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

Abstract

The invention belongs to the technical field of impurity removal of fine chemicals, and particularly relates to a method for removing impurity valeric acid in valproic acid in a sodium valproate synthesis process. The method for removing the impurity valeric acid comprises the following steps: adding methylbenzene and water into decarboxylated mother liquor, and carrying out suction filtration; standing and layering the filtrate, and removing a lower-layer water phase; adjusting the pH gt by a toluene layer; 10; standing for layering, keeping a water phase, adding methylbenzene, and adjusting the pH to be 1t; 2; adding hydrochloric acid and toluene into the residual water phase, standing for layering, reserving a toluene layer, carrying out first alkali extraction operation, standing for layering until the residual valeric acid in the toluene layer is lower than 0.1%, adding hydrochloric acid and toluene into the residual water phase, layering, reserving the toluene layer, and carrying out second alkali extraction operation until the residual valeric acid is lower than 0.1%; mixing toluene layers after two times of alkali extraction, then dropwise adding an alkali solution, adjusting the pH value, and treating to obtain a sodium valproate crude product; according to the method for removing the impurity valeric acid in the valproic acid in the sodium valproate synthesis process provided by the invention, the content of the valeric acid in the sodium valproate crude product is low, and the purity of the prepared sodium valproate is high.

Description

Technical Field

[0001] The present 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 the synthesis process of sodium valproate. Background Art

[0002] Sodium valproate, also known as sodium dipropylacetate, is a commonly used anti-epileptic drug with many advantages in the treatment of epilepsy, such as a broad anti-epileptic spectrum, high effectiveness, good safety, few drug interactions, and convenient administration. In addition to epilepsy treatment, the application of sodium valproate in other fields is also being continuously explored, such as bipolar disorder, migraine, etc. Generally speaking, sodium valproate still has certain clinical value in the future, but it needs to continuously optimize its own use in competition, and at the same time, with the help of technical means such as precision medicine, further clarify its applicable population to better play its therapeutic role.

[0003] Currently, the synthesis processes of sodium valproate mainly include the following methods: 1. Hydrolysis and acidification method: Using 2-cyano-2-propyl valerate as the raw material, it is catalytically hydrolyzed by sulfuric acid aqueous solution to generate a mixture of valproic acid and esters, and then hydrolyzed by alkali solution, extracted, acidified and rectified to obtain high-purity valproic acid (purity ≥ 99%), and finally neutralized with sodium hydroxide to form the sodium salt. By optimizing the catalyst and reaction conditions (120–160 °C), this method avoids the problem of generating toxic gases in the traditional nitrous acid oxidation process, has environmental protection and operation safety, and the yield reaches 76%.

[0004] 2. Diethyl malonate alkylation route: Diethyl malonate reacts with 1-bromopropane under the catalysis of sodium ethoxide to form diethyl dipropylmalonate, which is saponified and hydrolyzed with sodium hydroxide aqueous solution, acidified with hydrochloric acid to obtain dipropylmalonic acid, and decarboxylated by heating to 110-160 °C to generate crude valproic acid, which is neutralized to form the sodium salt after rectification and purification, as described in CN116082142A.

[0005] 3. Valproic acid salification method: Prepare high-purity valproic acid, crystallize with sodium hydroxide, and after salification, carry out treatment to obtain sodium valproate.

[0006] And the above hydrolysis and acidification method, that is, high-temperature decarboxylation of 2-cyano-2-propyl valeric acid with sulfuric acid, is the mainstream process for preparing sodium valproate at present. For example, CN113200844A discloses a method for preparing sodium valproate, which uses valeronitrile or methyl 2-cyano-2-propyl valerate as the starting material to prepare valproic acid by a one-pot method, uses sulfuric acid aqueous solution as the catalyst, reacts at 120~160 °C for 20h~40h to obtain valproic acid, and the yield is 70%~80%; however, this method has a high hydrolysis temperature and a long reaction time.

[0007] It can be seen that the current mainstream process for preparing sodium valproate is to carry out high-temperature decarboxylation of 2-cyano-2-propylvaleric acid with sulfuric acid. However, in the above process, it is not mentioned that valeric acid will be produced during the high-temperature decarboxylation of 2-cyano-2-propylvaleric acid with concentrated sulfuric acid. Since the chemical properties of valeric acid are similar to those of valproic acid, valeric acid cannot be completely removed through a simple solvent refining process. According to the quality requirements of the Chinese Pharmacopoeia and the European Pharmacopoeia for sodium valproate, the maximum residue limit of related substances in sodium valproate is 0.05%. And valeric acid is the main by-product of the sulfuric acid decarboxylation process. Therefore, the residue of valeric acid must be reduced to less than 0.1% when preparing the crude product, otherwise, it is impossible to obtain a qualified product with a residue of less than 0.05% through the refining process. The by-product valeric acid is generated as follows: 。

[0008] Therefore, how to reduce the valeric acid in the crude product to 0.1% has become a technical problem in the preparation of sodium valproate by the high-temperature decarboxylation method of 2-cyano-2-propylvaleric acid with concentrated sulfuric acid. SUMMARY OF THE INVENTION

[0009] The technical problem to be solved by the present invention is to overcome the above-mentioned defects existing in the prior art, and provide a method for removing valeric acid, an impurity of valproic acid, in the synthesis process of sodium valproate. The content of valeric acid in the crude sodium valproate is low, and the purity of the prepared sodium valproate is high.

[0010] The method for removing valeric acid, an impurity of valproic acid, in the synthesis process of sodium valproate according to the present invention includes the following steps: (1) Add toluene and water to the decarboxylation mother liquor, and perform suction filtration; let the filtrate stand for stratification, and separate the lower aqueous phase; add water to the toluene layer, and add an alkali solution to adjust the pH>10, let it stand for stratification, keep the aqueous phase, add toluene, and add hydrochloric acid to adjust the pH<2, let it stand for stratification, and obtain the toluene layer; (2) Add water to the toluene layer obtained in step (1), dropwise add an alkali solution, let it stand for stratification, which is used as the first alkali extraction operation. Repeat the above alkali extraction operation until the valeric acid residue in the toluene layer is less than 0.1%. Collect the toluene mother liquor and aqueous phase obtained from multiple standing stratifications; (3) Add toluene to the aqueous phase obtained from multiple standing stratifications collected in step (2), and add hydrochloric acid to adjust the pH<2, let it stand for stratification, and obtain the toluene layer; (4) Add water to the toluene layer obtained in step (3), dropwise add an alkali solution, let it stand for stratification, which is used as the second alkali extraction operation. Repeat the above alkali extraction operation until the valeric acid residue in the toluene layer is less than 0.1%. Collect the toluene mother liquor obtained from multiple standing stratifications; (5) Mix the toluene mother liquors collected in step (2) and step (4) to obtain a valproic acid solution with valeric acid removed.

[0011] The decarboxylation mother liquor described in step (1) is an oil-water mixture of valproic acid obtained by using methyl cyanoacetate and bromopropane as raw materials to react to obtain methyl 2-cyano-2-propylvalerate, hydrolyzing with an alkali solution to obtain 2-cyano-2-propylvaleric acid, and then performing a decarboxylation reaction.

[0012] The hydrochloric acid used to adjust the pH < 2 in step (1) is concentrated hydrochloric acid. After adjustment, the solution is stirred for 0.5 - 1.5 h, preferably 1 h.

[0013] The alkali solution used to adjust the pH > 10 in step (1) is a sodium hydroxide solution with a mass concentration of 30%. After adjustment, the solution is stirred for 0.5 - 1.5 h, preferably 1 h.

[0014] The repeated alkali extraction operation in step (2) is to add water to the toluene layer, dropwise add the alkali solution, and let it stand for separation. The mass ratio of the alkali solution added each time to the mass of methyl cyanoacetate is 0.08 - 0.16, preferably 0.08.

[0015] The repeated alkali extraction operation in step (4) is to add water to the toluene layer, dropwise add the alkali solution, and let it stand for separation. The mass ratio of the alkali solution added each time to the mass of methyl cyanoacetate is 0.06 - 0.16, preferably 0.08.

[0016] The number of times of multiple alkali extractions is 3 - 5 times, preferably 3 times.

[0017] Specifically, the method for removing the impurity valeric acid in valproic acid in the valproate synthesis process includes the following steps: (1) Add toluene and water to the decarboxylation mother liquor, and perform suction filtration; let the filtrate stand for separation, and separate the lower aqueous phase; add water to the toluene layer, and add a 30% sodium hydroxide solution by mass to adjust the pH > 10. After adjustment, stir the solution for 0.5 - 1.5 h, let it stand for separation, keep the aqueous phase, add toluene, and add concentrated hydrochloric acid to adjust the pH < 2. After adjustment, stir the solution for 0.5 - 1.5 h, let it stand for separation, and obtain the toluene layer; (2) Add water to the toluene layer in step (1), dropwise add the alkali solution, and let it stand for separation, which is used as the first alkali extraction operation. Repeat the above alkali extraction operation. The mass ratio of the alkali solution added each time to the mass of methyl cyanoacetate is 0.08 - 0.16 until the valeric acid residue in the toluene layer is less than 0.1%. Collect the toluene mother liquor and aqueous phase obtained from multiple standing separations; (3) Add toluene to the aqueous phase obtained from multiple standing separations collected in step (2), and add hydrochloric acid to adjust the pH < 2, let it stand for separation, and obtain the toluene layer; (4) Add water to the toluene layer in step (3), dropwise add an alkali solution, let it stand for layering, which serves as the second alkali extraction operation. Repeat the above alkali extraction operation. The mass ratio of the added alkali solution to the mass of methyl cyanoacetate each time is 0.06 - 0.16 until the valeric acid residue in the toluene layer is less than 0.1%. Collect the toluene mother liquor obtained from multiple standing and layering operations. (5) Mix the toluene mother liquors collected in step (2) and step (4) to obtain a valproic acid solution after removing valeric acid.

[0018] The synthetic process route of sodium valproate in the present invention is as follows: .

[0019] In order to solve the problem of excessive residue of valeric acid in sodium valproate in the present invention, the decarboxylation mother liquor is pretreated. First, the control point during the reaction is that the residue of 2 - propylvaleramide in the mother liquor is less than 1%, which serves as the reaction end point of the decarboxylation process. The present invention mainly discusses the alkali extraction process conditions. In order to improve the yield as much as possible, two alkali extraction operations are carried out in total (judged by the peak area of the main peak in the liquid phase diagram whether a third alkali extraction is needed. Normally, valeric acid can be removed completely with two alkali extractions without loss of valproic acid). Finally, the toluene layers after two alkali extractions are mixed, then an appropriate amount of purified water is added, and then the alkali is adjusted to form the sodium salt. After normal pressure concentration and drying, a high - quality crude sodium valproate is obtained, and the finished product of sodium valproate is obtained after one - time refining.

[0020] After the decarboxylation reaction solution of the present invention is treated with alkali and acid, in the first alkali extraction operation, the added alkali solution will convert valeric acid into sodium valerate and enter the aqueous phase, while the toluene layer contains un - salted valproic acid. After repeated alkali extraction operations, the valeric acid content in the toluene layer is reduced to less than 0.1%. After the aqueous phase is collected, the second alkali extraction operation is continued. First, the aqueous phase is acid - converted to convert sodium valproate in the aqueous phase into valproic acid, and then toluene extraction and multiple alkali extractions are carried out to obtain a toluene solution of valproic acid with a valeric acid content of less than 0.1%. The toluene solutions after two alkali extractions are mixed, improving the quality of valproic acid.

[0021] Compared with the prior art, the beneficial effects of the present invention are: In the synthetic process of sodium valproate in the present invention, the method for removing the impurity valeric acid of valproic acid has low energy consumption and a green and environmentally friendly process. Through two alkali extractions and pH control, the valeric acid in the decarboxylation mother liquor is reduced to less than 0.1%, and a crude sodium valproate with better quality is obtained. After one - time refining, a finished product of sodium valproate with high yield and high purity is obtained. Description of the Drawings

[0022] Figure 1 It is the HPLC chromatogram of the first - batch decarboxylation mother liquor in Example 1 (batch number Y2503018 - 1); Figure 2HPLC chromatogram of the mother liquor after the first batch of alkali extraction in Example 1 (batch number Y2503018-9); Figure 3 HPLC chromatogram of the first batch of crude product in Example 1 (batch number Y2503022); Figure 4 HPLC chromatogram of the first batch of finished product in Example 1 (batch number Y2503024); Figure 5 HPLC chromatogram of the mother liquor after decarboxylation of the second batch in Example 1 (batch number Y2503020-1); Figure 6 HPLC chromatogram of the mother liquor after the second batch of alkali extraction in Example 1 (batch number Y2503020-5); Figure 7 HPLC chromatogram of the second batch of crude product in Example 1 (batch number Y2503023); Figure 8 HPLC chromatogram of the second batch of finished product in Example 1 (batch number Y2504001); Figure 9 HPLC chromatogram of the mother liquor after decarboxylation of the third batch in Example 1 (batch number Y2503021-1); Figure 10 HPLC chromatogram of the mother liquor after the third batch of alkali extraction in Example 1 (batch number Y2503021-4); Figure 11 HPLC chromatogram of the third batch of crude product in Example 1 (batch number Y2503025); Figure 12 HPLC chromatogram of the third batch of finished product in Example 1 (batch number Y2504002); Figure 13 HPLC chromatogram of the decarboxylated mother liquor in Example 2 (batch number Y2407002-1); Figure 14 HPLC chromatogram of the first alkali extraction in Example 2 (batch number Y2407003-4-1); Figure 15 HPLC chromatogram of the first alkali extraction in Example 3 (batch number Y2407003-5-1); Figure 16 HPLC chromatogram of the first alkali extraction in Example 4 (batch number Y2407003-6-1); Figure 17 HPLC chromatogram of the first alkali extraction in Example 5 (batch number Y2407003-7-1); Figure 18 HPLC chromatogram of the first alkali extraction in Example 6 (batch number Y2407003-8-1); Figure 19HPLC chromatogram of the decarboxylation mother liquor in Example 7 (batch number Y2503011-1); Figure 20 HPLC chromatogram of the first alkali extraction, first time in Example 7 (batch number Y2503011-2); Figure 21 HPLC chromatogram of the first alkali extraction, second time in Example 7 (batch number Y2503011-3); Figure 22 HPLC chromatogram of the first alkali extraction, third time in Example 7 (batch number Y2503011-4); Figure 23 HPLC chromatogram of the first alkali extraction, fourth time in Example 7 (batch number Y2503011-5); Figure 24 HPLC chromatogram of the first alkali extraction, fifth time in Example 7 (batch number Y2503011-6); Figure 25 HPLC chromatogram of the second alkali extraction in Example 7 (batch number Y2503011-7); Figure 26 HPLC chromatogram of the decarboxylation mother liquor in Example 8 (batch number Y2407005-1); Figure 27 HPLC chromatogram of the mother liquor after the first alkali extraction in Example 8 (batch number Y2407005-2); Figure 28 HPLC chromatogram of the mother liquor after the second alkali extraction in Example 8 (batch number Y2407005-3-1); Figure 29 HPLC chromatogram of the mother liquor after the second alkali extraction in Example 9 (batch number Y2407005-4-1); Figure 30 HPLC chromatogram of the mother liquor after the second alkali extraction in Example 10 (batch number Y2407005-5-1); Figure 31 HPLC chromatogram of the mother liquor after the second alkali extraction in Example 11 (batch number Y2407005-6-1); Figure 32 HPLC chromatogram of the mother liquor after the second alkali extraction in Example 12 (batch number Y2407005-7-1); Figure 33 HPLC chromatogram of the mother liquor after the second alkali extraction in Example 13 (batch number Y2407005-8-1); Figure 34 HPLC chromatogram of the first alkali extraction in Comparative Example 1 (batch number Y2407003-1-1); Figure 35 HPLC chromatogram of the first alkali extraction in Comparative Example 2 (batch number Y2407003-2-1); Figure 36 It is the HPLC chromatogram of the first alkaline extraction of Comparative Example 3 (batch number Y2407003-3-1); Figure 37 It is the HPLC chromatogram of the mother liquor after the second alkaline extraction of Comparative Example 4 (batch number Y2407005-1-1); Figure 38 It is the HPLC chromatogram of the mother liquor after the second alkaline extraction of Comparative Example 5 (batch number Y2407005-2-1). Detailed implementation manners

[0023] The present invention will be further described below in conjunction with specific embodiments.

[0024] The decarboxylated mother liquor used in the following examples is an oil-water mixture of valproic acid obtained by using methyl cyanoacetate and bromopropane as raw materials, reacting to obtain methyl 2-cyano-2-propylvalerate, adding an alkali solution to react to obtain 2-cyano-2-propylvaleric acid, and then performing a decarboxylation reaction. The concentrated hydrochloric acid used is commercially available concentrated hydrochloric acid with a mass concentration of 36%.

[0025] Example 1 Determine the product process and detect parallel batch samples: According to a five-step process route (the process data of the first two steps are not shown in the following table because no valeric acid is generated in the first two steps), perform sample experiments on three batches of decarboxylated mother liquor (calculated based on the methyl cyanoacetate feed amount of 40 g) to determine the product process, and distinguish each batch of samples by numbering. The specific steps for removing the impurity valeric acid in valproic acid in the sodium valproate synthesis process are as follows: (1) Calculated based on the methyl cyanoacetate feed amount of 40 g, add 80 mL of toluene and 80 mL of purified water to the decarboxylated mother liquor (such as batch numbers Y2503018-1, Y2503020-1, Y2503021-1) respectively, and perform suction filtration; let the filtrate stand for layering, and separate the lower aqueous phase; add 120 mL of purified water to the toluene layer, and add a sodium hydroxide solution with a mass concentration of 30% to adjust the pH>10. After adjustment, stir the solution for 1 h, let it stand for layering, retain the aqueous phase, add 80 mL of toluene, and add concentrated hydrochloric acid to adjust the pH<2. After adjustment, stir the solution for 1 h, let it stand for layering, and obtain the toluene layer; (2) Add 80 mL of purified water to the toluene layer in step (1), dropwise add 3.2 g of 30% sodium hydroxide solution, stir for 1 h, let it stand for layering, which is the first alkaline extraction operation. Repeat the above alkaline extraction operation until the valeric acid residue in the toluene layer is lower than 0.1%, and collect the toluene mother liquor and aqueous phase obtained by multiple static layering; (3) Add 80 mL of toluene to the aqueous phase collected by multiple static layering in step (2), and add hydrochloric acid to adjust the pH<2, let it stand for layering, and obtain the toluene layer; (4) Add 40 mL of purified water to the toluene layer in step (3), dropwise add 2.4 g of 30% sodium hydroxide solution, let it stand for layering, which is the second alkali extraction operation. Repeat the above alkali extraction operation until the valeric acid residue in the toluene layer is less than 0.1%. Collect the toluene mother liquor obtained from multiple static layering operations. (5) Mix the toluene mother liquors collected in step (2) and step (4) as the mother liquor after alkali extraction (such as batch numbers Y2503018 - 9, Y2503020 - 5, Y2503021 - 4). Then add purified water to dissolve it, add sodium hydroxide to convert it into sodium salt, concentrate it under normal pressure, and obtain the crude product of sodium valproate (such as batch numbers Y2503022, Y2503023, Y2503025) after drying. After the first purification, obtain the finished product of sodium valproate (such as batch numbers Y2503024, Y2504001, Y2504002).

[0026] For each batch number of the above samples, corresponding content detections were carried out. The chromatograms of batch numbers Y2503018 - 1, Y2503020 - 1, and Y2503021 - 1 are as Figure 1 , Figure 5 , Figure 9 shown. The chromatograms of batch numbers Y2503018 - 9, Y2503020 - 5, and Y2503021 - 4 are as Figure 2 , Figure 6 , Figure 10 shown. The chromatograms of batch numbers Y2503022, Y2503023, and Y2503025 are as Figure 3 , Figure 7 , Figure 11 shown. The chromatograms of batch numbers Y2503024, Y2504001, and Y2504002 are as Figure 4 , Figure 8 , Figure 12 shown.

[0027] The relevant experimental results of the first batch are shown in Tables 1 - 5.

[0028] Table 1 Experimental Results of the First Batch

[0029] Table 2 Related Substances Table of Chromatographic Peaks of Y2503018 - 1

[0030] Table 3 Related Substances Table of Chromatographic Peaks of Y2503018 - 9

[0031] Table 4 Related Substances Table of Chromatographic Peaks of Y2503022

[0032] Table 5 Related Substances Table of Chromatographic Peaks of Y2503024

[0033] From the above, 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 (the peak emergence times are the same), and the substance with a retention time of 22.158 minutes is 2-propylvaleramide.

[0034] The relevant experimental results of the second batch are shown in Tables 6 - 10.

[0035] Table 6 Experimental Results of the Second Batch

[0036] Table 7 Related Substances Table of Chromatographic Peaks of Y2503020-1

[0037] Table 8 Related Substances Table of Chromatographic Peaks of Y2503020-5

[0038] Table 9 Related Substances Table of Chromatographic Peaks of Y2503023

[0039] Table 10 Related Substances Table of Chromatographic Peaks of Y2504001

[0040] From the above, the substance with a retention time of 14.53 - 14.61 minutes is valeric acid, the substance with a retention time of 17.9 - 18.2 minutes is valproic acid or sodium valproate, and the substance with a retention time of 21.8 - 22.2 minutes is 2-propylvaleramide.

[0041] The relevant experimental results of the third batch are shown in Tables 11 - 15.

[0042] Table 11 Experimental Results of the Third Batch

[0043] Table 12 Related Substances Table of Chromatographic Peaks of Y2503021-1

[0044] Table 13 Related Substances Table of Chromatographic Peaks of Y2503021-4

[0045] Table 14 Related Substances Table of Y2503025 Chromatographic Peaks

[0046] Table 15 Related Substances Table of Y2504002 Chromatographic Peaks

[0047] From the above, the substance with a retention time of 14.58 - 14.60 minutes is valeric acid, the substance with a retention time of 17.9 - 18.0 minutes is valproic acid or sodium valproate, and the substance with a retention time of 22.158 minutes is 2 - propylvaleramide.

[0048] The determination of the parameters of the first alkali extraction in the process of the present invention is carried out through the following Examples 2 - 6: Example 2 The specific steps of the first alkali extraction are as follows: Calculated based on the feeding amount of methyl cyanoacetate of 40 g, 80 mL of toluene and 80 mL of purified water were respectively added to the decarboxylation mother liquor (such as batch number Y2407002 - 1, and its content chromatogram is as Figure 13 shown), and then filtered by suction; 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 52 g of 30% sodium hydroxide solution was added to adjust the pH > 10. After adjustment, the solution was stirred for 1 h, then allowed to stand for stratification, and the aqueous phase was retained. 80 mL of toluene was added, and 50 g of concentrated hydrochloric acid was added to adjust the pH < 2. After adjustment, the solution was stirred for 1 h, then allowed to stand for stratification to obtain the toluene layer, which was evenly divided into 8 portions to investigate the alkali dosage of the first alkali extraction.

[0049] Take one portion of the toluene sample from the above 8 portions, add 10 mL of purified water, conduct the first alkali extraction, dropwise add 0.4 g (ratio 0.08) of 30% sodium hydroxide solution, stir for 0.5 h, allow to stand for stratification, and conduct continuous alkali extraction 3 times. Take a sample from the toluene layer for analysis (this sample is named batch number Y2407003 - 4 - 1), and conduct content chromatographic analysis on it. Its chromatogram is as Figure 14 shown. From Figure 14 it can be seen that in the first alkali extraction, when the mass ratio of the added sodium hydroxide solution to the mass of methyl cyanoacetate is 0.08, the residual valeric acid is 0.07% (14.832 minutes), and the content of valproic acid is 99.88% (18.230 minutes), meeting the in - process control requirements.

[0050] In this example, the sample of the raw material decarboxylation mother liquor with the batch number of Y2407002 - 1 was used, and its content chromatogram is as Figure 13 shown. From Figure 13It can be seen that in the decarboxylation reaction solution Y2407002-1, the valeric acid residue is 1.93% (14.812 minutes), and the valproic acid content is 95.84% (18.252 minutes).

[0051] Example 3 Take one part of the toluene layer sample from the 8 parts in Example 2, add 10 mL of purified water, and perform the first alkali extraction. Dropwise add 0.5 g (ratio 0.10) of 30% sodium hydroxide solution, stir for 1 h, let it stand for stratification, and perform continuous alkali extraction 4 times. Take a sample from the toluene layer for analysis (this sample is named batch number Y2407003-5-1), and perform chromatographic analysis on its content. Its chromatogram is as Figure 15 shown. From Figure 15 it can be seen that in the first alkali extraction, when the mass ratio of the added sodium hydroxide solution to methyl cyanoacetate is 0.10, the valeric acid residue is 0.04% (14.833 minutes), and the valproic acid content is 99.90% (18.227 minutes), meeting the in-process control requirements.

[0052] Example 4 Take one part of the toluene layer sample from the 8 parts in Example 2, add 10 mL of purified water, and perform the first alkali extraction. Dropwise add 0.6 g (ratio 0.12) of 30% sodium hydroxide solution, stir for 1.5 h, let it stand for stratification, and perform continuous alkali extraction 5 times. Take a sample from the toluene layer for analysis (this sample is named batch number Y2407003-6-1), and perform chromatographic analysis on its content. Its chromatogram is as Figure 16 shown. From Figure 16 it can be seen that in the first alkali extraction, when the mass ratio of the added sodium hydroxide solution to methyl cyanoacetate is 0.12, the valeric acid residue is 0.03% (14.833 minutes), and the valproic acid content is 99.92% (18.228 minutes), meeting the in-process control requirements.

[0053] Example 5 Take one part of the toluene layer sample from the 8 parts in Example 2, add 10 mL of purified water, and perform the first alkali extraction. Dropwise add 0.7 g (ratio 0.14) of 30% sodium hydroxide solution, stir for 0.5 h, let it stand for stratification, and perform continuous alkali extraction 4 times. Take a sample from the toluene layer for analysis (this sample is named batch number Y2407003-7-1), and perform chromatographic analysis on its content. Its chromatogram is as Figure 17 shown, and from Figure 17 it can be seen that in the first alkali extraction, when the mass ratio of the added sodium hydroxide solution to methyl cyanoacetate is 0.14, the valeric acid residue is 0.02% (14.836 minutes), and the valproic acid content is 99.93% (18.227 minutes), meeting the in-process control requirements.

[0054] Example 6 Take one toluene layer sample out of the 8 portions in Example 2, add 10 mL of purified water, and perform the first alkali extraction. Dropwise add 0.8 g (ratio 0.16) of 30% sodium hydroxide solution, stir for 1 h, let it stand for layering, and perform continuous alkali extraction 5 times. Take a sample from the toluene layer for analysis (this sample is named batch number Y2407003-8-1), and conduct chromatographic analysis of its content. Its chromatogram is as shown in Figure 18 shown. It can be seen from Figure 18 that in the first alkali extraction, when the mass ratio of the added sodium hydroxide solution to the mass of methyl cyanoacetate is 0.16, the valeric acid residue is 0.01% (14.838 minutes), and the content of valproic acid is 99.94% (18.226 minutes), meeting the in-process control requirements.

[0055] Example 7 The method for removing the impurity valeric acid of valproic acid in the valproate synthesis process described above includes the following steps: (1) Calculated based on the feeding amount of 40 g of methyl cyanoacetate, add 80 mL of toluene and 80 mL of purified water to the decarboxylation mother liquor (its content chromatogram is as shown in Figure 19 shown, named batch number Y2503011-1), filter by suction to remove carbonized substances; let the filtrate stand for layering, and separate the lower aqueous phase; add 120 mL of purified water to the toluene layer, and add 60 g of 30% sodium hydroxide solution by mass to adjust the pH > 10. After adjustment, stir the solution for 0.5 h, let it stand for layering, retain the aqueous phase, add 80 mL of toluene, and add 60 g of concentrated hydrochloric acid to adjust the pH < 2. After adjustment, stir the solution for 0.5 h, let it stand for layering, and obtain the toluene layer; (2) Add 80 mL of purified water to the toluene layer in step (1), perform the first alkali extraction operation, dropwise add 3.2 g of 30% sodium hydroxide solution by mass, stir for 1 h, let it stand for layering, and take a sample from the toluene layer for detection (its content chromatogram is as shown in Figure 20 shown, named batch number Y2503011-2); repeat the first alkali extraction, dropwise add 3.2 g of 30% sodium hydroxide solution to the toluene layer, add 80 mL of water, stir for 1 h, layer, and take a sample from the toluene layer for detection (its content chromatogram is as shown in Figure 21 shown, named batch number Y2503011-3); repeat the second alkali extraction, dropwise add 3.2 g of 30% sodium hydroxide solution to the toluene layer, add 80 mL of water, stir for 1 h, layer, and take a sample from the toluene layer for detection (its content chromatogram is as shown in Figure 22 shown, named batch number Y2503011-4); repeat the third alkali extraction, dropwise add 3.2 g of 30% sodium hydroxide solution to the toluene layer, add 80 mL of water, stir for 1 h, layer, and take a sample from the toluene layer for detection (its content chromatogram is as shown in Figure 23As shown, named batch number Y2503011-5); Repeat the 4th alkali extraction. Add 3.2 g of 30% sodium hydroxide solution dropwise to the toluene layer, add 80 mL of water, stir for 1 h, separate the layers, and take a sample from the toluene layer for detection (the content chromatogram is as Figure 24 shown, named batch number Y2503011-6); Collect the toluene mother liquor and aqueous phase obtained by standing and separating multiple times; (3) After mixing the aqueous phases remaining after the 5th alkali extraction collected in step (2), add 40 g of concentrated hydrochloric acid to adjust the pH < 2, stir for 1 h, then add 80 mL of toluene, stir for 0.5 h, stand and separate the layers to obtain the toluene layer; (4) Add 80 mL of water to the toluene layer in step (3), dropwise add the alkali solution, stand and separate the layers, which is used as the second alkali extraction operation. Repeat the above alkali extraction operation. Each time, add 2.4 g of 30% sodium hydroxide solution, continuously for 3 times. Take a sample from the toluene layer for detection (the content chromatogram is as Figure 25 shown, named batch number Y2503011-7), and collect the toluene mother liquor obtained by standing and separating multiple times; (5) Mix the toluene mother liquors collected in step (2) and step (4) to obtain a valproic acid solution after removing valeric acid.

[0056] For the above Figures 19 - 25 It can be seen that Figure 19 in the decarboxylation reaction solution, the residual valeric acid is 1.04% (14.595 minutes), and the valproic acid content is 95.34% (18.012 minutes); Figure 20 when the first dosage of the first alkali extraction is 0.08, the residual valeric acid is 0.42% (14.600 minutes), and the valproic acid content is 98.98% (17.999 minutes); Figure 21 when the dosage of repeating the first alkali extraction is 0.08, the residual valeric acid is 0.14% (14.601 minutes), and the valproic acid content is 99.24% (18.000 minutes); Figure 22 when the dosage of repeating the second alkali extraction is 0.08, the residual valeric acid is 0.04% (14.603 minutes), and the valproic acid content is 99.31% (17.999 minutes); Figure 23 when the dosage of repeating the third alkali extraction is 0.08, the residual valeric acid is 0.01% (14.604 minutes), and the valproic acid content is 99.28% (17.996 minutes) (because the valproic acid in the toluene layer is less and less, and the related substances increase, so the content decreases relatively). Figure 24 when the dosage of repeating the fourth alkali extraction is 0.08, the residual valeric acid is 0%, and the valproic acid content is 99.25% (17.994 minutes); It can be seen that the requirements of in-process control can be met after 3 times of the first alkali extraction. Figure 25 After continuously using 0.06 of the alkali for 3 times in the second alkali extraction, the residual valeric acid is 0%, and the valproic acid content is 99.55% (17.986 minutes).

[0057] Therefore, by comparing with the HPLC chromatogram of the first alkali extraction ( Figures 20 - 24 ), it was found that after three times of alkali extraction, the related substances were qualified. According to the peak area of the main peak, valproic acid was mainly in the toluene layer of the first alkali extraction. After the second alkali extraction, the peak area of the main peak decreased significantly, so the third alkali extraction was no longer carried out. Of course, if you want to further improve the yield, the third alkali extraction can be carried out. However, according to production experience, if the pH exceeds the standard during the adjustment of the crude product with alkali, it will cause the finished product to be unqualified. Therefore, once the situation of over-adjustment occurs during the adjustment of the crude product with alkali, the mother liquor of the third alkali extraction is added, which can improve the yield and further reduce the pH of the mother liquor to the qualified line (the pharmacopoeia requires pH = 7.5 - 8.5).

[0058] The determination of the parameters of the second alkali extraction in the process of the present invention is carried out through the following Examples 8 - 13: Example 8 The method for removing valeric acid, an impurity of valproic acid, in the valproate sodium synthesis process described above includes the following steps: (1) Calculated based on the feeding amount of methyl cyanoacetate of 40 g, add 80 mL of toluene and 80 mL of purified water to the decarboxylation mother liquor (its content chromatogram is as Figure 26 shown, named batch number Y2407005 - 1), filter by suction to remove carbonized substances; let the filtrate stand for layering, and separate the lower aqueous phase; add 120 mL of purified water to the toluene layer, and add 51 g of sodium hydroxide solution with a mass concentration of 30% to adjust the pH > 10. After adjustment, stir the solution for 0.5 h, let it stand for layering, retain the aqueous phase, add 80 mL of toluene, and add 39 g of concentrated hydrochloric acid to adjust the pH < 2. After adjustment, stir the solution for 0.5 h, let it stand for layering, and divide the obtained toluene layer into 8 equal parts to investigate the alkali dosage of the first alkali extraction.

[0059] (2) Add 80 mL of purified water to the toluene layer in step (1), perform the first alkali extraction operation, dropwise add 6.4 g of sodium hydroxide solution with a mass concentration of 30%, repeat the alkali extraction operation 3 times until the residual valeric acid in the toluene layer is lower than 0.1%, take samples from the toluene layer for detection (its content chromatogram is as Figure 27 shown, named batch number Y2407005 - 2), and collect the toluene mother liquor and aqueous phase obtained from multiple static layering operations; (3) After mixing the aqueous phases remaining after the three - time alkali extraction collected in step (2), add 50 mL of toluene, add 35 g of concentrated hydrochloric acid to adjust the pH < 2, stir for 0.5 h, let it stand for layering, and obtain the toluene layer, which is divided into 8 equal parts to investigate the process parameters of the second alkali extraction.

[0060] (4) Take one of the above 8 toluene samples, add 10 mL of water, and perform the second alkali extraction. Dropwise add 0.3 g (ratio 0.06) of 30% sodium hydroxide solution, stir for 0.5 h, separate the layers, and perform continuous alkali extraction 3 times. Take a sample from the toluene layer for analysis (as Figure 28 shown, named batch number Y2407005-3-1).

[0061] As Figure 26 can be seen, in the decarboxylation reaction solution (batch number Y2407005-1), the valeric acid residue is 1.71% (14.817 minutes), and the valproic acid content is 96.23% (18.234 minutes); As Figure 27 can be seen, after the first alkali extraction (batch number Y2407005-2), the valeric acid residue is 0.08% (14.835 minutes), and the valproic acid content is 99.75% (18.227 minutes); As Figure 28 can be seen, in the second alkali extraction, when the mass ratio of the added sodium hydroxide solution to methyl cyanoacetate is 0.06, the valeric acid residue is 0.06% (14.838 minutes), and the valproic acid content is 99.94% (18.224 minutes), meeting the in-process control requirements.

[0062] Example 9 Take one of the 8 toluene layer samples in Example 8, add 10 mL of purified water, and perform the second alkali extraction. Dropwise add 0.4 g (ratio 0.08) of 30% sodium hydroxide solution, stir for 1 h, let it stand and separate the layers, and perform continuous alkali extraction 4 times. Take a sample from the toluene layer for analysis (batch number Y2407005-4-1), and perform chromatographic analysis of its content. Its chromatogram is as Figure 29 shown. As Figure 29 can be seen, in the second alkali extraction, when the mass ratio of the added sodium hydroxide solution to methyl cyanoacetate is 0.08, the valeric acid residue is 0.04% (14.839 minutes), and the valproic acid content is 99.96% (18.224 minutes), meeting the in-process control requirements.

[0063] Example 10 Take one of the 8 toluene layer samples in Example 8, add 10 mL of purified water, and perform the second alkali extraction. Dropwise add 0.5 g (ratio 0.10) of 30% sodium hydroxide solution, stir for 1.5 h, let it stand and separate the layers, and perform continuous alkali extraction 3 times. Take a sample from the toluene layer for analysis (batch number Y2407005-5-1), and perform chromatographic analysis of its content. Its chromatogram is as Figure 30 shown. As Figure 30 can be seen, in the second alkali extraction, when the mass ratio of the added sodium hydroxide solution to methyl cyanoacetate is 0.10, the valeric acid residue is 0%, and the valproic acid content is 100.00% (18.225 minutes), meeting the in-process control requirements.

[0064] Example 11 Take one part of the toluene layer sample out of the 8 parts in Example 8, add 10 mL of purified water, and perform the second alkali extraction. Dropwise add 0.6 g (ratio 0.12) of 30% sodium hydroxide solution, stir for 1 h, let it stand for layering, and perform continuous alkali extraction 3 times. Take a sample from the toluene layer for analysis (batch number Y2407005-6-1), and perform chromatographic analysis of its content. Its chromatogram is as Figure 31 shown. From Figure 31 it can be seen that in the second alkali extraction, when the mass ratio of the added sodium hydroxide solution to the mass of methyl cyanoacetate is 0.12, the valeric acid residue is 0%, and the content of valproic acid is 100.00% (18.227 minutes), meeting the in-process control requirements.

[0065] Example 12 Take one part of the toluene layer sample out of the 8 parts in Example 8, add 10 mL of purified water, and perform the second alkali extraction. Dropwise add 0.7 g (ratio 0.14) of 30% sodium hydroxide solution, stir for 0.5 h, let it stand for layering, and perform continuous alkali extraction 4 times. Take a sample from the toluene layer for analysis (batch number Y2407005-7-1), and perform chromatographic analysis of its content. Its chromatogram is as Figure 32 shown. From Figure 32 it can be seen that in the second alkali extraction, when the mass ratio of the added sodium hydroxide solution to the mass of methyl cyanoacetate is 0.14, the valeric acid residue is 0%, and the content of valproic acid is 100.00% (18.233 minutes), meeting the in-process control requirements.

[0066] Example 13 Take one part of the toluene layer sample out of the 8 parts in Example 8, add 10 mL of purified water, and perform the second alkali extraction. Dropwise add 0.8 g (ratio 0.16) of 30% sodium hydroxide solution, stir for 1 h, let it stand for layering, and perform continuous alkali extraction 3 times. Take a sample from the toluene layer for analysis (batch number Y2407005-8-1), and perform chromatographic analysis of its content. Its chromatogram is as Figure 33 shown. From Figure 33 it can be seen that in the second alkali extraction, when the mass ratio of the added sodium hydroxide solution to the mass of methyl cyanoacetate is 0.16, the valeric acid residue is 0%, and the content of valproic acid is 100.00% (18.250 minutes), meeting the in-process control requirements.

[0067] Comparative Example 1 Take one part of the toluene layer sample out of the 8 parts in Example 2, add 10 mL of purified water, and perform the first alkali extraction. Dropwise add 0.1 g (ratio 0.02) of 30% sodium hydroxide solution, stir for 1.5 h, let it stand for layering, and perform continuous alkali extraction 3 times. Take a sample from the toluene layer for analysis (this sample is named batch number Y2407003-1-1), and perform chromatographic analysis of its content. Its chromatogram is as Figure 34 shown. FromFigure 34 It can be seen that in the first alkali extraction, when the mass ratio of the added sodium hydroxide solution to the mass of methyl cyanoacetate is 0.02, the valeric acid residue is 0.61% (14.823 minutes), and the content of valproic acid is 99.30% (18.229 minutes), which does not meet the in-process control requirements.

[0068] Comparative Example 2 Take one part of the toluene layer sample from the 8 parts in Example 2, add 10 mL of purified water, and conduct the first alkali extraction. Add 0.2 g (ratio 0.04) of 30% sodium hydroxide solution dropwise, stir for 1 h, let it stand for layer separation, and conduct continuous alkali extraction 4 times. Take a sample from the toluene layer for analysis (this sample is named batch number Y2407003-2-1), and conduct chromatographic analysis of its content. Its chromatogram is as Figure 35 shown. From Figure 35 It can be seen that in the first alkali extraction, when the mass ratio of the added sodium hydroxide solution to the mass of methyl cyanoacetate is 0.04, the valeric acid residue is 0.24% (14.829 minutes), and the content of valproic acid is 99.71% (18.229 minutes), which does not meet the in-process control requirements.

[0069] Comparative Example 3 Take one part of the toluene layer sample from the 8 parts in Example 2, add 10 mL of purified water, and conduct the first alkali extraction. Add 0.3 g (ratio 0.06) of 30% sodium hydroxide solution dropwise, stir for 0.5 h, let it stand for layer separation, and conduct continuous alkali extraction 5 times. Take a sample from the toluene layer for analysis (this sample is named batch number Y2407003-3-1), and conduct chromatographic analysis of its content. Its chromatogram is as Figure 36 shown. From Figure 36 It can be seen that in the first alkali extraction, when the mass ratio of the added sodium hydroxide solution to the mass of methyl cyanoacetate is 0.06, the valeric acid residue is 0.15% (14.829 minutes), and the content of valproic acid is 99.80% (18.228 minutes), which does not meet the in-process control requirements.

[0070] Comparative Example 4 Take one part of the toluene layer sample from the 8 parts in Example 8, add 10 mL of purified water, and conduct the second alkali extraction. Add 0.1 g (ratio 0.02) of 30% sodium hydroxide solution dropwise, stir for 1 h, let it stand for layer separation, and conduct continuous alkali extraction 3 times. Take a sample from the toluene layer for analysis (batch number Y2407005-1-1), and conduct chromatographic analysis of its content. Its chromatogram is as Figure 37 shown. From Figure 37 It can be seen that in the second alkali extraction, when the mass ratio of the added sodium hydroxide solution to the mass of methyl cyanoacetate is 0.02, the valeric acid residue is 0.32% (14.830 minutes), and the content of valproic acid is 99.58% (18.224 minutes), which does not meet the in-process control requirements.

[0071] Comparative Example 5 Take one part of the toluene layer sample out of the 8 parts in Example 8, add 10 mL of purified water, and perform the second alkali extraction. Dropwise add 0.2 g (ratio 0.04) of 30% sodium hydroxide solution, stir for 1.5 h, let it stand for layering, and perform continuous alkali extraction 4 times. Take samples from the toluene layer for analysis (batch number Y2407005-2-1), and conduct chromatographic analysis of its content. Its chromatogram is as shown in Figure 38 shown. It can be seen from Figure 38 that during the second alkali extraction, when the mass ratio of the added sodium hydroxide solution to the mass of methyl cyanoacetate is 0.04, the valeric acid residue is 0.13% (14.837 minutes), and the content of valproic acid is 99.82% (18.224 minutes), which does 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 with suction; The filtrate was allowed to stand for separation, and the lower aqueous phase was separated; water was added to the toluene layer, and an alkali solution was added to adjust the pH to > 10, and the phase was allowed to stand for separation, toluene was retained in the aqueous phase, 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; (2) adding water to the toluene layer of step (1), adding an alkali solution dropwise, and standing to separate the layers as the first alkali extraction operation, repeating the above alkali extraction operation until the residual valeric acid in the toluene layer is less than 0.1%, and collecting the toluene mother liquor and the aqueous phase after multiple standing to separate the layers; (3) adding toluene to the aqueous phase collected from the step (2) and allowed to stand for multiple stratifications, and adding hydrochloric acid to adjust the pH to less than 2, and allowing the phase to stand for stratification to obtain a toluene layer; (4) adding water to the toluene layer of step (3), adding an alkali solution dropwise, and standing to separate the layers as the second alkali extraction operation, repeating the above alkali extraction operation until the residual valeric acid in the toluene layer is less than 0.1%, and collecting the toluene mother liquor obtained by multiple standing to separate the layers; (5) Mixing the toluene mother liquors collected in step (2) and step (4) 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, characterized in that: The decarboxylation mother liquor in step (1) is prepared by reacting methyl cyanoacetate and propyl bromide as raw materials to obtain methyl 2-cyano-2-propyl valerate, which is then hydrolyzed by adding an alkaline solution to obtain 2-cyano-2-propyl valeric acid, and then undergoing a decarboxylation reaction to obtain an oil-water mixture of valproic acid.

3. The method for removing valeric acid, an impurity of valproic acid, in the sodium valproate synthesis process according to claim 2, characterized in that: In step (1), the hydrochloric acid with 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.

4. The method for removing valeric acid, an impurity of valproic acid, in the sodium valproate synthesis process according to claim 3, characterized in that: 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 a stirring time of 0.5 to 1.5 hours.

5. The method for removing valeric acid, an impurity of valproic acid, in the sodium valproate synthesis process according to claim 4, characterized in that: The above alkaline extraction operation of step (2) is repeated by adding water to the toluene layer, dropping the alkaline solution, and standing to separate the layers. The mass ratio of the alkaline solution added each time to the mass ratio of methyl cyanoacetate is 0.08-0.

16.

6. The method for removing valeric acid, an impurity of valproic acid, in the sodium valproate synthesis process according to claim 5, characterized in that: The above alkaline extraction operation of step (4) is repeated by adding water to the toluene layer, dropping the alkaline solution, and standing to separate the layers. The mass ratio of the alkaline solution added each time to the mass ratio of methyl cyanoacetate is 0.06-0.16.

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