A kind of preparation method of sodium valproate

Abstract

The present invention relates to the field of chemical pharmaceutical technology, and more particularly to a method for preparing sodium valproate. The preparation method includes: using diethyl malonate, 1-bromopropane and an inorganic base as raw materials, and carrying out an alkylation reaction under the action of a catalyst; wherein the catalyst is selected from one or more of potassium iodide, tetrabutylammonium iodide, sodium iodide, tetradecyltrimethylammonium iodide, and benzyltrimethylammonium iodide; the inorganic base is an alkaline hydroxide; the molar ratio of the diethyl malonate, 1-bromopropane and the inorganic base is 1:2~10:4~10. The sodium valproate prepared by the present invention has a high yield and high purity, and each impurity content is greatly reduced, and stability is significantly improved. Meanwhile, the preparation process of the present invention only uses conventional reagents, non-reactive solvents, and has no special requirements, and the process operation is simple and low in cost, and the requirements of pilot and amplified production technology can be met, and it is easy to industrialize large-scale production.

Description

Technical Field

[0001] The invention relates to the technical field of chemical pharmacy, and in particular to a method for preparing sodium valproate. Background Art

[0002] Sodium valproate is a drug used to treat generalized, partial or other types of epilepsy or to treat manic episodes associated with bipolar disorder. Sodium valproate can increase the concentration of γ-aminobutyric acid (GABA) and dopamine in the brain, while promoting the metabolism of the serotonin system. Sodium valproate can cause an increase in GABA concentration because it inhibits the production of γ-aminobutyric acid transaminase (GABA-t) and succinic semialdehyde dehydrogenase (SSA-dh), while activating glutamate decarboxylase (GAD). In addition, in the process of anti-mania and inhibiting the onset of migraine attacks, it has a certain promoting effect on the GABA neurotransmission process.

[0003] Through searching, the following preparation methods of sodium valproate have been published in the literature:

[0004] U.S. Patent No. 4127604A uses cyanoacetate as a starting material, reacts with 1-bromopropane in the presence of calcium chloride and sodium isopropoxide to generate dipropyl cyanoacetate, then hydrolyzes under alkaline conditions to obtain dipropyl cyanoacetic acid, removes the carboxyl group under high temperature of 165-175°C to obtain valproic acid, hydrolyzes under acidic conditions to obtain valproamide, then adds nitrite to oxidize to obtain valproic acid, and finally forms a salt with sodium hydroxide to obtain sodium valproate. The preparation method has a long route, and the sodium alcoholate used is easy to absorb moisture and deteriorate, and the reaction process has high requirements on equipment and environment.

[0005] Chinese patent CN110563572A uses methyl acetoacetate as the starting material, reacts with 1-bromopropane under the action of potassium carbonate and tetrabutylammonium bromide (TBAB) to generate dipropyl methyl acetoacetate, then removes the acyl group under sodium alcoholate conditions to obtain dipropyl acetate, hydrolyzes under alkaline conditions to obtain valproic acid, and forms a salt with sodium hydroxide to prepare sodium valproate. Sodium alcoholate is also used in this preparation method, which makes it easy to absorb moisture and deteriorate, so it also has extremely high requirements on the equipment and environment during the reaction process.

[0006] U.S. Patent No. 5,041,640A uses valeric acid as a starting material, reacts with magnesium oxide to form a salt and removes water, then adds n-butyl lithium to react, then reacts with 1-bromopropane, acidifies with hydrochloric acid to form valproic acid, and finally forms a salt with sodium hydroxide to obtain sodium valproate. This preparation method uses unstable n-butyl lithium, which makes the process operation difficult and dangerous, and is not suitable for industrial production.

[0007] Chinese patent CN111349003A uses ethyl valerate as the starting material, adds an ether solution of a pyrrole metal reagent, then adds 1-bromopropane for alkylation, and then hydrolyzes and acidifies to obtain valproic acid, which is then salted with sodium hydroxide to obtain sodium valproate. This preparation method also uses unstable metal reagents, which is difficult to operate and has a high price for metal reagents, which directly affects the cost of the product and does not have a market advantage.

[0008] Chinese patent CN102241582B uses diethyl malonate as the starting material, reacts with 1-bromopropane under the action of sodium ethoxide to generate diethyl dipropyl malonate, then hydrolyzes in a sodium hydroxide solution to obtain dipropyl malonic acid, decarboxylates at 140-180°C to obtain valproic acid, and then forms a salt with sodium hydroxide to obtain sodium valproate. This preparation method requires the use of a large amount of solvent, and the sodium alkoxide used is easy to absorb moisture and deteriorate, and has high requirements for equipment and environment. In addition, the yield of the whole process is low, and the total yield is below 75.3%.

[0009] At present, the existing preparation methods all require the use of reaction solvents. In addition, some preparation methods also require the use of unstable reagents such as sodium alcoholate, n-butyl lithium or metal reagents. From the perspective of industrial production, these directly or indirectly affect the operating difficulty and production cost of the method, making it difficult to have market advantages. In addition, the prepared sodium valproate has the problems of low yield, high impurity content and poor stability.

[0010] In order to improve the problems existing in the prior art, it is urgent to provide a preparation method of sodium valproate to improve the yield and purity of sodium valproate, reduce the content of impurities, and enhance stability. At the same time, the preparation method needs to meet the requirements of simple operation, low cost, and pilot and scale-up production technology. Summary of the invention

[0011] In view of the defects and shortcomings of the prior art, the present invention provides a method for preparing sodium valproate. The sodium valproate prepared by the preparation method of the present invention has a high yield (the total process yield is as high as 93.6% or more), high purity (the purity of sodium valproate is as high as 99.9% or more), greatly reduced impurity content (the impurity content is lower than 0.05%), and significantly improved stability. At the same time, there is no reaction solvent in the preparation process, the process operation is simple, the cost is low, and the technical requirements of pilot and scale-up production can be met. The purpose of the present invention is achieved through the following technical solutions:

[0012] A method for preparing sodium valproate, comprising:

[0013] Using diethyl malonate, 1-bromopropane and inorganic base as raw materials, an alkylation reaction is carried out under the action of a catalyst;

[0014] Wherein, the catalyst is selected from: one or more of potassium iodide, tetrabutylammonium iodide, sodium iodide, tetradecyltrimethylammonium iodide, benzyltrimethylammonium iodide;

[0015] The inorganic base is an alkaline hydroxide;

[0016] The molar ratio of diethyl malonate, 1-bromopropane and inorganic base is 1:2-10:4-10.

[0017] The present invention finds that when preparing sodium valproate through the above-mentioned alkylation reaction, a specific catalyst and an inorganic base are selected, and the molar ratio of diethyl malonate, 1-bromopropane and the inorganic base is controlled within the above-mentioned range, a sodium valproate product with high yield, high purity, low impurity content and high stability can be obtained. Moreover, the preparation process has no reaction solvent, simple process operation and low cost, and can meet the technical requirements of pilot and scale-up production.

[0018] Under the joint control of the above conditions, the total process yield can reach more than 85.0%, the purity of sodium valproate is as high as more than 99.30%, and the contents of various impurities and single impurities are all lower than 0.1%.

[0019] In some preferred embodiments, the catalyst is selected from one or more of potassium iodide, tetrabutylammonium iodide, and sodium iodide.

[0020] The present invention further finds that by using potassium iodide as a catalyst for the alkylation reaction, the total process yield can reach 93.6%, the purity of sodium valproate is as high as 99.92%, the content of each impurity is less than 0.01%, the yield and purity are the highest, the impurity content is significantly reduced, and the stability is the best.

[0021] In some preferred embodiments, the inorganic base is selected from: one or more of sodium hydroxide, potassium hydroxide, and cesium hydroxide; preferably sodium hydroxide and / or potassium hydroxide.

[0022] The present invention further finds that when sodium hydroxide is used as the inorganic base in the alkylation reaction, the total process yield can reach 93.6%, the purity of sodium valproate is as high as 99.92%, and the impurity content is less than 0.01%. The yield and purity are the highest, the impurity content is significantly reduced, and the stability is the best.

[0023] In some preferred embodiments, the molar ratio of diethyl malonate, 1-bromopropane and inorganic base is 1:2.5-6:5-8; preferably 1:4.5-6:7-8; more preferably 1:5-6:7-8.

[0024] The present invention further finds that the molar ratio of diethyl malonate, 1-bromopropane and sodium hydroxide for controlling the alkylation reaction is 1:5-6:7-8, the total process yield can reach 93.6%, the purity of sodium valproate is as high as 99.92%, the impurity content is less than 0.01%, the yield and purity are the highest, the impurity content is significantly reduced, and the stability is the best.

[0025] In some preferred embodiments, the amount of the catalyst used is 1 to 10%, preferably 3 to 8%, of the molar amount of diethyl malonate.

[0026] In some preferred embodiments, the preparation method further comprises:

[0027] After the alkylation reaction, a hydrolysis reaction, a decarboxylation reaction and a salt-forming reaction are performed;

[0028] The hydrolysis reaction comprises: recovering 1-bromopropane, mixing the residue with water, adjusting the pH to 1-2 to precipitate solid, and filtering to obtain the solid;

[0029] The decarboxylation reaction comprises: heating the solid and then distilling under reduced pressure to obtain valproic acid;

[0030] The salt-forming reaction comprises: mixing valproic acid and sodium hydroxide and then performing a salt-forming reaction.

[0031] In some preferred embodiments, in the salt-forming reaction, the molar ratio of valproic acid to sodium hydroxide is 1:1.0-1.1, preferably 1:1.02-1.06.

[0032] In some preferred embodiments, the preparation method further comprises:

[0033] After the salt-forming reaction, sodium valproate is obtained by decolorization, filtration, water distillation and drying; preferably, activated carbon is used for decolorization, and the amount of activated carbon used is 1-10% of the molar amount of diethyl malonate, and more preferably 3-6%.

[0034] In some preferred embodiments, the decolorization temperature is 20-60°C, preferably 20-40°C.

[0035] In some preferred embodiments, the drying process is performed including but not limited to vacuum drying.

[0036] According to tests, the sodium valproate prepared by the preparation method of the present invention has high yield (the total process yield can be as high as 93.6%), high purity (the purity of sodium valproate can be as high as 99.92%), greatly reduced impurity content (the impurity content can be as low as 0.01%), and significantly improved stability.

[0037] Those skilled in the art can further combine the above preferred conditions to obtain a preparation method with better effect.

[0038] Furthermore, the present invention also provides a sodium valproate product, which is prepared by any of the above embodiments.

[0039] In some embodiments, the impurities in the above-mentioned sodium valproate products include one or more of the following:

[0040]

[0041]

[0042] In some embodiments, the impurities are detected by gas chromatography.

[0043] In some embodiments, the gas chromatography detection conditions for the above impurities are as follows:

[0044] Chromatographic column: capillary column with polyethylene glycol (PEG-20M) as stationary liquid;

[0045] Initial temperature control process: 110-130°C, maintain for 20-30 minutes, then increase the temperature to 180-200°C at a rate of 3-5°C / min, maintain for 10-20 minutes;

[0046] Inlet temperature: 200~220℃;

[0047] Detector temperature: 200~220℃;

[0048] Injection volume: 0.5~2.0μL.

[0049] Compared with the prior art, the present invention has the following beneficial effects:

[0050] A method for preparing sodium valproate, wherein the sodium valproate prepared by the method has a high yield (the total process yield can be as high as 93.6%), high purity (the purity of sodium valproate can be as high as 99.92%), greatly reduced impurity content (the impurity content can be as low as 0.01%), and significantly improved stability. At the same time, the preparation process of the invention only uses conventional reagents and non-reactive solvents, has simple process operation, low cost, can meet the technical requirements of pilot and scale-up production, and is easy to industrialize and mass produce. The details are as follows:

[0051] 1) By changing the type of catalyst in the alkylation reaction process, the impurity content is reduced while the product yield, purity and stability are significantly improved.

[0052] Compared with the use of other types of catalysts, in the alkylation reaction process of the present invention, potassium iodide, tetrabutylammonium iodide, sodium iodide, tetradecyltrimethylammonium iodide, and benzyltrimethylammonium iodide are used as catalysts, so that the total process yield can reach more than 85%, the purity of sodium valproate is as high as more than 99.8%, and the impurity content is less than 0.05%, which significantly improves the yield and purity of the target product, reduces the impurity content, and enhances stability;

[0053] Among them, potassium iodide is used as the catalyst for the alkylation reaction, the total process yield can reach 93.6%, the purity of sodium valproate is as high as 99.92%, the content of each impurity is less than 0.01%, the yield and purity are the highest, the impurity content is significantly reduced, and the stability is the best.

[0054] 2) By controlling the molar ratio of diethyl malonate, 1-bromopropane and sodium hydroxide during the alkylation reaction, the impurity content can be reduced and the product yield, purity and stability can be significantly improved.

[0055] Compared with other molar dosage ratios, the molar dosage ratio of diethyl malonate, 1-bromopropane and sodium hydroxide in the alkylation reaction of the present invention is in the range of 1:2.0-10.0:4.0-10.0, the total process yield can reach more than 85.3%, the purity of sodium valproate is as high as more than 99.37%, and the impurity content is less than 0.1%, which significantly improves the yield and purity of the target product, reduces the impurity content, and enhances stability;

[0056] The molar ratio of diethyl malonate, 1-bromopropane and sodium hydroxide for controlling the alkylation reaction is 1:6.0:8.0. The total process yield can reach 93.6%, the purity of sodium valproate is as high as 99.92%, and the impurity content is less than 0.01%. The yield and purity are the highest, the impurity content is significantly reduced, and the stability is the best.

[0057] 3) By controlling the type of base to be an inorganic base during the alkylation reaction and omitting the use of an organic base, the impurity content is reduced while significantly improving the product yield, purity and stability.

[0058] 4) By changing the type of inorganic base in the alkylation reaction process, the impurity content is reduced while significantly improving the product yield, purity and impurity content.

[0059] Compared with the use of other types of alkaline substances, the present invention uses sodium hydroxide, potassium hydroxide, and cesium hydroxide as inorganic bases for the alkylation reaction, and the total process yield can reach more than 85%, the purity of sodium valproate is as high as more than 99.5%, and the impurity content is less than 0.08%; the yield and purity of the target product are further improved, the impurity content is reduced, and the stability is further improved;

[0060] Among them, when sodium hydroxide is used as the inorganic base in the alkylation reaction, the total process yield can reach 93.6%, the purity of sodium valproate is as high as 99.92%, and the impurity content is less than 0.01%. The yield and purity are the highest, the impurity content is significantly reduced, and the stability is the best.

[0061] 5) The preparation method of the present invention uses only conventional reagents, no solvents are used, no special requirements are required, the operation is simple, and the production cost is greatly reduced; the preparation method is simple and easy to implement, and it is easier to realize large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0062] In order to more clearly illustrate the technical solutions in the present invention or the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0063] Figure 1 A mixed detection spectrum of all impurities detected by the chromatographic detection method of Example 1;

[0064] Figure 2 The sodium valproate detection spectrum prepared in Example 1;

[0065] Figure 3 The sodium valproate detection spectrum prepared by method 2 of Example 2;

[0066] Figure 4 The sodium valproate detection spectrum prepared by method 3 of Example 3;

[0067] Figure 5 This is the detection spectrum of sodium valproate prepared by method 1 of Example 4. DETAILED DESCRIPTION

[0068] In order to make the purpose, technical solution and advantages of the present invention clearer, the technical solution of the present invention will be clearly and completely described below in conjunction with the drawings of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0069] If the specific technology or conditions are not specified in the examples, the technology or conditions described in the literature in this field or the product instructions are used. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased through regular channels. The present invention can be described in detail by the following examples. The purpose of the specific examples is to further illustrate the content of the present invention, but it is not intended to limit the present invention.

[0070] Example 1

[0071] 1-1. Feeding ratio:

[0072] composition Molar dosage / mol Dosage / g effect Diethyl malonate 2.0 320.3 raw material 1-Bromopropane 12.0 1470 raw material Sodium hydroxide 16.0 640 Inorganic base Potassium iodide 0.12 20.0 catalyst Purified water 50.0 900 Hydrolysis solvent Valproic acid 1.90 273.7 Intermediate products Sodium hydroxide 2.01 80.4 Salt-forming reagent Activated carbon 0.83 10 Decolorizing agent

[0073] 1-2. Preparation method:

[0074] 1) Alkylation reaction: Add 320.3 g (2 mol) of diethyl malonate, 1.47 kg (12 mol) of 1-bromopropane, 640.0 g (16 mol) of sodium hydroxide and 20.0 g of potassium iodide into a 3 L reaction bottle, control the temperature to 65-70° C. and stir to react for 6 h;

[0075] 2) Hydrolysis reaction: After the reaction is completed, 1-bromopropane is recovered by atmospheric distillation, 900.0 g of purified water is added to the residue, and the mixture is stirred at 70-80° C. for 5 h for hydrolysis reaction. The pH is adjusted to 1-2 with hydrochloric acid to precipitate solids, which are then filtered and collected;

[0076] 3) Decarboxylation reaction: subjecting the solid collected in step 2) to decarboxylation reaction at 160-170° C. until no bubbles are generated; subjecting the solid to vacuum distillation, collecting the fraction of -0.096 MPa / 120-125° C. to obtain 273.7 g of valproic acid;

[0077] 4) Salt-forming reaction: 273.7 g (1.90 mol) of valproic acid obtained in step 3) was added to a 2 L reaction bottle, and 80.4 g (2.01 mol) of sodium hydroxide and 300 mL of purified water were added under stirring to form salt for 1 hour;

[0078] 5) Decolorization: After the salt-forming reaction is completed, add 10.0 g of activated carbon and continue to stir and decolorize for 30 minutes;

[0079] 6) filtering, collecting the filtrate, and removing water by concentrating under reduced pressure to obtain a wet product of sodium valproate;

[0080] 7) Drying: The wet sodium valproate was dried under vacuum at 70° C. for 6 h to obtain white solid sodium valproate.

[0081] 1-3. Solution preparation:

[0082] Diluent: Select n-heptane as the diluent.

[0083] System suitability solution: Take sodium valproate reference substance and impurity reference substance, add diluent to prepare a solution containing 2.5 μg each of impurity A, impurity B, impurity C, impurity D, impurity F, impurity G, impurity I, impurity J, impurity K, impurity L and 5 mg of valproic acid per 1 mL of solution, as the system suitability solution.

[0084] Test solution: Weigh 0.5 g of sodium valproate, accurately weigh, place in a separatory funnel, add 10 mL of water, add 5 mL of dilute sulfuric acid, shake, extract with diluent 3 times, 20 mL each time, combine the diluents, place in a 100 mL volumetric flask, dilute to the scale with the diluent, and shake to obtain the test solution.

[0085] 1-4. Test conditions:

[0086] Chromatographic column: capillary column with polyethylene glycol (PEG-20M) as stationary liquid;

[0087] Initial temperature control process: 130°C, maintain for 20 min, then increase the temperature to 200°C at a rate of 5°C / min, maintain for 15 min;

[0088] Inlet temperature: 220°C;

[0089] Detector temperature: 220°C;

[0090] Injection volume: 1.0 μL.

[0091] 1-5. Experimental results:

[0092] Take 1.0 μL of the above system suitability solution and the test solution, and test the content of each impurity. With the acceptable impurity limit as the monitoring item, the yield, purity and impurity content of sodium valproate in the obtained white solid are as follows:

[0093]

[0094]

[0095] Note: ND means “not detected”.

[0096] Conclusion: System suitability solution results show that ( Figure 1 ), the above chromatographic conditions can be used to detect the impurities in sodium valproate, and the separation degree is greater than 2.0, and the impurities can be separated with good specificity;

[0097] In the preparation method of the present invention, potassium iodide is used as a catalyst for the alkylation reaction, sodium hydroxide is used as an inorganic base, and the molar ratio of diethyl malonate, 1-bromopropane and sodium hydroxide is 1:6.0:8.0:

[0098] The yield of the obtained white solid sodium valproate was 93.6%;

[0099] The purity of sodium valproate reached 99.92%, which is within the acceptable limit;

[0100] The test solution was tested and found that the content of each impurity was less than 0.01%, and the total impurity content was only 0.08%, which was far below the impurity limit (≤1.0%);

[0101] The above results and Figure 2 It can be seen that the sodium valproate synthesized by this preparation method has high yield, high purity, low content of various impurities and good stability.

[0102] Example 2 Selection of Catalyst Types for Alkylation Reaction

[0103] The difference between this embodiment and embodiment 1 is that the amount of catalyst used in the alkylation reaction remains unchanged, but the type of catalyst is changed, and the catalyst potassium iodide used in the alkylation reaction in step 1) of embodiment 1 is replaced by:

[0104] Method 1: Tetrabutylammonium iodide;

[0105] Method 2: Sodium iodide;

[0106] Method 3: Tetradecyltrimethylammonium iodide;

[0107] Method 4: Benzyltrimethylammonium iodide;

[0108] Method 5: Tetrabutylammonium chloride;

[0109] Method 6: Tetradecyltrimethylammonium chloride;

[0110] Other feed ratios, preparation methods, solution preparation and chromatographic conditions are the same as those in Example 1.

[0111] Take 1.0 μL of the test solution and test the content of each impurity. With the acceptable impurity limit as the monitoring item, the yield, purity and impurity content of sodium valproate in the obtained white solid are as follows:

[0112]

[0113] Note: ND means “not detected”.

[0114] Conclusion: Using the same molar amount of alkylation catalyst, changing the catalyst type significantly affects the yield, purity and stability of sodium valproate;

[0115] Example 1 When the alkylation reaction is carried out using potassium iodide as a catalyst, the yield of the obtained white solid sodium valproate is 93.6%, the purity reaches 99.92%, the content of each impurity is less than 0.01%, which is far below the impurity limit (≤0.1%); the single impurity content is 0.01%, which is far below the single impurity limit (≤0.1%); the total impurity content is only 0.08%, which is far below the total impurity limit (≤1.0%); the synthesized sodium valproate has high yield, high purity, low impurity content and good stability.

[0116] When an equivalent amount of catalyst tetrabutylammonium iodide is used in Example 2 Method 1, the yield of the obtained white solid sodium valproate is 90.2%, the purity reaches 99.88%, the content of each impurity is less than 0.03%, which is far below the impurity limit (≤0.1%); the single impurity content is 0.03%, which is far below the single impurity limit (≤0.1%); the total impurity content is only 0.12%, which is far below the total impurity limit (≤1.0%); the synthesized sodium valproate has high yield, high purity, low impurity content and good stability.

[0117] Example 2 Method 2 Using an equivalent amount of catalyst sodium iodide ( Figure 3 ), the yield of the obtained white solid sodium valproate is 90.3%, the purity reaches 99.89%, the content of each impurity is less than 0.03%, which is far below the impurity limit (≤0.1%); the single impurity content is 0.03%, which is far below the single impurity limit (≤0.1%); the total impurity content is only 0.11%, which is far below the total impurity limit (≤1.0%); the synthesized sodium valproate has high yield, high purity, low impurity content and good stability.

[0118] When an equivalent amount of the catalyst tetradecyltrimethylammonium iodide is used in Method 3 of Example 2, the yield of the obtained white solid sodium valproate is 85.0%, the purity reaches 99.83%, the content of each impurity is less than 0.06%, which is far below the limit of each impurity (≤0.1%); the single impurity content is 0.02%, which is far below the single impurity limit (≤0.1%); the total impurity content is only 0.17%, which is far below the total impurity limit (≤1.0%); the synthesized sodium valproate has high yield, high purity, low impurity content and good stability.

[0119] When an equivalent amount of the catalyst benzyltrimethylammonium iodide is used in Method 4 of Example 2, the yield of the obtained white solid sodium valproate is 85.2%, the purity reaches 99.81%, the content of each impurity is less than 0.05%, which is far below the limit of each impurity (≤0.1%); the single impurity content is 0.02%, which is far below the single impurity limit (≤0.1%); the total impurity content is only 0.19%, which is far below the total impurity limit (≤1.0%); the synthesized sodium valproate has high yield, high purity, low impurity content and good stability.

[0120] When an equivalent amount of tetrabutylammonium chloride catalyst is used in method 5 of Example 2, the yield of the obtained white solid sodium valproate is 55.3%, which is significantly lower than that of Example 1 by 40.9%; the purity reaches 97.90%, which is lower than the acceptable limit (≤99.0%); the impurity A content is 0.16%, which is higher than the impurity limit (≤0.1%); the impurity B content is 0.75%, which is much higher than the impurity limit (≤0.1%); the single impurity content is 0.69%, which is much higher than the single impurity limit (≤0.1%); the total impurity content is only 2.10%, which is higher than the total impurity limit (≤1.0%); the synthesized sodium valproate has a low yield, low purity, a significantly increased impurity content, and poor stability.

[0121] When an equivalent amount of the catalyst tetradecyltrimethylammonium chloride is used in method 6 of Example 2, the yield of the obtained white solid sodium valproate is 46.2%, which is significantly reduced by 50.6% compared with Example 1; the purity reaches 97.77%, which is lower than the acceptable limit (≤99.0%); the impurity A content is 0.17%, which is higher than the impurity limit (≤0.1%); the impurity B content is 0.49%, which is much higher than the impurity limit (≤0.1%); the single impurity content is 0.89%, which is much higher than the single impurity limit (≤0.1%); the total impurity content is only 2.23%, which is much higher than the total impurity limit (≤1.0%); the synthesized sodium valproate has a low yield, low purity, significantly increased impurity content, poor stability, and a qualified sodium valproate product cannot be obtained.

[0122] summary:

[0123] Changing the alkylation reaction catalyst significantly affects the purity, yield and stability of sodium valproate: when potassium iodide, tetrabutylammonium iodide, sodium iodide, tetradecyltrimethylammonium iodide, benzyltrimethylammonium iodide are used as catalysts (for example, methods 1 to 4 of Example 1 and Example 2), the yield is high (the yield is between 85.0% and 93.6%), the purity is high (the purity is between 99.81% and 99.92%), the impurity content is low (all less than 0.06%, far below the impurity limit standards), and the stability is good;

[0124] Among them, when potassium iodide is used as a catalyst (for example, Example 1), the yield is the highest (up to 93.6%), the purity is the highest (up to 99.92%), the impurity content is the lowest (less than 0.01%, significantly lower than the impurity limit standards), and the stability is the best;

[0125] When other catalysts are used (for example, methods 5 to 6 in Example 2), the synthesized sodium valproate has a low yield (as low as 46.2%), a low purity (as low as 97.77%, not meeting the limit standard>99.0%), a high content of various impurities (up to 0.89%, all higher than the limit standards of various impurities), poor stability, and a qualified sodium valproate product cannot be obtained.

[0126] Example 3 Selection of the molar ratio of diethyl malonate, 1-bromopropane and sodium hydroxide in the alkylation reaction

[0127] The difference between this embodiment and embodiment 1 is that the molar ratio of diethyl malonate, 1-bromopropane and sodium hydroxide in the alkylation reaction is changed:

[0128] Example 1: The molar ratio is: 1.0:6.0:8.0;

[0129] Method 1: The molar ratio is 1.0:2.0:4.0;

[0130] Method 2: The molar ratio is 1.0:2.5:5.0;

[0131] Method 3: The molar ratio is 1.0:4.5:7.0;

[0132] Method 4: The molar ratio is 1.0:10.0:10.0;

[0133] Method 5: The molar ratio is 1.0:1.0:3.0;

[0134] Method 6: The molar ratio is 1.0:11.0:11.0;

[0135] Other feed ratios, preparation methods, solution preparation and chromatographic conditions are the same as those in Example 1.

[0136] Take 1.0 μL of the test solution and test the content of each impurity. With the acceptable impurity limit as the monitoring item, the yield, purity and impurity content of sodium valproate in the obtained white solid are as follows:

[0137]

[0138]

[0139] Note: ND means “not detected”.

[0140] Conclusion: Changing the molar ratio of diethyl malonate, 1-bromopropane and sodium hydroxide in the alkylation reaction significantly affects the yield, purity and stability of the product.

[0141] When the molar ratio of diethyl malonate, 1-bromopropane and sodium hydroxide in the alkylation reaction is 1.0:6.0:8.0, the yield of the obtained white solid sodium valproate is 93.6%, the purity reaches 99.92%, the content of each impurity is less than 0.01%, which is far below the impurity limit (≤0.1%); the single impurity content is 0.01%, which is far below the single impurity limit (≤0.1%); the total impurity content is only 0.08%, which is far below the total impurity limit (≤1.0%); the synthesized sodium valproate has high yield, high purity, low impurity content and good stability.

[0142] When the molar ratio of diethyl malonate, 1-bromopropane and sodium hydroxide in the alkylation reaction of Example 3 Method 1 is 1.0:2.0:4.0, the yield of the obtained white solid sodium valproate is 86.3%, the purity reaches 99.54%, and the content of each impurity is less than 0.09%; the single impurity content is 0.06%, which is far below the single impurity limit (≤0.1%); the total impurity content is only 0.46%, which is far below the total impurity limit (≤1.0%); the synthesized sodium valproate has high yield, high purity, low impurity content and good stability.

[0143] When the molar ratio of diethyl malonate, 1-bromopropane and sodium hydroxide in the alkylation reaction of Example 3 Method 2 is 1.0:2.5:5.0, the yield of the obtained white solid sodium valproate is 85.3%, the purity reaches 99.70%, and the content of each impurity is less than 0.09%; the single impurity content is 0.05%, which is far below the single impurity limit (≤0.1%); the total impurity content is only 0.30%, which is far below the total impurity limit (≤1.0%); the synthesized sodium valproate has high yield, high purity, low impurity content and good stability.

[0144] Example 3 Method 3 The molar ratio of diethyl malonate, 1-bromopropane and sodium hydroxide in the alkylation reaction is 1.0:4.5:7.0 ( Figure 4 ), the yield of the obtained white solid sodium valproate is 86.0%, the purity reaches 99.78%, and the content of each impurity is less than 0.05%; the single impurity content is 0.05%, which is far below the single impurity limit (≤0.1%); the total impurity content is only 0.22%, which is far below the total impurity limit (≤1.0%); the synthesized sodium valproate has high yield, high purity, low impurity content and good stability.

[0145] When the molar ratio of diethyl malonate, 1-bromopropane and sodium hydroxide in the alkylation reaction of Example 3 Method 4 is 1.0:10.0:10.0, the yield of the obtained white solid sodium valproate is 85.8%, the purity reaches 99.37%, and the content of each impurity is less than 0.10%; the single impurity content is 0.09%, which is far below the single impurity limit (≤0.1%); the total impurity content is only 0.63%, which is far below the total impurity limit (≤1.0%); the synthesized sodium valproate has high yield, high purity, low impurity content and good stability.

[0146] When the molar ratio of diethyl malonate, 1-bromopropane and sodium hydroxide in the alkylation reaction of Example 3 Method 5 is 1.0:1.0:3.0, the yield of the obtained white solid sodium valproate is 40.3%, which is significantly reduced by 57.0% compared with Example 1; the purity is 98.91%, which is lower than the acceptable limit (>99.0%); the total impurity content is 1.09%, which is higher than the total impurity limit (≤1.0%); the synthesized sodium valproate has a low yield, a significantly increased impurity content, and poor stability.

[0147] When the molar ratio of diethyl malonate, 1-bromopropane and sodium hydroxide in the alkylation reaction of Example 3 Method 6 is 1.0:11.0:11.0, the yield of white solid sodium valproate obtained is 80.3%, the purity reaches 98.57%, the content of each impurity is less than 0.11%, the single impurity content is 0.18%, which is significantly higher than the impurity limit (≤0.1%); the total impurity content is only 1.43%, which is significantly higher than the total impurity limit (≤1.0%); the impurity content of the synthesized sodium valproate is significantly increased, and the stability is poor.

[0148] summary:

[0149] Changing the molar ratio of diethyl malonate, 1-bromopropane and sodium hydroxide in the alkylation reaction significantly affects the yield, purity and stability of the product:

[0150] During the alkylation reaction, the molar ratio of diethyl malonate, 1-bromopropane and sodium hydroxide is in the range of 1:2.0-10.0:4.0-10.0 (for example, methods 1-4 of Example 1 and Example 3), the sodium valproate has a high yield (the yield is 85.3-93.6%), a high purity (the purity is 99.37-99.92%), a low content of each impurity (all less than 0.1%, lower than the limit standard of each impurity), and good stability;

[0151] In the alkylation reaction, the molar ratio of diethyl malonate, 1-bromopropane and sodium hydroxide is in the range of 1:4.5-6.0:7.0-8.0 (for example, in Example 1 and Example 3, Method 3), the yield of sodium valproate is higher (the yield is 86.0-93.6%), the purity is higher (the purity is as high as 99.78-99.92%), the content of each impurity is lower (≤0.05%, all lower than the impurity limit standards), and the stability is better;

[0152] When the molar ratio of diethyl malonate, 1-bromopropane and sodium hydroxide in the alkylation reaction is 1:6.0:8.0 (for example, Example 1), the sodium valproate has the highest yield (up to 93.6%), the highest purity (up to 99.92%), the lowest impurity content (≤0.01%, significantly lower than the impurity limit standard), and the best stability;

[0153] On the contrary, when the alkylation reaction adopts other molar ratios of diethyl malonate: 1-bromopropane: sodium hydroxide (for example, methods 5 to 6 in Example 3), the yield of sodium valproate is low (as low as 40.3%), the purity is low (as low as 98.57%, not meeting the limit standard>99.0%), the impurity content is high (up to 0.50%, which is significantly higher than the impurity limit standards), the stability is poor, and a qualified sodium valproate product cannot be obtained.

[0154] Example 4 Selection of Inorganic Base for Alkylation Reaction

[0155] The difference between this embodiment and embodiment 1 is that the inorganic base of the alkylation reaction is changed:

[0156] Embodiment 1: The inorganic base is sodium hydroxide;

[0157] Method 1: The inorganic base is potassium hydroxide;

[0158] Method 2: The inorganic base is cesium hydroxide;

[0159] Method 3: The inorganic base is potassium carbonate;

[0160] Method 4: The inorganic base is sodium carbonate;

[0161] Other feed ratios, preparation methods, solution preparation and chromatographic conditions are the same as those in Example 1.

[0162] Take 1.0 μL of the test solution and test the content of each impurity. With the acceptable impurity limit as the monitoring item, the yield, purity and impurity content of sodium valproate in the obtained white solid are as follows:

[0163]

[0164]

[0165] Note: ND means “not detected”.

[0166] Conclusion: Changing the inorganic base in the alkylation reaction significantly affects the yield, purity and impurity content of sodium valproate.

[0167] Example 1 When the inorganic base of the alkylation reaction is sodium hydroxide, the yield of the obtained white solid sodium valproate is 93.6%, the purity reaches 99.92%, the content of each impurity is less than 0.01%, which is far below the single impurity limit (≤0.1%); the single impurity content is 0.01%, which is far below the single impurity limit (≤0.1%); the total impurity content is only 0.08%, which is far below the total impurity limit (≤1.0%); the synthesized sodium valproate has high yield, high purity, low impurity content and good stability;

[0168] Example 4 Method 1 Alkylation reaction The inorganic base is potassium hydroxide ( Figure 5 ), the yield of the obtained white solid sodium valproate is 89.2%, the purity reaches 99.79%, the content of each impurity is less than 0.04%, which is far below the single impurity limit (≤0.1%); the single impurity content is 0.04%, which is lower than the single impurity limit (≤0.1%); the total impurity content is only 0.21%, which is far below the impurity limit (≤1.0%); the synthesized sodium valproate has high yield, high purity, low impurity content and good stability;

[0169] Example 4 Method 2 Alkylation Reaction When the inorganic base is cesium hydroxide, the yield of the obtained white solid sodium valproate is 85.0%, the purity reaches 99.59%, and the content of each impurity is less than 0.08%, which is far below the single impurity limit (≤0.1%); the single impurity content is 0.08%, which is lower than the single impurity limit (≤0.1%); the total impurity content is only 0.41%, which is far below the impurity limit (≤1.0%); the synthesized sodium valproate has high yield, high purity, low impurity content and good stability;

[0170] Example 4 Method 3 Alkylation Reaction When the inorganic base is potassium carbonate, the yield of the obtained white solid sodium valproate is 46.2%, and the purity reaches 98.66%, which is lower than the acceptable limit (>99.0%); the content of impurity A is 0.81%, which is significantly higher than the limit of impurity A (≤0.1%); the content of impurity B is 0.11%, which is higher than the limit of impurity B (≤0.1%); the single impurity content is 0.23%, which is significantly higher than the single impurity limit (≤0.1%); the total impurity content is only 1.34%, which is significantly higher than the total impurity limit (≤1.0%); the yield of the synthesized sodium valproate is significantly reduced, the purity is significantly reduced, the impurity content is significantly increased, and the stability is poor;

[0171] Example 4 Method 4 When the inorganic base for the alkylation reaction is sodium carbonate, the yield of the obtained white solid sodium valproate is 38.2%, the purity reaches 97.87%, the impurity A content is 0.98%, which is significantly higher than the limit of impurity A (≤0.1%); the impurity B content is 0.18%, which is higher than the limit of impurity B (≤0.1%); the single impurity content is 0.45%, which is much higher than the single impurity limit (≤0.1%); the total impurity content is only 2.13%, which is significantly higher than the total impurity limit (≤1.0%); the yield of the synthesized sodium valproate is significantly reduced, the purity is significantly reduced, the impurity content is significantly increased, and the stability is poor.

[0172] summary:

[0173] The inorganic base in the alkylation reaction significantly affects the yield, purity and impurity content of sodium valproate: when the inorganic base in the alkylation reaction is sodium hydroxide, potassium hydroxide and cesium hydroxide (for example, methods 1 to 2 of Example 1 and Example 4), the synthesized sodium valproate has a high yield (85.0 to 93.6%), a high purity (99.59 to 99.92%), a low content of each impurity (≤0.08%, lower than the limit standard of each impurity), and good stability;

[0174] Among them, when sodium hydroxide is used as the inorganic base in the alkylation reaction, the synthesized sodium valproate has the highest yield (up to 93.6%), the highest purity (up to 99.92%), the lowest impurity content (≤0.01%, all significantly lower than the impurity limit standards), and the best stability;

[0175] However, when other inorganic bases are used (for example, methods 3 to 4 of Example 4), the synthesized sodium valproate has a low yield (as low as 38.2%), a low purity (as low as 97.87%, not meeting the acceptable limit standard>99.0%), a significantly increased impurity content (up to 0.98%, significantly higher than the impurity limit standards), poor stability, and a qualified sodium valproate product cannot be obtained.

[0176] Comparative Example 1

[0177] Sodium valproate was prepared according to the preparation method of patent CN102241582B, as follows:

[0178] 1) Alkylation reaction: In a 1L four-necked flask, 96g of diethyl malonate and 172.7g of 1-bromopropane were mixed, the temperature was raised to 50°C, and an ethanol solution containing 19.0% sodium ethoxide was continuously added, and the temperature was maintained at 50-70°C. After the addition was completed, the temperature was raised to reflux state for reaction for 3h, and the temperature was raised to 120°C for distillation to recover ethanol. The temperature was then lowered to below 90°C, 200g of purified water was added to completely dissolve sodium bromide, and the desalted layer was separated by standing, and the oil layer was diethyl dipropyl malonate;

[0179] 2) Hydrolysis reaction: add 55 g of 96% sodium hydroxide and 300 mL of water, heat to 80-90° C. and reflux for hydrolysis for 4 h, then slowly distill and recover ethanol, slowly add 143 g of 30% hydrochloric acid, and make the pH of the brine layer reach 1-2 to precipitate dipropylmalonic acid;

[0180] 3) Decarboxylation reaction: dipropylmalonic acid is dissolved in valproic acid, and the sodium chloride water layer is separated to obtain a mixed acid. After the mixed acid is allowed to stand and become clean, it can be slowly heated to 180°C and maintained for 1 hour. After no more carbon dioxide gas is released, the crude valproic acid of the first two batches is weighed and taken out, and then the distillation device is changed, stirring is started, the vacuum degree is increased to stabilize at -0.096MPa, and the temperature is increased for distillation. The fraction with a top temperature of 136-138°C is collected, and a total of 4.5g of the front fraction, 66.5g of the fine valproic acid and 2g of the residue are obtained;

[0181] 4) Salt-forming reaction: Add 60 mL of water and 19.4 g of sodium hydroxide to 66.5 g of fine valproic acid to make the pH of the solution 8.5-9.5. First, distill the water to 120°C and then add 400 mL of toluene. Reflux the toluene through a water separator to carry water. Sodium valproate gradually crystallizes into fine needle-shaped crystals.

[0182] 5) Filter, cool and vacuum filter, and wash the remaining toluene with chloroform.

[0183] 6) Drying: After drying at 90° C., 55 g of sodium valproate product was obtained with a total yield of 55.2%.

[0184] Other chromatographic conditions were the same as in Example 1.

[0185] Take 1.0 μL of the test solution and test the content of each impurity. With the acceptable impurity limit as the monitoring item, the yield, purity and impurity content of sodium valproate in the obtained white solid are as follows:

[0186]

[0187] Note: ND means “not detected”.

[0188] in conclusion:

[0189] By adopting the preparation method of Example 1 of the present invention, the yield of the obtained white solid sodium valproate is 93.6%, the purity reaches 99.92%, the content of each impurity is less than 0.01%, the single impurity content is 0.01%, which is far below the impurity limit (≤0.1%); the total impurity content is only 0.08%, which is far below the impurity limit (≤1.0%); the synthesized sodium valproate has a high yield (93.6%), high purity (99.92%), low impurity content (≤0.01%), and good stability;

[0190] Comparative Example 1: Sodium valproate was prepared and tested according to the preparation method of patent CN102241582B. The results show:

[0191] (1) The yield of sodium valproate was 55.2%, which was significantly lower than that of Example 1 of the present invention by 41.0%, and the yield was low;

[0192] (2) The purity of sodium valproate was 97.85%, which was lower than the acceptable limit (≥99.0%), and it was impossible to obtain a sodium valproate product with qualified purity;

[0193] (3) The content of impurity A is 0.12%, which is higher than the limit of impurity A (≤0.1%); the content of impurity B is 0.12%, which is higher than the limit of impurity B (≤0.1%); the content of single impurity is 0.36%, which is significantly higher than the limit of single impurity (≤0.1%), and is significantly increased by 35 times compared with Example 1; the content of total impurities is 2.15%, which is significantly higher than the limit of total impurities (≤1.0%), and is significantly increased by 42 times compared with Example 1; the contents of impurity A, impurity B, single impurities and total impurities are all higher than the limit standards, and are significantly higher than Example 1.

[0194] summary:

[0195] The yield of sodium valproate synthesized by the preparation method of the present invention (e.g., Example 1) is significantly improved (up to 93.6%), the purity is significantly improved (up to 99.92%), the content of each impurity is significantly reduced (≤0.01%, significantly lower than the limit standard of each impurity), and the stability is good;

[0196] However, using the preparation method in the comparative document, the yield of synthesized sodium valproate is significantly reduced (as low as 55.2%), the purity is significantly reduced (97.85%, not meeting the purity limit >99.0%), the impurity content is significantly increased (up to 0.36%, significantly higher than the impurity limit standard), the stability is poor, and a qualified sodium valproate product cannot be obtained; in addition, the preparation method is complicated and difficult to apply to industrial production.

[0197] Comparative Example 2

[0198] The difference from Example 1 is that the inorganic base in the alkylation reaction is changed to an organic base:

[0199] Method 1: The organic base is sodium methoxide;

[0200] Method 2: The organic base is sodium ethoxide;

[0201] Other feed ratios, preparation methods, solution preparation and chromatographic conditions are the same as those in Example 1.

[0202] Take 1.0 μL of the test solution and test the content of each impurity. With the acceptable impurity limit as the monitoring item, the yield, purity and impurity content of sodium valproate in the obtained white solid are as follows:

[0203]

[0204]

[0205] Note: ND means “not detected”.

[0206] in conclusion:

[0207] Example 1 The alkylation reaction uses inorganic base sodium hydroxide, and the yield of the obtained white solid sodium valproate is 93.6%, the purity reaches 99.92%, the content of each impurity is less than 0.01%, the single impurity content is 0.01%, which is far below the impurity limit (≤0.1%); the total impurity content is only 0.08%, which is far below the impurity limit (≤1.0%); the synthesized sodium valproate has a high yield (93.6%), high purity (99.92%), low impurity content (≤0.01%), and good stability;

[0208] Comparative Example 2 Method 1-2 When the alkylation reaction uses organic bases sodium methoxide and sodium ethoxide respectively, due to the high activity of sodium ethoxide, it is easy to react with 1-bromopropane, resulting in a decrease in yield (at least 50%), and the alkylation reaction is difficult to complete, the impurity content increases (up to 9 times), and the stability is poor;

[0209] Comparative Example 2 Method 1 The yield of the finished sodium valproate prepared by sodium methoxide was 50.3%, which was significantly decreased by 46.2% compared with Example 1; the content of impurity C and impurity K was 0.10%, and impurity C and impurity K were not detected in Example 1, and the impurity content was significantly increased compared with Example 1; the single impurity content was 0.1%, which was significantly increased by 9 times compared with Example 1; the total impurity content was 0.48%, which was significantly increased by 5 times compared with Example 1; the yield of the synthesized sodium valproate was significantly reduced, the purity was significantly reduced, the impurity content was significantly increased, and the stability was poor;

[0210] Comparative Example 2 Method 2 The yield of the finished sodium valproate prepared by sodium ethoxide was 54.1%, which was significantly decreased by 42.2% compared with Example 1; the single impurity content was 0.10%, which was significantly increased by 9 times compared with Example 1; the total impurity content was 0.50%, which was significantly increased by more than 5 times compared with Example 1; the yield and purity of the synthesized sodium valproate were significantly reduced, the impurity content was significantly increased, and the stability was poor;

[0211] In addition, in the above-mentioned comparative example 2, methods 1 to 2, water absorption occurs during the feeding process of sodium alcohol, and inert gas protection is required throughout the process to eliminate the influence of moisture; and alcohol needs to be added as a reaction solvent to carry out the reaction; after the reaction is completed, excess sodium alcohol is difficult to remove; the process operation is difficult and complicated, and it is not suitable for industrial production.

[0212] summary:

[0213] In the preparation method of sodium valproate, inorganic base is used instead of organic base for alkylation reaction, which can significantly improve the yield (increased by more than 50%) and purity of the finished sodium valproate, reduce the impurity content (reduced by up to 9 times), and have good stability. At the same time, no reaction solvent is required during the reaction process, which can simplify the process operation and meet the technical requirements of pilot and scale-up production;

[0214] When an inorganic base is used as the base for the alkylation reaction (for example, Example 1), the yield of the synthesized sodium valproate is significantly improved (up to 93.6%), the purity is significantly improved (up to 99.92%), the content of each impurity is significantly reduced (≤0.01%, significantly lower than the limit standard of each impurity), and the stability is good;

[0215] However, when an organic base is used as the base for the alkylation reaction (for example, methods 1 to 2 in comparative example 2), the yield of the synthesized sodium valproate is significantly reduced (as low as 50.3%), the purity is significantly reduced (98.50%, which does not meet the purity limit>99.0%), the impurity content is significantly increased (up to 0.50%, which is higher than the impurity limit standard), the stability is poor, and a qualified sodium valproate product cannot be obtained.

[0216] In summary, the present invention provides a method for preparing sodium valproate, wherein the sodium valproate prepared by the method has high yield (up to 93.6%) and high purity (up to 99.92%), few impurities (≤0.01%), and good stability. At the same time, the process of the present invention has no reaction solvent, simple process operation, low cost, and can meet the technical requirements of pilot and scale-up production.

[0217] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some of the technical features therein. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing sodium valproate, characterized in that, include: Using diethyl malonate, 1-bromopropane and inorganic base as raw materials, an alkylation reaction is carried out under the action of a catalyst; After the alkylation reaction, a hydrolysis reaction, a decarboxylation reaction and a salt-forming reaction are performed; Wherein, the catalyst is potassium iodide; The inorganic base is sodium hydroxide; The molar ratio of diethyl malonate, 1-bromopropane and inorganic base is 1:6:7-8.

2. The preparation method according to claim 1, characterized in that: The amount of the catalyst used is 1% to 10% of the molar amount of diethyl malonate.

3. The preparation method according to claim 2, characterized in that: The amount of the catalyst used is 3% to 8% of the molar amount of diethyl malonate.

4. The preparation method according to any one of claims 1 to 3, characterized in that The hydrolysis reaction comprises: recovering 1-bromopropane, mixing the residue with water, adjusting the pH to 1-2 to precipitate solid, and filtering to obtain the solid; The decarboxylation reaction comprises: heating the solid and then distilling under reduced pressure to obtain valproic acid; The salt-forming reaction comprises: mixing valproic acid and sodium hydroxide and then performing a salt-forming reaction.

5. The preparation method according to claim 4, characterized in that: In the salt-forming reaction, the molar ratio of valproic acid to sodium hydroxide is 1:1.0-1.

1.

6. The preparation method according to claim 5, characterized in that: In the salt-forming reaction, the molar ratio of valproic acid to sodium hydroxide is 1:1.02-1.

06.

7. The preparation method according to claim 4, characterized in that: The method further comprises: after the salt-forming reaction, decolorizing, filtering, distilling water and drying to obtain sodium valproate.

8. The preparation method according to claim 7, characterized in that: Activated carbon is used for decolorization, and the amount of activated carbon used is 1% to 10% of the molar amount of diethyl malonate.

9. The preparation method according to claim 8, characterized in that: Activated carbon is used for decolorization, and the amount of activated carbon used is 3% to 6% of the molar amount of diethyl malonate.

10. The preparation method according to claim 7, characterized in that: The decolorization temperature is 20~60℃.

11. The preparation method according to claim 10, characterized in that: The decolorization temperature is 20~40℃.

12. The preparation method according to claim 1, characterized in that: The impurities in the prepared sodium valproate are any one or more of the following substances: 。 13. The preparation method according to claim 12, characterized in that: The detection method of impurities in the sodium valproate is gas chromatography.

14. The preparation method according to claim 13, characterized in that: The detection conditions of the gas chromatography are as follows: Chromatographic column: capillary column with polyethylene glycol as stationary liquid; Initial temperature control process: 110~130℃, maintain for 20~30min, then increase the temperature to 180~200℃ at a rate of 3~5℃ / min, maintain for 10~20min; Inlet temperature: 200~220℃; Detector temperature: 200~220℃; Injection volume: 0.5~2.0μL.

15. The preparation method according to claim 14, characterized in that: The polyethylene glycol is PEG-20M.

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