CN117623911A - Refining method of valproic acid - Google Patents
Refining method of valproic acid Download PDFInfo
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- CN117623911A CN117623911A CN202311781739.6A CN202311781739A CN117623911A CN 117623911 A CN117623911 A CN 117623911A CN 202311781739 A CN202311781739 A CN 202311781739A CN 117623911 A CN117623911 A CN 117623911A
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- NIJJYAXOARWZEE-UHFFFAOYSA-N Valproic acid Chemical compound CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 title claims abstract description 117
- 229960000604 valproic acid Drugs 0.000 title claims abstract description 84
- 238000000034 method Methods 0.000 title claims abstract description 31
- 238000007670 refining Methods 0.000 title claims abstract description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 40
- 239000003960 organic solvent Substances 0.000 claims abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000010438 heat treatment Methods 0.000 claims abstract description 17
- 239000007787 solid Substances 0.000 claims abstract description 15
- 239000002253 acid Substances 0.000 claims abstract description 11
- 238000001816 cooling Methods 0.000 claims abstract description 9
- 238000002425 crystallisation Methods 0.000 claims abstract description 9
- 230000008025 crystallization Effects 0.000 claims abstract description 9
- 239000000047 product Substances 0.000 claims abstract description 9
- 238000003756 stirring Methods 0.000 claims abstract description 8
- 238000000605 extraction Methods 0.000 claims abstract description 7
- 239000003513 alkali Substances 0.000 claims abstract description 6
- 239000012074 organic phase Substances 0.000 claims abstract description 6
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 claims abstract description 5
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 claims abstract description 5
- 238000005804 alkylation reaction Methods 0.000 claims abstract description 5
- 239000012043 crude product Substances 0.000 claims abstract description 5
- 230000029936 alkylation Effects 0.000 claims abstract description 4
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 4
- 238000004090 dissolution Methods 0.000 claims abstract description 4
- 238000001035 drying Methods 0.000 claims abstract description 4
- 230000007062 hydrolysis Effects 0.000 claims abstract description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 4
- 230000020477 pH reduction Effects 0.000 claims abstract description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000007858 starting material Substances 0.000 claims abstract description 4
- 238000005406 washing Methods 0.000 claims abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 24
- 238000004821 distillation Methods 0.000 claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 150000001298 alcohols Chemical class 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000013341 scale-up Methods 0.000 abstract description 2
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 61
- 239000012535 impurity Substances 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 239000008213 purified water Substances 0.000 description 10
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 description 9
- 229940084026 sodium valproate Drugs 0.000 description 9
- 239000012452 mother liquor Substances 0.000 description 8
- 238000001914 filtration Methods 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- DIRSQLKNZQKDBK-UHFFFAOYSA-N 2,2-dipropylpropanedioic acid Chemical compound CCCC(C(O)=O)(C(O)=O)CCC DIRSQLKNZQKDBK-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 1
- 230000003556 anti-epileptic effect Effects 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000003303 reheating Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- GYBMSOFSBPZKCX-UHFFFAOYSA-N sodium;ethanol;ethanolate Chemical compound [Na+].CCO.CC[O-] GYBMSOFSBPZKCX-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
- C07C51/38—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by decarboxylation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
- C07C51/44—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation by distillation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/48—Separation; Purification; Stabilisation; Use of additives by liquid-liquid treatment
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/20—Air quality improvement or preservation, e.g. vehicle emission control or emission reduction by using catalytic converters
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- Engineering & Computer Science (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for refining valproic acid, which comprises the following steps: diethyl malonate and bromopropane are used as starting materials, and are subjected to sodium ethylate alkylation, strong alkali hydrolysis, strong acid acidification and heating decarboxylation, and then distilled to obtain a crude product of valproic acid; adding the crude valproic acid product into a first organic solvent, adding sodium hydroxide and water into the first organic solvent, stirring, heating for dissolution, and cooling for crystallization; dissolving the separated solid with dilute acid solution, adding a second organic solvent for extraction, washing an organic phase, drying, concentrating and rectifying to obtain refined valproic acid. The prepared valproic acid has the advantages of good purity, high yield, simple and convenient operation and suitability for industrial scale-up production.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a method for refining valproic acid.
Background
The statements herein merely provide background information related to the present disclosure and may not necessarily constitute prior art.
Sodium valproate is a nitrogen-free spectral antiepileptic, and is suitable for various types of epileptic seizures.
Valproic acid is a key precursor for preparing sodium valproate, is also an important auxiliary material in the research of pharmaceutical dosage forms, and a preparation method thereof is widely researched.
In the synthesis of sodium valproate (Wu Chang increase, chemical engineer, 2015, 08 th) the target product is prepared by alkylation of sodium ethoxide, hydrolysis by strong alkali, acidification by strong acid and reheating decarboxylation by taking diethyl malonate and bromopropane as starting materials, and the reaction equation is as follows:
the method is easy to produce impurities in the first alkylation reaction, the valproic acid product has poor purity, and the distillation temperature range is narrower, so that the yield is lower.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention aims to provide a method for refining valproic acid. The method is simple to operate, and the obtained valproic acid has good purity and is suitable for industrial mass production.
In order to achieve the above object, the present invention is realized by the following technical scheme:
a method for refining valproic acid, comprising the following steps:
diethyl malonate and bromopropane are used as starting materials, and are subjected to sodium ethylate alkylation, strong alkali hydrolysis, strong acid acidification and heating decarboxylation, and then distilled to obtain a crude product of valproic acid;
adding the crude valproic acid product into a first organic solvent, adding sodium hydroxide and water into the first organic solvent, stirring, heating for dissolution, and cooling for crystallization;
dissolving the separated solid with dilute acid solution, adding a second organic solvent for extraction, washing an organic phase, drying, concentrating and rectifying to obtain refined valproic acid.
The crude valproic acid is prepared by the method of sodium valproate synthesis (Wu Chang increase, chemical engineer, 2015, 08), and the distillation temperature range is 100-102 ℃/1.11Pa for improving the purity of the crude valproic acid in the preparation method, but the small distillation temperature range leads to lower valproic acid yield.
The first organic solvent is used for dissolving valproic acid; naOH and valproic acid are solid after being semi-sodium salt, and can be purified by crystallization; the addition of a small amount of water can promote the dissolution of NaOH, so that the salifying system can reach homogeneous phase rapidly, or NaOH is not easy to dissolve in acetonitrile, and the NaOH can be dissolved and cleared only after a long time of reflux. Valproic acid and sodium hydroxide become valproic acid semi-sodium salt, and solid can be separated out after cooling in a system; most of valproic acid impurities are organic acids, and can also form salts with NaOH, so that solid is hardly precipitated when the temperature is reduced in a system. After cooling and filtering, the solid sodium valproate is purer, and then the solid sodium valproate is prepared into the valproic acid by acid regulation, so that the solid sodium valproate is purer; while the salt formed by the impurities is mostly dissolved in the mother liquor and removed.
In some embodiments, the distillation temperature range is 90-105 ℃/1.11Pa. According to the invention, the distillation temperature interval is adjusted to 90-105 ℃/1.11Pa, so that the yield of the valproic acid can be effectively improved, impurities in the crude valproic acid obtained by distillation are increased, and the valproic acid product with the purity meeting the requirement can be obtained through a subsequent refining method, and the yield of the valproic acid and the purity of the valproic acid can be improved by the method.
In some embodiments, the first organic solvent is selected from one or a combination of acetonitrile, alcohols, acetone, or tetrahydrofuran. Experiments show that the solvents can dissolve the valproic acid and can be mutually dissolved with water, but the solubility of the valproic acid semi-sodium is small, so that the valproic acid can be purified.
Preferably, the first organic solvent is acetonitrile. Alcohols and valproic acid can form ester under high temperature condition, impurities can be introduced, and the semi-sodium salt is not easy to separate out; tetrahydrofuran is unpleasant and has a great taste; the yield is 10% lower under the same condition of acetone, and acetonitrile has the best purifying effect on valproic acid.
Preferably, the mass ratio of the crude valproic acid to the first organic solvent is 1:10-30, preferably 1:15-30.
In some embodiments, the molar ratio of crude valproic acid to sodium hydroxide is 1:0.4-0.6, preferably 1:0.45-0.55, and more preferably 1:0.5.
In some embodiments, the mass ratio of valproic acid to water is 1:0.1-0.5, preferably 1:0.15-0.5.
In some embodiments, the temperature of stirring and heating to dissolve is 60-85 ℃, preferably 70-80 ℃;
the heating time is 0.5-2h, preferably 0.5-1h.
In some embodiments, the crystallization temperature is from-10 ℃ to 30 ℃, preferably from 0 ℃ to 10 ℃;
the crystallization time is 1-3h, preferably 1-2h.
In some embodiments, the dilute acid solution is dilute hydrochloric acid or dilute sulfuric acid.
Preferably, the molar ratio of valproic acid to sulfuric acid is 1:0.25-0.4, preferably 1:0.3-0.35.
In some embodiments, the second organic solvent is selected from one or more of n-heptane, n-hexane, dichloromethane, ethyl acetate, toluene, preferably n-heptane.
Preferably, the mass ratio of valproic acid to the second organic solvent is 1:3-10, preferably 1:4-6.
In some embodiments, the organic phase is dried with anhydrous sodium sulfate.
The beneficial effects achieved by one or more embodiments of the present invention described above are as follows:
valproic acid does not provide quality standards in the chinese pharmacopoeia, the european pharmacopoeia (EP 11.0) with stricter limits. After the valproic acid obtained by the method described in the synthesis of sodium valproate (Wu Chang increase, chemical engineer, 2015, 08) has large front and rear fractions, and does not reach the EP standard, the refined product meets the EP standard (single impurity is less than 0.05%, and total impurity is less than 0.2%).
The valproic acid prepared by the method has the advantages of good purity, high yield, simple and convenient operation and suitability for industrial scale-up production.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention.
FIG. 1 is a gas chromatogram of a crude valproic acid prepared in example 1 of the present invention;
FIG. 2 is a gas chromatogram of valproic acid refined in example 1 of the present invention;
FIG. 3 is a gas chromatogram of valproic acid refined in example 2 of the present invention;
FIG. 4 is a gas chromatogram of the crude valproic acid prepared in comparative example 1 of the present invention;
FIG. 5 is a gas chromatogram of valproic acid after refining crude valproic acid prepared in comparative example 1 of comparative example 2 of the present invention;
FIG. 6 is a gas chromatogram of valproic acid after refining crude valproic acid prepared in example 1 in comparative example 3 of the present invention.
FIG. 7 is a gas chromatogram of valproic acid after refining crude valproic acid prepared in example 1 in comparative example 4 of the present invention.
FIG. 8 is a gas chromatogram of valproic acid after refining crude valproic acid prepared in example 1 in comparative example 5 of the present invention.
Detailed Description
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
In order to enable those skilled in the art to more clearly understand the technical scheme of the present invention, the technical scheme of the present invention will be described in detail with reference to specific embodiments.
Example 1
Adding 1912g of 20% sodium ethoxide-ethanol solution into a 5L three-port bottle, stirring and heating to 60 ℃, dripping 300.0g of diethyl malonate, heating and refluxing for 2h, cooling to 70 ℃, slowly dripping 690g of bromopropane (with obvious reaction heat release and heating), continuously preserving heat for 4h after dripping, cooling to 20-30 ℃, filtering, concentrating and evaporating mother liquor to obtain a yellow solid-liquid mixture, adding a solution prepared by 900ml of ethanol and 270g of NaOH-900ml of purified water, refluxing and reacting for 6h, adding 900ml of purified water, regulating pH=1 by using concentrated hydrochloric acid, preserving heat and crystallizing for 2h at 20-30 ℃, filtering, washing with water to obtain 239.7g of dipropylmalonic acid, and obtaining white solid with the yield of 68.0%.
200g of dipropylmalonic acid is put into a 500ml reaction bottle, heated to an internal temperature of 180 ℃, and when the reactants are completely melted and no bubbles are generated, the heating is stopped. Distillation under reduced pressure, collecting 90-105deg.C/1.11 Pa fraction to obtain colorless transparent liquid, i.e. valproic acid crude product 145.6g with yield 95.1%, GLC (EP method) measuring purity 99.227%, maximum single impurity 0.72% (purity disqualification), as shown in figure 1.
And (3) refining: adding 300ml of acetonitrile and 20.0g of crude valproic acid into a 500ml reaction bottle, stirring, adding 2.8g of NaOH and 3.0g of purified water, heating to above 70 ℃, preserving heat for 1h, cooling, crystallizing at 0-10 ℃ for 2h, filtering, and leaching with acetonitrile to obtain a white solid; the solid is put back into a 500ml reaction bottle, 100ml of n-heptane and 4.2g of concentrated sulfuric acid-60 ml of purified water are added to prepare a solution, the solution is extracted and separated, the organic phase is washed with 60ml of purified water, dried by anhydrous sodium sulfate and filtered to obtain colorless mother liquor, the colorless mother liquor is concentrated by a rotary evaporator, and after no liquid flows down, the distillation is carried out under reduced pressure, and the fraction of 90-105 ℃/1.11Pa is collected. 18.6g of a colourless oily liquid are obtained in 93.0% yield. GLC (EP method) measured a purity of 99.983% and a maximum single impurity of 0.017% (purity acceptable), see FIG. 2.
Example 2
Adding 300ml of acetonitrile and 20.0g of the crude valproic acid product in comparative example 1 into a 500ml reaction bottle, stirring, adding 2.8g of NaOH and 3.0g of purified water, heating to above 70 ℃, preserving heat for 1h, cooling, crystallizing for 2h at 0-10 ℃, filtering, and leaching with acetonitrile to obtain a white solid; the solid is put back into a 500ml reaction bottle, 100ml of n-heptane and 4.2g of concentrated sulfuric acid-60 ml of purified water are added to prepare a solution, the solution is extracted and separated, the organic phase is washed with 60ml of purified water, dried by anhydrous sodium sulfate and filtered to obtain colorless mother liquor, the colorless mother liquor is concentrated by a rotary evaporator, and after no liquid flows down, the distillation is carried out under reduced pressure, and the fraction of 90-105 ℃/1.11Pa is collected. 18.1g of a colourless oily liquid are obtained in 90.5% yield. GLC (EP method) showed 100.00% purity with no other impurity peaks (acceptable purity) as shown in FIG. 3.
Comparative example 1
Valproic acid was prepared as described in synthesis of sodium valproate.
100g of dipropylmalonic acid is put into a 500ml reaction bottle, heated to an internal temperature of 180 ℃, and the heating is stopped when the reactants are completely melted and no bubbles are generated. Distillation under reduced pressure, collecting fraction of 100-102 deg.C/1.11 Pa to obtain colorless transparent liquid, i.e. valproic acid crude product 63.3g, yield 82.6%, and GLC (EP method) measured purity 99.601%, maximum single impurity 0.121% (purity disqualification), as shown in figure 4.
Comparative example 2
30.0g of the crude valproic acid obtained in comparative example 1 was again rectified and fractions of 102-105 ℃/1.11Pa were collected to give a colorless transparent liquid, i.e., 26.7g of valproic acid, 89.0% yield, 99.853% purity as measured by GLC (EP method), 0.071% maximum single impurity (purity off-specification), see FIG. 5.
Comparative example 3
The acid and the alkali are changed, enough alkali is used for salifying valproic acid, and the crystallization and the filtration steps are omitted by extraction and back extraction purification.
20.0g of the crude valproic acid product in example 1 is put into a 100ml reaction bottle, 50ml of purified water and 5.6g of NaOH are added, the mixture is fully stirred for 1h at room temperature, 40ml of n-heptane is added for extraction, water phase is collected, concentrated sulfuric acid is used for adjusting pH to be=1, then n-heptane is used for extraction, anhydrous sodium sulfate is used for drying, the filtration is carried out, colorless mother liquor is obtained, the mother liquor is concentrated in a rotary evaporator, no liquid flow exists, then the distillation is carried out under reduced pressure, and fractions of 90-105 ℃/1.11Pa are collected. A colorless transparent liquid, i.e., 18.4g of valproic acid was obtained in a yield of 93.0%, and a GLC (EP method) gave a purity of 99.764% and a maximum of 0.092% (purity failure) as shown in FIG. 6.
Comparative example 4
The difference from example 1 is that: the "purified water 3.0 g" in the purification step was omitted, and the same as in example 1 was repeated. Valproic acid was 99.861% pure with a maximum single impurity of 0.077% (purity off-specification), see FIG. 7.
Comparative example 5
The difference from example 1 is that: the procedure of example 1 was repeated except that 300ml of acetonitrile and 300ml of ethyl acetate were used in the purification step. The solid obtained by the reaction is sticky, is easy to attach to the bottle wall, is difficult to filter and is extremely difficult to operate. The valproic acid purity was 99.804% and the maximum single impurity was 0.081% (purity off-specification), see FIG. 8.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A method for refining valproic acid is characterized in that: the method comprises the following steps:
diethyl malonate and bromopropane are used as starting materials, and are subjected to sodium ethylate alkylation, strong alkali hydrolysis, strong acid acidification and heating decarboxylation, and then distilled to obtain a crude product of valproic acid;
adding the crude valproic acid product into a first organic solvent, adding sodium hydroxide and water into the first organic solvent, stirring, heating for dissolution, and cooling for crystallization;
dissolving the separated solid with dilute acid solution, adding a second organic solvent for extraction, washing an organic phase, drying, concentrating and rectifying to obtain refined valproic acid.
2. The method for preparing valproic acid according to claim 1, characterized in that: the temperature range of the distillation is 90-105 ℃/1.11Pa.
3. The method for preparing valproic acid according to claim 1, characterized in that: the first organic solvent is selected from one or a combination of acetonitrile, alcohols, acetone or tetrahydrofuran;
preferably, the first organic solvent is acetonitrile.
4. A process for the preparation of valproic acid according to claim 3, characterized in that: the mass ratio of the crude valproic acid to the first organic solvent is 1:10-30, preferably 1:15-30.
5. The method for preparing valproic acid according to claim 1, characterized in that: the molar ratio of the crude valproic acid to the sodium hydroxide is 1:0.4-0.6, preferably 1:0.45-0.55.
6. The method for preparing valproic acid according to claim 1, characterized in that: the mass ratio of valproic acid to water is 1:0.1-0.5, preferably 1:0.15-0.5.
7. The method for preparing valproic acid according to claim 1, characterized in that: stirring, heating and dissolving at 60-85deg.C, preferably 70-80deg.C;
the heating time is 0.5-2h, preferably 0.5-1h.
8. The method for preparing valproic acid according to claim 1, characterized in that: the crystallization temperature is-10 ℃ to 30 ℃, preferably 0 ℃ to 10 ℃;
the crystallization time is 1-3h, preferably 1-2h.
9. The method for preparing valproic acid according to claim 1, characterized in that: the dilute acid solution is dilute hydrochloric acid or dilute sulfuric acid;
preferably, the molar ratio of valproic acid to sulfuric acid is 1:0.25-0.4, preferably 1:0.3-0.35.
10. The method for preparing valproic acid according to claim 1, characterized in that: the second organic solvent is selected from one or more of n-heptane, n-hexane, dichloromethane, ethyl acetate and toluene, preferably n-heptane;
preferably, the mass ratio of valproic acid to the second organic solvent is 1:3-10, preferably 1:4-6.
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