A method for controlling a process impurity of 2-ethylpentanoic acid in valproic acid

Abstract

This invention belongs to the field of pharmaceutical intermediate separation technology, specifically relating to a method for controlling the process impurity 2-ethylpentanoic acid (EP-B) in the preparation of valproic acid or sodium valproate via the diethyl malonate method. This invention precisely controls the content of the process impurity 2-ethylpentanoic acid (EP-B) in valproic acid or sodium valproate by controlling the content of 2-ethyl-2-propylmalonic acid in dipropylmalonic acid. A polar solvent is added to crude dipropylmalonic acid, the mixture is heated and stirred for a certain period, cooled, filtered, and dried to obtain high-purity dipropylmalonic acid concentrate. The dipropylmalonic acid concentrate is then decarboxylated to obtain high-purity valproic acid (RRT = 1.00), 99.779%; 2-ethylpentanoic acid (RRT = 0.90), 0.020%; and valeric acid (RRT = 0.77), 0.039%. The valproic acid product quality meets the requirements of the European Pharmacopoeia. This invention solves the problems of quality control and process evaluation in the preparation of valproic acid or sodium valproate by the diethyl malonate method.

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 the preparation of diethyl propylmalonic acid may contain 2-ethyl-2-propylmalonic acid diester (II); II is hydrolyzed in subsequent processes to produce 2-ethyl-2-propylmalonic acid as a byproduct (I); 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). The resulting diethyl 2-ethyl-2-propylmalonic acid (I, melting point 90~93℃) was hydrolyzed to obtain 2-ethyl-2-propylmalonic acid (I, melting point 90~93℃). 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 3 h (reactor pressure 3.0 bar ~ 4.0 bar) 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 residue limit for related substances (single impurities) 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. 2-Ethyl-2-propylmalonic acid can be effectively separated by slurry extraction to obtain high-purity dipropylmalonic acid.

[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 by means of 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 can be 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 valproic acid (RRT=1.00) with a purity of 99.779%. The product had a single impurity of less than 0.05%, a total impurity of less than 0.2%, and a purity of 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 by 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 phase transfer catalysis using selected ethyl malonate diester. 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 (to be reused next time). 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 methanol to the filter cake and reflux to slurry the inorganic salt (1~2 times). Filter to obtain filtrate 2. Use the filter cake to recover potassium chloride. Combine filtrate 2 and filtrate 1, and distill at atmospheric pressure to recover methanol. Then, at 80℃~ DMF was recovered under reduced pressure at 90 °C; the residue was then subjected to hydrolysis of diethyl dipropylmalonate.

[0058] (2) Add potassium hydroxide aqueous solution (KOH 16 g, H2O 16 mL) and 10 mL ethanol to diethyl dipropylmalonic acid, heat to 90℃ for 3 h, and hydrolyze to obtain solid by rotary evaporation. Add 50 mL of water to dissolve the solid, adjust the pH to 1~1.5 with concentrated hydrochloric acid, and a solid will precipitate 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] 1 13.427 0.70 48957 6883 0.397 69207 -- 2 14.467 0.76 3806 576 0.031 90044 5.24 3 16.720 0.88 9009 1357 0.073 121269 11.70 4 19.096 1.00 12155773 1482644 98.612 111329 11.29 5 21.500 1.13 5517 721 0.045 199493 11.41 6 24.054 1.26 7701 1149 0.062 241670 13.15 7 24.332 1.27 67937 10009 0.551 244756 1.42 8 26.106 1.37 18494 2718 0.150 281461 9.02 9 27.777 1.45 3353 491 0.027 318516 8.48 10 35.372 1.85 6351 580 0.052 220422 30.49 total 12326899 1507127 100.000

[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°C to 115°C for 1 hour; cooled to 20 ± 5°C, filtered and dried to obtain refined dipropylmalonic acid with a yield of 96.0%.

[0066] A sample of dipropylmalonic acid was analyzed by HPLC, and the results are shown in Figure 2 and Table 2.

[0067] Table 2 HPLC detection results of Example 2

[0068] 1 13.873 0.71 18058 2889 0.086 110616 -- 2 17.197 0.88 4690 860 0.022 217798 21.16 3 17.569 0.90 3719 660 0.018 215213 2.48 4 19.617 1.00 20879347 2192893 99.288 116865 10.75 5 22.237 1.13 7469 1172 0.036 273389 13.11 6 25.043 1.28 11750 1994 0.056 386711 16.94 7 26.858 1.37 9612 1499 0.046 390291 10.90 8 28.566 1.46 8628 1364 0.041 446233 9.95 9 33.984 1.73 40413 6082 0.192 588833 31.12 10 35.786 1.82 5129 779 0.024 641056 10.13 11 37.819 1.93 22300 1408 0.106 121386 6.63 12 41.301 2.11 17861 2095 0.085 526003 10.52 total 21028976 2213695 100.000

[0069] according to Figure 2 As 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 = 1.13): 2-propyl-2-butylmalonic acid, 0.036%; peak 7 (retention time 26.858 min, RRT = 1.37): monoethyl dipropylmalonic acid, 0.046%; peak 8 (retention time 28.56 ...086%): 2-propylmalonic acid, 0.086%; peak 8 (retention time 28.566 min, RRT = 0.086%): 2-propylmalonic acid, 0 1.46): Dipropylmalonium monopropyl, 0.041%; Peak 9 (retention time 33.984 min, RRT = 1.73): Diethyl dipropylmalonium, 0.192%.

[0070] Example 3

[0071] Preparation of valproic acid

[0072] In Example 1, crude dipropylmalonic acid was decarboxylated at 160-180℃ to obtain valproic acid; crude valproic acid was sampled and subjected to GC detection, and the results are shown in Figure 3 and Table 3.

[0073] Table 3 GC detection results of Example 3

[0074] 1 5.841 0.20 23817 3390 0.007 17916 -- 2 8.302 0.28 146949 23273 0.045 38059 14.28 3 10.216 0.34 136284 24027 0.042 75285 12.00 4 22.933 0.77 266263 53932 0.082 519669 92.09 5 26.938 0.90 199341 42218 0.061 814382 32.47 6 29.923 1.00 325677508 43501559 99.745 400133 19.35 7 34.488 1.15 60467 12484 0.019 1215052 29.04 total 326510628 43660883 100.000

[0075] As shown in Figure 3 and 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 dipropylmalonic acid concentrate was decarboxylated at 160-180℃ to obtain valproic acid; samples of the valproic acid concentrate were subjected to GC detection, and the results are shown in Figure 4 and Table 4.

[0079] Table 4 GC detection results of Example 4

[0080] 1 5.859 0.20 114260 16014 0.038 14827 -- 2 6.239 0.21 63444 9154 0.021 15314 1.93 3 8.306 0.28 97280 16367 0.032 45767 11.58 4 10.219 0.34 88426 16607 0.029 80346 12.77 5 18.689 0.62 128760 26219 0.042 352839 62.73 6 22.938 0.77 117227 21562 0.039 477718 32.86 7 26.949 0.90 59980 11441 0.020 694327 30.60 8 29.912 1.00 302793429 42038562 99.779 400275 18.61 total 303462807 42155924 100.000

[0081] As shown in Figure 4 and Table 4, peak 3 is ethyl valproate (RRT=0.28), 0.032%; peak 4 is propyl valproate (RRT=0.34), 0.029%; peak 6 is valeric acid (RRT=0.77), 0.039%; peak 7 is 2-ethylvaleric acid (RRT=0.90), 0.020%; and peak 8 is 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 20 mL of ethanol were added, and the mixture was heated to 90℃ for 3 h for hydrolysis. The solid was obtained by rotary evaporation. 50 mL of water was added to dissolve the solid, 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 28.3 g of white solid 2-ethyl-2-propylmalonic acid, mp. 117~118℃, yield 81.4%. 2-Ethyl-2-propylmalonic acid: 1 H NMR (400 MHz, DMSO-d6) δ: 12.65 (bs, 2H, 2×COOH), 1.77 (q, J = 7.6 Hz, 2H, CH2), 1.72 ~ 1.67 (m, 2H, CH2), 1.16 ~ 1.08 (m, 2H, CH2), 0.89 (t, J = 7.2 Hz, 3H, CH3 ), 0.76 ( t, J = 7.6 Hz, 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] 1 13.741 0.70 0.128 23616 3331 2537 84519 1.16 -- 2 16.617 0.87 99.646 18385233 1968083 2537 72049 0.86 13.49 3 19.064 1.00 0.030 5504 729 2537 162488 1.42 11.84 4 24.175 1.26 0.040 7296 1032 2537 263611 1.10 28.59 5 25.155 1.32 0.157 28923 3683 2537 231464 1.10 5.03

[0091] according to Figure 5As 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 (400 MHz, 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 = 7.6 Hz, 3H, CH3), 0.83 (t, J = 7.6 Hz, 3H, CH3); 13 C NMR (101 MHz, 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 shown in Figure 6 and Table 6.

[0097] Table 6 GC detection results of Example 6

[0098] 1 5.096 0.17 13162 2478 0.025 25017 -- 2 7.004 0.23 33164 7575 0.063 63812 14.98 3 24.193 0.80 28408 5989 0.054 597732 145.48 4 27.530 0.90 52153181 8268214 99.740 389400 22.87 5 29.701 0.98 10858 2367 0.021 990326 15.16 6 30.245 1.00 37299 8080 0.071 1070861 4.66 7 30.572 1.01 13277 2719 0.025 994489 2.75 total 52289349 8297422 100.00

[0099] according to Figure 6 As shown in Table 6, in GC, peak 3 is 2-methylvaleric acid (RRT=0.80), 0.054%; peak 4 is 2-ethylvaleric acid (RRT=0.90), 99.740%; and peak 6 is 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 of separating 2-ethyl-2-propylmalonic acid process impurities from crude dipropylmalonic acid using a pulping technique, and precisely controlling the content of 2-ethylvalerate in valproic acid or sodium valproate to no more than 0.02%, involves: adding a polar solvent to the crude dipropylmalonic acid, heating and pulping for a certain period of time, cooling, filtering and drying to obtain high-purity refined dipropylmalonic acid; and then decarboxylating the refined dipropylmalonic acid to obtain high-purity valproic acid. The polar solvent is selected from propanol or isopropanol and water; The pulping temperature is selected from 105℃ to 115℃; The pulping time is selected from 0.5h, 1.0h, 1.5h, 2.0h, 2.5h, 3.0h, or 3.5h; 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 slurry mixing 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 2-ethylpentanoic acid precursor compound is 2-ethyl-2-propylmalonic acid, which was found using retrosynthetic analysis. The precursor compound of valproic acid, dipropylmalonic acid, was identified using retrosynthetic analysis. 。 3. The control method according to claim 2, characterized in that... The preparation method of the aforementioned 2-ethyl-2-propylmalonic acid includes 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 aforementioned 2-ethyl-2-propylmalonic acid, the preparation reaction being as follows: X is chosen as either 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... The pulping time is selected from 0.5h, 1.0h or 1.5h.

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 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%; 2-ethylvaleric acid, 0.020%. The purity of the valproic acid was 99.779%. The single impurity of the product was less than 0.05%, the total impurity was less than 0.2%, and the purity was greater than 99.5%, which met the European Pharmacopoeia standard.

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