A cyanoacetate method for preparing valproic acid

Abstract

The present invention relates to a cyanoacetate method for preparing valproic acid via a 2-propyl-2-cyanovalerate intermediate shown in formula I: cyanoacetate and 1-chloropropane are reacted in a K 2 CO 3 Under the action of the composite catalytic dipropylation, 2-propyl-2-cyanovalerate shown in Ⅰ is obtained, and the latter is hydrolyzed and decarboxylated to obtain valproic acid, and the preparation reaction is as follows: #imgabs0#R is selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl or pentyl; the catalyst for dipropylation is composed of catalyst A and catalyst B; catalyst A is selected from tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium iodide, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium iodide, tetramethylammonium chloride, tetramethylammonium bromide or tetramethylammonium iodide; catalyst B is selected from KBr or KI; the dipropylation reaction temperature is selected from 60°C to 120°C; the reaction time is selected from 1.0h to 12h. Impurities in the obtained valproic acid or sodium valproate: total impurities are less than 0.2%, single impurities are less than 0.05%; the valproic acid content is greater than 99.90%. The cyanoacetate method for preparing valproic acid or sodium valproate meets the quality requirements.

Description

Technical Field

[0001] The present invention relates to a method for preparing valproic acid through 2-propyl-2-cyanopentanoate by adopting a cyanoacetate method. Background Art

[0002] Sodium valproate, developed by Abbott, the third-largest pharmaceutical company in the United States, was approved by the US FDA in 1983 for the treatment of epilepsy. It was subsequently approved for the treatment of bipolar disorder in 1995 and for the prevention of migraines in 1996. Sodium valproate is primarily used for the treatment of epilepsy, either as a monotherapy or as an add-on therapy. It can be used to treat generalized epilepsy, partial epilepsy, and focal seizures, with or without generalized seizures. It is also used for mania and manic episodes associated with bipolar disorder. The main ingredient of sodium valproate tablets is sodium valproate, while the main ingredients of sodium valproate extended-release tablets are sodium valproate and valproic acid. Sodium valproate has broad-spectrum antiepileptic activity and is the preferred antiepileptic drug in clinical practice both domestically and internationally.

[0003] In 1984, Li Xinyuan et al. [Synthesis of valproic acid-type antiepileptic drugs by solid-liquid phase transfer catalytic reaction. Pharmaceutical Industry, 1984, 5: 4-6; Li Xinyuan. Synthesis of a new antiepileptic drug - valproic acid amide. Pharmaceutical Industry, 1981, (11): 1-2] selected methyl cyanoacetate, 1-bromopropane and solid potassium carbonate, dipropylated under the catalysis of quaternary ammonium salt, and then hydrolyzed, decarboxylated and salified to prepare sodium valproate / magnesium valproate or valproic acid amide.

[0004]

[0005] Indian patent [IN486MU2014A, 2015-09-25] selects ethyl cyanoacetate and 1-bromopropane for dipropylation in the presence of sodium propoxide to produce ethyl 2-propyl-2-cyanovalerate. The latter is then catalytically hydrolyzed to produce 2-propyl-2-cyanovaleric acid in a yield of 90% to 94%. 2-propyl-2-cyanovaleric acid is then hydrolyzed with sulfuric acid to produce valproic acid in a yield of 85% to 90%. The preparation reaction is as follows:

[0006]

[0007] British patent [GB2068962A, 1981-08-19] describes the preparation of valproic acid by hydrolysis of valproonitrile by sulfuric acid catalysis. The preparation reaction is as follows:

[0008]

[0009] Shanghai Qingping Pharmaceutical Co., Ltd. [A new method for preparing valproic acid, CN 2021103366414, published on August 3, 2021; A method for preparing sodium valproate, CN 2021103339474, published on August 3, 2021; A method for preparing valproic acid, CN 2021103366274, published on July 27, 2021] describes a method for preparing valproic acid and sodium valproate: using valproonitrile or 2-cyano-2-propylpentanoic acid as raw materials and sulfuric acid as a catalyst, the reaction is carried out at 120-160°C for 20-40 hours to produce valproic acid with a yield of 70%-80%. The synthesis route is as follows:

[0010]

[0011] Shanghai Qingping Pharmaceutical Co., Ltd. [A method for preparing 2-R1 valeric acid, ZL 202110336630.6, published on July 23, 2021] describes the reaction of methyl cyanoacetate, methanol and 1-bromopropane at 45-60°C, with the addition of 30-40% sodium methoxide methanol solution. After the reaction is completed, the methanol is rotary evaporated to obtain a crude product, which is purified to obtain methyl 2-cyanovalerate; the methyl 2-cyanovalerate is then methylated, ethylated or isopropylated, hydrolyzed and decarboxylated to obtain 2-methylvaleric acid (L), 2-ethylvaleric acid (B) or 2-isopropylvaleric acid (C), respectively [Wei Zhenghua. Chinese Journal of Pharmaceutical Industry, Synthesis of 2-isopropylvaleric acid, 2023, 54(05):739-741]:

[0012]

[0013] Tao Jing et al. [A method for preparing dipropyl malonate diester, Chinese invention patent..CN103183612A, 2013.07.03; A method for preparing 2-propyl valeric acid, CN103183599B, ​​2015.04.01] described a method for preparing valproic acid; wherein methyl malonate and 1-chloropropane were reacted to prepare dipropyl methyl malonate propyl ester, and the crude product (dipropyl methyl malonate propyl ester) yield was 70.5%.

[0014]

[0015] Valproic acid is prepared using 1-chloropropane as a raw material. Due to the low activity of 1-chloropropane, the dipropylation reaction produces methyl dipropyl malonate with a low yield (70.5%), which is a difficult problem in the production process technology.

[0016] European Pharmacopoeia EP10.0 and British Pharmacopoeia

[0017] BP2020 [European Directorate for the Quality of Medicines & Health Care. European Pharmacopoeia 10th Edition]. Druckerei CH Beck, 2020, 3849-3850] reported impurities in sodium valproate, including valeric acid (A), valeronitrile (H), valeramide (E), 2-methylvaleric acid (L), 2-ethylvaleric acid (B), 2-isopropylvaleric acid (C), 2-methyl-2-ethylvaleric acid (K), dipropylvaleric acid (D), valproamide (F), 2-propionitrile (I), dipropylvaleramide (G) and dipropionitrile (J):

[0018]

[0019] Chengdu Beite Pharmaceutical Co., Ltd. et al. [Mou Yong et al. A method for detecting related substances of sodium valproate oral solution, ZL202111671016.1, 2023.11.14] described that the impurities contained in sodium valproate (prepared by methyl acetoacetate method) oral solution are 2-hexanone (an impurity produced by monopropylated ketone decomposition), 3-propyl-2-hexanone (an impurity produced by dipropylated ketone decomposition), methyl 2-propyl valerate, valeric acid (EP-A), 2-isopropyl valeric acid (EP-C) or 2-methyl-2-ethyl valeric acid (EP-K).

[0020]

[0021] Chongqing Jianneng Pharmaceutical Development Co., Ltd. [Liu Ping et al. Determination of Related Substances in Sodium Valproate Oral Solution, ZL201811629988.2, authorized on May 13, 2022] describes the detection of impurities in sodium valproate oral solution (prepared by the allyl halide method); 2-allyl-4-pentenoic acid (USP-A), 2-ethylpentanoic acid (EP-B), 2-isopropylpentanoic acid (EP-C), or 2-methyl-2-ethylpentanoic acid (EP-K) were detected:

[0022]

[0023] Chongqing Jianneng Pharmaceutical Development Co., Ltd. [Li Chaoyang et al. A method for qualitative analysis of trace impurities in sodium valproate raw materials by HPLC-MS, CN2020115724317, May 7, 2021] describes the detection of trace impurities L and B in sodium valproate products:

[0024]

[0025] Currently, the residual impurity 2-methylvaleric acid L in sodium valproate API is high. Pharmacological tests have shown that 2-methylvaleric acid L is a vasoirritant, which can cause vasoirritation in sodium valproate injection [Chen Dafeng et al., A Highly Safe Pharmaceutical Composition and Its Preparation Method, ZL201911306074.7, licensed on March 21, 2023]. To reduce vascular irritation, it is necessary to control the content of 2-methylvaleric acid L, a byproduct in the production of sodium valproate API. Sichuan Kred Pharmaceutical Co., Ltd. [A Highly Safe Pharmaceutical Composition and Its Preparation Method, ZL 2019 11306074.7, licensed on March 21, 2023] describes a highly safe pharmaceutical composition that can reduce the vasoirritation of sodium valproate injection; the composition contains no less than 90% sodium valproate and no more than 0.014% 2-methylvaleric acid L.

[0026] Hunan Xiangzhong Pharmaceutical Co., Ltd. and Hunan University [A composite catalytic preparation method for 2-cyano-2-valproic acid methyl ester, ZL2022101320660, authorized on March 31, 2023] disclose a method for preparing valproic acid by selecting 1-chloropropane as raw material and adopting the methyl cyanoacetate method; Hunan Xiangzhong Pharmaceutical Co., Ltd. and Hunan University [A method for detecting impurities in valproic acid prepared by the methyl cyanoacetate method, CN 202311045924.9, November 17, 2023] describes a method for detecting impurities in valproic acid products: valeric acid (A), 2-methylvaleric acid (L), 2-isopropylvaleric acid (C), dipropylvaleric acid (D), 2-propylhexanoic acid (X), valeramide (F) or 2-propionvaleronitrile (I) impurities may be produced in the process. Summary of the Invention

[0027] The present invention provides a method for preparing valproic acid via the 2-propyl-2-cyanopentanoate intermediate shown in formula I using the cyanoacetate method, characterized in that cyanoacetate and 1-chloropropane are subjected to a composite catalytic dipropylation reaction under the action of K2CO3 to produce 2-propyl-2-cyanopentanoate shown in formula I, which is then hydrolyzed and decarboxylated to produce valproic acid. The preparation reaction is as follows:

[0028]

[0029] R is selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl or pentyl;

[0030] The dipropylation catalyst consists of catalyst A and catalyst B; catalyst A is selected from tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium iodide, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium iodide, tetramethylammonium chloride, tetramethylammonium bromide or tetramethylammonium iodide; catalyst B is selected from KBr or KI;

[0031] The dipropylated solvent is selected from THF, DMF, DMC, DMSO;

[0032] K2CO3 is selected from 100 mesh K2CO3, 150 mesh K2CO3, 200 mesh K2CO3, 250 mesh K2CO3, 300 mesh K2CO3 or 350 mesh K2CO3; the dipropylation reaction temperature is selected from 60°C to 120°C; the reaction time is selected from 1.0h to 12h;

[0033] The amount of dipropylation catalyst used is selected from cyanoacetate: catalyst = 1: 0.01-0.02 (mol / mol).

[0034] The amount of dipropylation feed is selected from the molar ratio of cyanoacetate: 1-chloropropane = 1: 2.0-2.5.

[0035] The amount of dipropylated potassium carbonate used is selected from the molar ratio of cyanoacetate:potassium carbonate = 1:1.10-1.99.

[0036] The amount of dipropylated potassium carbonate used is preferably a molar ratio of cyanoacetate to potassium carbonate of 1:1.10 to 1.80.

[0037] The amount of dipropylated potassium carbonate used is preferably a molar ratio of cyanoacetate to potassium carbonate of 1:1.10 to 1.60.

[0038] The amount of dipropylated potassium carbonate used is preferably a molar ratio of cyanoacetate to potassium carbonate of 1:1.10 to 1.40.

[0039] The present invention also provides a method for preparing valproic acid by a cyanoacetate method, preferably a methyl cyanoacetate method, characterized in that the methyl cyanoacetate method is selected. The preparation reaction of valproic acid is as follows:

[0040]

[0041] The process impurities of preparing valproic acid P by the methyl cyanoacetate method are valeric acid (A), 2-methylvaleric acid (L), 2-isopropylvaleric acid (C), 2-propylhexanoic acid or valproamide (F). The reaction to produce 2-methylvaleric acid (L) is as follows:

[0042]

[0043] The present invention also provides a method for preparing valproic acid by a cyanoacetic acid ester method, preferably an ethyl cyanoacetate method, characterized in that the ethyl cyanoacetate method is selected, and the preparation reaction of valproic acid is as follows:

[0044]

[0045] The impurities in the ethyl cyanoacetate method for preparing valproic acid P are valeric acid (A), 2-ethylpentanoic acid (B), 2-isopropylpentanoic acid (C), 2-propylhexanoic acid, or valproamide (F). The reaction to produce 2-ethylpentanoic acid (B) is as follows:

[0046]

[0047] The present invention also provides a cyanoacetate method, preferably a propyl cyanoacetate method, characterized in that the propyl cyanoacetate method is selected to prepare valproic acid, and the preparation reaction of valproic acid is as follows:

[0048]

[0049] The process impurities of preparing valproic acid P by the propyl cyanoacetate method are valeric acid (A), 2-isopropyl valeric acid (C), 2-propyl hexanoic acid or valproamide (F).

[0050] Compared with the prior art, the present invention has the following advantages:

[0051] 1. In the present invention, a composite catalytic dipropylation method using cyanoacetic acid ester and 1-chloropropane is adopted. 1-chloropropane is in sufficient supply, has abundant sources, and is inexpensive. The amount of potassium carbonate used in the dipropylation is selected from a molar ratio of cyanoacetic acid ester: potassium carbonate = 1:1.10 to 1.99.

[0052] 2. The intermediates and products in the process are of high purity, the production cost of raw materials is low and the quality is good.

[0053] 3. It is clarified that when different cyanoacetic acid esters are selected as raw materials, different impurities are produced in the process of preparing valproic acid: for example, the methyl cyanoacetate method produces impurity L; the ethyl cyanoacetate method produces impurity B. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 shows a high performance liquid chromatogram of 2-cyano-2-propanoic acid (methyl cyanoacetate method).

[0055] Figure 2 shows a high performance liquid chromatogram of 2-cyano-2-propanoic acid (ethyl cyanoacetate method).

[0056] Figure 32 - Gas chromatogram of propylvaleronitrile.

[0057] Attachment Figure 4 Gas chromatogram of valproic acid (ethyl cyanoacetate method).

[0058] Attachment Figure 5 Gas chromatogram of valproic acid (methyl cyanoacetate method). DETAILED DESCRIPTION

[0059] The present invention is further described in detail below with reference to the embodiments.

[0060] Example 1

[0061] Preparation of methyl 2-cyano-2-valproate and 2-cyano-2-valproate

[0062]

[0063] To a 2L reactor, add 99.1g (1.0mol) of methyl cyanoacetate, 0.02mol of TBAB, 1.18g of potassium bromide, 263.2g (1.9mol) of K2CO3 (300 mesh), 400ml (377.6g) of DMF, and 180g (2.29mol) of 1-chloropropane (2-chloropropane and 1-chlorobutane content less than 0.03%) in sequence. After addition, stir in an oil bath at 75°C for 2 hours. The reaction solution gradually darkens in color. Stir and react at 95°C (oil bath) for 3 hours (LC monitoring of the reaction endpoint occurs when the monosubstituted product is ≤3%). After completion of the reaction, cool to below 45°C, filter, wash the filter cake until white, and drain. The filtrate was recovered under reduced pressure until almost no distillate was produced, and the temperature was lowered to below 30° C. 300 mL of petroleum ether was added, and the organic phase was washed with 10% NaOH and then with water. The petroleum ether was recovered under normal pressure and then distilled under reduced pressure to obtain 174 g of methyl 2-cyano-2-valproate as a colorless transparent liquid with a yield of 95%.

[0064] 10% NaOH was added to methyl 2-cyano-2-valproate, and the mixture was hydrolyzed at 60-70°C for 3 h. Methanol was recovered by rotary evaporation, and 100 ml of water was added. Concentrated hydrochloric acid (about 130 ml) was added under ice bath to neutralize the mixture to pH 1. A white solid was precipitated, filtered, and dried to obtain 183 g of 2-cyano-2-valproate monohydrate as a white solid. HPLC analysis showed that the product was 99.73% (attached). Figure 1 ).

[0065] Methyl 2-cyano-2-propanoate: 1H NMR (400 MHz, DMSO-d6) δ: 3.76 (s, 3H, OCH3), 1.85-1.75 (m, 4H, CH2×2), 1.52-1.38 (m, 2H, CH2), 1.30-1.17 (m, 2H, CH2), 0.91 (t, J=7.2 Hz, 6H, CH3×2).

[0066] 2-Cyano-2-propanoic acid: 1HNMR (400 MHz, DMSO-d6) δ: 13.76 (s, 1H, CO2H), 1.84-1.67 (m, 4H, CH2×2), 1.54-1.41 (m, 2H, CH2), 1.36-1.21 (m, 2H, CH2), 0.92 (t, J=7.2 Hz, 6H, CH3×2).

[0067] Example 2

[0068] Preparation of ethyl 2-cyano-2-valproate and 2-cyano-2-valproate

[0069]

[0070] In a 2L reactor, 113.1g (1.0mol) of ethyl cyanoacetate, 0.02mol of TEAB, 1.18g of potassium bromide, 207g (1.5mol) of K2CO3 (300 mesh), 283g of DMF, and 172.7g (2.2mol) of 1-chloropropane were added in sequence. After addition, the reaction was stirred at 85°C (oil bath) for 2h, then raised to 100°C (oil bath) and stirred for 3h (LC monitoring of the reaction endpoint). After the reaction, the temperature was lowered to below 45°C, filtered, and the filter cake washed with recovered DMF until white and drained. The filtrate was recovered under reduced pressure until almost no distillate was present. The temperature was then lowered to below 30°C, petroleum ether was added, and the organic phase was washed with 10% NaOH and then with water. The petroleum ether was recovered at normal pressure and then distilled under reduced pressure to yield 191.14g of ethyl 2-cyano-2-propylvalerate as a colorless, transparent liquid in a yield of 96.89%.

[0071] 10% NaOH was added to ethyl 2-cyano-2-propylvalerate, and the mixture was hydrolyzed at 60-80°C for 3 h. Ethanol was recovered by rotary evaporation, and 100 ml of water was added. Concentrated hydrochloric acid (about 130 ml) was added under ice bath to neutralize the mixture to pH 1. A white solid was precipitated, filtered, and dried to obtain 185 g of 2-cyano-2-propylvaleric acid monohydrate as a white solid. HPLC analysis showed that the product had a pH of 99.95% (appended). Figure 2 ).

[0072] Ethyl 2-cyano-2-propanoate: 1H NMR (400 MHz, DMSO-d6) δ: 4.22 (q, J = 7.2 Hz, 2H, OCH2), 1.84-1.75 (m, 4H, CH2×2), 1.52-1.39 (m, 2H, CH2), 1.31-1.18 (m, 5H, CH2+CH3), 0.91 (t, J = 7.2 Hz, 6H, CH3×2).

[0073] 2-Cyano-2-propanoic acid: 1HNMR (400 MHz, DMSO-d6) δ: 13.76 (s, 1H, CO2H), 1.84-1.67 (m, 4H, CH2×2), 1.54-1.41 (m, 2H, CH2), 1.36-1.21 (m, 2H, CH2), 0.92 (t, J=7.2 Hz, 6H, CH3×2).

[0074] Example 3

[0075] Preparation of Propylvaleronitrile

[0076]

[0077] Add 180g (wet weight) of 2-cyano-2-propylpentanoic acid into the decarboxylation distillation flask, adjust the oil bath temperature to 140℃, and after the water is evaporated, raise the internal temperature to 130-160℃ for decarboxylation and keep warm for 3h. After the decarboxylation is completed, collect the low-boiling substances until the internal temperature reaches 180℃, and then collect the normal boiling substances. Collect the normal boiling substances under normal pressure until the internal temperature reaches 210℃ when there is no distillate. Then reduce the pressure (gradually increase the vacuum degree) and collect until the internal temperature reaches 210℃. The collection end point is when no distillate is distilled out. 112.54g of colorless transparent liquid is obtained, with a yield of 89.09% (calculated as ethyl cyanoacetate) and GC 94.44% (attached Figure 3 ).

[0078] Example 4

[0079] Preparation of valproic acid

[0080]

[0081] In a 250 ml reaction flask, add 43 g of water, slowly add 85 g (0.84 mol) of 98% concentrated sulfuric acid while cooling, control the internal temperature below 60°C, add 50 g (0.4 mol) of valproate nitrile (prepared by the ethyl cyanoacetate method), slowly raise the temperature to 130°C ± 4°C, and keep warm for 16 ± 2 h. During this period, monitor the reaction endpoint by HPLC (valproate amide% ≤ 0.5%).

[0082] After the reaction is complete, cool to 40°C, slowly add 50g of water, separate the layers, discard the aqueous layer, and extract the organic layer once with 50g of water. Transfer the extracted organic layer to a reaction flask, slowly add 73.33g of a 25% aqueous sodium hydroxide solution (1.15eq of sodium hydroxide), and incubate at 60°C for 0.5h to complete the reaction, generating an aqueous solution of sodium valproate. Cool the solution to 30°C and extract twice with 50ml of dichloromethane. Slowly add 28g of 98% concentrated sulfuric acid to the aqueous layer to neutralize it to pH = 1. Separate the layers and discard the aqueous layer to obtain crude valproic acid.

[0083] The crude valproic acid obtained above was extracted twice with 100 ml of water, separated, and the washed crude valproic acid was transferred to a 100 ml reaction flask, then heated to 140° C., and low-boiling substances were distilled off under reduced pressure, and valproic acid was collected. After the distillation was complete, the distillation was stopped to obtain 54.22 g of valproic acid with a yield of 94% and a GC content of 99.93% (determined according to a method for detecting impurities in valproic acid prepared by a methyl cyanoacetate method, CN 202311045924.9, and the detection method disclosed on November 17, 2023, is shown in the attached results). Figure 4 ); the specific results are listed in Table 1.

[0084] Table 1

[0085]

[0086] Valproic acid: 1H NMR (400 MHz, DMSO-d6) δ: 11.99 (s, 1H, COOH), 2.24-2.18 (m, 1H, CH), 1.53-1.44 (m, 2H, CH2), 1.39-1.34 (m, 2H, CH2), 1.32-1.22 (m, 4H, CH2×2), 0.86 (t, J=7.2 Hz, 6H, CH3×2).

[0087] Example 5

[0088] Preparation and detection results of valproic acid

[0089] In a 250ml reaction flask, add 43g of water, cool in an oil bath, then slowly add 84g (0.84mol) of 98% concentrated sulfuric acid, control the internal temperature below 60°C, then add 50g (0.4mol) of valproate nitrile (prepared by the methyl cyanoacetate method), slowly raise the temperature to 130°C±2°C, and keep warm for 26±2h, then raise the temperature to 140°C±2°C, and keep warm for 4±2h. Monitor the reaction endpoint (valproate amide ≤0.5%) by HPLC.

[0090] After the reaction is complete, the temperature is lowered to 40°C, 50g of water is slowly added, the layers are separated, the aqueous layer is discarded, and the organic layer is extracted once with 50g of water; the extracted organic layer is transferred to a reaction flask, 73.33g of a 25% aqueous sodium hydroxide solution (1.15eq of sodium hydroxide) is slowly added, and the temperature is maintained at 60°C for 0.5h. The reaction is completed to produce an aqueous solution of sodium valproate. The solution is cooled to 30°C and extracted twice with 50ml of dichloromethane. The organic layer is collected for processing, and 28g of concentrated sulfuric acid (98%) is slowly added to the aqueous layer to neutralize it to pH = 1. The layers are separated and the aqueous layer is discarded to obtain crude valproic acid.

[0091] The crude valproic acid obtained above was extracted twice with 100 ml of water, separated into layers, and the washed crude valproic acid was transferred to a 100 ml reaction flask, then heated to below 140° C., and low-boiling substances were distilled off under reduced pressure, and the valproic acid was collected. After the distillation was complete, the distillation was stopped to obtain 53 g of valproic acid with a yield of 92.0%.

[0092] According to the method of Example 15 in [A method for detecting impurities in valproic acid prepared by methyl cyanoacetate, CN 202311045924.9, published on November 17, 2023], the purity of valproic acid was 99.92% (see attached Figure 5 ); The specific results are listed in Table 2.

[0093] Table 2

[0094]

[0095] In this specification, the present invention has been described with reference to specific embodiments thereof. However, it will be apparent that various modifications and variations may be made without departing from the spirit and scope of the present invention. Therefore, the description is to be regarded as illustrative rather than restrictive.

Claims

1. A method for preparing valproic acid via the ethyl cyanoacetate intermediate of 2-propyl-2-cyanovaleric acid ethyl ester shown in formula Ib by the ethyl cyanoacetate method, characterized in that The ethyl cyanoacetate method was selected to prepare valproic acid. The preparation reaction of valproic acid is as follows: The specific operation of preparing valproic acid is as follows: (1) In a 2L reaction kettle, 1.0 mol of ethyl cyanoacetate, 0.02 mol of tetraethylammonium bromide, 1.18 g of potassium bromide, 1.5 mol of 300 mesh K2CO3, 283 g of DMF, and 2.2 mol of 1-chloropropane were added in sequence; after the addition, the mixture was stirred in an oil bath at 85°C for 2 h, then heated to 100°C for 3 h in an oil bath, and the reaction endpoint was monitored by LC; after the reaction, the mixture was cooled to below 45°C, filtered, and the filter cake was washed with recovered DMF until it turned white, and then dried; the filtrate was recovered under reduced pressure until almost no distillation was produced, the mixture was cooled to below 30°C, petroleum ether was added, the organic phase was washed with 10% NaOH, and then washed with water, the petroleum ether was recovered under normal pressure, and then distilled under reduced pressure to obtain 191.14 g of colorless transparent liquid ethyl 2-cyano-2-propylvalerate, with a yield of 96.89%; (2) Add 10% NaOH to ethyl 2-cyano-2-propylvaleric acid ester, hydrolyze at 60-80°C for 3 h, recover ethanol by rotary evaporation, add 100 ml of water, neutralize to pH 1 by adding 130 ml of concentrated hydrochloric acid under ice bath, precipitate a white solid, filter, and dry to obtain 185 g of 2-cyano-2-propylvaleric acid monohydrate as a white solid, HPLC 99.95%; (3) Add 180 g of 2-cyano-2-propylpentanoic acid in a decarboxylation distillation flask, adjust the oil bath temperature to 140°C, and after the water is evaporated, raise the internal temperature to 130-160°C for decarboxylation and heat preservation reaction for 3 hours; after the decarboxylation is completed, collect low-boiling products until the internal temperature reaches 180°C, and then collect normal boiling products. Collect normal boiling products under normal pressure until the internal temperature reaches 210°C when no distillate is produced, then reduce the pressure, gradually increase the vacuum degree, and collect until the internal temperature reaches 210°C. The collection end point is when no distillate is produced; 112.54 g of colorless transparent liquid valproate nitrile is obtained, with a yield of 89.09% based on ethyl cyanoacetate and a GC yield of 94.44%; (4) In a 250 ml reaction bottle, add 43 g of water, slowly add 85 g of 98% concentrated sulfuric acid while cooling, control the internal temperature below 60°C, add 50 g of valproate nitrile, slowly raise the temperature to 130°C ± 4°C, and keep warm for 16 ± 2 h. During this period, HPLC monitors the reaction endpoint: valproate amide % ≤ 0.5%; After the reaction, cool to 40°C, slowly add 50g of water, separate the layers, discard the water layer, and extract the organic layer once with 50g of water; transfer the extracted organic layer to a reaction bottle, slowly add 73.33g of 25% sodium hydroxide aqueous solution, keep warm at 60°C for 0.5h, and the reaction is completed to generate a sodium valproate aqueous solution. Cool the solution to 30°C, extract twice with 50ml of dichloromethane, slowly add 28g of 98% concentrated sulfuric acid to the water layer to neutralize to pH = 1, separate the layers, and discard the water layer to obtain crude valproic acid; The crude valproic acid obtained above was extracted twice with 100 ml of water, separated into layers, and the washed crude valproic acid was transferred to a 100 ml reaction bottle, then heated to 140° C., low boiling materials were distilled off under reduced pressure, and valproic acid was collected. After the distillation was complete, the distillation was stopped to obtain 54.22 g of valproic acid, with a yield of 94% and a GC of 99.93%.

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