CN113200844A - Preparation method of sodium valproate - Google Patents
Preparation method of sodium valproate Download PDFInfo
- Publication number
- CN113200844A CN113200844A CN202110333947.4A CN202110333947A CN113200844A CN 113200844 A CN113200844 A CN 113200844A CN 202110333947 A CN202110333947 A CN 202110333947A CN 113200844 A CN113200844 A CN 113200844A
- Authority
- CN
- China
- Prior art keywords
- valproate
- water
- aqueous solution
- acid
- cyano
- 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.)
- Pending
Links
- NIJJYAXOARWZEE-UHFFFAOYSA-N di-n-propyl-acetic acid Natural products CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 title claims abstract description 138
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 title claims abstract description 98
- 229940084026 sodium valproate Drugs 0.000 title claims abstract description 64
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 83
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 69
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 68
- 229960000604 valproic acid Drugs 0.000 claims abstract description 66
- 239000007864 aqueous solution Substances 0.000 claims abstract description 61
- 239000000203 mixture Substances 0.000 claims abstract description 35
- 229940102566 valproate Drugs 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 16
- 239000003513 alkali Substances 0.000 claims abstract description 12
- 239000000243 solution Substances 0.000 claims abstract description 10
- TZHBUTDMKLWZDI-UHFFFAOYSA-N 2-cyanopropan-2-yl pentanoate Chemical compound CCCCC(=O)OC(C)(C)C#N TZHBUTDMKLWZDI-UHFFFAOYSA-N 0.000 claims abstract description 9
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 7
- 230000007062 hydrolysis Effects 0.000 claims abstract description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 69
- 235000019198 oils Nutrition 0.000 claims description 38
- 238000010438 heat treatment Methods 0.000 claims description 14
- -1 propyl 2-cyano-2-propylvalerate Chemical compound 0.000 claims description 14
- 235000019476 oil-water mixture Nutrition 0.000 claims description 13
- 238000001694 spray drying Methods 0.000 claims description 11
- 238000005191 phase separation Methods 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 9
- UZRGQIZTJOPZGE-UHFFFAOYSA-N 2-cyano-2-propylpentanoic acid Chemical compound CCCC(C(O)=O)(C#N)CCC UZRGQIZTJOPZGE-UHFFFAOYSA-N 0.000 claims description 8
- BIGPRXCJEDHCLP-UHFFFAOYSA-N ammonium bisulfate Chemical compound [NH4+].OS([O-])(=O)=O BIGPRXCJEDHCLP-UHFFFAOYSA-N 0.000 claims description 8
- 238000004821 distillation Methods 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 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
- 238000004321 preservation Methods 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
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 3
- 239000000126 substance Substances 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
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 238000007865 diluting Methods 0.000 claims description 2
- CVMXOHNPQYTUOZ-UHFFFAOYSA-N ethyl 2-cyano-2-propylpentanoate Chemical compound CCCC(CCC)(C#N)C(=O)OCC CVMXOHNPQYTUOZ-UHFFFAOYSA-N 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
- MFPLOZTTYKIUQU-UHFFFAOYSA-N methyl 2-cyano-2-propylpentanoate Chemical group CCCC(CCC)(C#N)C(=O)OC MFPLOZTTYKIUQU-UHFFFAOYSA-N 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 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
- 239000012670 alkaline solution Substances 0.000 claims 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 abstract description 57
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 abstract description 12
- 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
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 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
- 239000007789 gas Substances 0.000 abstract description 6
- 239000003054 catalyst Substances 0.000 abstract description 4
- 230000002378 acidificating effect Effects 0.000 abstract description 3
- 235000010288 sodium nitrite Nutrition 0.000 abstract description 3
- 239000002253 acid Substances 0.000 abstract description 2
- 150000001408 amides Chemical class 0.000 abstract description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 abstract description 2
- 230000007797 corrosion Effects 0.000 abstract description 2
- 238000005260 corrosion Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 239000012071 phase Substances 0.000 description 49
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 238000001816 cooling Methods 0.000 description 15
- WPRYUWYMOZQHIY-UHFFFAOYSA-N methyl 2-propylpentanoate Chemical compound CCCC(CCC)C(=O)OC WPRYUWYMOZQHIY-UHFFFAOYSA-N 0.000 description 11
- 239000000047 product Substances 0.000 description 8
- 238000010907 mechanical stirring Methods 0.000 description 5
- HNBDRPTVWVGKBR-UHFFFAOYSA-N n-pentanoic acid methyl ester Natural products CCCCC(=O)OC HNBDRPTVWVGKBR-UHFFFAOYSA-N 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000007921 spray Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 230000001502 supplementing effect Effects 0.000 description 5
- 239000008399 tap water Substances 0.000 description 5
- 235000020679 tap water Nutrition 0.000 description 5
- 206010010904 Convulsion Diseases 0.000 description 4
- 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
- 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 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000013067 intermediate product Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 238000005903 acid hydrolysis reaction Methods 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- WIKWUBHEBLFWHH-UHFFFAOYSA-N ethyl 2-propylpentanoate Chemical compound CCCC(CCC)C(=O)OCC WIKWUBHEBLFWHH-UHFFFAOYSA-N 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- FGPPDYNPZTUNIU-UHFFFAOYSA-N pentyl pentanoate Chemical compound CCCCCOC(=O)CCCC FGPPDYNPZTUNIU-UHFFFAOYSA-N 0.000 description 2
- 239000007858 starting material Substances 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
- 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
- 206010061334 Partial seizures Diseases 0.000 description 1
- 206010034759 Petit mal epilepsy Diseases 0.000 description 1
- 208000037012 Psychomotor seizures Diseases 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 238000001953 recrystallisation 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
- 208000005809 status epilepticus Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229940070710 valerate Drugs 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
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/06—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid amides
-
- 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
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
-
- 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)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of sodium valproate, which comprises the steps of taking 2-cyano-2-propyl valerate as a raw material, taking a sulfuric acid aqueous solution as a catalyst, obtaining a valproic acid and valproate mixture at 120-160 ℃, then using an alkali solution for hydrolysis to obtain a valproate aqueous solution, extracting, acidifying and rectifying to obtain valproic acid, wherein the reaction yield can reach 76%, and the purity of the valproic acid can reach 99%. Compared with the traditional mechanism that the nitrous acid oxidizes the amide to the carboxylic 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 sodium valproate preparation, and in particular relates to a preparation method of sodium valproate.
Background
The chemical name of the sodium valproate is 2-sodium valproate, and the molecular formula is as follows: the C8H15NaO2 has a molecular weight of 166.2, is white odorless crystalline powder easily soluble in water, has extremely strong hygroscopicity, and is suitable for preventing and treating various epileptic seizures, such as petit-mal seizures, focal seizures, psychomotor seizures, mixed seizures, status epilepticus and personality behavior disorder caused by epilepsy.
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.
Another example is: 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, after valpronitrile is hydrolyzed into valproate by 80% sulfuric acid, the reaction mechanism of the reaction system is as follows:
reaction equation 1:
reaction equation 2: NaNO2+H2SO4→NaHSO4+HNO2
Reaction 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 preparation method of sodium valproate, aiming at the defects in the prior art.
In order to achieve the purpose, the invention adopts the technical scheme that:
a preparation method of sodium valproate is provided, which comprises the following steps:
adding water, sulfuric acid and 2-cyano-2-propyl valerate into a reaction kettle, heating up, refluxing and dividing water, carrying out hydrolysis and deacidification reactions, keeping the temperature for 15-40 h at 120-150 ℃, and controlling the temperature until the reaction is finished to obtain an oil-water mixture;
step two, separating oil from water of the oil-water mixture obtained in the step one to obtain a yellow oily mixture of valproic acid and valproate;
adding an alkali solution into the yellow oily mixture obtained in the second step, carrying out heat preservation reaction for 4-6 hours at the temperature of 60-80 ℃, extracting a water phase after the reaction is finished by using an organic solvent, and discarding an oil phase to obtain a valproate aqueous solution;
step four, adding sulfuric acid into the valproate aqueous solution obtained in the step three to neutralize until the pH value is 1-2, discarding a water phase after phase separation, extracting an oil phase which is a crude valproate product with water, and then performing reduced pressure distillation to obtain valproic acid;
and fifthly, adding the valproic acid obtained in the fourth step into a reaction kettle, slowly dropwise adding a sodium hydroxide solution until the pH value is 8-10, and spray-drying the obtained sodium valproate aqueous solution to obtain the sodium valproate.
Further, the preparation method comprises the following steps:
adding water, sulfuric acid and 2-cyano-2-propyl valerate into a reaction kettle, heating to 120 ℃, refluxing and dividing water, performing hydrolysis and deacidification reactions, preserving heat for 20-40 hours at 120-150 ℃, and controlling until the reaction is finished to obtain an oil-water mixture;
step two, adding water into the oil-water mixture obtained in the step one, diluting sulfuric acid in a system, enabling an oil phase to be layered quickly, standing for layering, wherein the upper oil phase is a mixture of valproic acid and valproate, and the lower oil phase is an aqueous solution of ammonium bisulfate and sulfuric acid; washing the upper oil phase with water to obtain a yellow oily mixture of valproic acid and valproate;
adding aqueous alkali with the concentration of 15-30% into the yellow oily mixture obtained in the second step, and carrying out heat preservation reaction for 4-6 hours at the temperature of 60-80 ℃ so as to convert valproic acid into valproate and convert valproate into valproate and alcohol, extracting the water phase after the reaction is finished by using an organic solvent, and discarding the oil phase to obtain a valproate aqueous solution;
step four, adding sulfuric acid into the valproate aqueous solution obtained in the step three to neutralize until the pH value is 1-2, discarding a water phase after phase separation, extracting an oil phase which is a crude valproate product with water, and then performing reduced pressure distillation to obtain valproic acid;
and fifthly, adding the valproic acid obtained in the fourth step into a reaction kettle, slowly dropwise adding a sodium hydroxide aqueous solution with the concentration of 15-20% to obtain a sodium valproate aqueous solution, adjusting the pH value to 8-10, and spray-drying the obtained sodium valproate aqueous solution to obtain the sodium valproate.
The mechanism of the method for preparing valproic acid of the present invention is as follows, taking 2-cyano-2-propyl-methyl valerate as an example: the carboxylic acid methyl ester of the 2-cyano-2-propyl-methyl valerate is subjected to hydrolysis reaction in a sulfuric acid aqueous solution to generate an intermediate product of the 2-cyano-2-propyl valerate and generate a byproduct of methanol; performing deacidification reaction on carboxylic acid group of 2-cyano-2-propylpentanoic acid at 120-160 ℃ to generate carbon dioxide gas and an intermediate product of valproate; carrying out acid hydrolysis on a cyano group of the valpronitrile at 120-160 ℃ in a sulfuric acid aqueous solution to obtain an intermediate product, namely valproamide, and carrying out acid hydrolysis on the valproamide at 120-160 ℃ in the sulfuric acid aqueous solution to generate valproic acid and ammonium bisulfate; the valproic acid and the byproduct methanol in the system are subjected to esterification reaction under the catalysis of sulfuric acid to generate a mixture of methyl valproate and valproic acid; hydrolyzing the mixture of the methyl valproate and the valproic acid by using an aqueous solution of sodium hydroxide to obtain sodium valproate, then acidifying the sodium valproate to obtain valproic acid, and carrying out post-treatment on the valproic acid to obtain qualified valproic acid;
and (3) carrying out acid-base neutralization on the qualified valproic acid and the sodium hydroxide aqueous solution to prepare a sodium valproate aqueous solution, and carrying out spray drying to obtain valproic acid as follows:
further, in the first step, the molar amount of the sulfuric acid is 1.9 to 3 times that of the 2-cyano-2-propylvaleric acid.
Further, the chemical structural formula of the 2-cyano-2-propyl valerate is shown as formula (1):
wherein R is an alkyl group.
Further preferably, the 2-cyano-2-propylvalerate is methyl 2-cyano-2-propylvalerate, ethyl 2-cyano-2-propylvalerate, propyl 2-cyano-2-propylvalerate, butyl 2-cyano-2-propylvalerate, or isopropyl 2-cyano-2-propylvalerate.
Further, in the third 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 amount of the base in the alkali solution is 1.05 to 1.8 times the molar amount of the 2-cyano-2-propylpentanoic acid.
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:
the method comprises the steps of taking 2-cyano-2-propyl valerate as a raw material, taking a sulfuric acid aqueous solution as a catalyst, obtaining a mixture of valproic acid and methyl valproate at 120-160 ℃, hydrolyzing with an alkali solution to obtain a valproate aqueous solution, extracting, acidifying and rectifying to obtain valproic acid, wherein the reaction yield can reach 76%, and the purity of a valproic acid product can reach 99%.
Compared with the traditional mechanism that the nitrous acid oxidizes the amide to the carboxylic 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.
In the third step of the process, the sodium valproate aqueous solution is obtained by directly reacting the aqueous solution of sodium hydroxide with valproic acid, and the sodium valproate aqueous solution is obtained by spray drying, so that the operation process is simplified, and the problem of dissolution residue caused by recrystallization of an organic solvent is avoided.
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
(1) Preparation of valproic acid:
adding 214kg of tap water into a reaction kettle, starting a mechanical stirring paddle and cooling circulating water, slowly dropwise adding 214kg of concentrated sulfuric acid (concentrated sulfuric acid 2eq), controlling the internal temperature below 60 ℃, then adding 200kg of 2-cyano-2-isopropyl methyl valerate in batches, uniformly stirring, heating to 120 ℃, refluxing and dehydrating for 8.5-9 hours to 140 ℃, preserving the temperature for 20-40 hours at 140 ℃, and stopping the reaction until the sum of the integral areas of valproic acid and methyl valproate is more than 97% through central control to obtain an oil-water mixture;
cooling to 100 ℃, slowly adding 85kg of water, cooling to 25-30 ℃ for layering, wherein the upper oil phase is a mixture of valproic acid and valproate, the lower oil phase is an aqueous solution of ammonium bisulfate and sulfuric acid, discarding the water phase, and washing the organic phase with 170kg of water to obtain 168kg of yellow oily mixture;
transferring the yellow oily mixture into a 1000L reaction kettle, adding 192kg of 25% NaOH aqueous solution (NaOH 1.1eq) into the reaction kettle, heating the mixture to 60 ℃, keeping the temperature for 4 hours for reaction, converting valproic acid into sodium valproate, converting methyl valproate into sodium valproate and methanol, supplementing 256kg of water, discarding the oil phase after layering, and extracting the water phase with 128kg of dichloromethane for three times to obtain the sodium valproate aqueous solution;
the sodium valproate aqueous solution is transferred to a 1000L reaction kettle and stirred, 69kg of concentrated sulfuric acid (98%) is added in batches to neutralize until the pH value is 2, the mixture is cooled to 30 ℃, phase separation is carried out, a water phase is discarded, an oil phase is extracted by 170kg of water and then reduced pressure distillation is carried out, 129kg of valproic acid product is obtained, the yield is 82%, and the purity is higher than 99%.
(2) Preparation of sodium valproate:
adding 100kg of the above valproic acid into a reaction kettle, adding 15% sodium hydroxide aqueous solution into the reaction kettle to obtain sodium valproate aqueous solution with pH of 8.0, setting the air inlet temperature of a spray dryer at 200 deg.C, and spray drying to obtain 94.5kg of sodium valproate with yield of 82%
Example 2
(1) Preparation of valproic acid:
adding 257kg of tap water into a reaction kettle, starting a mechanical stirring paddle and cooling circulating water, slowly dropwise adding 257kg of concentrated sulfuric acid (concentrated sulfuric acid is 2.4eq), controlling the internal temperature below 60 ℃, then adding 200kg of 2-cyano-2-isopropyl methyl valerate in batches, uniformly stirring, heating to 120 ℃, refluxing and dehydrating for 8.5-9 hours to 130 ℃, keeping the temperature for 20-40 hours at 130 ℃, and stopping the reaction until the sum of the integral areas of the valproic acid and the methyl valproate is more than 97%, thereby obtaining an oil-water mixture;
cooling to 100 ℃, slowly adding 85kg of water, cooling to 25-30 ℃ for layering, wherein the upper oil phase is a mixture of valproic acid and valproate, the lower oil phase is an aqueous solution of ammonium bisulfate and sulfuric acid, discarding the water phase, and washing the organic phase with 170kg of water to obtain 168kg of yellow oily mixture;
transferring the yellow oily mixture into a 1000L reaction kettle, adding 209.5kg of 25% NaOH aqueous solution (NaOH 1.2eq) to the reaction kettle, heating the reaction kettle to 60 ℃, keeping the temperature for reaction for 4 hours to convert valproic acid into sodium valproate, convert methyl valproate into sodium valproate and methanol, supplementing 256kg of water, discarding the oil phase after layering, and extracting the water phase with 128kg of dichloromethane for three times to obtain the sodium valproate aqueous solution;
the sodium valproate aqueous solution is transferred to a 1000L reaction kettle and stirred, 69kg of concentrated sulfuric acid (98%) is added in batches to neutralize until the pH value is 2, the mixture is cooled to 30 ℃, the aqueous phase is discarded after phase separation, the oil phase is extracted by 170kg of water and then is distilled under reduced pressure, 126kg of valproic acid product is obtained, the yield is 80%, and the purity is more than 98%.
(2) Preparation of sodium valproate:
adding 100kg of valproic acid into a reaction kettle, adding a 15% sodium hydroxide aqueous solution into the reaction kettle to obtain a sodium valproate aqueous solution with the pH value of 8.3, setting the air inlet temperature of a spray dryer to 210 ℃, and carrying out spray drying to obtain 96.8kg of sodium valproate with the yield of 84%.
Example 3
(1) Preparation of valproic acid:
adding 256kg of tap water into a reaction kettle, starting a mechanical stirring paddle and cooling circulating water, slowly dropwise adding 256kg of concentrated sulfuric acid (2.4 eq) at an internal temperature of below 60 ℃, adding 200kg of 2-cyano-2-isopropyl methyl valerate in batches, uniformly stirring, heating to 120 ℃, carrying out reflux dehydration for 8.5-9 hours to 140 ℃, carrying out heat preservation for 20-30 hours at 140 ℃, and stopping reaction until the sum of the integral areas of valproic acid and methyl valproate is more than 98% by using gas phase detection under the condition of central control, thereby obtaining an oil-water mixture;
cooling to 100 ℃, slowly adding 85kg of water, cooling to 25-30 ℃ for layering, wherein the upper oil phase is a mixture of valproic acid and valproate, the lower oil phase is an aqueous solution of ammonium bisulfate and sulfuric acid, discarding the water phase, and washing the organic phase with 170kg of water to obtain 168kg of yellow oily mixture;
transferring the yellow oily mixture into a 1000L reaction kettle, adding 209.5kg of 25% NaOH aqueous solution (NaOH 1.2eq) to the reaction kettle, heating the reaction kettle to 60 ℃, keeping the temperature for reaction for 4 hours to convert valproic acid into sodium valproate, convert methyl valproate into sodium valproate and methanol, supplementing 256kg of water, discarding the oil phase after layering, and extracting the water phase with 128kg of dichloromethane for three times to obtain the sodium valproate aqueous solution;
the sodium valproate aqueous solution is transferred to a 1000L reaction kettle and stirred, 71kg of concentrated sulfuric acid (98%) is added in batches to neutralize until the pH value is 2, the mixture is cooled to 30 ℃, phase separation is carried out, a water phase is discarded, an oil phase is extracted by 170kg of water and then reduced pressure distillation is carried out, 134kg of valproic acid product is obtained, the yield is 86%, and the purity is more than 99%.
(2) Preparation of sodium valproate:
adding 100kg of valproic acid into a reaction kettle, adding a 15% sodium hydroxide aqueous solution into the reaction kettle to obtain a sodium valproate aqueous solution with the pH value of 8.5, setting the air inlet temperature of a spray dryer to be 220 ℃, and carrying out spray drying to obtain 99kg of sodium valproate with the yield of 86%.
Example 4
(1) Preparation of valproic acid:
adding 256kg of tap water into a reaction kettle, starting a mechanical stirring paddle and cooling circulating water, slowly dropwise adding 256kg of concentrated sulfuric acid (2.4 eq) at an internal temperature of below 60 ℃, adding 200kg of 2-cyano-2-isopropyl ethyl valerate in batches, uniformly stirring, heating to 120 ℃, carrying out reflux dehydration for 8.5-9 hours to 150 ℃, carrying out heat preservation for 18-30 hours at 150 ℃, and stopping reaction until the sum of the integral areas of valproic acid and ethyl valproate is more than 98% by using gas phase detection under the condition of central control, thereby obtaining an oil-water mixture;
cooling to 100 ℃, slowly adding 85kg of water, cooling to 25-30 ℃ for layering, wherein the upper oil phase is a mixture of valproic acid and valproate, the lower oil phase is an aqueous solution of ammonium bisulfate and sulfuric acid, discarding the water phase, and washing the organic phase with 170kg of water to obtain 168kg of yellow oily mixture;
transferring the yellow oily mixture into a 1000L reaction kettle, adding 244kg of 25% NaOH aqueous solution (NaOH 1.4eq) to the reaction kettle, heating to 60 ℃, keeping the temperature for 4 hours for reaction, converting valproic acid into sodium valproate, converting ethyl valproate into sodium valproate and ethanol, supplementing 256kg of water, discarding the oil phase after layering, and extracting the water phase with 128kg of dichloromethane for three times to obtain the sodium valproate aqueous solution;
the sodium valproate aqueous solution is transferred to a 1000L reaction kettle and stirred, 82kg of concentrated sulfuric acid (98%) is added in batches to neutralize until the pH value is 2, the mixture is cooled to 30 ℃, phase separation is carried out, a water phase is discarded, an oil phase is extracted by 170kg of water and then reduced pressure distillation is carried out, and a valproic acid product 132kg is obtained, the yield is 84%, and the purity is higher than 99%.
(2) Preparation of sodium valproate:
adding 100kg of valproic acid into a reaction kettle, adding a 15% sodium hydroxide aqueous solution into the reaction kettle to obtain a sodium valproate aqueous solution with the pH value of 8.7, setting the air inlet temperature of a spray dryer to be 230 ℃, and carrying out spray drying to obtain 100.26kg of sodium valproate with the yield of 87%.
Example 5
(1) Preparation of valproic acid:
adding 300kg of tap water into a reaction kettle, starting a mechanical stirring paddle and cooling circulating water, slowly dropwise adding 300kg of concentrated sulfuric acid (2.8 eq) at an internal temperature of below 60 ℃, adding 200kg of 2-cyano-2-isopropyl methyl valerate in batches, uniformly stirring, heating to 120 ℃, refluxing and dehydrating for 8.5-9 hours to 140 ℃, preserving heat for 18-30 hours at 140 ℃, and stopping reaction until the sum of the integral areas of valproic acid and methyl valproate is more than 98% by using gas phase detection under the condition of central control, so as to obtain an oil-water mixture;
cooling to 100 ℃, slowly adding 85kg of water, cooling to 25-30 ℃ for layering, wherein the upper oil phase is a mixture of valproic acid and valproate, the lower oil phase is an aqueous solution of ammonium bisulfate and sulfuric acid, discarding the water phase, and washing the organic phase with 170kg of water to obtain 168kg of yellow oily mixture;
transferring the yellow oily mixture into a 1000L reaction kettle, adding 280kg of 25% NaOH aqueous solution (NaOH 1.6eq) to the reaction kettle, heating the reaction kettle to 60 ℃, keeping the temperature for 4 hours to react so that valproic acid is converted into sodium valproate, methyl valproate is converted into sodium valproate and methanol, supplementing 256kg of water, discarding the oil phase after layering, and extracting the water phase with 128kg of dichloromethane for three times to obtain the sodium valproate aqueous solution;
the sodium valproate aqueous solution is transferred to a 1000L reaction kettle and stirred, 92.8kg of concentrated sulfuric acid (98%) is added in batches to neutralize until the pH value is 2, the mixture is cooled to 30 ℃, phase separation is carried out, a water phase is discarded, an oil phase is extracted by 170kg of water and then is subjected to reduced pressure distillation, and a valproic acid product of 137kg is obtained, wherein the yield is 87%, and the purity is more than 99%.
(2) Preparation of sodium valproate:
adding 100kg of the above valproic acid into a reaction kettle, adding 15% sodium hydroxide aqueous solution into the reaction kettle to obtain sodium valproate aqueous solution with pH of 8.9, setting the air inlet temperature of a spray dryer at 230 deg.C, and spray drying to obtain 101.4kg of sodium valproate with yield of 88%
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 (8)
1. A preparation method of sodium valproate is characterized by comprising the following steps:
adding water, sulfuric acid and 2-cyano-2-propyl valerate into a reaction kettle, heating up, refluxing and dividing water, carrying out hydrolysis and deacidification reactions, keeping the temperature for 15-40 h at 120-150 ℃, and controlling the temperature until the reaction is finished to obtain an oil-water mixture;
step two, separating oil from water of the oil-water mixture obtained in the step one to obtain a yellow oily mixture of valproic acid and valproate;
adding an alkali solution into the yellow oily mixture obtained in the second step, carrying out heat preservation reaction for 4-6 hours at the temperature of 60-80 ℃, extracting a water phase after the reaction is finished by using an organic solvent, and discarding an oil phase to obtain a valproate aqueous solution;
step four, adding sulfuric acid into the valproate aqueous solution obtained in the step three to neutralize until the pH value is 1-2, discarding a water phase after phase separation, extracting an oil phase which is a crude valproate product with water, and then performing reduced pressure distillation to obtain valproic acid;
and fifthly, adding the valproic acid obtained in the fourth step into a reaction kettle, slowly dropwise adding a sodium hydroxide solution until the pH value is 8-10, and spray-drying the obtained sodium valproate aqueous solution to obtain the sodium valproate.
2. The process according to claim 1, comprising the steps of:
adding water, sulfuric acid and 2-cyano-2-propyl valerate into a reaction kettle, heating to 120 ℃, refluxing and dividing water, performing hydrolysis and deacidification reactions, keeping the temperature for 20-40 hours at 120-150 ℃, and controlling the temperature until the reaction is finished to obtain an oil-water mixture;
step two, adding water into the oil-water mixture obtained in the step one, diluting sulfuric acid in a system, enabling an oil phase to be layered quickly, standing for layering, wherein the upper oil phase is a mixture of valproic acid and valproate, and the lower oil phase is an aqueous solution of ammonium bisulfate and sulfuric acid; washing the upper oil phase with water to obtain a yellow oily mixture of valproic acid and valproate;
adding aqueous alkali with the concentration of 15-30% into the yellow oily mixture obtained in the second step, and carrying out heat preservation reaction for 4-6 hours at the temperature of 60-80 ℃ so as to convert valproic acid into valproate and convert valproate into valproate and alcohol, extracting the water phase after the reaction is finished by using an organic solvent, and discarding the oil phase to obtain a valproate aqueous solution;
step four, adding sulfuric acid into the valproate aqueous solution obtained in the step three to neutralize until the pH value is 1-2, discarding a water phase after phase separation, extracting an oil phase which is a crude valproate product with water, and then performing reduced pressure distillation to obtain valproic acid;
and fifthly, adding the valproic acid obtained in the fourth step into a reaction kettle, slowly dropwise adding a sodium hydroxide aqueous solution with the concentration of 15-20% to obtain a sodium valproate aqueous solution, adjusting the pH value to 8-10, and spray-drying the obtained sodium valproate aqueous solution to obtain the sodium valproate.
3. The method according to claim 2, wherein in the first step, the molar amount of the sulfuric acid is 1.9 to 3 times that of the 2-cyano-2-propylpentanoic acid.
4. The method for preparing sodium valproate according to claim 2, wherein the chemical structural formula of the 2-cyano-2-propyl valerate is represented by formula (1):
wherein R is an alkyl group.
5. The method according to claim 4, wherein the 2-cyano-2-propylvalerate is methyl 2-cyano-2-propylvalerate, ethyl 2-cyano-2-propylvalerate, propyl 2-cyano-2-propylvalerate, butyl 2-cyano-2-propylvalerate, or isopropyl 2-cyano-2-propylvalerate.
6. The method for preparing sodium valproate according to claim 2, wherein in step three, the alkali in the alkali solution is one or more of sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate and lithium hydroxide.
7. The method for preparing sodium valproate according to claim 2, wherein in step three, the molar amount of the base in the alkaline solution is 1.05 to 1.8 times the molar amount of the 2-cyano-2-propylpentanoic acid.
8. The method for preparing valproic acid according to claim 2, 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 |
|---|---|---|---|
| CN202110333947.4A CN113200844A (en) | 2021-03-29 | 2021-03-29 | Preparation method of sodium valproate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110333947.4A CN113200844A (en) | 2021-03-29 | 2021-03-29 | Preparation method of sodium valproate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113200844A true CN113200844A (en) | 2021-08-03 |
Family
ID=77025794
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110333947.4A Pending CN113200844A (en) | 2021-03-29 | 2021-03-29 | Preparation method of sodium valproate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113200844A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114763328A (en) * | 2022-02-14 | 2022-07-19 | 湖南大学 | Preparation method and application of 2-cyano-2-valproic 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 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101811983A (en) * | 2009-02-19 | 2010-08-25 | 中国石油化工股份有限公司 | Preparation method of 2,3-diisopropyl-2-cyano diethyl succinate compound |
| CN102241582A (en) * | 2010-05-10 | 2011-11-16 | 山东方明药业股份有限公司 | Synthesis technology of sodium valproate |
| IN2014MU00486A (en) * | 2014-02-11 | 2015-09-25 | Unichem Lab Ltd |
-
2021
- 2021-03-29 CN CN202110333947.4A patent/CN113200844A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101811983A (en) * | 2009-02-19 | 2010-08-25 | 中国石油化工股份有限公司 | Preparation method of 2,3-diisopropyl-2-cyano diethyl succinate compound |
| CN102241582A (en) * | 2010-05-10 | 2011-11-16 | 山东方明药业股份有限公司 | Synthesis technology of sodium valproate |
| IN2014MU00486A (en) * | 2014-02-11 | 2015-09-25 | Unichem Lab Ltd |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114763328A (en) * | 2022-02-14 | 2022-07-19 | 湖南大学 | Preparation method and application of 2-cyano-2-valproic 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 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113200844A (en) | Preparation method of sodium valproate | |
| CN112159362B (en) | Method for purifying intermediate 4,4-dimethylisoxazole-3-one | |
| CN100537521C (en) | Method for synthesizing N,N dimethyl acetamide in high purity | |
| CN103724167B (en) | Environment-friendly synthesis method of high-yield perfluoromethylvinyl ether (PMVE) | |
| CN113173845A (en) | Method for preparing valproic acid | |
| WO2015177093A1 (en) | Process for making 2,5-dihalogenated phenol | |
| CN113200848A (en) | Novel preparation method of valproic acid | |
| CN103724320A (en) | Preparation method of 2-isopropyl thioxanthone | |
| CN108003096B (en) | Method for preparing ethoxyquinoline through WO3/AC/SO3H concerted catalysis | |
| CN109721496B (en) | Synthetic method of 3-nitro-o-xylene | |
| CN104817462A (en) | Producing method of triisopropanolamine | |
| CN106045860A (en) | Novel efficient cetane number improver and preparation method thereof | |
| CN110668983A (en) | Synthesis method of novel pentaerythritol tetra (3-mercaptopropionate) | |
| CN110759806A (en) | Preparation method of 2-chloro-4-fluorotoluene | |
| CN111153794A (en) | Method for synthesizing ethyl palmitate by using dodecyl trimethyl ammonium chloride-based eutectic solvent catalyst | |
| CN110054558B (en) | Preparation method of 1-trifluoromethylcyclopropane-1-formic acid | |
| CN114014781A (en) | Synthesis process of 2-bromo-2, 2-difluoroacetonitrile | |
| CN106866392B (en) | Method for preparing 4-hydroxycyclopenta-2-enone from furfuryl alcohol | |
| CN106966901A (en) | A kind of preparation method of 6- hydroxyls -8- Lipase Catalyzed Resolution of Racemic Ethyl | |
| CN111018810A (en) | Device and method for continuously producing α -acetyl-gamma-butyrolactone | |
| CN112174801B (en) | Method for coproducing glycolic acid and 1,1,1, 2-tetrafluoroethane by one-pot method | |
| CN110172041B (en) | Novel method for synthesizing hexazinone | |
| CN115466233B (en) | Synthesis method of buvaracetam intermediate (R) -4-propyl-dihydrofuran-2-one | |
| WO2010127575A1 (en) | One-step synthesis method of 2,9-dimethyl-4,7-diphenyl-1,10- phenanthroline | |
| CN115197116B (en) | Preparation method of N-phenylmaleimide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20210803 |
|
| RJ01 | Rejection of invention patent application after publication |