CN113200848A - Novel preparation method of valproic acid - Google Patents
Novel preparation method of valproic acid Download PDFInfo
- Publication number
- CN113200848A CN113200848A CN202110336641.4A CN202110336641A CN113200848A CN 113200848 A CN113200848 A CN 113200848A CN 202110336641 A CN202110336641 A CN 202110336641A CN 113200848 A CN113200848 A CN 113200848A
- Authority
- CN
- China
- Prior art keywords
- acid
- valproic acid
- cyano
- water
- phase
- 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 Valproic acid Chemical compound CCCC(C(O)=O)CCC NIJJYAXOARWZEE-UHFFFAOYSA-N 0.000 title claims abstract description 50
- 229960000604 valproic acid Drugs 0.000 title claims abstract description 42
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 53
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 43
- 239000007864 aqueous solution Substances 0.000 claims abstract description 25
- UZRGQIZTJOPZGE-UHFFFAOYSA-N 2-cyano-2-propylpentanoic acid Chemical compound CCCC(C(O)=O)(C#N)CCC UZRGQIZTJOPZGE-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 17
- 239000007858 starting material Substances 0.000 claims abstract description 4
- 238000005580 one pot reaction Methods 0.000 claims abstract description 3
- 239000012071 phase Substances 0.000 claims description 51
- AEQFSUDEHCCHBT-UHFFFAOYSA-M sodium valproate Chemical compound [Na+].CCCC(C([O-])=O)CCC AEQFSUDEHCCHBT-UHFFFAOYSA-M 0.000 claims description 20
- 229940102566 valproate Drugs 0.000 claims description 17
- 239000008346 aqueous phase Substances 0.000 claims description 14
- 239000003513 alkali Substances 0.000 claims description 10
- 238000005191 phase separation Methods 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 9
- 238000010438 heat treatment 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
- 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
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 239000002585 base Substances 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
- 238000004821 distillation 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
- 238000004519 manufacturing process Methods 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 32
- 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
- 230000002378 acidificating effect Effects 0.000 abstract description 4
- 239000007789 gas Substances 0.000 abstract description 4
- 235000010288 sodium nitrite Nutrition 0.000 abstract description 4
- 238000005903 acid hydrolysis reaction Methods 0.000 abstract description 3
- 150000001408 amides Chemical class 0.000 abstract description 3
- 239000002253 acid Substances 0.000 abstract description 2
- 239000003054 catalyst Substances 0.000 abstract description 2
- 230000007797 corrosion Effects 0.000 abstract description 2
- 238000005260 corrosion Methods 0.000 abstract description 2
- 230000001590 oxidative effect Effects 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 150000001735 carboxylic acids Chemical class 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 238000001816 cooling Methods 0.000 description 10
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 206010010904 Convulsion Diseases 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 229940084026 sodium valproate Drugs 0.000 description 3
- 239000012445 acidic reagent Substances 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-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
- 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
- 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
- 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
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229950001902 dimevamide Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 208000028316 focal seizure Diseases 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal 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
- 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
- IPWFJLQDVFKJDU-UHFFFAOYSA-N pentanamide Chemical compound CCCCC(N)=O IPWFJLQDVFKJDU-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002243 precursor Substances 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
- 208000005809 status epilepticus Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000005406 washing Methods 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
-
- 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
- C07C51/487—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to chemical modification
-
- 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)
- General Chemical & Material Sciences (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a new preparation method of valproic acid, which takes 2-cyano-2-propylvaleric acid as a starting material to prepare the valproic acid by a one-pot method. The method takes 2-cyano-2-propylvaleric acid as a raw material, uses a sulfuric acid aqueous solution as a catalyst, and prepares the valproic acid at the temperature of 120-160 ℃, wherein the reaction yield can reach 80%, and the purity of a valproic acid product can reach 99%; the preparation process is simple, the steps are short, and the labor and equipment cost investment for controlling the intermediate and preparing in industry is greatly reduced. The method adopts a sulfuric acid hydrolysis mechanism of 2-cyano-2-propylvaleric acid, and compared with a traditional mechanism of oxidizing amide with nitrous acid into 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 preparation of valproic acid, and particularly relates to a novel preparation method of valproic acid.
Background
The chemical name of the sodium valproate is 2-sodium valproate, and the molecular formula is as follows: the C8H15NaO2 has molecular weight of 166.2, is white odorless crystalline powder easily soluble in water, has strong hygroscopicity, and is suitable for preventing and treating various 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 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 novel 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 new preparation method of the valproic acid is provided, the new preparation method takes 2-cyano-2-valproic acid as a starting material to prepare the valproic acid by a one-pot method, and comprises the following steps:
adding water, sulfuric acid and 2-cyano-2-propylvaleric acid into a reaction bottle, heating to 120-160 ℃, preserving heat for 15-40 hours, and controlling the temperature until the reaction is finished;
step two, after the reaction is finished, adding water into the reaction liquid for dilution and phase separation, extracting the separated oil phase with water again, adding an alkali aqueous solution into the extracted oil phase, and preserving heat for 4-6 hours at the temperature of 60-65 ℃ 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: performing deacidification reaction on 2-cyano-2-propylpentanoic acid at 120-160 ℃ under the condition that sulfuric acid is used as an acid reagent to generate an intermediate product, namely valproonitrile, and releasing carbon dioxide gas; carrying out acid hydrolysis reaction on propionitrile under the catalysis of sulfuric acid at 120-160 ℃ to generate an intermediate product, namely, valeramide; carrying out hydrolysis reaction on valproate at 120-160 ℃ in sulfuric acid serving as an acid reagent to generate a final product, namely a crude valproic acid product and ammonium bisulfate, adding an alkali aqueous solution into the crude valproic acid product to obtain valproate, and extracting, acidifying, phase splitting, washing and distilling the valproic acid product to obtain valproic acid; the preparation of valproic acid from 2-cyano-2-propylpentanoic acid requires only one reaction step, and the reaction mechanism is 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, 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 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 takes 2-cyano-2-propylvaleric acid as a raw material, uses a sulfuric acid aqueous solution as a catalyst, and prepares the valproic acid at the temperature of 120-160 ℃, wherein the reaction yield can reach 80%, and the purity of a valproic acid product can reach 98%; the preparation process is simple, the steps are short, and the labor and equipment cost investment for controlling the intermediate and preparing in industry is greatly reduced.
The method of the invention adopts a sulfuric acid hydrolysis mechanism of 2-cyano-2-propylvaleric acid, only generates carbon dioxide gas in the reaction process, and compared with the traditional mechanism that nitrous acid oxidizes amide into 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.
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 231g of water into a reaction bottle, cooling in a water bath, slowly adding 231g of concentrated sulfuric acid (2 eq) while controlling the internal temperature below 60 ℃, adding 200g (1eq) of 2-cyano-2-propylvaleric acid, installing a water separator, changing an oil bath pot, heating, starting to reflux and separate water to 140 ℃, preserving heat at 140 ℃ 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 265g of 25% sodium hydroxide aqueous solution (sodium hydroxide 1.4eq), 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, 81g 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 119g of valproic acid with a yield of 70.2% and a purity of 99%.
Example 2
Preparation of valproic acid:
adding 278g of water into a reaction bottle, cooling in a water bath, slowly adding 278g of concentrated sulfuric acid (2.4 eq) into the reaction bottle, controlling the internal temperature to be below 60 ℃, then adding 200g (1eq) of 2-cyano-2-propylvaleric acid, installing a water separator, changing an oil bath pot, heating, starting to reflux water to 130 ℃, keeping the temperature at 130 ℃ for 20-40 hours, 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 265g of 25% sodium hydroxide aqueous solution (sodium hydroxide 1.4eq), 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, 81g 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 112.5g of valproic acid in 66% yield and 98% purity.
Example 3
Preparation of valproic acid:
adding 278g of water into a reaction bottle, cooling in a water bath, slowly adding 278g of concentrated sulfuric acid (2.4 eq) into the reaction bottle, controlling the internal temperature to be below 60 ℃, then adding 200g (1eq) of 2-cyano-2-propylvaleric acid, installing a water separator, changing an oil bath pot, heating, starting to reflux water to 140 ℃, keeping the temperature at 140 ℃ for 20-30 hours, and controlling the temperature until the reaction is finished;
cooling to 30 ℃, slowly adding 130g 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 227g 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 100ml of dichloromethane, the oil phase was discarded, 75g 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 136g of valproic acid with 80% yield and 99% purity.
Example 4
Preparation of valproic acid:
adding 278g of water into a reaction bottle, cooling in a water bath, slowly adding 278g of concentrated sulfuric acid (2.4 eq) into the reaction bottle, controlling the internal temperature to be below 60 ℃, then adding 200g (1eq) of 2-cyano-2-propylvaleric acid, installing a water separator, changing an oil bath pot, heating, starting to reflux water to 150 ℃, keeping the temperature at 150 ℃ for 20-30 hours, and controlling the temperature until the reaction is finished;
cooling to 30 ℃, slowly adding 130g 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 227g 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 100ml of dichloromethane, the oil phase was discarded, 75g 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 obtain 141g of valproic acid with 83% yield and 99% purity.
Example 5
Preparation of valproic acid:
adding 325g of water into a reaction bottle, cooling in a water bath, slowly adding 325g of concentrated sulfuric acid (2.8 eq) at an internal temperature of below 60 ℃, adding 200g (1eq) of 2-cyano-2-propylvaleric acid, installing a water separator, changing an oil bath pot, heating, circulating water to 140 ℃, preserving heat at 140 ℃ for 15-30 hours, and controlling the temperature until the reaction is finished;
cooling to 30 ℃, slowly adding 190g 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 217.4g of 25% sodium hydroxide aqueous solution (sodium hydroxide 1.15eq) 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 100ml of dichloromethane, the oil phase was discarded, 110g 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 122g of valproic acid with a yield of 72% and a purity of 99%.
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 new preparation method of valproic acid is characterized in that 2-cyano-2-valproic acid is used as a starting material to prepare the valproic acid by a one-pot method, and the method comprises the following steps:
adding water, sulfuric acid and 2-cyano-2-propylvaleric acid into a reaction bottle, heating to 120-160 ℃, preserving heat for 15-40 hours, and controlling the temperature until the reaction is finished;
step two, after the reaction is finished, adding water into the reaction liquid for dilution and phase separation, extracting the separated oil phase with water again, adding an alkali aqueous solution into the extracted oil phase, and preserving heat for 4-6 hours at the temperature of 60-65 ℃ 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 novel method for preparing valproic acid according to claim 1, wherein in step one, the molar amount of sulfuric acid is 1.9 to 3 times that of the 2-cyano-2-propylvaleric acid.
3. The novel 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 novel method for producing valproic acid according to claim 1, wherein 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-propylvaleric acid.
5. The novel 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 |
|---|---|---|---|
| CN202110336641.4A CN113200848A (en) | 2021-03-29 | 2021-03-29 | Novel preparation method of valproic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110336641.4A CN113200848A (en) | 2021-03-29 | 2021-03-29 | Novel preparation method of valproic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113200848A true CN113200848A (en) | 2021-08-03 |
Family
ID=77025864
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110336641.4A Pending CN113200848A (en) | 2021-03-29 | 2021-03-29 | Novel preparation method of valproic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113200848A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116143586A (en) * | 2022-12-16 | 2023-05-23 | 上海青平药业有限公司 | Preparation method of 2-ethyl-2-methyl valeric acid |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4127604A (en) * | 1977-03-15 | 1978-11-28 | Labaz | Process for the preparation of acetic acid derivatives |
| GB2068962A (en) * | 1980-02-13 | 1981-08-19 | Sanofi Sa | Process for preparing valproic acid |
| DE3103776A1 (en) * | 1977-03-15 | 1982-01-07 | Sanofi, 75008 Paris | Process for the preparation of di-n-propylacetic acid |
| CN101811982A (en) * | 2009-02-19 | 2010-08-25 | 中国石油化工股份有限公司 | 2,3-diisopropyl-2.3-dicyano-diethyl succinate compound, preparation method and application thereof |
| CN103183599A (en) * | 2011-12-30 | 2013-07-03 | 北大方正集团有限公司 | Method for preparing 2-valproic acid |
| IN2014MU00486A (en) * | 2014-02-11 | 2015-09-25 | Unichem Lab Ltd |
-
2021
- 2021-03-29 CN CN202110336641.4A patent/CN113200848A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4127604A (en) * | 1977-03-15 | 1978-11-28 | Labaz | Process for the preparation of acetic acid derivatives |
| DE3103776A1 (en) * | 1977-03-15 | 1982-01-07 | Sanofi, 75008 Paris | Process for the preparation of di-n-propylacetic acid |
| GB2068962A (en) * | 1980-02-13 | 1981-08-19 | Sanofi Sa | Process for preparing valproic acid |
| CN101811982A (en) * | 2009-02-19 | 2010-08-25 | 中国石油化工股份有限公司 | 2,3-diisopropyl-2.3-dicyano-diethyl succinate compound, preparation method and application thereof |
| CN103183599A (en) * | 2011-12-30 | 2013-07-03 | 北大方正集团有限公司 | Method for preparing 2-valproic acid |
| IN2014MU00486A (en) * | 2014-02-11 | 2015-09-25 | Unichem Lab Ltd |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116143586A (en) * | 2022-12-16 | 2023-05-23 | 上海青平药业有限公司 | Preparation method of 2-ethyl-2-methyl valeric acid |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112739646B (en) | Supercritical purification method of bis (fluorosulfonyl) imide | |
| CN101880247A (en) | Method for producing naphthalene sulfonic formaldehyde condensation compound | |
| CN113200848A (en) | Novel preparation method of valproic acid | |
| CN113200844A (en) | Preparation method of sodium valproate | |
| JP5497052B2 (en) | Adiabatic process for producing mononitrobenzene | |
| CN113173845A (en) | Method for preparing valproic acid | |
| JP5276022B2 (en) | Method for preparing reducing agent composition | |
| CN107488136B (en) | Method for preparing ethyl hydrogen sulfate | |
| CN112159362B (en) | Method for purifying intermediate 4,4-dimethylisoxazole-3-one | |
| EP3145900A1 (en) | Process for making 2,5-dihalogenated phenol | |
| CN108910846B (en) | Method for preparing low-arsenic yellow phosphorus by using microchannel reactor | |
| CN109053679B (en) | Preparation method of dessimutan oxidant | |
| CN110759806A (en) | Preparation method of 2-chloro-4-fluorotoluene | |
| CN115583891A (en) | Preparation method of high-purity sodium sarcosinate aqueous solution | |
| CN111717901B (en) | Method for preparing bis (fluorosulfonyl) imide by using anhydride-water system | |
| RU2013128462A (en) | METHOD FOR PRODUCING NITRIC ACID | |
| CN103030552B (en) | Method for one-time synthesis of 2-phenylpropionic acid by strawberry aldehyde | |
| CN105753710A (en) | Environmentally friendly preparation technology of 2,2-bis(3-nitro-4-hydroxyphenyl)hexafluoropropane | |
| CN104557491A (en) | Preparation method of acrolein | |
| CN114181083B (en) | Method for preparing crotonate compound by one-step method | |
| CN110117223A (en) | A kind of method that Ozonation prepares simultaneously separating-purifying azelaic acid | |
| CN113845421B (en) | Method for preparing ethyl propiolate by one-pot method | |
| CN110511126B (en) | Method for treating byproduct nitroalkane in ammoxidation oximation reaction catalyzed by TS-1 | |
| CN102633753B (en) | Method for synthesizing carbobenzoxyserine-beta-lactone | |
| CN102875431B (en) | Preparation method of disulfide |
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 | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20210803 |