Post-treatment method for preparing dipropylmalonic acid crude product by dimethyl malonate method

Abstract

The invention belongs to the technical field of separation of drug intermediates, and particularly relates to a method for preparing a high-purity dipropylmalonic acid refined product by adding a polar solvent into a dipropylmalonic acid crude product, heating, pulping for a certain time, cooling, filtering and drying. Decarboxylating the refined dipropylmalonic acid product to obtain high-purity valproic acid; distilling the filtrate to recover the polar solvent to obtain 2-methyl-2-propylmalonic acid, and carrying out decarboxylation on the 2-methyl-2-propylmalonic acid to obtain 2-methylpentanoic acid; 2-methylvaleric acid is used as a perfume additive. According to the method disclosed by the invention, the process impurity 2-methyl-2-propylmalonic acid in dipropylmalonic acid is separated, and the process impurity 2-methylvaleric acid (EP-L) in valproic acid or sodium valproate is precisely separated; the quality of the valproic acid product prepared by the method disclosed by the invention meets the requirements of European Pharmacopoeia EP-11 (2023). According to the invention, the problems of quality control and process evaluation of valproic acid or sodium valproate prepared by a dimethyl malonate method are solved.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical intermediate separation technology, specifically relating to the recovery and application of 2-methyl-2-propylmalonic acid in crude dipropylmalonic acid; and a method for separating 2-methylvaleric acid, a process impurity, from sodium valproate prepared by the dimethyl malonate method. Background Technology

[0002] 2-Methylvalerate, also known as dihydrostrawberry acid, is a colorless or pale yellow liquid, soluble in water and organic solvents such as ethanol; bp. 195–196℃; it has a strong, pungent, and unpleasant acid odor, and when highly diluted, it has an oily acid odor and a grassy aroma. It is used to formulate flavorings for dairy products, tomatoes, strawberries, grapes, cocoa, chocolate, coffee, and other food products.

[0003] Chinese patent CN 118373737A discloses a method for preparing valproic acid, which involves preparing dipropylmalonate from dimethyl malonate and 1-chloropropane, hydrolyzing dipropylmalonate to obtain dipropylmalonic acid, decarboxylating dipropylmalonic acid to obtain valproic acid, and forming valproic acid into a salt to obtain sodium valproate raw material. In the sodium valproate raw material, technicians detected an impurity—2-methylvaleric acid (L).

[0004] Regarding the pathway of 2-methylvaleric acid formation, Chinese patent CN 117430509A suggests that dimethyl dipropylmalonate contains dimethyl 2-methyl-2-propylmalonate (II), which generates 2-methyl-2-propylmalonic acid (I) during hydrolysis. This 2-methyl-2-propylmalonic acid is then transferred to the sodium valproate raw material in subsequent reactions, forming a process impurity—2-methylvaleric acid (L). The specific reaction is as follows:

[0005]

[0006] There are currently no reports on methods for separating 2-methylvaleric acid from sodium valproate raw materials, nor are there any methods for separating 2-methylvaleric acid, a process impurity, from valproic acid prepared by the dimethyl malonate method.

[0007] Because 2-methylvaleric acid and valproic acid (2-propylvaleric acid) have similar physical and chemical properties, 2-methylvaleric 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-methylvaleric acid must be reduced to below 0.1% when preparing the crude product; otherwise, a qualified product with a residue of less than 0.05% cannot be obtained through purification processes.

[0008] Currently, sodium valproate raw material has a high residual level of 2-methylvaleric acid. Chinese patent CN 112972449A discloses pharmacological tests showing that 2-methylvaleric acid is vascular irritant, which can cause sodium valproate injections to be vascular irritating. Chinese patent CN 112972449A discloses a pharmaceutical composition with a sodium valproate content of not less than 90% and a 2-methylvaleric acid content of not more than 0.014%, which can reduce the vascular irritation of sodium valproate.

[0009] Therefore, controlling the content of 2-methylvaleric acid has become a technical challenge in the high-temperature decarboxylation of dipropylmalonic acid to prepare sodium valproate. Summary of the Invention

[0010] This invention also provides a post-processing method for crude dipropylmalonic acid prepared by the dimethyl malonate method; characterized in that a polar solvent is added to the crude dipropylmalonic acid, the mixture is heated and pulped 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. The filtrate is distilled to recover the polar solvent, yielding 2-methyl-2-propylmalonic acid, which is then decarboxylated to obtain 2-methylvaleric acid; the 2-methylvaleric acid is used as a fragrance additive.

[0011] The polar solvent is selected from one or more of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, sec-butanol, tert-butanol, and water.

[0012] The pulping temperature is selected from 55℃~65℃, 65℃~75℃, 75℃~85℃, 85℃~95℃ or 95℃~105℃.

[0013] The pulping time can be selected from 0.5h, 1.0h, 1.5h, 2.0h, 2.5h, 3.0h or 3.5h.

[0014] 2-Methylvalerate and valproic acid (2-propylvalerate) are homologues of monocarboxylic acids with similar physical properties. Both are liquids with similar boiling points. Although 2-methylvalerate is present in low concentrations, its lower boiling point makes it easier to distill off. Therefore, 2-methylvalerate is difficult to completely separate by distillation. The liquid compounds—2-methylvalerate and its precursors—dipropylmalonic acid (mp. 157–158 °C) and 2-methyl-2-propylmalonic acid (mp. 106–108 °C) are homologues of dicarboxylic acids with significantly different melting points. 2-methyl-2-propylmalonic acid has high solubility in thermally polar solvents, and can be effectively separated by slurry mixing. This invention separates these dicarboxylic acid homologues based on their differences in solubility in thermally polar solvents, precisely removing impurities from the difficult-to-separate liquid carboxylic acid homologues.

[0015] This invention provides a method for separating 2-methylvaleric acid, a process impurity, in the preparation of sodium valproate by the dimethyl malonate method. By separating the 2-methyl-2-propylmalonic acid process impurity from crude dipropylmalonic acid, valproic acid or the process impurity 2-methylvaleric acid (EP-L) in sodium valproate can be accurately separated.

[0016] The purpose of this invention is to find the precursor compound of 2-methylvaleric acid—2-methyl-2-propylmalonic acid—using a retrosynthetic analysis method.

[0017]

[0018] The purpose of this invention is to identify the valproic acid precursor compound, dipropylmalonic acid, using a retrosynthetic analysis method.

[0019]

[0020] The purpose of this invention is to prepare the precursor compound of 2-methylvaleric acid—2-methyl-2-propylmalonic acid—using an organic synthesis method.

[0021]

[0022] X is chosen as chlorine or bromine, R 1 and R 2 Choose methyl, ethyl, or propyl, respectively.

[0023] The purpose of this invention is to separate the process impurity 2-methylvaleric acid (EP-L) from valproic acid or sodium valproate through a source control method.

[0024] This invention provides a method for separating the process impurity 2-methylvaleric acid from sodium valproate prepared by the dimethyl malonate method. The method is characterized by accurately separating valproic acid or the process impurity 2-methylvaleric acid (EP-L) from sodium valproate by separating the content of the 2-methyl-2-propylmalonic acid process impurity in dipropylmalonic acid.

[0025] To accurately detect the content of 2-methyl-2-propylmalonic acid process impurities in dipropylmalonic acid, HPLC detection requires a 2-methyl-2-propylmalonic acid reference standard. Therefore, this invention also provides a method for preparing 2-methyl-2-propylmalonic acid, characterized in that the method may include the following steps: propylating dimethyl methylmalonic acid with 1-halopropane under phase transfer catalysis to obtain dimethyl 2-methyl-2-propylmalonic acid; hydrolyzing the dimethyl 2-methyl-2-propylmalonic acid to obtain the 2-methyl-2-propylmalonic acid.

[0026]

[0027] X is chosen as chlorine or bromine, R 1 and R 2 Choose methyl, ethyl, or propyl, respectively.

[0028] This invention involves adding a polar solvent to crude dipropylmalonic acid, heating and pulping for a certain time, cooling, filtering, and drying to obtain high-purity refined dipropylmalonic acid. The refined dipropylmalonic acid is then decarboxylated to obtain high-purity valproic acid. The process impurities detected by GC in the high-purity valproic acid are: 2-methylvaleric acid (RRT = 0.80), 0.004%; isopropylvaleric acid (RRT = 0.96), 0.032%; 2-propylhexanoic acid (RRT = 1.09), 0.047%. The purity of the high-purity valproic acid (RRT = 1.00) is 99.916%. The single impurity is less than 0.05%, the total impurity is less than 0.2%, and the purity is greater than 99.5%. The quality of the valproic acid product meets the requirements of the European Pharmacopoeia EP-11 (2023).

[0029] Compared with the prior art, the present invention has the following advantages:

[0030] (1) Separate the process impurity 2-methylvaleric acid (EP-L) from valproic acid or sodium valproate by source control method.

[0031] (2) The precursor compound of 2-methylvaleric acid, 2-methyl-2-propylmalonic acid, was found using retrosynthetic analysis:

[0032]

[0033] (3) The precursor compound of valproic acid, dipropylmalonic acid, was found using retrosynthetic analysis:

[0034]

[0035] (4) 2-Methylvalerate can be used as a flavoring additive in some foods. A polar solvent is added to crude dipropylmalonic acid, the mixture is heated and pulped for a certain time, cooled, filtered, and dried to obtain a high-purity refined dipropylmalonic acid. The refined dipropylmalonic acid is then decarboxylated to obtain high-purity valerate. The filtrate is distilled to recover the polar solvent, yielding 2-methyl-2-propylmalonic acid. 2-methyl-2-propylmalonic acid is then decarboxylated to obtain 2-methylvalerate. 2-Methylvalerate is used as a flavoring additive. This invention simplifies a difficult problem and makes comprehensive use of resources, turning waste into treasure. Attached Figure Description

[0036] 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.

[0037] Figure 1 High-performance liquid chromatogram of crude dipropylmalonic acid;

[0038] Figure 2 High-performance liquid chromatogram of dipropylmalonic acid (PPI);

[0039] Figure 3 Gas chromatogram of crude valproic acid;

[0040] Figure 4 Gas chromatogram of refined valproic acid;

[0041] Figure 5. High performance liquid chromatogram of 2-methyl-2-propylmalonic acid as a single reference standard;

[0042] Figure 6. Gas chromatogram of 2-methylvaleric acid; Detailed Implementation

[0043] 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.

[0044] Example 1

[0045] Preparation of dipropylmalonic acid

[0046] (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) and 13.2 g (0.10 mol) dimethyl malonate. Add 19.64 g (0.25 mol) 1-chloropropane dropwise. Stir the reaction at 75℃~130℃ for 12.0 h and recover the 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 base 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 recover methanol by atmospheric distillation. Then recover DMF by vacuum distillation at 80℃~90℃ (to be recycled). The residue is then subjected to hydrolysis of dimethyl dipropyl malonate.

[0047] (2) Add potassium hydroxide aqueous solution (KOH 16g, H2O 16mL) and 10mL methanol to the pale yellow liquid of dipropylmalonic acid, heat to 90℃ for 3h for hydrolysis, and rotary evaporate to obtain solid. Add 50mL of water to dissolve the solid, adjust the pH to 1-1.5 with concentrated hydrochloric acid, and 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.

[0048] Crude dipropylmalonic acid was sampled and analyzed by HPLC. The results are as follows: Figure 1 As shown in Table 1.

[0049] Table 1. HPLC detection data of crude dipropylmalonic acid

[0050]

[0051] according to Figure 1 As shown in Table 1, peak 1 (retention time 13.372 min, RRT = 0.70): 2-propylmalonic acid, 0.033%; peak 2 (retention time 15.922 min, RRT = 0.84): 2-methyl-2-propylmalonic acid, 0.243%; peak 4 (retention time 19.015 min, RRT = 1.00): dipropylmalonic acid, 98.310%; peak 5 (retention time 24.288 min, RRT = 1.28): monomethyl dipropylmalonic acid, 0.190%; peak 8 (retention time 27.711 min, RRT = 1.46): monopropyl dipropylmalonic acid, 0.888%.

[0052] Example 2

[0053] Preparation of high-quality dipropylmalonic acid

[0054] In Example 1, crude dipropylmalonic acid was added to 40 ml of propanol or isopropanol and 10 ml of water, and stirred at 95℃±10℃ for 0.5 h. The mixture was then cooled to 20±5℃ to crystallize, filtered, and dried to obtain refined dipropylmalonic acid with a yield of 96%. The filtrate was distilled to recover propanol or isopropanol, and then filtered and dried to obtain 2-methyl-2-propylmalonic acid. 2-methyl-2-propylmalonic acid was decarboxylated to obtain 2-methylvaleric acid. 2-Methylvaleric acid was used as a fragrance additive.

[0055] 2-Methyl-2-propylmalonic acid: mp. 106~108℃; 1 HNMR (400MHz, DMSO-d6) δ: 12.60 (s, 2H, COOH×2), 1.69~1.64 (m, 2H, CH2), 1.23 (s, 3H, CH3), 1.21~1.14 (m, 2H, CH2), 0.86 (t, J=7.2Hz, 3H, CH3).

[0056] 2-Methylvalerate: 1 H NMR (400MHz, DMSO-d6) δ: 11.05 (s, 1H, COOH), 2.30~2.22 (m, 1H, CH), 1.55~1.45 (m, 1H, 0.5C H2), 1.28~1.21 (m, 3H, CH2+0.5CH2), 1.00 (d, J=7.2Hz, 3H, CH3), 0.81 (t, J=7.2Hz, 3H, CH3).

[0057] A sample of high-purity dipropylmalonic acid was analyzed by HPLC, and the results are as follows: Figure 2 As shown in Table 2.

[0058] Table 2. HPLC Detection Data of Dipropylmalonic Acid (Pure Dipropylmalonic Acid)

[0059]

[0060] according to Figure 2 As shown in Table 2, peak 1 (retention time 13.136 min, RRT = 0.69): 2-propylmalonic acid, 0.017%; peak 2 (retention time 15.905 min, RRT = 0.83): 2-methyl-2-propylmalonic acid, 0.035%; peak 3 (retention time 19.185 min, RRT = 1.00): dipropylmalonic acid, 99.127%; peak 4 (retention time 21.524 min, RRT = 1.12): 2-propyl-2-butylmalonic acid, 0.032%; peak 5 (retention time 24.606 min, RRT = 1.28): monomethyl dipropylmalonic acid, 0.096%.

[0061] Example 3

[0062] Preparation of valproic acid

[0063] In Example 1, crude dipropylmalonic acid was decarboxylated at 160–180 °C to obtain valproic acid.

[0064] A sample of crude valproic acid was subjected to GC analysis, and the results are as follows: Figure 3 As shown in Table 3.

[0065] Table 3. GC detection results of crude valeric acid.

[0066]

[0067] according to Figure 3As shown in Table 3, peak 1, valeric acid (RRT = 0.77), 0.011%; peak 2, 2-methylvaleric acid (RRT = 0.80), 0.156%; peak 3, isopropylvaleric acid (RRT = 0.96), 0.020%; peak 4, valproic acid (RRT = 1.00), 99.569%; peak 5, 2-propylhexanoic acid (RRT = 1.09), 0.029%; and peak 6, dipropylvaleric acid (RRT = 1.19), 0.215%.

[0068] Example 4

[0069] Preparation of valproic acid

[0070] In Example 2, the dipropylmalonic acid concentrate was decarboxylated at 160–180 °C to obtain valproic acid, with a yield of 98%.

[0071] A sample of refined valproic acid was subjected to GC analysis, and the results were as follows: Figure 4 As shown in Table 4.

[0072] Table 4. GC detection results of valeric acid.

[0073]

[0074] according to Figure 4 As shown in Table 4, peak 1, 2-methylvaleric acid (RRT = 0.80), 0.004%; peak 2, isopropylvaleric acid (RRT = 0.96), 0.032%; peak 3, valproic acid (RRT = 1.00), 99.916%; and peak 4, 2-propylhexanoic acid (RRT = 1.09), 0.047%. The quality of the valproic acid product meets the requirements of the European Pharmacopoeia.

[0075] Example 5

[0076] Preparation of 2-methyl-2-propylmalonic acid

[0077]

[0078] 0.2 mol dimethyl malonate, 0.01 mol tetramethylammonium bromide, 0.03 mol KBr, 0.3 mol K₂CO₃, 120 mL DMF, and 0.32 mol 1-chloropropane were added sequentially. The mixture was stirred at 90 °C for 1 h, at 110 °C for 7 h, and at 125 °C for 4 h. After the reaction was complete, the mixture was cooled and filtered to obtain filtrate 1. After the reaction was complete, the mixture was cooled to room temperature and filtered again. The filter cake was an inorganic base salt (KCl and KHCO₃). DMF was recovered from filtrate 1 under reduced pressure at 80–90 °C (for reuse in the next reaction), yielding a pale yellow residue. The residue and filter cake were combined, and 15 mL H₂O and 10 mL methanol were added. The mixture was heated to 100–120 °C for 3 h for hydrolysis, and the solid was obtained by rotary evaporation. The solid was dissolved in 50 mL of water, and the pH was adjusted to 1–1.5 with concentrated hydrochloric acid. A solid precipitated out and was filtered.

[0079] The filtrate was combined with inorganic salts and concentrated, crystallized and dried to recover KCl; the solid was recrystallized in methanol aqueous solution to give 16.6 g of 2-methyl-2-propylmalonic acid; mp. 106~108℃; yield 51.7%.

[0080] 1 HNMR (400MHz, DMSO-d6) δ: 12.60 (s, 2H, COOH×2), 1.69~1.64 (m, 2H, CH2), 1.23 (s, 3H, CH3), 1.21~1.14 (m, 2H, CH2), 0.86 (t, J=7.2Hz, 3H, CH3).

[0081] 2-Methyl-2-propylmalonic acid was used as a single reference standard for HPLC analysis, and the results are as follows: Figure 5 As shown in Table 5.

[0082] Table 52 HPLC Detection Data of 2-Methyl-2-propylmalonic acid

[0083]

[0084] according to Figure 5 As shown in Table 5, peak 2 (retention time 15.871 min): 2-methyl-2-propylmalonic acid, 99.472%.

[0085] Example 6

[0086] Preparation of 2-methylvaleric acid

[0087]

[0088] 16.0 g of 2-methyl-2-propylmalonic acid was placed in a single-necked round-bottom flask and decarboxylated at 180–190 °C for 2 h to obtain 11.36 g of dark brown liquid. Distillation yielded 7.2 g of colorless 2-methylvaleric acid, with a yield of 62.1%.

[0089] 2-Methylvalerate was sampled and analyzed by GC. The results are as follows: Figure 6 As shown in Table 6.

[0090] Table 6. GC detection results of 2-methylvaleric acid

[0091]

[0092] according to Figure 6 As shown in Table 6, the GC purity of 2-methylvaleric acid is 99.754%.

[0093] 1 H NMR (400MHz, DMSO-d6) δ: 11.05 (s, 1H, COOH), 2.30~2.22 (m, 1H, CH), 1.55~1.45 (m, 1H, 0.5C H2), 1.28~1.21 (m, 3H, CH2+0.5CH2), 1.00 (d, J=7.2Hz, 3H, CH3), 0.81 (t, J=7.2Hz, 3H, CH3).

[0094] 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 post-processing method for crude dipropylmalonic acid prepared by the dimethyl malonate method; characterized in that... A polar solvent is added to crude dipropylmalonic acid, and the mixture is heated and stirred for a certain period of time. After cooling to a certain temperature, a solid is obtained, which is then filtered and dried to obtain high-purity refined dipropylmalonic acid. The refined dipropylmalonic acid is decarboxylated to obtain high-purity valproic acid. The filtrate is distilled to recover the polar solvent, yielding 2-methyl-2-propylmalonic acid. The 2-methyl-2-propylmalonic acid is then decarboxylated to obtain 2-methylvaleric acid.

2. The method according to claim 1, 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.

3. The method according to claim 1, characterized in that... The pulping temperature is selected from 55℃~65℃, 65℃~75℃, 75℃~85℃, 85℃~95℃ or 95℃~105℃.

4. The method according to claim 1, 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.

5. The 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: 2-methylvaleric acid, 0.004%; isopropylvaleric acid, 0.032%; and 2-propylhexanoic acid, 0.047%. The high-purity valproic acid has a purity of 99.916%; the product has less than 0.05% single impurities, less than 0.2% total impurities, and a purity greater than 99.5%, which meets the standards of the European Pharmacopoeia.

6. The method according to claim 1, characterized in that... A polar solvent is added to crude dipropylmalonic acid prepared by the dimethyl malonate method, and the mixture is heated and stirred for a certain period of time; then cooled and filtered; the filtrate is distilled to recover the polar solvent and obtain 2-methyl-2-propylmalonic acid, which is then decarboxylated to obtain 2-methylvaleric acid; the 2-methylvaleric acid is used as a fragrance additive.

7. The method according to claim 1, characterized in that... The method of separating 2-methyl-2-propylmalonic acid process impurities from dipropylmalonic acid is used to ensure that the content of 2-methylvaleric acid process impurities in valproic acid or sodium valproate is not higher than 0.014%. 2-Methylvalerate and valproic acid are homologues of carboxylic acids, both liquids with similar boiling points. Although 2-methylvalerate is present in low concentrations, it is easier to distill off due to its lower boiling point. Therefore, 2-methylvalerate is difficult to completely separate by distillation. The liquid compound 2-methylvalerate and its precursor, dipropylmalonic acid, are homologues of dicarboxylic acids with significantly different melting points. 2-Methyl-2-propylmalonic acid has high solubility in thermally polar solvents, and can be effectively separated by slurry mixing. Separation is achieved by exploiting the difference in solubility of solid dicarboxylic acid homologues in thermally polar solvents, precisely removing impurities from the difficult-to-separate liquid carboxylic acid homologues.

8. The method according to claims 1 and 7, characterized in that... The precursor compound of 2-methylvaleric acid, 2-methyl-2-propylmalonic acid, was identified using retrosynthetic analysis. The precursor compound of valproic acid, dipropylmalonic acid, was identified using retrosynthetic analysis.

9. The method according to claims 1 and 7, characterized in that... 2-Methylvalerate precursor compound 2-methyl-2-propylmalonic acid was prepared by organic synthesis. X is chosen as either chlorine or bromine, R 1 and R 2 Choose methyl, ethyl, or propyl, respectively.

10. The method according to claims 1 and 7, characterized in that... 2-Methylvalerate, a process impurity, can be separated from valproic acid or sodium valproate by source control methods.

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