Method for removing valeric acid, an impurity of valproic acid, in sodium valproate synthesis process

Abstract

The present invention belongs to the technical field of impurity removal of fine chemicals, and specifically relates to a method for removing valeric acid, an impurity of valproic acid, in a sodium valproate synthesis process. The method for removing valeric acid as an impurity of the present invention comprises the following steps: adding toluene and water to a decarboxylation mother liquor, and filtering with suction; allowing the filtrate to stand for separation, and removing the lower aqueous phase; adjusting the pH of the toluene layer to >10; standing for separation, retaining the aqueous phase, adding toluene, and adjusting the pH to <2; standing for separation, performing a first alkaline extraction operation on the toluene layer, standing for separation, until the residual valeric acid in the toluene layer is less than 0.1%, adding hydrochloric acid and toluene to the remaining aqueous phase, separating, retaining the toluene layer, and performing a second alkaline extraction operation until the residual valeric acid is less than 0.1%; after the two alkaline extractions, the toluene layers are mixed, and then an alkaline solution is added dropwise to adjust the pH, and the crude sodium valproate is obtained. The method for removing valeric acid as an impurity of valproic acid in a sodium valproate synthesis process provided by the present invention has a low valeric acid content in the crude sodium valproate, and the prepared sodium valproate has high purity.

Description

Technical Field

[0001] The invention belongs to the technical field of impurity removal of fine chemicals, and particularly relates to a method for removing valeric acid, an impurity of valproic acid, in a sodium valproate synthesis process. Background Art

[0002] Sodium valproate, also known as sodium dipropyl acetate, is a commonly used anti-epileptic drug with numerous advantages in the treatment of epilepsy, including a broad spectrum of efficacy, high efficacy, good safety, minimal drug interactions, and ease of administration. Beyond epilepsy treatment, sodium valproate is also being explored for other applications, such as bipolar disorder and migraine. Overall, sodium valproate will continue to have significant clinical value in the future, but its use needs to be continuously optimized amidst competition. Furthermore, with the help of technologies such as precision medicine, its intended intended population can be further clarified to better maximize its therapeutic effects.

[0003] At present, the synthesis process of sodium valproate mainly includes the following methods:

[0004] 1. The hydrolysis-acidification method uses 2-cyano-2-propylvalerate as the raw material, undergoing catalytic hydrolysis with aqueous sulfuric acid to produce a mixture of valproic acid and the ester. This is then hydrolyzed with an alkaline solution, extracted, acidified, and distilled to obtain high-purity valproic acid (≥99%). Finally, it is neutralized with sodium hydroxide to form the sodium salt. By optimizing the catalyst and reaction conditions (120–160°C), this method avoids the production of toxic gases associated with traditional nitrous acid oxidation processes, making it environmentally friendly and operationally safe, with a yield of 76%.

[0005] 2. Alkylation of diethyl malonate: Diethyl malonate reacts with 1-bromopropane in the presence of sodium ethoxide to produce diethyl dipropyl malonate, which is then saponified and hydrolyzed with aqueous sodium hydroxide solution and acidified with hydrochloric acid to obtain dipropylmalonic acid. This is then heated to 110-160°C for decarboxylation to produce crude valproic acid, which is then purified by distillation and neutralized to form its sodium salt, as described in CN116082142A.

[0006] 3. The valproic acid salt formation method is to prepare high-purity valproic acid, crystallize it with sodium hydroxide, and after salt formation, it is treated to obtain sodium valproate.

[0007] The above hydrolysis and acidification method, i.e., high-temperature decarboxylation of 2-cyano-2-propylpentanoic acid with sulfuric acid, is the mainstream process for preparing sodium valproate. For example, CN113200844A discloses a method for preparing sodium valproate, which uses valproonitrile or methyl 2-cyano-2-propylpentanoate as starting materials to prepare valproic acid through a one-pot process. A sulfuric acid aqueous solution is used as a catalyst, and the reaction is carried out at 120-160°C for 20-40 hours to obtain valproic acid with a yield of 70%-80%. However, this method has a high hydrolysis temperature and a long reaction time.

[0008] It can be seen that high-temperature decarboxylation of 2-cyano-2-propylpentanoic acid with sulfuric acid is the mainstream process for preparing sodium valproate. However, none of the above processes mentions that valeric acid will be produced during the high-temperature decarboxylation of 2-cyano-2-propylpentanoic acid with concentrated sulfuric acid. Because valeric acid has similar chemical properties to valproic acid, it is impossible to completely remove valeric acid through a simple solvent refining process. According to the quality requirements of the Chinese Pharmacopoeia and the European Pharmacopoeia for sodium valproate, the maximum limit of the residual related substances in sodium valproate is 0.05%, and valeric acid is the most important by-product of the sulfuric acid decarboxylation process. Therefore, the residual valeric acid must be reduced to below 0.1% when preparing the crude product, otherwise it is impossible to obtain a qualified product with a residue below 0.05% through the refining process. The generation of valeric acid by-products is shown below:

[0009] .

[0010] Therefore, how to reduce the valeric acid content in the crude product to 0.1% becomes a technical problem in the preparation of sodium valproate by high-temperature decarboxylation of 2-cyano-2-propyl valeric acid in concentrated sulfuric acid. Summary of the Invention

[0011] The technical problem to be solved by the present invention is to overcome the above-mentioned defects of the prior art and provide a method for removing valeric acid, an impurity of valproic acid, in a sodium valproate synthesis process. The valeric acid content in the crude sodium valproate is low and the prepared sodium valproate has high purity.

[0012] The method for removing valeric acid, an impurity of valproic acid in the sodium valproate synthesis process of the present invention, comprises the following steps:

[0013] (1) Add toluene and water to the decarboxylation mother liquor and filter with suction; let the filtrate stand to separate and separate the lower aqueous phase; add water to the toluene layer, and add alkaline solution to adjust the pH to >10, let it stand to separate, retain the aqueous phase, add toluene, and add hydrochloric acid to adjust the pH to <2, let it stand to separate, and obtain the toluene layer;

[0014] (2) adding water to the toluene layer of step (1), adding alkaline solution dropwise, and standing to separate the layers as the first alkaline extraction operation, repeating the above alkaline extraction operation until the residual valeric acid in the toluene layer is less than 0.1%, and collecting the toluene mother liquor and aqueous phase after multiple standing and separation;

[0015] (3) adding toluene to the aqueous phase collected in step (2) and separated by multiple layers, and adding hydrochloric acid to adjust the pH to <2, and separating by separation to obtain a toluene layer;

[0016] (4) Add water to the toluene layer of step (3), add alkaline solution dropwise, and let it stand for stratification as the second alkaline extraction operation. Repeat the above alkaline extraction operation until the residual valeric acid in the toluene layer is less than 0.1%, and collect the toluene mother liquor obtained by multiple stratifications;

[0017] (5) The toluene mother liquors collected in step (2) and step (4) are mixed to obtain a valproic acid solution from which valeric acid has been removed.

[0018] The decarboxylation mother liquor in step (1) is prepared by reacting methyl cyanoacetate with bromopropane as raw materials to obtain methyl 2-cyano-2-propylvalerate, which is then hydrolyzed by adding an alkaline solution to obtain 2-cyano-2-propylvaleric acid, and then undergoing a decarboxylation reaction to obtain an oil-water mixture of valproic acid.

[0019] In step (1), the hydrochloric acid with a pH value less than 2 is concentrated hydrochloric acid, and the solution is stirred after the adjustment. The stirring time is 0.5 to 1.5 hours, preferably 1 hour.

[0020] In step (1), the alkaline solution with a pH value greater than 10 is adjusted to a sodium hydroxide solution with a mass concentration of 30%. After adjustment, the solution is stirred for 0.5 to 1.5 hours, preferably 1 hour.

[0021] The above alkaline extraction operation in step (2) is repeated by adding water to the toluene layer, adding the alkaline solution dropwise, and standing to separate the layers. The mass ratio of the alkaline solution added each time to the mass ratio of methyl cyanoacetate is 0.08 to 0.16, preferably 0.08.

[0022] The above alkaline extraction operation in step (4) is repeated by adding water to the toluene layer, adding alkaline solution dropwise, and standing to separate the layers. The mass ratio of the alkaline solution added each time to the mass ratio of methyl cyanoacetate is 0.06 to 0.16, preferably 0.08.

[0023] The number of multiple alkaline extractions is 3 to 5 times, preferably 3 times.

[0024] Specifically, the method for removing valeric acid, an impurity of valproic acid in the sodium valproate synthesis process, comprises the following steps:

[0025] (1) Add toluene and water to the decarboxylation mother liquor and filter with suction; let the filtrate stand and separate, and remove the lower aqueous phase; add water to the toluene layer, and add 30% sodium hydroxide solution to adjust the pH to >10, stir the solution after adjustment, and the stirring time is 0.5~1.5h, let it stand and separate, retain the aqueous phase, add toluene, and add concentrated hydrochloric acid to adjust the pH to <2, and stir the solution after adjustment, and the stirring time is 0.5~1.5h, let it stand and separate to obtain the toluene layer;

[0026] (2) adding water to the toluene layer of step (1), adding alkaline solution dropwise, and standing to separate the layers. This is the first alkaline extraction operation. Repeat the above alkaline extraction operation. The mass ratio of the added alkaline solution to the mass of methyl cyanoacetate is 0.08 to 0.16 each time, until the residual valeric acid in the toluene layer is less than 0.1%. The toluene mother liquor and the aqueous phase obtained by multiple standing separations are collected.

[0027] (3) adding toluene to the aqueous phase collected in step (2) and separated by multiple layers, and adding hydrochloric acid to adjust the pH to <2, and separating by separation to obtain a toluene layer;

[0028] (4) adding water to the toluene layer of step (3), adding alkaline solution dropwise, and standing to separate the layers. This is the second alkaline extraction operation. Repeat the above alkaline extraction operation. The mass ratio of the added alkaline solution to the mass of methyl cyanoacetate is 0.06 to 0.16 each time, until the residual valeric acid in the toluene layer is less than 0.1%. Collect the toluene mother liquor after multiple standing separations.

[0029] (5) The toluene mother liquors collected in step (2) and step (4) are mixed to obtain a valproic acid solution from which valeric acid has been removed.

[0030] The sodium valproate synthesis process of the present invention is as follows:

[0031] .

[0032] To address the problem of excessive residual valeric acid in sodium valproate, the present invention pretreats the decarboxylation mother liquor. First, the reaction control point is to achieve a 2-propylvaleramide residue in the mother liquor below 1%, which serves as the reaction endpoint of the decarboxylation process. The present invention primarily discusses the alkaline extraction process conditions. To maximize yield, two alkaline extractions are performed (the need for a third alkaline extraction is determined by the peak area of the main peak in the liquid phase diagram; two alkaline extractions are sufficient to completely remove valeric acid without loss). Finally, the toluene layers after the two alkaline extractions are combined, and purified water is added. The mixture is then alkali-adjusted to a sodium salt, concentrated under normal pressure, and dried to obtain a high-quality crude sodium valproate product. A final refined product of sodium valproate is obtained after a single step.

[0033] According to the invention, after the decarboxylation reaction liquid is subjected to alkali treatment and acid treatment, the added alkali solution in the first alkali extraction operation converts valeric acid into sodium valerate and enters the aqueous phase, while the toluene layer contains unsalified valproic acid. After repeated alkali extraction operations, the valeric acid content in the toluene layer is reduced to below 0.1%. After the aqueous phase is collected, a second alkali extraction operation is performed, in which the aqueous phase is first subjected to acid conversion to convert the sodium valproate in the aqueous phase into valproic acid. Toluene is then used for extraction, and alkali extraction is performed multiple times to obtain a toluene solution of valproic acid with a valeric acid content of less than 0.1%. The toluene solutions after the two alkali extractions are mixed, thereby improving the quality of the valproic acid.

[0034] Compared with the prior art, the present invention has the following beneficial effects:

[0035] The method for removing valeric acid, an impurity of valproic acid in a sodium valproate synthesis process of the present invention has low energy consumption and is green and environmentally friendly. The valeric acid in a decarboxylation mother liquor is reduced to below 0.1% by two alkali extractions and pH control, thereby preparing a crude sodium valproate product of good quality. After one refining, a finished sodium valproate product with high yield and high purity is obtained. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 This is the HPLC spectrum of the first batch of decarboxylation mother liquor in Example 1 (Batch No. Y2503018-1);

[0037] Figure 2 This is the HPLC spectrum of the mother liquor after the first batch of alkali extraction in Example 1 (Batch No. Y2503018-9);

[0038] Figure 3 This is the HPLC spectrum of the first batch of crude product in Example 1 (Batch No. Y2503022);

[0039] Figure 4 This is the HPLC spectrum of the first batch of finished products in Example 1 (Batch No. Y2503024);

[0040] Figure 5 This is the HPLC spectrum of the second batch of decarboxylation mother liquor in Example 1 (Batch No. Y2503020-1);

[0041] Figure 6 This is the HPLC spectrum of the mother liquor after alkali extraction of the second batch of Example 1 (Batch No. Y2503020-5);

[0042] Figure 7 This is the HPLC spectrum of the second batch of crude product in Example 1 (Batch No. Y2503023);

[0043] Figure 8 This is the HPLC spectrum of the second batch of finished product in Example 1 (Batch No. Y2504001);

[0044] Figure 9 This is the HPLC spectrum of the third batch of decarboxylation mother liquor in Example 1 (Batch No. Y2503021-1);

[0045] Figure 10 This is the HPLC spectrum of the mother liquor after alkali extraction of the third batch of Example 1 (Batch No. Y2503021-4);

[0046] Figure 11 This is the HPLC spectrum of the third batch of crude product in Example 1 (Batch No. Y2503025);

[0047] Figure 12 This is the HPLC spectrum of the third batch of finished product in Example 1 (Batch No. Y2504002);

[0048] Figure 13 HPLC spectrum of the decarboxylation mother liquor of Example 2 (Batch No. Y2407002-1);

[0049] Figure 14 This is the HPLC spectrum of the first alkaline extraction of Example 2 (Batch No. Y2407003-4-1);

[0050] Figure 15 This is the HPLC spectrum of the first alkaline extraction of Example 3 (Batch No. Y2407003-5-1);

[0051] Figure 16 This is the HPLC spectrum of the first alkaline extraction of Example 4 (Batch No. Y2407003-6-1);

[0052] Figure 17 This is the HPLC spectrum of the first alkaline extraction of Example 5 (Batch No. Y2407003-7-1);

[0053] Figure 18 This is the HPLC spectrum of the first alkaline extraction of Example 6 (Batch No. Y2407003-8-1);

[0054] Figure 19 HPLC spectrum of the decarboxylation mother liquor of Example 7 (Batch No. Y2503011-1);

[0055] Figure 20 This is the first HPLC spectrum of the first alkaline extraction of Example 7 (Batch No. Y2503011-2);

[0056] Figure 21 This is the second HPLC spectrum of the first alkaline extraction of Example 7 (Batch No. Y2503011-3);

[0057] Figure 22 This is the third HPLC spectrum of the first alkaline extraction of Example 7 (Batch No. Y2503011-4);

[0058] Figure 23 This is the 4th HPLC spectrum of the first alkaline extraction of Example 7 (Batch No. Y2503011-5);

[0059] Figure 24 This is the 5th HPLC spectrum of the first alkaline extraction of Example 7 (Batch No. Y2503011-6);

[0060] Figure 25 This is the HPLC spectrum of the second alkaline extraction of Example 7 (Batch No. Y2503011-7);

[0061] Figure 26 This is the HPLC spectrum of the decarboxylation mother liquor of Example 8 (Batch No. Y2407005-1);

[0062] Figure 27 This is the HPLC spectrum of the mother liquor after the first alkaline extraction of Example 8 (Batch No. Y2407005-2);

[0063] Figure 28This is the HPLC spectrum of the mother liquor after the second alkaline extraction of Example 8 (Batch No. Y2407005-3-1);

[0064] Figure 29 This is the HPLC spectrum of the mother liquor after the second alkaline extraction of Example 9 (Batch No. Y2407005-4-1);

[0065] Figure 30 This is the HPLC spectrum of the mother liquor after the second alkaline extraction of Example 10 (Batch No. Y2407005-5-1);

[0066] Figure 31 This is the HPLC spectrum of the mother liquor after the second alkaline extraction of Example 11 (Batch No. Y2407005-6-1);

[0067] Figure 32 This is the HPLC spectrum of the mother liquor after the second alkaline extraction of Example 12 (Batch No. Y2407005-7-1);

[0068] Figure 33 This is the HPLC spectrum of the mother liquor after the second alkaline extraction of Example 13 (Batch No. Y2407005-8-1);

[0069] Figure 34 This is the HPLC spectrum of the first alkaline extraction of Comparative Example 1 (Batch No. Y2407003-1-1);

[0070] Figure 35 This is the HPLC spectrum of the first alkaline extraction of Comparative Example 2 (Batch No. Y2407003-2-1);

[0071] Figure 36 This is the HPLC spectrum of the first alkaline extraction of Comparative Example 3 (Batch No. Y2407003-3-1);

[0072] Figure 37 HPLC spectrum of the mother liquor after the second alkaline extraction of Comparative Example 4 (Batch No. Y2407005-1-1);

[0073] Figure 38 This is the HPLC spectrum of the mother liquor after the second alkaline extraction of Comparative Example 5 (Batch No. Y2407005-2-1). DETAILED DESCRIPTION

[0074] The present invention will be further described below with reference to specific embodiments.

[0075] The decarboxylation mother liquor used in the following examples was prepared by reacting methyl cyanoacetate and bromopropane to obtain methyl 2-cyano-2-propylvalerate, followed by the addition of an alkaline solution to obtain 2-cyano-2-propylvaleric acid, and then decarboxylating the resulting valproic acid to obtain an oil-water mixture. The concentrated hydrochloric acid used was commercially available 36% concentrated hydrochloric acid.

[0076] Example 1

[0077] Determine the product process and test parallel batch samples:

[0078] Following the five-step process (data for the first two steps are not shown in the table below because no valeric acid is produced in the first two steps), three batches of decarboxylation mother liquor samples were tested (based on a 40g methyl cyanoacetate feed) to determine the product process. Each batch of samples was numbered and identified. The method for removing valeric acid, an impurity of valproic acid, from the sodium valproate synthesis process described above, specifically involves the following steps:

[0079] (1) Based on the feed amount of 40 g of methyl cyanoacetate, add 80 mL of toluene and 80 mL of purified water to the decarboxylation mother liquor (such as batch number Y2503018-1, Y2503020-1, and Y2503021-1) respectively, and filter with suction; let the filtrate stand to separate, and separate the lower aqueous phase; add 120 mL of purified water to the toluene layer, and add 30% sodium hydroxide solution to adjust the pH to >10. After adjustment, stir the solution for 1 hour, let it stand to separate, retain the aqueous phase, add 80 mL of toluene, and add concentrated hydrochloric acid to adjust the pH to <2. After adjustment, stir the solution for 1 hour, let it stand to separate, and obtain the toluene layer;

[0080] (2) Add 80 mL of purified water to the toluene layer of step (1), add 3.2 g of 30% sodium hydroxide solution dropwise, stir for 1 hour, and let stand for stratification as the first alkaline extraction operation. Repeat the above alkaline extraction operation until the residual valeric acid in the toluene layer is less than 0.1%. Collect the toluene mother liquor and aqueous phase after multiple layers of standing;

[0081] (3) adding 80 mL of toluene to the aqueous phase collected in step (2) and separated by multiple layers, and adding hydrochloric acid to adjust the pH to <2, and separating by separation to obtain a toluene layer;

[0082] (4) Add 40 mL of purified water to the toluene layer of step (3), add 2.4 g of 30% sodium hydroxide solution dropwise, and let it stand for stratification as the second alkaline extraction operation. Repeat the above alkaline extraction operation until the residual valeric acid in the toluene layer is less than 0.1%. Collect the toluene mother liquor obtained by multiple standing layers.

[0083] (5) The toluene mother liquors collected in step (2) and step (4) are mixed as the mother liquor after alkali extraction (such as batch numbers Y2503018-9, Y2503020-5, and Y2503021-4), and purified water is added to dissolve the mixture. Sodium hydroxide is added to convert the mixture into sodium salt, and the mixture is concentrated under normal pressure and dried to obtain a crude sodium valproate product (such as batch numbers Y2503022, Y2503023, and Y2503025). The crude sodium valproate product (such as batch numbers Y2503024, Y2504001, and Y2504002) is obtained after one-time refining.

[0084] For each batch of samples above, the corresponding content test was carried out. The chromatograms of batches Y2503018-1, Y2503020-1, and Y2503021-1 are as follows: Figure 1 、 Figure 5 、 Figure 9 The chromatograms of batch numbers Y2503018-9, Y2503020-5, and Y2503021-4 are shown in the figure. Figure 2 、 Figure 6 、 Figure 10 The chromatograms of batch numbers Y2503022, Y2503023, and Y2503025 are shown in Figure 2. Figure 3 、 Figure 7 、 Figure 11 The chromatograms of batch numbers Y2503024, Y2504001, and Y2504002 are shown in Figure 2. Figure 4 、 Figure 8 、 Figure 12 shown.

[0085] The first batch of relevant experimental results are shown in Tables 1 to 5.

[0086] Table 1 Results of the first batch of experiments

[0087]

[0088] Table 2 Related substances of chromatographic peaks of Y2503018-1

[0089]

[0090] Table 3 Related substances of Y2503018-9 chromatographic peak

[0091]

[0092] Table 4 Related substances of Y2503022 chromatographic peak

[0093]

[0094] Table 5 Related substances of Y2503024 chromatographic peak

[0095]

[0096] From the above, it can be concluded that the substance with a retention time of 14.53-14.61 minutes is valeric acid, the substance with a retention time of 17.9-18.1 minutes is valproic acid or sodium valproate (with the same peak time), and the substance with a retention time of 22.158 minutes is 2-propylvaleramide.

[0097] The relevant experimental results of the second batch are shown in Tables 6 to 10.

[0098] Table 6 Results of the second batch of experiments

[0099]

[0100] Table 7 Related substances of Y2503020-1 chromatographic peak

[0101]

[0102] Table 8 Related substances of Y2503020-5 chromatographic peak

[0103]

[0104] Table 9 Related substances of Y2503023 chromatographic peak

[0105]

[0106] Table 10 Related substances of Y2504001 chromatographic peak

[0107]

[0108] From the above, it can be concluded that the substance with a retention time of 14.53 to 14.61 minutes is valeric acid, the substance with a retention time of 17.9 to 18.2 minutes is valproic acid or sodium valproate, and the substance with a retention time of 21.8 to 22.2 minutes is 2-propylvaleramide.

[0109] The relevant experimental results of the third batch are shown in Tables 11 to 15.

[0110] Table 11 Results of the third batch of experiments

[0111]

[0112] Table 12 Related substances of Y2503021-1 chromatographic peak

[0113]

[0114] Table 13 Related substances of Y2503021-4 chromatographic peak

[0115]

[0116] Table 14 Related substances of Y2503025 chromatographic peak

[0117]

[0118] Table 15 Related substances of Y2504002 chromatographic peak

[0119]

[0120] From the above, it can be concluded that the substance with a retention time of 14.58 to 14.60 minutes is valeric acid, the substance with a retention time of 17.9 to 18.0 minutes is valproic acid or sodium valproate, and the substance with a retention time of 22.158 minutes is 2-propylvaleramide.

[0121] The first alkali extraction parameters in the process of the present invention are determined by the following Examples 2 to 6:

[0122] Example 2

[0123] The specific steps of the first alkali extraction are:

[0124] Based on the feed amount of 40 g of methyl cyanoacetate, the following were added to the decarboxylation mother liquor (e.g., batch number Y2407002-1, whose content chromatogram is shown in FIG. Figure 13 80 mL of toluene and 80 mL of purified water were added to the mixture (as shown), and the mixture was filtered with suction; the filtrate was allowed to stand and separate, and the lower aqueous phase was separated; 120 mL of purified water was added to the toluene layer, and 52 g of a 30% sodium hydroxide solution was added to adjust the pH to >10. After adjustment, the solution was stirred for 1 hour, and the mixture was allowed to stand and separate. The aqueous phase was retained, 80 mL of toluene was added, and 50 g of concentrated hydrochloric acid was added to adjust the pH to <2. After adjustment, the solution was stirred for 1 hour, and the mixture was allowed to stand and separate to obtain a toluene layer, which was equally divided into 8 parts to investigate the amount of alkali used in the first alkali extraction.

[0125] Take one toluene sample from the above 8 parts, add 10mL purified water, perform the first alkaline extraction, add 0.4g (ratio 0.08) 30% sodium hydroxide solution dropwise, stir for 0.5h, let stand to separate, perform alkaline extraction 3 times continuously, take a sample of the toluene layer for analysis (this sample is named batch number Y2407003-4-1), and perform chromatographic analysis on its content. The chromatogram is shown as follows: Figure 14 As shown. Figure 14 It can be seen that in the first alkaline extraction, when the mass ratio of the added mass of sodium hydroxide solution to the mass of methyl cyanoacetate was 0.08, the residual valeric acid was 0.07% (14.832 minutes), and the valproic acid content was 99.88% (18.230 minutes), which met the central control requirements.

[0126] The batch number of the raw material decarboxylation mother liquor used in this embodiment is a sample of Y2407002-1, and the chromatogram of its content is as shown in FIG. Figure 13 As shown. Figure 13 It can be seen that the valeric acid content in the decarboxylation reaction liquid Y2407002-1 was 1.93% (14.812 minutes) and the valproic acid content was 95.84% (18.252 minutes).

[0127] Example 3

[0128] Take a toluene layer sample from the 8 parts in Example 2, add 10mL of purified water, perform the first alkaline extraction, add 0.5g (ratio 0.10) of 30% sodium hydroxide solution dropwise, stir for 1h, let stand and separate, perform alkaline extraction 4 times continuously, take a sample of the toluene layer for analysis (this sample is named batch number Y2407003-5-1), and perform chromatographic analysis of its content. The chromatogram is shown as follows Figure 15 As shown. Figure 15 It can be seen that in the first alkaline extraction, when the mass ratio of the added mass of sodium hydroxide solution to the mass of methyl cyanoacetate was 0.10, the residual valeric acid was 0.04% (14.833 minutes), and the valproic acid content was 99.90% (18.227 minutes), which met the central control requirements.

[0129] Example 4

[0130] Take a toluene layer sample from the 8 parts in Example 2, add 10mL of purified water, perform the first alkaline extraction, add 0.6g (ratio 0.12) of 30% sodium hydroxide solution dropwise, stir for 1.5h, let stand and separate, perform alkaline extraction 5 times continuously, take a sample of the toluene layer for analysis (this sample is named batch number Y2407003-6-1), and perform chromatographic analysis of its content. The chromatogram is shown as follows Figure 16 As shown. Figure 16 It can be seen that in the first alkaline extraction, when the mass ratio of the added mass of sodium hydroxide solution to the mass of methyl cyanoacetate was 0.12, the residual valeric acid was 0.03% (14.833 minutes), and the valproic acid content was 99.92% (18.228 minutes), which met the central control requirements.

[0131] Example 5

[0132] Take a toluene layer sample from the 8 parts in Example 2, add 10mL of purified water, perform the first alkaline extraction, add 0.7g (ratio 0.14) of 30% sodium hydroxide solution dropwise, stir for 0.5h, let stand and separate, perform alkaline extraction 4 times continuously, take a sample of the toluene layer for analysis (this sample is named batch number Y2407003-7-1), and perform chromatographic analysis of its content. The chromatogram is shown as follows Figure 17 As shown by Figure 17 It can be seen that in the first alkaline extraction, when the mass ratio of the added mass of sodium hydroxide solution to the mass of methyl cyanoacetate was 0.14, the residual valeric acid was 0.02% (14.836 minutes), and the valproic acid content was 99.93% (18.227 minutes), which met the central control requirements.

[0133] Example 6

[0134] Take a toluene layer sample from the 8 parts in Example 2, add 10mL of purified water, perform the first alkaline extraction, add 0.8g (ratio 0.16) of 30% sodium hydroxide solution dropwise, stir for 1h, let stand and separate, perform alkaline extraction 5 times continuously, and take a sample of the toluene layer for analysis (this sample is named batch number Y2407003-8-1). The content is analyzed by chromatography, and the chromatogram is shown as follows: Figure 18 As shown. Figure 18 It can be seen that in the first alkaline extraction, when the mass ratio of the added mass of sodium hydroxide solution to the mass of methyl cyanoacetate was 0.16, the residual valeric acid was 0.01% (14.838 minutes), and the valproic acid content was 99.94% (18.226 minutes), which met the central control requirements.

[0135] Example 7

[0136] The method for removing valeric acid, an impurity of valproic acid in the sodium valproate synthesis process, comprises the following steps:

[0137] (1) Based on the feed amount of 40 g of methyl cyanoacetate, add the following to the decarboxylation mother liquor (its content chromatogram is as follows Figure 19 80 mL of toluene and 80 mL of purified water were added to the mixture (as shown, batch number Y2503011-1), and the mixture was filtered to remove carbonized materials; the filtrate was allowed to stand for stratification, and the lower aqueous phase was separated; 120 mL of purified water was added to the toluene layer, and 60 g of a 30% sodium hydroxide solution was added to adjust the pH to >10. After adjustment, the solution was stirred for 0.5 h, and allowed to stand for stratification. The aqueous phase was retained, 80 mL of toluene was added, and 60 g of concentrated hydrochloric acid was added to adjust the pH to <2. After adjustment, the solution was stirred for 0.5 h, and allowed to stand for stratification to obtain a toluene layer;

[0138] (2) Add 80 mL of purified water to the toluene layer of step (1), perform the first alkaline extraction operation, dropwise add 3.2 g of 30% sodium hydroxide solution, stir for 1 hour, let stand and separate, take a sample of the toluene layer for testing (its content chromatogram is as follows Figure 20 Repeat the first alkaline extraction, add 3.2g of 30% sodium hydroxide solution to the toluene layer, add 80mL of water, stir for 1h, separate the layers, and take a sample of the toluene layer for testing (its content chromatogram is shown in Figure 1). Figure 21 Repeat the second alkaline extraction, add 3.2g 30% sodium hydroxide solution to the toluene layer, add 80mL water, stir for 1h, separate the layers, and take a sample of the toluene layer for testing (its content chromatogram is shown in Figure 1). Figure 22 Repeat the alkali extraction for the third time, add 3.2g of 30% sodium hydroxide solution to the toluene layer, add 80mL of water, stir for 1h, separate the layers, and take a sample of the toluene layer for testing (its content chromatogram is shown in FIG. Figure 23Repeat the alkali extraction for the fourth time, add 3.2g of 30% sodium hydroxide solution to the toluene layer, add 80mL of water, stir for 1h, separate the layers, and take a sample of the toluene layer for testing (its content chromatogram is shown in FIG. Figure 24 As shown, named batch number Y2503011-6); the toluene mother liquor and the aqueous phase were collected after multiple layers of static separation;

[0139] (3) The aqueous phase remaining after five alkaline extractions collected in step (2) was mixed and 40 g of concentrated hydrochloric acid was added to adjust the pH to <2, stirred for 1 h, and then 80 mL of toluene was added, stirred for 0.5 h, and allowed to stand for stratification to obtain a toluene layer;

[0140] (4) Add 80 mL of water to the toluene layer of step (3), add alkaline solution dropwise, and let it stand for stratification. Repeat the above alkaline extraction operation as the second alkaline extraction operation, adding 2.4 g of 30% sodium hydroxide solution each time, for 3 consecutive times, and take a sample of the toluene layer for detection (its content chromatogram is as follows Figure 25 As shown, named batch number Y2503011-7), the toluene mother liquor was collected after multiple layers of static separation;

[0141] (5) The toluene mother liquors collected in step (2) and step (4) are mixed to obtain a valproic acid solution from which valeric acid has been removed.

[0142] For the above Figure 19-Figure 25 It can be seen that Figure 19 The residual valeric acid in the decarboxylation reaction solution was 1.04% (14.595 minutes), and the valproic acid content was 95.34% (18.012 minutes); Figure 20 When the first alkali extraction dosage was 0.08, the residual valeric acid was 0.42% (14.600 minutes), and the valproic acid content was 98.98% (17.999 minutes); Figure 21 When the amount of alkaline extraction in the first repetition was 0.08, the residual valeric acid was 0.14% (14.601 minutes), and the valproic acid content was 99.24% (18.000 minutes); Figure 22 When the amount of alkaline extraction in the second repetition was 0.08, the residual valeric acid was 0.04% (14.603 minutes), and the valproic acid content was 99.31% (17.999 minutes); Figure 23 When the dosage of alkaline extraction was repeated for the third time at 0.08, the residual valeric acid was 0.01% (14.604 minutes), and the valproic acid content was 99.28% (17.996 minutes) (because the valproic acid in the toluene layer was decreasing and the related substances were increasing, so the content was relatively reduced). Figure 24 When the dosage of the fourth repeated alkaline extraction was 0.08, the valeric acid residue was 0% and the valproic acid content was 99.25% (17.994 minutes). It can be seen that the in-process control requirements can be met after the first alkaline extraction is repeated three times. Figure 25After the second alkaline extraction with an alkali dosage of 0.06 for three consecutive times, the valeric acid residue was 0% and the valproic acid content was 99.55% (17.986 minutes).

[0143] Therefore, the HPLC spectrum of the first alkaline extraction ( Figure 20-24 ) comparison revealed that after three alkaline extractions, the relevant substances had qualified. Based on the main peak area, valproic acid was primarily found in the toluene layer of the first alkaline extraction. After the second alkaline extraction, the main peak area decreased significantly, so a third alkaline extraction was not performed. Of course, a third alkaline extraction could be performed to further improve the yield. However, according to production experience, if the pH exceeds the standard during the crude product alkaline adjustment, the finished product will fail. Therefore, if the crude product is over-adjusted during the alkaline adjustment process, adding the mother liquor from the third alkaline extraction can improve the yield and further reduce the mother liquor pH to the qualified level (Pharmacopoeia requires pH = 7.5-8.5).

[0144] The second alkali extraction parameters in the process of the present invention are determined by the following Examples 8 to 13:

[0145] Example 8

[0146] The method for removing valeric acid, an impurity of valproic acid in the sodium valproate synthesis process, comprises the following steps:

[0147] (1) Based on the feed amount of 40 g of methyl cyanoacetate, add the following to the decarboxylation mother liquor (its content chromatogram is as follows Figure 26 As shown in the figure, 80 mL of toluene and 80 mL of purified water were added to the product (named batch number Y2407005-1), and the product was filtered to remove carbonized materials; the filtrate was allowed to stand and separate, and the lower aqueous phase was separated; 120 mL of purified water was added to the toluene layer, and 51 g of 30% sodium hydroxide solution was added to adjust the pH to >10. After adjustment, the solution was stirred for 0.5 h, and allowed to stand and separate. The aqueous phase was retained, 80 mL of toluene was added, and 39 g of concentrated hydrochloric acid was added to adjust the pH to <2. After adjustment, the solution was stirred for 0.5 h, and allowed to stand and separate. The toluene layer was divided into 8 equal parts to investigate the amount of alkali used in the first alkali extraction.

[0148] (2) Add 80 mL of purified water to the toluene layer of step (1), perform the first alkaline extraction operation, dropwise add 6.4 g of 30% sodium hydroxide solution, repeat the alkaline extraction operation 3 times until the residual valeric acid in the toluene layer is less than 0.1%, and take a sample of the toluene layer for detection (its content chromatogram is as shown in FIG. Figure 27 As shown, named batch number Y2407005-2), the toluene mother liquor and the aqueous phase were collected after multiple layers of static separation;

[0149] (3) After mixing the remaining aqueous phase after three alkaline extractions collected in step (2), 50 mL of toluene was added, and 35 g of concentrated hydrochloric acid was added to adjust the pH to <2. The mixture was stirred for 0.5 h, and allowed to stand for stratification to obtain a toluene layer, which was divided into 8 equal parts to investigate the process parameters of the second alkaline extraction.

[0150] (4) Take one toluene sample from the above 8 parts, add 10 mL of water, perform the second alkaline extraction, add 0.3 g (ratio 0.06) of 30% sodium hydroxide solution dropwise, stir for 0.5 h, separate the layers, perform alkaline extraction three times continuously, and take samples of the toluene layer for analysis (such as Figure 28 As shown, the batch number is named Y2407005-3-1).

[0151] Depend on Figure 26 It can be seen that the residual valeric acid in the decarboxylation reaction solution (batch number Y2407005-1) is 1.71% (14.817 minutes) and the valproic acid content is 96.23% (18.234 minutes);

[0152] Depend on Figure 27 It can be seen that after the first alkaline extraction (batch number Y2407005-2), the residual valeric acid content was 0.08% (14.835 minutes) and the valproic acid content was 99.75% (18.227 minutes);

[0153] Depend on Figure 28 It can be seen that in the second alkaline extraction, when the mass ratio of the added mass of sodium hydroxide solution to the mass of methyl cyanoacetate was 0.06, the residual valeric acid was 0.06% (14.838 minutes), and the valproic acid content was 99.94% (18.224 minutes), which met the central control requirements.

[0154] Example 9

[0155] Take a toluene layer sample from the 8 parts in Example 8, add 10mL of purified water, perform a second alkaline extraction, add 0.4g (ratio 0.08) of 30% sodium hydroxide solution dropwise, stir for 1h, let stand and separate, perform alkaline extraction 4 times continuously, and take a sample of the toluene layer for analysis (batch number Y2407005-4-1). The content is analyzed by chromatography, and the chromatogram is shown as follows: Figure 29 As shown. Figure 29 It can be seen that in the second alkaline extraction, when the mass ratio of the added mass of sodium hydroxide solution to the mass of methyl cyanoacetate was 0.08, the residual valeric acid was 0.04% (14.839 minutes), and the valproic acid content was 99.96% (18.224 minutes), which met the central control requirements.

[0156] Example 10

[0157] Take a toluene layer sample from the 8 parts in Example 8, add 10mL of purified water, perform a second alkaline extraction, add 0.5g (ratio 0.10) of 30% sodium hydroxide solution dropwise, stir for 1.5h, let stand and separate, perform alkaline extraction 3 times continuously, and take a sample of the toluene layer for analysis (batch number Y2407005-5-1). The content is analyzed by chromatography, and the chromatogram is shown as follows: Figure 30 As shown. Figure 30 It can be seen that in the second alkaline extraction, when the mass ratio of the added mass of sodium hydroxide solution to the mass of methyl cyanoacetate was 0.10, the residual valeric acid was 0% and the valproic acid content was 100.00% (18.225 minutes), which met the central control requirements.

[0158] Example 11

[0159] Take a toluene layer sample from the 8 parts in Example 8, add 10mL of purified water, perform a second alkaline extraction, add 0.6g (ratio 0.12) of 30% sodium hydroxide solution dropwise, stir for 1h, let stand and separate, perform alkaline extraction 3 times continuously, and sample the toluene layer for analysis (batch number Y2407005-6-1). The content is analyzed by chromatography, and the chromatogram is as shown below. Figure 31 As shown. Figure 31 It can be seen that in the second alkaline extraction, when the mass ratio of the added mass of sodium hydroxide solution to the mass of methyl cyanoacetate was 0.12, the residual valeric acid was 0% and the valproic acid content was 100.00% (18.227 minutes), which met the central control requirements.

[0160] Example 12

[0161] Take a toluene layer sample from the 8 parts in Example 8, add 10mL of purified water, perform a second alkaline extraction, add 0.7g (ratio 0.14) of 30% sodium hydroxide solution dropwise, stir for 0.5h, let stand and separate, perform alkaline extraction 4 times continuously, and take a sample of the toluene layer for analysis (batch number Y2407005-7-1). The content is analyzed by chromatography, and the chromatogram is shown as follows: Figure 32 As shown. Figure 32 It can be seen that in the second alkaline extraction, when the mass ratio of the added mass of sodium hydroxide solution to the mass of methyl cyanoacetate was 0.14, the residual valeric acid was 0% and the valproic acid content was 100.00% (18.233 minutes), which met the central control requirements.

[0162] Example 13

[0163] Take a toluene layer sample from the 8 parts in Example 8, add 10mL of purified water, perform a second alkaline extraction, add 0.8g (ratio 0.16) of 30% sodium hydroxide solution dropwise, stir for 1h, let stand and separate, perform alkaline extraction 3 times continuously, and take a sample of the toluene layer for analysis (batch number Y2407005-8-1). The content is analyzed by chromatography, and the chromatogram is shown as follows: Figure 33 As shown. Figure 33It can be seen that in the second alkaline extraction, when the mass ratio of the added mass of sodium hydroxide solution to the mass of methyl cyanoacetate was 0.16, the residual valeric acid was 0% and the valproic acid content was 100.00% (18.250 minutes), which met the central control requirements.

[0164] Comparative Example 1

[0165] Take a toluene layer sample from the 8 parts in Example 2, add 10mL of purified water, perform the first alkaline extraction, add 0.1g (ratio 0.02) of 30% sodium hydroxide solution dropwise, stir for 1.5h, let stand and separate, perform alkaline extraction 3 times continuously, take a sample of the toluene layer for analysis (this sample is named batch number Y2407003-1-1), and perform chromatographic analysis of its content. The chromatogram is shown as follows Figure 34 As shown. Figure 34 It can be seen that in the first alkaline extraction, when the mass ratio of the added mass of sodium hydroxide solution to the mass of methyl cyanoacetate was 0.02, the residual valeric acid was 0.61% (14.823 minutes) and the valproic acid content was 99.30% (18.229 minutes), which did not meet the in-process control requirements.

[0166] Comparative Example 2

[0167] Take a toluene layer sample from the 8 parts in Example 2, add 10mL of purified water, perform the first alkaline extraction, add 0.2g (ratio 0.04) of 30% sodium hydroxide solution dropwise, stir for 1h, let stand and separate, perform alkaline extraction 4 times continuously, take a sample of the toluene layer for analysis (this sample is named batch number Y2407003-2-1), and perform chromatographic analysis of its content. The chromatogram is shown as follows Figure 35 As shown. Figure 35 It can be seen that in the first alkaline extraction, when the mass ratio of the added mass of sodium hydroxide solution to the mass of methyl cyanoacetate was 0.04, the residual valeric acid was 0.24% (14.829 minutes) and the valproic acid content was 99.71% (18.229 minutes), which did not meet the in-process control requirements.

[0168] Comparative Example 3

[0169] Take a toluene layer sample from the 8 parts in Example 2, add 10mL of purified water, perform the first alkaline extraction, add 0.3g (ratio 0.06) of 30% sodium hydroxide solution dropwise, stir for 0.5h, let stand and separate, perform alkaline extraction 5 times continuously, take a sample of the toluene layer for analysis (this sample is named batch number Y2407003-3-1), and perform chromatographic analysis of its content. The chromatogram is shown as follows Figure 36 As shown. Figure 36 It can be seen that in the first alkaline extraction, when the mass ratio of the added mass of sodium hydroxide solution to the mass of methyl cyanoacetate was 0.06, the residual valeric acid was 0.15% (14.829 minutes) and the valproic acid content was 99.80% (18.228 minutes), which did not meet the in-process control requirements.

[0170] Comparative Example 4

[0171] Take a toluene layer sample from the 8 parts in Example 8, add 10mL of purified water, perform a second alkaline extraction, add 0.1g (ratio 0.02) of 30% sodium hydroxide solution dropwise, stir for 1h, let stand and separate, perform alkaline extraction 3 times continuously, and take a sample of the toluene layer for analysis (batch number Y2407005-1-1). The content is analyzed by chromatography, and the chromatogram is shown as follows: Figure 37 As shown. Figure 37 It can be seen that in the second alkaline extraction, when the mass ratio of the added mass of sodium hydroxide solution to the mass of methyl cyanoacetate was 0.02, the residual valeric acid was 0.32% (14.830 minutes) and the valproic acid content was 99.58% (18.224 minutes), which did not meet the in-process control requirements.

[0172] Comparative Example 5

[0173] Take a toluene layer sample from the 8 parts in Example 8, add 10mL of purified water, perform a second alkaline extraction, add 0.2g (ratio 0.04) of 30% sodium hydroxide solution dropwise, stir for 1.5h, let stand and separate, perform alkaline extraction 4 times continuously, take a sample of the toluene layer for analysis (batch number Y2407005-2-1), perform chromatographic analysis of its content, and its chromatogram is as shown below. Figure 38 As shown. Figure 38 It can be seen that in the second alkaline extraction, when the mass ratio of the added mass of sodium hydroxide solution to the mass of methyl cyanoacetate was 0.04, the residual valeric acid was 0.13% (14.837 minutes) and the valproic acid content was 99.82% (18.224 minutes), which did not meet the in-process control requirements.

Claims

1. A method for removing valeric acid, an impurity of valproic acid, in a sodium valproate synthesis process, characterized in that: The following steps are involved: (1) Add toluene and water to the decarboxylation mother liquor and filter; The filtrate was allowed to stand for separation, and the lower aqueous phase was removed; water was added to the toluene layer, and an alkaline solution was added to adjust the pH to >10, and the phase was allowed to stand for separation. The aqueous phase was retained, toluene was added, and hydrochloric acid was added to adjust the pH to <2, and the phase was allowed to stand for separation to obtain a toluene layer; The decarboxylation mother liquor is prepared by reacting methyl cyanoacetate and bromopropane as raw materials to obtain methyl 2-cyano-2-propylvalerate, which is then hydrolyzed by adding an alkaline solution to obtain 2-cyano-2-propylvaleric acid, and then undergoing a decarboxylation reaction to obtain an oil-water mixture of valproic acid; (2) adding water to the toluene layer of step (1), adding alkaline solution dropwise, and standing to separate the layers as the first alkaline extraction operation, repeating the above alkaline extraction operation until the residual valeric acid in the toluene layer is less than 0.1%, and collecting the toluene mother liquor and aqueous phase after multiple standing and separation; The mass ratio of the added mass of the alkaline solution to the mass of the methyl cyanoacetate in each alkaline extraction operation is 0.08 to 0.16; (3) adding toluene to the aqueous phase collected in step (2) and separated by multiple layers, and adding hydrochloric acid to adjust the pH to <2, and separating by separation to obtain a toluene layer; (4) Add water to the toluene layer of step (3), add alkaline solution dropwise, and let it stand for stratification as the second alkaline extraction operation. Repeat the above alkaline extraction operation until the residual valeric acid in the toluene layer is less than 0.1%, and collect the toluene mother liquor obtained by multiple stratifications; The mass ratio of the added mass of the alkaline solution to the mass of the methyl cyanoacetate in each alkaline extraction operation is 0.06 to 0.16; (5) The toluene mother liquors collected in step (2) and step (4) are mixed to obtain a valproic acid solution from which valeric acid has been removed.

2. The method for removing valeric acid, an impurity of valproic acid, in the sodium valproate synthesis process according to claim 1, wherein: In step (1), the hydrochloric acid having a pH value less than 2 is adjusted to concentrated hydrochloric acid, and the solution is stirred after adjustment for a stirring time of 0.5 to 1.5 hours.

3. The method for removing valeric acid, an impurity of valproic acid, in the sodium valproate synthesis process according to claim 2, wherein: In step (1), the alkaline solution with a pH value greater than 10 is adjusted to a sodium hydroxide solution with a mass concentration of 30%. After the adjustment, the solution is stirred for 0.5 to 1.5 hours.

4. The method for removing valeric acid, an impurity of valproic acid, in the sodium valproate synthesis process according to claim 3, wherein: The above alkaline extraction operation is repeated in step (2), which is to add water to the toluene layer, dropwise add the alkaline solution, and allow to stand for separation.

5. The method for removing valeric acid, an impurity of valproic acid, in the sodium valproate synthesis process according to claim 4, wherein: The alkaline extraction operation in step (4) is repeated to add water to the toluene layer, dropwise add the alkaline solution, and allow to stand for separation.

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