother solution is concentrated, thereby obtain the solid mixt that contains Sodium hydrogen divalproate;
2) solid mixt step 1) being obtained mixes with alkaline solution, described solid mixt is dissolved, thereby obtain mixing solutions;
3) by step 2) mixing solutions that obtains mixes with inorganic salt, and to produce valproate precipitation, separation, obtains described valproate precipitation; And
4) valproate precipitation step 3) being obtained is mixed with acid solution, obtains organic layer, described organic layer is carried out to fractionation, thereby obtain valproic acid.
2. method according to claim 1, wherein, the solvent in described Sodium hydrogen divalproate crystalline mother solution is acetone, butanone, ethanol or butanols, more preferably acetone.
3. the pH of mixing solutions method according to claim 1, wherein, step 2) obtaining is 7.5-9.5, more preferably 8.0.
4. method according to claim 1, wherein, described alkaline solution is sodium hydroxide solution.
5. method according to claim 4, wherein, the concentration of described sodium hydroxide solution is 10-30%(w/v), 25%(w/v more preferably).
6. method according to claim 1, wherein, step 2) also comprise: to adding the gac processing of decolouring in described mixing solutions.
7. method according to claim 1, wherein, the inorganic salt in step 3) are magnesium chloride or calcium chloride.
8. method according to claim 1, wherein, described acid solution is hydrochloric acid soln.
9. method according to claim 8, wherein, the concentration of described hydrochloric acid soln is 1-10mol/L, more preferably 2mol/L.
10. method according to claim 1, wherein, in step 4), carries out vacuum fractionation by described organic layer, and the temperature of described vacuum fractionation is 112-114 ℃, and pressure is 7-8mmHg.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210339737.7A CN103664570B (en) | 2012-09-13 | 2012-09-13 | The recoverying and utilizing method of divalproex sodium crystallization mother liquor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210339737.7A CN103664570B (en) | 2012-09-13 | 2012-09-13 | The recoverying and utilizing method of divalproex sodium crystallization mother liquor |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103664570A true CN103664570A (en) | 2014-03-26 |
| CN103664570B CN103664570B (en) | 2016-03-23 |
Family
ID=50303466
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210339737.7A Active CN103664570B (en) | 2012-09-13 | 2012-09-13 | The recoverying and utilizing method of divalproex sodium crystallization mother liquor |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103664570B (en) |
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 |
-
2012
- 2012-09-13 CN CN201210339737.7A patent/CN103664570B/en active Active
Patent 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103664570B (en) | 2016-03-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105348154B (en) | The recovery method of sulfosalicylic acid in a kind of Doxycycline production waste liquid | |
| BRPI0922836B1 (en) | process for the preparation of a monovalent succinate salt | |
| CN102766185A (en) | Method for respectively recovering ursodesoxycholic acid and chenodeoxycholic acid from ursodesoxycholic acid waste mother liquor | |
| CN103086845A (en) | Method for preparing L-menthol | |
| CN103664570B (en) | The recoverying and utilizing method of divalproex sodium crystallization mother liquor | |
| CN103508974A (en) | Method for treating methyl 2-(aminosulfonyl)benzoate crystallization mother solution | |
| CN101028988A (en) | Purification method of beta-methylnaphthalene | |
| CN103664574B (en) | Recycle the method for divalproex sodium crystallization mother liquor | |
| JP2001187760A (en) | Method for purifying 1,1,1,5,5,5-hexafluoroacetylacetone | |
| CN108439435A (en) | A kind of method that direct method prepares potassium nitrate | |
| CN114621107A (en) | Method for recycling product from dapoxetine hydrochloride mother liquor | |
| CN101492400B (en) | Method for preparing high-purity acamprosate calcium | |
| CN103254102B (en) | A kind of method of purifying acrylamide alkyl sulfonic acid | |
| CN103588685A (en) | Triketone ammonium salt compounds and preparation method and application thereof | |
| CN110603227B (en) | Process for producing aqueous zinc halide solution | |
| CN106565581A (en) | A method for comprehensive recovery and utilization of lithium containing mixed salts in a polyphenylene sulfide production process | |
| US9604895B2 (en) | Lactate production process | |
| CN104743722B (en) | Comprehensive treatment method for high-concentration sodium sulfate wastewater generated in dicumyl peroxide production | |
| CN102219793B (en) | Method for purifying D (-)-sulbenicillin sodium | |
| CN102070537B (en) | Rosuvastatin calcium compound and novel refining method thereof | |
| CN101941898B (en) | Purification method of vitamin K3 | |
| JP2014065637A (en) | Method of producing lithium iodide aqueous solution and use thereof | |
| CN103304405B (en) | A kind of method of selective chlorination | |
| CN108484581A (en) | A kind of new Candesartan dimer impurity and its synthetic method | |
| WO2012070423A1 (en) | Process for preparing adamantane polyol |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CP03 | Change of name, title or address |
Address after: 100871, Beijing, Haidian District Cheng Fu Road 298, founder building, 9 floor Patentee after: PEKING UNIVERSITY FOUNDER GROUP Co.,Ltd. Patentee after: PKU HEALTHCARE Corp.,Ltd. Patentee after: PKU HEALTHCARE INDUSTRY Group Address before: 100871, Beijing, Haidian District, Cheng Fu Road, No. 298, Zhongguancun Fangzheng building, 5 floor Patentee before: PEKING UNIVERSITY FOUNDER GROUP Co.,Ltd. Patentee before: SOUTHWEST SYNTHETIC PHARMACEUTICAL Corp.,Ltd. Patentee before: Pku Healthcare Industry Group Co.,Ltd. |
|
| CP03 | Change of name, title or address | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20221020 Address after: 3007, Hengqin international financial center building, No. 58, Huajin street, Hengqin new area, Zhuhai, Guangdong 519031 Patentee after: New founder holdings development Co.,Ltd. Patentee after: PKU HEALTHCARE Corp.,Ltd. Patentee after: Peking University Medical Management Co.,Ltd. Address before: 100871, Beijing, Haidian District Cheng Fu Road 298, founder building, 9 floor Patentee before: PEKING UNIVERSITY FOUNDER GROUP Co.,Ltd. Patentee before: PKU HEALTHCARE Corp.,Ltd. Patentee before: PKU HEALTHCARE INDUSTRY Group |
|
| TR01 | Transfer of patent right |