Method for controlling process impurity 2-ethyl valeric acid in valproic acid

Abstract

The invention belongs to the technical field of separation of drug intermediates, and particularly relates to a control method for a process impurity 2-ethyl valeric acid (EP-B) in preparation of valproic acid or sodium valproate by a diethyl malonate method. According to the method disclosed by the invention, the content of 2-ethyl-2-propylmalonic acid process impurities in dipropylmalonic acid is controlled, so that the content of 2-ethylvaleric acid (EP-B) which is a process impurity in valproic acid or sodium valproate is accurately controlled; adding a polar solvent into the dipropylmalonic acid crude product, heating, pulping for a certain time, cooling, filtering and drying to obtain a high-purity dipropylmalonic acid refined product; high-purity valproic acid (RRT is equal to 1.00) is prepared through decarboxylation of the dipropyl malonic acid fine product, and the purity is 99.779%; 0.020% of 2-ethyl valeric acid (RRT is equal to 0.90); and valeric acid (RRT = 0.77), 0.039%. The valproic acid product quality meets the requirements of European Pharmacopoeia. According to the method, the problems of quality control and process evaluation of valproic acid or sodium valproate prepared by a diethyl malonate method are solved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate separation technology, specifically relating to a method for controlling the process impurity 2-ethylpentanoic acid in the preparation of valproic acid or sodium valproate by the diethyl malonate method. Background Technology

[0002] Sichuan Keruide Pharmaceutical Co., Ltd. [A method for preparing dipropylmalonate, an intermediate of valproic acid, CN 202111473302.7, 2023.06.06] disclosed a method for preparing dipropylmalonate by reacting diethyl malonate and 1-bromopropane in an amide solvent under the action of a base and a phase transfer catalyst; controlling the impurity content of dipropylmalonate to ≤0.17% (GC); the purity of dipropylmalonate to ≥98.16% (GC); and the yield to ≥85%.

[0003]

[0004] Sichuan Keruide Pharmaceutical Co., Ltd. [A method for detecting impurities related to dipropylmalonic acid, ZL201911229436.7, 2022.10.28] uses high performance liquid chromatography to detect the presence of propylmalonic acid, propylmalonic acid monomethyl ester, dipropylmalonic acid, propylmalonic acid monoethyl ester, dipropylmalonic acid monomethyl ester, dipropylmalonic acid monoethyl ester, or dipropylmalonic acid diethyl ester in the dipropylmalonic acid reaction solution; as detailed in its patent specification. Figure 1 The results show that some unknown impurities have not been confirmed. It is unknown whether 2-ethyl-2-propylmalonic acid is present. 2-ethyl-2-propylmalonic acid is a key intermediate in the production of 2-ethylpentanoic acid, a process impurity in valproic acid.

[0005] Chinese invention patents [A method for preparing and hydrolyzing 2-alkyl-2-propylmalonic acid diester, CN117430509A, 2024.01.23; A method and application for preparing dipropylmalonic acid using chloropropane as an alkylating agent, CN116768697B, 2024.03.29] disclose the reaction of diethyl malonate and 1-chloropropane to prepare diethyl dipropylmalonic acid diester:

[0006]

[0007] Chinese invention patent [A method for the preparation and hydrolysis of 2-alkyl-2-propylmalonic acid diester, CN117430509A, 2024.1.23] speculates that 2-ethyl-2-propylmalonic acid diester (II) may be present in the preparation of dipropylmalonic acid diester; II is hydrolyzed in subsequent processes to produce 2-ethyl-2-propylmalonic acid (I) as a byproduct; this impurity is transferred to the target product in subsequent reactions, forming a process impurity—2-ethylpentanoic acid (B)—in the production of sodium valproate.

[0008]

[0009] Xi'an Yuanda Detian Pharmaceutical Co., Ltd. [A method for detecting sodium valproate and related substances in sodium valproate injection, ZL202011522863.7, 2023.9.22] describes impurities in sodium valproate products as valeric acid and 2-ethylvaleric acid (B). Beijing Yuekang Kechuang Pharmaceutical Technology Co., Ltd. [A method for preparing sodium valproate, CN202310028759.X, 2023.5.9] uses gas chromatography to detect impurities in sodium valproate products prepared by the diethyl malonate method. The main process impurity detected in the optimal example 1 is 2-ethylvaleric acid (B).

[0010] Cabrera-Rivera et al. [Solvent-and Catalyst-Free Microwave-Assisted Decarboxylation of Malonic Acid Derivatives. Green and Sustainable Chemistry, 2017, 07(4): 270-280] used t-BuOK as a base to first convert diethyl 2-propylmalonic acid into the corresponding enol in dry tetrahydrofuran, and then reacted it with iodoethane to obtain diethyl 2-ethyl-2-propylmalonic acid (II). After hydrolysis, 2-ethyl-2-propylmalonic acid (I, melting point 90-93℃) was obtained. The latter was decarboxylated by microwave heating at 180-190℃ to obtain 2-ethylpentanoic acid (B).

[0011]

[0012] In 1989, Steffen et al. [Process for C-alkylation of unsubstituted and monosubstituted malonic acid esters. DE3737377, 1989-05-18] selected C2H5ONa as the base and diethyl 2-ethyl-2-propylmalonate as the solvent. Diethyl 2-ethylmalonate was reacted with 1-bromopropane at 100℃~110℃ for 3h (reactor pressure 3.0bar~4.0bar) to prepare diethyl 2-ethyl-2-propylmalonate II, with a yield of 91%.

[0013]

[0014] Liu Yuyang [Master's Thesis, Hunan University, 2024] prepared 2-ethyl-2-propylmalonic acid by reacting diethyl 2-propylmalonic acid with 1-bromoethane, followed by decarboxylation of the latter to prepare impurity B.

[0015]

[0016] There are currently no reports on methods for controlling 2-ethylpentanoic acid in valproic acid or sodium valproate raw materials, nor are there any methods for controlling the process impurity 2-ethylpentanoic acid in the preparation of valproic acid or sodium valproate by the diethyl malonate method.

[0017] Those skilled in the art know that 2-ethylpentanoic acid and valproic acid have similar physical properties, and 2-ethylpentanoic acid cannot be completely separated through purification processes. According to the quality requirements for sodium valproate in the Chinese Pharmacopoeia and the European Pharmacopoeia, the maximum limit for related substances (single impurities) residue in sodium valproate is 0.05%. Therefore, the residue of 2-ethylpentanoic acid must be reduced to below 0.1% during the preparation of the crude product; otherwise, a qualified product with a residue of less than 0.05% cannot be obtained through purification processes.

[0018] Therefore, controlling the content of 2-ethylpentanoic acid has become a technical challenge in the preparation of valproic acid or sodium valproate by the diethyl malonate method. Summary of the Invention

[0019] The purpose of this invention is to provide a method for controlling the process impurity 2-ethylpentanoic acid in the preparation of valproic acid or sodium valproate by the diethyl malonate method. This invention achieves precise control of 2-ethylpentanoic acid in valproic acid or sodium valproate raw materials by controlling the content of 2-ethyl-2-propylmalonic acid impurity in the preparation of dipropylmalonic acid by the diethyl malonate method.

[0020] 2-Ethylpentanoic acid and valproic acid (2-propylpentanoic acid) are homologues of monocarboxylic acids. Both are liquids with similar boiling points. Although the content of 2-ethylpentanoic acid in valproic acid or sodium valproate raw materials is low, it is easier to distill off due to its lower boiling point. Therefore, 2-ethylpentanoic acid is difficult to completely separate by distillation. The liquid compounds—2-ethylpentanoic acid and its precursors—dipropylmalonic acid (mp. 157–158℃) and 2-ethyl-2-propylmalonic acid (mp. 117–118℃) are homologues of dicarboxylic acids with significant differences in melting points. 2-Ethyl-2-propylmalonic acid has a lower melting point and higher solubility in hot polar solvents. High-purity dipropylmalonic acid can be effectively separated by slurry extraction.

[0021] This invention separates dicarboxylic acid homologues based on the difference in their solid melting points and their differences in solubility in hot polar solvents, thus precisely removing difficult-to-separate liquid carboxylic acid homologue impurities.

[0022] This invention provides a method for controlling the process impurity 2-ethylpentanoic acid in the preparation of valproic acid or sodium valproate by the diethyl malonate method. By controlling the content of the process impurity 2-ethyl-2-propylmalonic acid in dipropylmalonic acid, the content of the process impurity 2-ethylpentanoic acid (EP-B) in valproic acid or sodium valproate is precisely controlled.

[0023] This invention also provides a method for finding the precursor compound of 2-ethylpentanoic acid—2-ethyl-2-propylmalonic acid—using retrosynthetic analysis:

[0024]

[0025] This invention also provides a method for identifying dipropylmalonic acid, a precursor compound of valproic acid, using retrosynthetic analysis.

[0026]

[0027] This invention also provides a method for preparing the precursor compound of 2-ethylpentanoic acid—2-ethyl-2-propylmalonic acid—using organic synthesis:

[0028]

[0029] X is chosen as chlorine or bromine, R 1 and R 2 Choose methyl, ethyl, or propyl, respectively.

[0030] The present invention also provides a method for separating the process impurity 2-ethylpentanoic acid (EP-B) from valproic acid or sodium valproate through source control.

[0031] A polar solvent is added to crude dipropylmalonic acid, the mixture is heated and stirred for a certain period of time, cooled, filtered and dried to obtain high-purity refined dipropylmalonic acid; the refined dipropylmalonic acid is then decarboxylated to obtain high-purity valproic acid.

[0032] The polar solvent is selected from one or more of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol, tert-butanol, and water.

[0033] The pulping temperature is selected from 65℃~75℃, 75℃~85℃, 85℃~95℃, 95℃~105℃ or 105℃~115℃.

[0034] The pulping time can be selected from 0.5h, 1.0h, 1.5h, 2.0h, 2.5h, 3.0h or 3.5h.

[0035] To accurately detect the content of 2-ethyl-2-propylmalonic acid process impurities in dipropylmalonic acid, HPLC detection requires a 2-ethyl-2-propylmalonic acid reference standard. Therefore, this invention also provides a method for preparing 2-ethyl-2-propylmalonic acid, characterized in that the method may include the following steps: propylating ethylmalonic acid diester with 1-halopropane under phase transfer catalysis to obtain diethyl 2-ethyl-2-propylmalonic acid; hydrolyzing the 2-ethyl-2-propylmalonic acid diester to obtain the 2-ethyl-2-propylmalonic acid.

[0036]

[0037] X is chosen as chlorine or bromine, R 1 and R 2 Choose methyl, ethyl, or propyl, respectively.

[0038] A polar solvent was added to crude dipropylmalonic acid, and the mixture was heated and pulped for a certain period of time. After cooling, the mixture was filtered and dried to obtain high-purity refined dipropylmalonic acid. The refined dipropylmalonic acid was then decarboxylated to obtain high-purity valproic acid. The process impurities detected by GC in the high-purity valproic acid were: ethyl valproate (RRT=0.28), 0.032%; propyl valproate (RRT=0.34), 0.029%; valeric acid (RRT=0.77), 0.039%; 2-ethylvaleric acid (RRT=0.90), 0.020%; and the purity of valproic acid (RRT=1.00) was 99.779%. The product had less than 0.05% single impurities, less than 0.2% total impurities, and a purity greater than 99.5%, which meets the European Pharmacopoeia standard.

[0039] Compared with the prior art, the present invention has the following advantages:

[0040] (1) Separate the process impurity 2-ethylpentanoic acid (EP-B) from valproic acid or sodium valproate by source control method.

[0041] (2) The precursor compound of 2-ethylpentanoic acid, 2-ethyl-2-propylmalonic acid, was found using retrosynthetic analysis:

[0042]

[0043] (3) The precursor compound of valproic acid, dipropylmalonic acid, was found using retrosynthetic analysis:

[0044]

[0045] (4) 2-Ethyl-2-propylmalonic acid was prepared by selective ethyl malonate diester via phase transfer catalysis. The preparation reaction is as follows:

[0046] Attached Figure Description

[0047] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0048] Figure 1 High-performance liquid chromatogram of crude dipropylmalonic acid;

[0049] Figure 2 High-performance liquid chromatogram of dipropylmalonic acid (PPI);

[0050] Figure 3 Gas chromatogram of crude valproic acid;

[0051] Figure 4 Gas chromatogram of refined valproic acid;

[0052] Figure 5. High performance liquid chromatogram of 2-ethyl-2-propylmalonic acid single reference standard;

[0053] Figure 6. Gas chromatogram of 2-ethylpentanoic acid single reference standard. Detailed Implementation

[0054] To further illustrate the present invention, the following detailed description of the invention's solutions, in conjunction with the accompanying drawings and embodiments, is provided, but should not be construed as limiting the scope of protection of the present invention.

[0055] Example 1

[0056] Preparation of dipropylmalonic acid

[0057] (1) Add 3.0 mmol TBAB and 50 mL DMF to a three-necked flask and stir with an electric stirrer. Then add 0.15 mol potassium carbonate (200 mesh), 16.0 g (0.10 mol) diethyl malonate, and dropwise add 19.64 g (0.25 mol) 1-chloropropane. React at 85℃±10℃ (75℃~95℃) for 4 h; at 105℃±10℃ (95℃~115℃) for 4 h; and at 115℃~130℃ for 4 h. Recover excess 1-chloropropane (see below). (Direct application); after the reaction is complete, cool to room temperature and filter. The filter cake is an inorganic alkali salt (KCl and KHCO3); filtrate 1 is a pale yellow liquid; add 60 mL of methanol to the filter cake and reflux to slurry the inorganic salt (1-2 times), filter to obtain filtrate 2. The filter cake is used to recover potassium chloride. Filtrate 2 and filtrate 1 are combined, and methanol is recovered by atmospheric distillation. Then, DMF is recovered under reduced pressure at 80℃-90℃. The residue is then subjected to subsequent hydrolysis of diethyl dipropylmalonate.

[0058] (2) Add potassium hydroxide aqueous solution (KOH 16g, H2O 16mL) and 10mL ethanol to diethyl dipropylmalonic acid, heat to 90℃ for 3h, and hydrolyze to obtain solid by rotary evaporation. Add 50mL of water to dissolve the solid, adjust the pH to 1-1.5 with concentrated hydrochloric acid, and a solid precipitates out. Filter the solid. Combine the filtrate with the filter cake from step (1), concentrate, crystallize and dry to recover KCl. The solid is crude dipropylmalonic acid.

[0059] Crude dipropylmalonic acid was sampled and analyzed by HPLC. The results are as follows: Figure 1 As shown in Table 1.

[0060] Table 1. HPLC detection results of Example 1

[0061]

[0062] according to Figure 1 As shown in Table 1, peak 1 (retention time 13.427 min, RRT = 0.70): 2-propylmalonic acid, 0.397%; peak 3 (retention time 16.720 min, RRT = 0.88): 2-ethyl-2-propylmalonic acid, 0.073%; peak 4 (retention time 19.096 min, RRT = 1.00): dipropylmalonic acid, 98.612%; peak 5 (retention time 21.500 min, RRT = 1.13): 2-propyl-2-butylmalonic acid, 0.045%; peak 8 (retention time 26.106 min, RRT = 1.37): monoethyl dipropylmalonic acid, 0.150%; peak 9 (retention time 27.777 min, RRT = 1.45): monopropyl dipropylmalonic acid, 0.027%.

[0063] Example 2

[0064] Preparation of high-quality dipropylmalonic acid

[0065] In Example 1, crude dipropylmalonic acid was added to 40 ml of propanol or isopropanol and 10 ml of water, and stirred at 105℃±115℃ for 1 h; cooled to 20±5℃, filtered and dried to obtain refined dipropylmalonic acid with a yield of 96.0%.

[0066] A sample of high-purity dipropylmalonic acid was analyzed by HPLC, and the results are as follows: Figure 2 As shown in Table 2.

[0067] Table 2. HPLC detection results of Example 2

[0068]

[0069] according to Figure 2As shown in Table 2, peak 1 (retention time 13.873 min, RRT = 0.71): 2-propylmalonic acid, 0.086%; peak 2 (retention time 17.197 min, RRT = 0.88): 2-ethyl-2-propylmalonic acid, 0.022%; peak 4 (retention time 19.617 min, RRT = 1.00): dipropylmalonic acid, 99.288%; peak 5 (retention time 22.237 min, RRT = 0.88)... =1.13): 2-propyl-2-butylmalonic acid, 0.036%; Peak 7 (retention time 26.858 min, RRT = 1.37): Dipropylmalonyl monoethyl malonate, 0.046%; Peak 8 (retention time 28.566 min, RRT = 1.46): Dipropylmalonyl monopropyl malonate, 0.041%; Peak 9 (retention time 33.984 min, RRT = 1.73): Diethyl dipropylmalonate, 0.192%.

[0070] Example 3

[0071] Preparation of valproic acid

[0072] In Example 1, crude dipropylmalonic acid was decarboxylated at 160–180 °C to obtain valproic acid; samples of crude valproic acid were subjected to GC analysis, and the results are as follows. Figure 3 As shown in Table 3.

[0073] Table 3. GC detection results in Example 3

[0074]

[0075] according to Figure 3 As shown in Table 3, peak 2, ethyl valproate (RRT = 0.28), 0.045%; peak 3, propyl valproate (RRT = 0.34), 0.042%; peak 4, valeric acid (RRT = 0.77), 0.082%; peak 5, 2-ethylvaleric acid (RRT = 0.90), 0.061%; and peak 6, valproic acid (RRT = 1.00), 99.745%.

[0076] Example 4

[0077] Preparation of valproic acid

[0078] In Example 2, the refined dipropylmalonic acid was decarboxylated at 160–180 °C to obtain valproic acid; samples of the refined valproic acid were subjected to GC analysis, and the results are as follows. Figure 4 As shown in Table 4.

[0079] Table 4 GC detection results in Example 4

[0080]

[0081] according to Figure 4 As shown in Table 4, peak 3, ethyl valproate (RRT = 0.28), 0.032%; peak 4, propyl valproate (RRT = 0.34), 0.029%; peak 6, valeric acid (RRT = 0.77), 0.039%; peak 7, 2-ethylvaleric acid (RRT = 0.90), 0.020%; and peak 8, valproic acid (RRT = 1.00), 99.779%.

[0082] The quality of valproic acid products meets the requirements of the European Pharmacopoeia.

[0083] Example 5

[0084] Preparation of 2-ethyl-2-propylmalonic acid

[0085]

[0086] (1) Add 0.2 mol diethyl ethyl malonate, 0.01 mol tetraethylammonium bromide, 0.03 mol KBr, 0.3 mol K2CO3, 120 mL DMF, and 0.32 mol 1-chloropropane sequentially. React at 70℃~90℃ for 2~4 h; at 90℃~110℃ for 2~4 h; and at 110℃~130℃ for 2~4 h. After the reaction is complete, cool to room temperature and filter. Filter cake 1 is an inorganic base salt (KCl and KHCO3). Filtrate 1 is a pale yellow liquid. Add 60 mL of ethanol to the filter cake to remove the inorganic salt. Filter the filter cake to obtain filtrate 2. Filter cake 2 (inorganic salt) is used to recover potassium chloride. Filtrate 2 and filtrate 1 are combined and the ethanol is recovered by atmospheric distillation. Then, DMF is recovered under reduced pressure at 80℃~90℃ (for recycling). The residue is then subjected to hydrolysis of diethyl 2-ethyl-2-propylmalonic acid.

[0087] (2) In the pale yellow liquid of diethyl 2-ethyl-2-propylmalonic acid, potassium hydroxide aqueous solution (KOH 32g, H2O 32mL) and 20mL ethanol were added. The mixture was heated to 90℃ and hydrolyzed for 3h. The solid was obtained by rotary evaporation. The solid was dissolved in 50mL of water, and the pH was adjusted to 1-1.5 with concentrated hydrochloric acid. A solid precipitated out. The solid was filtered, and the filtrate 3 and filter cake 2 (inorganic salt) were concentrated, crystallized, and dried to recover KCl. The solid was recrystallized in methanol aqueous solution to obtain 28.3g of white solid 2-ethyl-2-propylmalonic acid, mp. 117-118℃, yield 81.4%. 2-Ethyl-2-propylmalonic acid: 1HNMR (400MHz, DMSO-d6) δ: 12.65 (bs, 2H, 2×COOH), 1.77 (q, J=7.6Hz, 2H, CH2), 1.72~1.67 ( m, 2H, CH2), 1.16~1.08 (m, 2H, CH2), 0.89 (t, J=7.2Hz, 3H, CH3), 0.76 (t, J=7.6Hz, 3H, CH3).

[0088] 2-Ethyl-2-propylmalonic acid was sampled and analyzed by HPLC. The results are as follows: Figure 5 As shown in Table 5.

[0089] Table 5. HPLC Detection Results of Example 5

[0090]

[0091] according to Figure 5 As shown in Table 5, peak 1 (retention time 13.741 min, RRT = 0.70): 2-propylmalonic acid, 0.128%; peak 2 (retention time 16.617 min, RRT = 0.87): 2-ethyl-2-propylmalonic acid, 99.646%; peak 3 (retention time 19.064 min, RRT = 1.00): dipropylmalonic acid, 0.030%.

[0092] Example 6

[0093] Preparation of 2-ethylpentanoic acid (B) (decarboxylation of 2-ethyl-2-propylmalonic acid)

[0094]

[0095] 20.0 g of 2-ethyl-2-propylmalonic acid was placed in a single-necked round-bottom flask and decarboxylated at 180–190 °C for 2 h to obtain a yellow liquid. The liquid was then distilled, and 11.5 g of the fraction collected at 102 °C / 16 mmHg was obtained, with a yield of 77.1%. 2-Ethylpentanoic acid: 1 H NMR (400MHz, DMSO-d6) δ: 12.02 (s, 1H, COOH), 2.15~2.12 (m, 1H, CH), 1.53~1.19 (m, 6H, CH2CH2+CH2), 0.85 (t, J=7.6Hz, 3H, CH3), 0.83 (t, J=7.6Hz, 3H, CH3); 13 C NMR (101MHz, DMSO-d6) δ: 176.94, 46.31, 33.76, 24.93, 20.15, 13.94, 11.72.

[0096] 2-Ethylpentanoic acid was sampled and analyzed by GC. The results are as follows: Figure 6As shown in Table 6.

[0097] Table 6. GC detection results in Example 6

[0098]

[0099] according to Figure 6 As shown in Table 6, GC peak 3, 2-methylvaleric acid (RRT = 0.80), 0.054%; peak 4, 2-ethylvaleric acid (RRT = 0.90), 99.740%; peak 6, valproic acid (RRT = 1.00), 0.071%.

[0100] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. Other embodiments can be obtained based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for controlling the process impurity 2-ethylpentanoic acid in the preparation of valproic acid or sodium valproate by the diethyl malonate method, characterized in that... The process impurity 2-ethyl-2-propylmalonic acid in crude dipropylmalonic acid is separated by pulping technology, and the content of the process impurity 2-ethylvalerate in valproic acid or sodium valproate is precisely controlled to be no more than 0.02%. 2-Ethylpentanoic acid and valproic acid are homologues of monocarboxylic acids. Both are liquids with similar boiling points. Although the content of 2-ethylpentanoic acid in valproic acid or sodium valproate is low, it is easier to distill off due to its lower boiling point. Therefore, it is difficult to completely separate 2-ethylpentanoic acid by distillation. The liquid compound 2-ethylpentanoic acid and its precursor compound dipropylmalonic acid and 2-ethyl-2-propylmalonic acid are homologues of dicarboxylic acids. 2-Ethyl-2-propylmalonic acid has a lower melting point and higher solubility in hot polar solvents. It can be effectively separated by slurrying to obtain high-purity dipropylmalonic acid. Separation is achieved by utilizing the difference in the solid melting points and solubility of the dicarboxylic acid homologues in hot polar solvents, thus accurately removing impurities from the difficult-to-separate liquid monocarboxylic acid homologues.

2. The control method according to claim 1, characterized in that... The precursor compound of 2-ethylpentanoic acid, 2-ethyl-2-propylmalonic acid, was identified using retrosynthetic analysis. The precursor compound of valproic acid, dipropylmalonic acid, was identified using retrosynthetic analysis.

3. The control method according to claim 1, characterized in that... 2-Ethylpentanoic acid precursor compound, 2-ethyl-2-propylmalonic acid, was prepared by organic synthesis. The preparation reaction is as follows: X is chosen as chlorine or bromine, R 1 and R 2 Methyl, ethyl, or propyl groups were selected, respectively; PTC was used as the phase transfer catalyst.

4. The control method according to claim 1, characterized in that... 2-Ethylpentanoic acid, a process impurity, can be separated from valproic acid or sodium valproate by source control methods.

5. The control method according to claim 1, characterized in that... A polar solvent was added to crude dipropylmalonic acid, and the mixture was heated and stirred for a certain period of time. After cooling, the mixture was filtered and dried to obtain high-purity refined dipropylmalonic acid. The refined dipropylmalonic acid was then decarboxylated to obtain high-purity valproic acid. The purity of valproic acid was 99.779%; 2-ethylvalerate was 0.020%; and valerate was 0.039%. The quality of the valproic acid product met the requirements of the European Pharmacopoeia.

6. The control method according to claim 5, characterized in that... The polar solvent is selected from one or more of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol, tert-butanol, and water.

7. The control method according to claim 5, characterized in that... The pulping temperature is selected from 65℃~75℃, 75℃~85℃, 85℃~95℃, 95℃~105℃ or 105℃~115℃.

8. The control method according to claim 5, characterized in that... The pulping time can be selected from 0.5h, 1.0h, 1.5h, 2.0h, 2.5h, 3.0h or 3.5h.

9. The control method according to claim 3, characterized in that... The preparation method of the 2-ethyl-2-propylmalonic acid may include the following steps: propylating ethylmalonic acid diester with 1-halopropane under phase transfer catalysis to obtain 2-ethyl-2-propylmalonic acid diester; hydrolyzing the 2-ethyl-2-propylmalonic acid diester to obtain the 2-ethyl-2-propylmalonic acid, the preparation reaction is as follows: X is chosen as chlorine or bromine, R 1 and R 2 Methyl, ethyl, or propyl groups were selected, respectively; PTC was used as the phase transfer catalyst.

10. The control method according to claim 5, characterized in that... A polar solvent was added to crude dipropylmalonic acid, and the mixture was heated and pulped for a certain period of time. After cooling, the mixture was filtered and dried to obtain high-purity refined dipropylmalonic acid. The refined dipropylmalonic acid was then decarboxylated to obtain high-purity valproic acid. The process impurities detected by GC in the high-purity valproic acid were: ethyl valproate, 0.032%; propyl valproate, 0.029%; valeric acid, 0.039%; and 2-ethylvaleric acid, 0.020%. The purity of the valproic acid is 99.779%; the single impurity of the product is less than 0.05%, the total impurity is less than 0.2%, and the purity is greater than 99.5%, which meets the standards of the European Pharmacopoeia.

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