CN113173845A - Method for preparing valproic acid - Google Patents
Method for preparing valproic acid Download PDFInfo
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- CN113173845A CN113173845A CN202110336627.4A CN202110336627A CN113173845A CN 113173845 A CN113173845 A CN 113173845A CN 202110336627 A CN202110336627 A CN 202110336627A CN 113173845 A CN113173845 A CN 113173845A
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- valproic acid
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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 61
- 229960000604 valproic acid Drugs 0.000 title claims abstract description 31
- 238000000034 method Methods 0.000 title claims abstract description 24
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 35
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 31
- 239000007864 aqueous solution Substances 0.000 claims abstract description 18
- 239000007858 starting material Substances 0.000 claims abstract description 5
- 238000005580 one pot reaction Methods 0.000 claims abstract description 3
- 239000012071 phase Substances 0.000 claims description 34
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 claims description 14
- 239000003513 alkali Substances 0.000 claims description 11
- 229940102566 valproate Drugs 0.000 claims description 11
- 239000008346 aqueous phase Substances 0.000 claims description 10
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 9
- 238000005191 phase separation Methods 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 239000012895 dilution Substances 0.000 claims description 2
- 238000010790 dilution Methods 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 239000002585 base Substances 0.000 claims 1
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 abstract description 12
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 abstract description 10
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 abstract description 9
- JCXJVPUVTGWSNB-UHFFFAOYSA-N nitrogen dioxide Inorganic materials O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 abstract description 8
- MGWGWNFMUOTEHG-UHFFFAOYSA-N 4-(3,5-dimethylphenyl)-1,3-thiazol-2-amine Chemical compound CC1=CC(C)=CC(C=2N=C(N)SC=2)=C1 MGWGWNFMUOTEHG-UHFFFAOYSA-N 0.000 abstract description 6
- 239000002253 acid Substances 0.000 abstract description 6
- 239000003054 catalyst Substances 0.000 abstract description 4
- 235000010288 sodium nitrite Nutrition 0.000 abstract description 4
- 230000002378 acidificating effect Effects 0.000 abstract description 3
- 150000001408 amides Chemical class 0.000 abstract description 3
- 230000001590 oxidative effect Effects 0.000 abstract description 3
- 238000005903 acid hydrolysis reaction Methods 0.000 abstract description 2
- 230000007797 corrosion Effects 0.000 abstract description 2
- 238000005260 corrosion Methods 0.000 abstract description 2
- 239000007789 gas Substances 0.000 abstract description 2
- 239000002994 raw material Substances 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 abstract 4
- 150000001735 carboxylic acids Chemical class 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000001816 cooling Methods 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 206010010904 Convulsion Diseases 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 229940084026 sodium valproate Drugs 0.000 description 3
- UZRGQIZTJOPZGE-UHFFFAOYSA-N 2-cyano-2-propylpentanoic acid Chemical group CCCC(C(O)=O)(C#N)CCC UZRGQIZTJOPZGE-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 230000020477 pH reduction Effects 0.000 description 2
- FGPPDYNPZTUNIU-UHFFFAOYSA-N pentyl pentanoate Chemical compound CCCCCOC(=O)CCCC FGPPDYNPZTUNIU-UHFFFAOYSA-N 0.000 description 2
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 2
- -1 sodium alkoxide Chemical class 0.000 description 2
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 1
- UMJGAWHIMHSGMU-UHFFFAOYSA-N 2,2-dipropylpentanoic acid Chemical compound CCCC(CCC)(CCC)C(O)=O UMJGAWHIMHSGMU-UHFFFAOYSA-N 0.000 description 1
- MLIREBYILWEBDM-UHFFFAOYSA-M 2-cyanoacetate Chemical compound [O-]C(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-M 0.000 description 1
- 206010000117 Abnormal behaviour Diseases 0.000 description 1
- XJFQVBJESIEXKM-UHFFFAOYSA-N CCCCC(OCC(C)(C)C#N)=O Chemical compound CCCCC(OCC(C)(C)C#N)=O XJFQVBJESIEXKM-UHFFFAOYSA-N 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- ICMAFTSLXCXHRK-UHFFFAOYSA-N Ethyl pentanoate Chemical compound CCCCC(=O)OCC ICMAFTSLXCXHRK-UHFFFAOYSA-N 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 206010034759 Petit mal epilepsy Diseases 0.000 description 1
- 208000037012 Psychomotor seizures Diseases 0.000 description 1
- 239000012445 acidic reagent Substances 0.000 description 1
- BIGPRXCJEDHCLP-UHFFFAOYSA-N ammonium bisulfate Chemical compound [NH4+].OS([O-])(=O)=O BIGPRXCJEDHCLP-UHFFFAOYSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 208000028316 focal seizure Diseases 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- HNBDRPTVWVGKBR-UHFFFAOYSA-N n-pentanoic acid methyl ester Natural products CCCCC(=O)OC HNBDRPTVWVGKBR-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 208000005809 status epilepticus Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- NIJJYAXOARWZEE-UHFFFAOYSA-M valproate Chemical compound CCCC(C([O-])=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
-
- 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
-
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing valproic acid, which takes valacitrile as a starting material to prepare the valproic acid by a one-pot method. According to the method, valproic acid is prepared from valpronitrile as a raw material by using a sulfuric acid aqueous solution as a catalyst at 120-160 ℃, the reaction yield can reach 70%, and the purity of a valproic acid product can reach 99%. The method adopts the mechanism of sulfuric acid hydrolysis, and compared with the traditional mechanism of oxidizing amide into carboxylic acid by nitrous acid, the method avoids the pollution of atmosphere and water body caused by the conversion of sodium nitrite into nitrous acid in an acidic environment and the further conversion of nitrous acid into nitric oxide and nitrogen dioxide gas under an acid condition, improves the operation safety of operators, and avoids the corrosion of nitric oxide and nitrogen dioxide to equipment.
Description
Technical Field
The invention relates to the technical field of preparation of valproic acid, and particularly relates to a method for preparing valproic acid.
Background
Sodium valproate is chemically named as 2-propylvalerate and is suitable for preventing and treating various types of epileptic seizures, such as petit mal, focal seizure, psychomotor seizure, mixed seizure, status epilepticus and personality behavior disorder caused by epilepsy. Valproic acid is used as a precursor for preparing sodium valproate, and the preparation method thereof is widely studied. For example: in patent CN111349003A, ethyl valerate is used as a starting material, and a catalytic reaction is performed in an ether solution in a pyrrole metal catalyst to generate 2-propyl-ethyl valerate, then the 2-propyl-ethyl valerate is hydrolyzed by using sodium hydroxide to obtain a crude product of sodium valproate, and valproic acid is obtained by distilling off ethanol, acidifying and desalting, and the reaction equation is as follows:
however, the above method uses ether as a solvent and is industrially dangerous, and uses pyrrole metal as a catalyst, which is not common industrially and is dangerous, and tripropylacetate impurities are easily produced in the first reaction step.
For example: in patent US4127604, cyanoacetate and bromopropane are used as starting materials, sodium alkoxide is used as an alkali reagent to perform a catalytic reaction to prepare 2-cyano-2-propylmethyl valerate, and propionitrile is obtained through hydrolysis, acidification and high-temperature deacidification; valpronitrile is hydrolyzed by 80% sulfuric acid to become valproamide, and valproic acid is obtained after nitrous acid is further added into a reaction system for oxidation, wherein the reaction equation is as follows (wherein the compound A is 2-cyano-2-propyl methyl valerate, the compound B is 2-cyano-2-propyl valeric acid, the compound C is valpronitrile, and the compound D is):
however, in the above method, compound B (2-cyano-2-propylpentanoic acid) requires decarboxylation at a high temperature (160 to 190 ℃ C.) to produce valonitrile (compound C); after valproonitrile is hydrolyzed into valproate by 80% sulfuric acid, the reaction mechanism of the reaction system for oxidizing amide to obtain valproic acid by using sodium nitrite aqueous solution under an acidic condition is as follows:
equation 1:
equation 2: NaNO2+H2SO4→NaHSO4+HNO2
Equation 3: 2HNO2→NO↑+NO2↑+H2O
During the reaction, sodium nitrite and sulfuric acid react to generate nitrous acid as shown in equation 2, and then are further decomposed into nitric oxide and nitrogen dioxide as shown in equation 3, and the acidic toxic oxides of nitric oxide and nitrogen dioxide corrode metal equipment of plants and plants, and cause great pollution to the environment, so that the method has certain danger from the aspect of operation.
Disclosure of Invention
The invention aims to provide a method for preparing valproic acid aiming at the defects in the prior art.
In order to achieve the purpose, the invention adopts the technical scheme that:
the method for preparing the valproic acid by taking the valacitrile as a starting material and adopting a one-pot method comprises the following steps:
adding water, sulfuric acid and propionitrile into a reaction bottle, heating to 120-160 ℃, preserving heat for 20-40 h, and controlling the temperature until the reaction is finished;
step two, after the reaction is stopped, adding water into the reaction liquid for dilution and phase separation, extracting the separated oil phase with water again, and adding an alkali aqueous solution into the extracted oil phase to generate a valproate aqueous solution;
extracting the aqueous solution of valproate by using an organic solvent, discarding an oil phase, and adding sulfuric acid into the aqueous phase to neutralize the aqueous phase until the pH value is 1-2; and (4) phase separation is carried out again, the water phase is discarded, and the oil phase is extracted by water and then is subjected to reduced pressure distillation to obtain the valproic acid.
The mechanism of the method for preparing valproic acid is as follows: under the condition that sulfuric acid is used as an acid reagent, valacitrile is converted into an intermediate product, namely valacinamide, at 120-160 ℃, the valacinamide is further hydrolyzed and converted into a crude valacic acid product under the condition, ammonium bisulfate is generated at the same time, the crude valacic acid product is salified by using an aqueous solution of alkali, and the valacic acid product is obtained through solvent extraction, acidification, distillation and purification:
further, in the first step, the mass ratio of the sulfuric acid to the propionitrile is (1.6-2.4): 1.
further, in the second step, the alkali in the alkali solution is one or more of sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate and lithium hydroxide.
Further, the molar weight of the alkali in the alkali solution is 1.1-1.5 times of that of the propionitrile.
Further, in the third step, the organic solvent is chloroform, ethyl acetate, isopropyl acetate or toluene.
By adopting the technical scheme, compared with the prior art, the invention has the following technical effects:
according to the method, valproic acid is prepared from valpronitrile as a raw material by using a sulfuric acid aqueous solution as a catalyst at 120-160 ℃, the reaction yield can reach 70%, and the purity of a valproic acid product can reach 99%.
The method adopts the sulfuric acid hydrolysis mechanism of the propionitrile, and compared with the traditional mechanism of oxidizing amide into carboxylic acid by nitrous acid, the method avoids the pollution of atmosphere and water body caused by the conversion of sodium nitrite into nitrous acid in an acid environment and the further conversion of nitrous acid into nitric oxide and nitrogen dioxide gas under the acid condition, improves the operation safety of operators, and avoids the corrosion of nitric oxide and nitrogen dioxide to equipment.
Detailed Description
The present invention is further illustrated by the following examples, which are not to be construed as limiting the invention. It should be noted that the embodiments and features of the embodiments may be combined with each other without conflict.
Example 1
Preparation of valproic acid:
adding 200g of water into a reaction bottle, cooling in a water bath, slowly adding 450g of concentrated sulfuric acid (with the concentration of 98%) to control the internal temperature to be below 60 ℃, then adding 200g of propionitrile, slowly heating to 135 ℃, preserving heat for 20-40 h, and controlling the temperature until the reaction is finished;
cooling to 30 ℃, slowly adding 350g of water, after phase separation, discarding the water phase, and extracting the oil phase once by using 100g of water; transferring the extracted oil phase to a reaction bottle, slowly adding 332g of 25% sodium hydroxide aqueous solution (sodium hydroxide 1.3eq), keeping the temperature at 60 ℃ for 4 hours, and finishing the reaction to generate a valproate aqueous solution;
the aqueous solution of valproate was cooled to 30 ℃, extracted 3 times with 100ml of dichloromethane, the oil phase was discarded, 112g of concentrated sulfuric acid (98% concentration) was slowly added to the aqueous phase to neutralize the solution to pH 1, the phases were separated, the aqueous phase was discarded, the oil phase was extracted twice with 100ml of water, the phases were separated, and the oil phase was distilled under reduced pressure using an oil pump to give 161g of valproic acid in 70% yield and 99% purity.
Example 2
Preparation of valproic acid:
adding 200g of water into a reaction bottle, cooling in a water bath, slowly adding 380g of concentrated sulfuric acid (with the concentration of 98%) to control the internal temperature to be below 60 ℃, then adding 200g of propionitrile, slowly heating to 140 ℃, preserving the temperature for 20-40 h, and controlling the temperature until the reaction is finished;
cooling to 30 ℃, slowly adding 180g of water, after phase separation, discarding the water phase, and extracting the oil phase once by using 100g of water; transferring the extracted oil phase to a reaction bottle, slowly adding 306.8g of 25% sodium hydroxide aqueous solution (sodium hydroxide 1.2eq), keeping the temperature at 60 ℃ for 4 hours, and finishing the reaction to generate a valproate aqueous solution;
the aqueous solution of valproate was cooled to 30 ℃, extracted 3 times with 150ml of dichloromethane, the oil phase was discarded, 104g of concentrated sulfuric acid (98% concentration) was slowly added to the aqueous phase to neutralize the solution to pH 1, the phases were separated, the aqueous phase was discarded, the oil phase was extracted once with 100ml of water, the phases were separated, and the oil phase was distilled under reduced pressure using an oil pump to obtain 184g of valproic acid with a yield of 80% and a purity of 99%.
Example 3
Preparation of valproic acid:
adding 180g of water into a reaction bottle, cooling in a water bath, slowly adding 352g of concentrated sulfuric acid (with the concentration of 98%) to control the internal temperature to be below 60 ℃, adding 200g of propionitrile, dividing reflux into water to be 150 ℃, preserving the heat at 150 ℃ for 20-40 h, and controlling the temperature until the reaction is finished;
cooling to 30 ℃, slowly adding 120g of water, after phase separation, discarding the water phase, and extracting the oil phase once by 200g of water; transferring the extracted oil phase to a reaction bottle, slowly adding 345g of 25% sodium hydroxide aqueous solution (sodium hydroxide 1.35eq) at 60 ℃, preserving the temperature for 4 hours, and finishing the reaction to generate a valproate aqueous solution;
the aqueous solution of valproate was cooled to 30 ℃, extracted 3 times with 200ml of dichloromethane, the oil phase was discarded, 120g of concentrated sulfuric acid (98% concentration) was slowly added to the aqueous phase to neutralize the solution to pH 1, the phases were separated, the aqueous phase was discarded, the oil phase was extracted twice with 100ml of water, the phases were separated, and the oil phase was distilled under reduced pressure using an oil pump to give 170g of valproic acid in 74% yield and 99% purity.
While the invention has been described with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes in form and detail may be made therein without departing from the spirit and scope of the invention.
Claims (5)
1. A method for preparing valproic acid, which is characterized in that valproic acid is prepared from valacil as a starting material by a one-pot method, and comprises the following steps:
adding water, sulfuric acid and propionitrile into a reaction bottle, heating to 120-160 ℃, preserving heat for 20-40 h, and controlling the temperature until the reaction is finished;
step two, after the reaction is stopped, adding water into the reaction liquid for dilution and phase separation, extracting the separated oil phase with water again, and adding an alkali solution into the extracted oil phase to generate a valproate aqueous solution;
extracting the aqueous solution of valproate by using an organic solvent, discarding an oil phase, and adding sulfuric acid into the aqueous phase to neutralize the aqueous phase until the pH value is 1-2; and (4) phase separation is carried out again, the water phase is discarded, and the oil phase is extracted by water and then is subjected to reduced pressure distillation to obtain the valproic acid.
2. The method for preparing valproic acid according to claim 1, wherein in step one, the mass ratio of the sulfuric acid to the valproonitrile is (1.6-2.4): 1.
3. the method for preparing valproic acid according to claim 1, wherein in step two, the alkali in the alkali solution is one or more of sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate and lithium hydroxide.
4. The method for preparing valproic acid according to claim 1, wherein the molar amount of the base in said alkali solution in the second step is 1.1 to 1.5 times the molar amount of said valproonitrile.
5. The method for preparing valproic acid according to claim 1, wherein in step three, the organic solvent is chloroform, ethyl acetate, isopropyl acetate or toluene.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110336627.4A CN113173845A (en) | 2021-03-29 | 2021-03-29 | Method for preparing valproic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110336627.4A CN113173845A (en) | 2021-03-29 | 2021-03-29 | Method for preparing valproic acid |
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| Publication Number | Publication Date |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116143658A (en) * | 2022-12-16 | 2023-05-23 | 上海青平药业有限公司 | A method for simultaneously preparing tripropylacetonitrile, tripropylamide, and tripropylacetic acid |
| WO2023221851A1 (en) * | 2022-05-16 | 2023-11-23 | 湖南省湘中制药有限公司 | Method for co-producing valproamide and sodium valproate |
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|---|---|---|---|---|
| GB2068962A (en) * | 1980-02-13 | 1981-08-19 | Sanofi Sa | Process for preparing valproic acid |
| CN102643188A (en) * | 2012-05-09 | 2012-08-22 | 岳阳亚王精细化工有限公司 | Method for preparing 5-bromovalerate |
| CN105085242A (en) * | 2014-05-25 | 2015-11-25 | 山东方明药业集团股份有限公司 | Synthetic method of high-quality acetonedicarboxylic acid and acetonedicarboxylate |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2068962A (en) * | 1980-02-13 | 1981-08-19 | Sanofi Sa | Process for preparing valproic acid |
| CN102643188A (en) * | 2012-05-09 | 2012-08-22 | 岳阳亚王精细化工有限公司 | Method for preparing 5-bromovalerate |
| CN105085242A (en) * | 2014-05-25 | 2015-11-25 | 山东方明药业集团股份有限公司 | Synthetic method of high-quality acetonedicarboxylic acid and acetonedicarboxylate |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2023221851A1 (en) * | 2022-05-16 | 2023-11-23 | 湖南省湘中制药有限公司 | Method for co-producing valproamide and sodium valproate |
| GB2634661A (en) * | 2022-05-16 | 2025-04-16 | Hunan Xiangzhong Pharmaceutical Co Ltd | Method for co-producing valproamide and sodium valproate |
| CN116143658A (en) * | 2022-12-16 | 2023-05-23 | 上海青平药业有限公司 | A method for simultaneously preparing tripropylacetonitrile, tripropylamide, and tripropylacetic acid |
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