Preparation method of 2-cyano-2-propyl valerate and valproic acid

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 2-cyano-2-propyl valerate and valproic acid. The preparation method of the 2-cyano-2-propyl valerate comprises the following steps: mixing cyanoacetate, 1-halopropane, a catalyst and a non-protonic solvent to carry out a first propylation reaction, and mixing the obtained 2-cyanovalerate, 1-halopropane, the catalyst and a protonic solvent to carry out a second propylation reaction to obtain the 2-cyano-2-propyl valerate, the temperature of the second propylation reaction is 80-90 DEG C. The propylation is carried out step by step, the aprotic solvent is used in the first propylation reaction, the speed of the side reaction ester exchange reaction can be reduced, the protic solvent is used in the second propylation reaction, the reaction activity is enhanced, the reaction temperature is reduced to 80-90 DEG C, and the occurrence probability of the side reaction ester exchange is greatly reduced; and the purity (more than 99%) and the yield of the 2-cyano-2-propyl valerate are improved.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a method for preparing 2-cyano-2-propyl valerate and valproic acid. Background Art

[0002] Sodium valproate is a drug for treating epilepsy, and can also be used to treat bipolar disorder and prevent migraine. The main ingredients of sodium valproate sustained-release tablets are sodium valproate and valproic acid, and sodium valproate is obtained by salting valproic acid.

[0003] The synthetic route of valproic acid (2-propylpentanoic acid) mainly includes the following three types according to the starting materials: ① Using cyanoacetic acid ester as the starting material, dipropylation with halogenated propane, and then ester hydrolysis, decarboxylation, and nitrile hydrolysis; ② Using acetoacetic acid ester as the starting material, dipropylation with halogenated propane, and then ester hydrolysis and sodium alcohol deacetylation; ③ Using malonic acid ester as the starting material, dipropylation with halogenated propane, and then ester hydrolysis and decarboxylation. Among them, using cyanoacetic acid ester as the starting material is more common, for example, using methyl cyanoacetate (or ethyl cyanoacetate), 1-bromopropane and solid potassium carbonate, dipropylation (80-110°C) under the catalysis of quaternary ammonium salt to prepare the intermediate methyl 2-cyano-2-propylpentanoate (or ethyl ester), and then ester hydrolysis, decarboxylation, and nitrile hydrolysis.

[0004]

[0005] Impurities in valproic acid (or sodium valproate) APIs may include 2-methylvaleric acid (L) or 2-ethylvaleric acid (B), as well as 2-isopropylvaleric acid (C), 2-propylvaleramide (F), 2-propylhexanoic acid (X), etc. The presence of impurities will affect the efficacy and even be toxic to the human body. As pharmacological tests have shown, 2-methylvaleric acid (L) is vascular irritant, which will cause sodium valproate injection to be vascular irritant.

[0006] As a key intermediate in the preparation of valproic acid, the quality of 2-cyano-2-propyl valerate plays a decisive role in the process of preparing valproic acid using cyanoacetate as the starting material. At present, the preparation of the intermediate 2-cyano-2-propyl valerate by dipropylation using cyanoacetate as the starting material has the problems of high impurity content and low purity. The impurities in the intermediate will be further transferred to the final product valproic acid, affecting the yield and purity of valproic acid. Summary of the invention

[0007] In view of this, the object of the present invention is to provide a method for preparing 2-cyano-2-propyl valerate and valproic acid. The preparation method of the present invention can produce 2-cyano-2-propyl valerate with high purity and yield and less impurities, and further produce valproic acid with high purity and high yield.

[0008] The present invention provides a method for preparing 2-cyano-2-propyl valerate, comprising the following steps:

[0009] Mixing cyanoacetate, a first 1-halopropane, a first propylation catalyst and a first organic solvent to perform a first propylation reaction to obtain 2-cyanovaleric acid ester; the first organic solvent is an aprotic solvent;

[0010] The 2-cyanovaleric acid ester, the second 1-halopropane, the second propylation catalyst and the second organic solvent are mixed to carry out a second propylation reaction to obtain 2-cyano-2-propyl valeric acid ester; the second organic solvent is a protic solvent, and the temperature of the second propylation reaction is 80-90° C.;

[0011] The first propylation catalyst and the second propylation catalyst independently include a heteropolyacid salt, a phase transfer catalyst and a surfactant.

[0012] Preferably, the aprotic solvent comprises toluene and / or xylene.

[0013] Preferably, the protic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide.

[0014] Preferably, the mass ratio of the heteropolyacid salt to the phase transfer catalyst is 0.01-0.03:1; the mass ratio of the sum of the mass of the heteropolyacid salt and the phase transfer catalyst to the surfactant is (0.9-1.2):(0.3-0.6).

[0015] Preferably, the heteropolyacid salt includes one or more of ammonium phosphomolybdate, sodium phosphomolybdate, ammonium phosphotungstate and sodium phosphotungstate; the phase transfer catalyst includes one or more of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium iodide, dodecyltrimethylammonium chloride, dodecyltrimethylammonium bromide, dodecyltrimethylammonium iodide, hexadecyltrimethylammonium chloride, hexadecyltrimethylammonium bromide and hexadecyltrimethylammonium iodide.

[0016] Preferably, the surfactant comprises polyethylene glycol, and the polyethylene glycol comprises PEG400, PEG600 or PEG1000.

[0017] Preferably, the temperature of the first propylation reaction is 60-120° C., and the reaction time is 4-8 hours.

[0018] Preferably, the first 1-halopropane and the second 1-halopropane are both 1-chloropropane.

[0019] The present invention also provides a method for preparing valproic acid, comprising the following steps:

[0020] 2-cyano-2-propyl valerate is obtained according to the preparation method of 2-cyano-2-propyl valerate described in the above technical scheme;

[0021] The 2-cyano-2-propyl valerate is subjected to ester hydrolysis to obtain 2-cyano-2-propyl valeric acid;

[0022] Decarboxylating the 2-cyano-2-propylpentanoic acid to obtain 2-propylpentanenitrile;

[0023] The 2-propylvaleronitrile is subjected to nitrile hydrolysis to obtain valproic acid.

[0024] Preferably, the decarboxylation is as follows: the 2-cyano-2-propylpentanoic acid, toluene and 4-dimethylaminopyridine are mixed and heated; the heating temperature is 110-130° C. and the heating time is 5 hours.

[0025] Compared with the prior art, the present invention has the following beneficial effects:

[0026] The invention provides a method for preparing 2-cyano-2-propyl valerate, comprising the following steps: mixing cyanoacetate, a first 1-halopropane, a first propylation catalyst and a first organic solvent for a first propylation reaction to obtain 2-cyano valerate; the first organic solvent is an aprotic solvent; mixing the 2-cyano valerate, a second 1-halopropane, a second propylation catalyst and a second organic solvent for a second propylation reaction to obtain 2-cyano-2-propyl valerate; the second organic solvent is a protic solvent, and the temperature of the second propylation reaction is 80-90 DEG C; the first propylation catalyst and the second propylation catalyst independently comprise a heteropolyacid salt, a phase transfer catalyst and a surfactant.

[0027] The present invention performs propylation in steps. In the first propylation reaction, an aprotic solvent is used to reduce the speed of the side reaction transesterification reaction. In the second propylation reaction, a protic solvent is selected to enhance the reaction activity, and the reaction temperature is reduced to 80-90° C., so that the probability of the side reaction transesterification is greatly reduced. Combined with the use of the propylation catalyst of the present invention, the preparation method of the present invention reduces the occurrence of side reactions such as transesterification, reduces the amount of by-products that may be produced thereby, and improves the purity of the intermediate (2-cyano-2-propyl valerate), all of which are above 99%, and the yield is high. The present invention reduces the generation of 2-cyano-2-methyl (or ethyl) valerate, thereby reducing the source of 2-ethyl valerate (B) or 2-methyl valerate (L) in valproic acid, and the obtained valproic acid has high purity and yield.

[0028] Furthermore, the present invention adopts cyanoacetate and 1-halopropane to complete the propylation method under the co-catalysis of heteropolyacid salt, phase transfer catalyst and surfactant, thereby reducing the reaction temperature and controlling the occurrence of some side reactions; the present invention uses 1-chloropropane as a raw material, and the source of 1-chloropropane is abundant and the price is low, which is conducive to reducing the production cost.

[0029] The present invention also provides a method for preparing valproic acid. Furthermore, in the preparation process of 2-propylvaleronitrile, toluene is used as a solvent and a catalyst 4-dimethylaminopyridine (DMAP) is added, which can reduce the decarboxylation temperature to 110° C. to 130° C., greatly reduce the generation of high-temperature by-products, ensure product quality, and improve product yield.

[0030] The preparation method of the present invention can obtain an intermediate (2-cyano-2-propyl valerate) and a final product (valproic acid) with high purity, high yield and good quality. The production cost of the raw material medicine can be reduced by at least 20 yuan / kg compared with the current preparation process cost, and more than 5 million yuan can be saved annually. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0032] Figure 1 It is the 2-cyano-2-propylpentanoic acid (methyl cyanoacetate method) high performance liquid chromatography of Example 1;

[0033] Figure 2 The HPLC chromatogram of 2-cyano-2-propylpentanoic acid (ethyl cyanoacetate method) of Example 2;

[0034] Figure 3 It is the gas chromatogram of 2-propylvaleronitrile (ethyl cyanoacetate method) of Example 4;

[0035] Figure 4 It is the gas chromatogram of 2-propylpentanoic acid (ethyl cyanoacetate method) of Example 5;

[0036] Figure 5 It is the gas chromatogram of 2-propyl valeric acid (methyl cyanoacetate method) of Example 6;

[0037] Figure 6 It is the high performance liquid chromatography diagram of 2-cyano-2-propylpentanoic acid (original methyl cyanoacetate method) of Comparative Example 1;

[0038] Figure 7The HPLC chromatogram of 2-cyano-2-propylpentanoic acid (ethyl orthocyanoacetate method) of Comparative Example 2 is shown;

[0039] Figure 8 The gas chromatogram of 2-propylvaleronitrile (ethyl orthocyanoacetate method) of Comparative Example 4 is shown;

[0040] Fig. 9 The gas chromatogram of 2-propylpentanoic acid (ethyl orthocyanoacetate method) of Comparative Example 5;

[0041] Fig.10 The gas chromatogram of 2-propylpentanoic acid (methyl cyanoacetate method) of Comparative Example 6;

[0042] Fig.11 The gas chromatogram of ethyl 2-cyano-2-propylpentanoate (unmodified) of Comparative Example 2;

[0043] Fig.12 The gas chromatogram of ethyl 2-cyano-2-propylpentanoate (after improvement) of Example 2;

[0044] Fig.13 It is the liquid phase chromatogram of methyl 2-cyano-2-propylpentanoate (methyl cyanoacetate method) of Comparative Example 7;

[0045] Fig.14 This is the liquid chromatogram of 2-cyano-2-propylpentanoic acid (methyl cyanoacetate method) of Comparative Example 7. DETAILED DESCRIPTION

[0046] The present invention provides a method for preparing 2-cyano-2-propyl valerate, comprising the following steps:

[0047] Mixing cyanoacetate, a first 1-halopropane, a first propylation catalyst and a first organic solvent to perform a first propylation reaction to obtain 2-cyanovaleric acid ester; the first organic solvent is an aprotic solvent;

[0048] The 2-cyanovaleric acid ester, the second 1-halopropane, the second propylation catalyst and the second organic solvent are mixed to carry out a second propylation reaction to obtain 2-cyano-2-propyl valeric acid ester; the second organic solvent is a protic solvent, and the temperature of the second propylation reaction is 80-90° C.;

[0049] The first propylation catalyst and the second propylation catalyst independently include a heteropolyacid salt, a phase transfer catalyst and a surfactant.

[0050] In the present invention, unless otherwise specified, the materials and equipment used are commercially available products in the art.

[0051] The present invention mixes cyanoacetate, a first 1-halopropane, a first propylation catalyst and a first organic solvent to carry out a first propylation reaction to obtain 2-cyanovaleric acid ester; the first organic solvent is a non-protonic solvent.

[0052] In the present invention, the cyanoacetate preferably includes methyl cyanoacetate, ethyl cyanoacetate, propyl cyanoacetate, isopropyl cyanoacetate, butyl cyanoacetate, tert-butyl cyanoacetate or pentyl cyanoacetate, and the structural formula of the cyanoacetate is shown below:

[0053]

[0054] In the formula, R is selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl or pentyl.

[0055] In the present invention, the first 1-halopropane preferably includes 1-chloropropane.

[0056] In the present invention, the molar ratio of the cyanoacetate to the first 1-halopropane is preferably 1:1 to 1.2, more preferably 1:1.1.

[0057] In the present invention, the first propylation catalyst comprises a heteropolyacid salt, a phase transfer catalyst and a surfactant;

[0058] The heteropolyacid salt preferably includes one or more of ammonium phosphomolybdate, sodium phosphomolybdate, ammonium phosphotungstate and sodium phosphotungstate;

[0059] The phase transfer catalyst preferably includes one or more of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium iodide, dodecyltrimethylammonium chloride, dodecyltrimethylammonium bromide, dodecyltrimethylammonium iodide, hexadecyltrimethylammonium chloride, hexadecyltrimethylammonium bromide and hexadecyltrimethylammonium iodide;

[0060] The mass ratio of the heteropoly acid salt to the phase transfer catalyst is preferably 0.01 to 0.03:1, more preferably 0.02:1;

[0061] The surfactant preferably includes polyethylene glycol, and the polyethylene glycol preferably includes PEG400, PEG600 or PEG1000. The mass ratio of the sum of the mass of the heteropolyacid salt and the phase transfer catalyst to the surfactant is preferably (0.9-1.2):(0.3-0.6), and can be specifically 1.02:0.4.

[0062] In the present invention, the molar ratio of the cyanoacetate to the first propylation catalyst is preferably 1:0.01-0.02.

[0063] In the present invention, the first organic solvent preferably includes toluene and / or xylene, and toluene is more preferred. The use of aprotic solvents in the first propylation of the present invention can slow down the transesterification rate and reduce the generation of transesterification impurities.

[0064] In the present invention, when the cyanoacetic acid ester, the first 1-halopropane, the first propylation catalyst and the first organic solvent are mixed, preferably an alkali metal carbonate or an alkali metal hydroxide is added, the alkali metal carbonate or the alkali metal hydroxide is an acid binding agent, the alkali metal carbonate preferably includes sodium carbonate or potassium carbonate, more preferably potassium carbonate, the alkali metal hydroxide preferably includes sodium hydroxide or potassium hydroxide; the particle size of the potassium carbonate (K2CO3) is preferably 100 mesh, 200 mesh or 300 mesh, more preferably 200 mesh or 300 mesh. The molar ratio of the cyanoacetic acid ester to the alkali metal carbonate is preferably 1:0.6-1.2, more preferably 1:0.6-1, specifically 1:0.6, 1:0.8 or 1:1.

[0065] In the present invention, the temperature of the first propylation reaction is preferably 60 to 120°C, more preferably 80 to 110°C, specifically 80, 100°C or 110°C; the reaction time is preferably 4 to 8 hours, more preferably 4 to 6 hours. Taking 1-chloropropane as an example, cyanoacetate is subjected to the first propylation reaction in K2CO3, a catalyst and a solvent toluene, and the reaction formula is shown below:

[0066]

[0067] In the present invention, after the first propylation reaction, the method preferably further includes: separating the obtained reaction liquid into solid and liquid, and removing the first organic solvent from the obtained liquid; the method of the solid-liquid separation is preferably filtration, and the method of removing the first organic solvent is preferably reduced pressure distillation.

[0068] After obtaining 2-cyanovaleric acid ester, the present invention mixes the 2-cyanovaleric acid ester, a second 1-halopropane, a second propylation catalyst and a second organic solvent to carry out a second propylation reaction to obtain 2-cyano-2-propyl valeric acid ester; the second organic solvent is a protic solvent, and the temperature of the second propylation reaction is 80-90°C.

[0069] In the present invention, the second 1-halopropane is of the same type as the first 1-halopropane, and will not be described in detail herein.

[0070] In the present invention, the molar ratio of the 2-cyanovaleric ester to the 1-halopropane is preferably 1:1 to 1.2, more preferably 1:1.1.

[0071] In the present invention, the second propylation catalyst preferably has the same composition as the first propylation catalyst, which will not be described in detail herein.

[0072] In the present invention, the molar ratio of the 2-cyanovaleric ester to the second propylation catalyst is preferably 1:0.01-0.02.

[0073] In the present invention, the second organic solvent preferably includes one or more of N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DME) and dimethyl sulfoxide (DMSO), and more preferably DMF. During the second propylation, since the reaction resistance increases, the present invention selects a protic solvent to enhance the reaction activity.

[0074] In the present invention, when the 2-cyanovaleric acid ester, the second 1-halopropane, the second propylation catalyst and the second organic solvent are mixed, preferably an alkali metal carbonate or an alkali metal hydroxide is added, the alkali metal carbonate preferably includes sodium carbonate or potassium carbonate, more preferably potassium carbonate, and the alkali metal hydroxide preferably includes sodium hydroxide or potassium hydroxide; the particle size of the potassium carbonate (K2CO3) is preferably 100 mesh, 200 mesh or 300 mesh, more preferably 200 mesh or 300 mesh. The molar ratio of the 2-cyanovaleric acid ester to the alkali metal carbonate is preferably 1:0.6-1.2, more preferably 1:0.6-1, specifically 1:0.6, 1:0.7, 1:0.8 or 1:1.

[0075] In the present invention, the temperature of the second propylation reaction is 80-90°C, and the time is preferably 2-5 hours, more preferably 3 hours; the present invention reduces the reaction temperature to 80-90°C, so that the probability of transesterification is greatly reduced, and the generation of impurities is reduced. Taking 1-chloropropane as an example, 2-cyanovaleric acid ester undergoes a second propylation reaction in K2CO3, a catalyst and a solvent DMF, and the reaction formula is shown below:

[0076]

[0077] In the present invention, the second propylation reaction preferably further comprises: solid-liquid separation of the obtained reaction liquid, removal of the second organic solvent from the obtained liquid, and washing; the solid-liquid separation method is preferably filtration, and the removal of the second organic solvent is preferably reduced pressure distillation.

[0078] The present invention also provides a method for preparing valproic acid, comprising the following steps:

[0079] 2-cyano-2-propyl valerate is obtained according to the preparation method of 2-cyano-2-propyl valerate described in the above technical scheme;

[0080] The 2-cyano-2-propyl valerate is subjected to ester hydrolysis to obtain 2-cyano-2-propyl valeric acid;

[0081] Decarboxylating the 2-cyano-2-propylpentanoic acid to obtain 2-propylpentanenitrile;

[0082] The 2-propylvaleronitrile is subjected to nitrile hydrolysis to obtain valproic acid.

[0083] The present invention hydrolyzes the 2-cyano-2-propyl valeric acid ester to obtain 2-cyano-2-propyl valeric acid.

[0084] In the present invention, the ester hydrolysis is preferably carried out in an alkaline solution, and the alkaline solution preferably includes a potassium hydroxide solution or a sodium hydroxide solution. The concentration of the potassium hydroxide solution is preferably 10 wt %.

[0085] In the present invention, the temperature of the ester hydrolysis is preferably 60-80°C, and the time is preferably 3 hours. After the ester hydrolysis, the process preferably further comprises: recovering the alcohol under reduced pressure, adjusting the pH value of the remaining liquid to 1, and the precipitated solid is 2-cyano-2-propylpentanoic acid.

[0086] After obtaining 2-cyano-2-propylpentanoic acid, the present invention decarboxylates 2-cyano-2-propylpentanoic acid to obtain 2-propylvaleronitrile.

[0087] In the present invention, the decarboxylation temperature is preferably 110-130° C., more preferably 110-120° C., and the decarboxylation time is preferably 5 hours.

[0088] In the present invention, the decarboxylation is preferably: the 2-cyano-2-propyl valeric acid, an organic solvent and a catalyst are mixed to carry out a decarboxylation reaction; the organic solvent is preferably toluene, the catalyst is preferably 4-dimethylaminopyridine (DMAP), and the mass ratio of the 2-cyano-2-propyl valeric acid to the catalyst is preferably 100:5. The present invention uses toluene as a solvent and adds the catalyst DMAP, which can reduce the decarboxylation temperature to 110°C to 130°C, greatly reducing the degree of generation of high-temperature by-products, ensuring product quality, and improving yield.

[0089] After obtaining 2-propylvaleronitrile, the present invention performs nitrile hydrolysis on the 2-propylvaleronitrile to obtain valproic acid.

[0090] In the present invention, the nitrile hydrolysis is preferably carried out in a 60-80% sulfuric acid solution, the temperature of the nitrile hydrolysis is preferably 120-160° C., more preferably 130-140° C., and the time is preferably 12-36 h, more preferably 24 h.

[0091] Taking ester hydrolysis in potassium hydroxide solution and nitrile hydrolysis in sulfuric acid solution as an example, the reaction formula for preparing 2-cyano-2-propyl valeric acid from 2-cyano-2-propyl valeric acid ester, then to 2-propyl valeronitrile, and finally to valproic acid (2-propyl valeric acid) is as shown below:

[0092]

[0093] In order to further illustrate the present invention, the preparation methods of 2-cyano-2-propyl valerate and valproic acid provided by the present invention are described in detail below in conjunction with the accompanying drawings and examples, but they should not be construed as limiting the scope of protection of the present invention.

[0094] In the following Examples 1, 3 and 6, valproic acid (2-propyl valeric acid) was prepared according to the methyl cyanoacetate method, and the reaction formula is shown below:

[0095]

[0096] In the following Examples 2, 4 and 5, valproic acid (2-propyl valeric acid) was prepared according to the ethyl cyanoacetate method, and the reaction formula is shown below:

[0097]

[0098] Example 1

[0099] 1. Preparation of methyl 2-cyanovalerate:

[0100] In a dry and clean 2L reactor, add 99.1g (1mol) methyl cyanoacetate (anhydrous), 3.024g catalyst (mass ratio of ammonium phosphomolybdate: TPAB: PEG1000 = 0.02:1:0.4, total molar number 0.01mol), 110.4g (0.8mol) K2CO3 (300 mesh), 300mL toluene, 86.35g (1.1mol) 1-chloropropane. After the addition, set the oil bath temperature to 110℃ and react for 4h under stirring (LC monitors the reaction endpoint, methyl cyanoacetate ≤1%). After the reaction, cool to below 45℃, filter, wash the filter cake until it turns white, and drain. The filtrate was decompressed to recover toluene (-0.08 MPa) and then continued to be heated to distill (150°C) until almost no distillation was produced, to obtain 136.9 g of colorless liquid methyl 2-cyanovalerate with a yield of 97% (based on methyl cyanoacetate) and a GC purity of 99.12%.

[0101] Methyl 2-cyanovalerate: 1 H NMR (400MHz, DMSO-d6) δ: 3.72 (s, 3H, OCH3), 2.78 (s, 1H, CH), 1.59-1.50 (m, 2H, CH2), 1.35-1.30 (m, 2H, CH2), 0.89 (t, J=7.2Hz, 3H, CH3).

[0102] 2. Preparation of methyl 2-cyano-2-propylpentanoate:

[0103] Add 3.024g of catalyst (mass ratio of ammonium phosphomolybdate: TPAB: PEG1000 = 0.02:1:0.4, total molar number 0.01mol), 138g (1.0mol) of K2CO3 (300 mesh), 300mL of DMF, and 86.35g (1.1mol) of 1-chloropropane to the above-obtained methyl 2-cyanovalerate. After the addition, stir and then react at 90°C (oil bath) for 3h (LC monitors the reaction endpoint, monosubstituted product ≤1%). After the reaction, cool to below 45°C, filter, wash the filter cake until it turns white, and drain. The filtrate was recovered under reduced pressure until almost no distillation was produced, and the temperature was lowered to below 30° C., petroleum ether (300 mL) was added for dilution, the organic phase was washed with 10 wt % NaOH solution, and then washed with water, the petroleum ether was recovered under normal pressure, and then distilled under reduced pressure to obtain 168.86 g of colorless transparent liquid 2-cyano-2-propylpentanoic acid methyl ester, with a yield of 95% (based on methyl cyanoacetate) and a GC purity of 99.23%.

[0104] Methyl 2-cyano-2-propylpentanoate: 1 H NMR (400MHz, 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=7.2Hz, 6H, CH3×2).

[0105] 3. Preparation of 2-cyano 2-propyl valeric acid (2-cyano valeric acid):

[0106] 10 wt% KOH solution was added to methyl 2-cyano-2-propylpentanoate, and the mixture was hydrolyzed at 60°C for 3 h. After methanol was recovered under reduced pressure, 100 mL of water was added, and concentrated hydrochloric acid (about 130 mL) was added dropwise under ice bath to neutralize the mixture to pH 1. A white solid was precipitated, and the mixture was filtered and dried to obtain 168.64 g of monohydrated 2-cyano-2-propylpentanoic acid as a white solid. The yield was 97.74%, and the HPLC purity was 99.75%. Figure 1 High performance liquid chromatogram of 2-cyano-2-propylpentanoic acid (methyl cyanoacetate method).

[0107] 2-Cyano-2-propylpentanoic acid: 1 HNMR (400MHz, DMSO-d6) δ: 13.76 (s, 1H, CO2 H), 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=7.2Hz, 6H, CH3×2).

[0108] Example 2

[0109] 1. Preparation of ethyl 2-cyanovalerate:

[0110] In a dry and clean 2L reactor, add 113.1g (1mol) ethyl cyanoacetate (anhydrous), 3.024g catalyst (mass ratio of ammonium phosphomolybdate: TPAB: PEG1000 = 0.02:1:0.4, total molar number 0.01mol), 110.4g (0.8mol) K2CO3 (300 mesh), 300mL toluene, 86.35g (1.1mol) 1-chloropropane. After the addition, set the oil bath temperature to 110°C and react for 4h under stirring (LC monitors the reaction end point, ethyl cyanoacetate ≤1%). After the reaction, cool to below 45°C, filter, wash the filter cake until it is white, and drain. After the filtrate is decompressed to recover toluene, continue to heat and distill until there is basically no distillation, and obtain 152.1g of colorless liquid ethyl 2-cyanovalerate, with a yield of 98% (based on ethyl cyanoacetate) and a GC purity of 99.20%.

[0111] Ethyl 2-cyanovalerate: 1 HNMR (400MHz, DMSO-d6) δ: 4.24 (q, J=7.2Hz, 2H, OCH2), 2.78 (s, 1H, CH), 1.59-1.50 (m, 2H, CH2), 1.35-1.30 (m, 2H, CH2), 0.89 (t, J=7.2Hz, 3H, CH3).

[0112] 2. Preparation of ethyl 2-cyano-2-propyl valerate:

[0113] Add 3.024g of catalyst (mass ratio of ammonium phosphomolybdate: TPAB: PEG1000 = 0.02:1:0.4, total molar number 0.01mol), 138g (1.0mol) of K2CO3 (300 mesh), 300mL of DMF, and 86.35g (1.1mol) of 1-chloropropane to the above-obtained ethyl 2-cyanovalerate. After the addition, stir and then react at 90°C (oil bath) for 3h (LC monitors the reaction endpoint, monosubstituted product ≤1%). After the reaction, cool to below 45°C, filter, wash the filter cake until it turns white, and drain. The filtrate was recovered under reduced pressure until almost no distillation was produced, and the temperature was lowered to below 30° C., petroleum ether (300 mL) was added for dilution, the organic phase was washed with 10 wt % NaOH solution, and then washed with water, the petroleum ether was recovered under normal pressure, and then distilled under reduced pressure to obtain 185.6 g of colorless transparent liquid 2-cyano-2-propylpentanoic acid ethyl ester, with a yield of 96% (based on ethyl cyanoacetate) and a GC purity of 99.54%.

[0114] Ethyl 2-cyano-2-propylpentanoate: 1HNMR (400MHz, DMSO-d6) δ: 4.22 (q, J=7.2Hz, 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=7.2Hz, 6H, CH3×2).

[0115] 3. Preparation of 2-cyano-2-propylpentanoic acid:

[0116] 10 wt% KOH solution was added to ethyl 2-cyano-2-propylpentanoate, and the mixture was hydrolyzed at 60°C for 3 h. After ethanol was recovered under reduced pressure, 100 mL of water was added, and concentrated hydrochloric acid (about 130 mL) was added dropwise under ice bath to neutralize the mixture to pH 1. A white solid was precipitated, and the mixture was filtered and dried to obtain 173.63 g of monohydrated 2-cyano-2-propylpentanoic acid as a white solid. The yield was 98.54%, and the HPLC purity was 99.96%. Figure 2 High performance liquid chromatogram of 2-cyano-2-propylpentanoic acid (ethyl cyanoacetate method).

[0117] 2-Cyano-2-propylpentanoic acid: 1 HNMR (400MHz, DMSO-d6) δ: 13.76 (s, 1H, CO2 H), 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=7.2Hz, 6H, CH3×2).

[0118] Example 3 Preparation of 2-propylvaleronitrile

[0119]

[0120] 300g toluene, 175g (wet weight) 2-cyano-2-propyl valeric acid prepared in Example 1, and 5% DMAP based on the mass of 2-cyano-2-propyl valeric acid were added to the decarboxylation distillation flask in sequence, heated to 50°C, separated, and washed with 50mL×2 water. After the separation, the oil bath temperature was adjusted to 120°C. After the water was evaporated, the internal temperature was controlled to be 110°C for decarboxylation and heat preservation reaction for 5h. After the decarboxylation, low boiling products were collected to an internal temperature of 180°C, and normal boiling products were collected. Normal boiling products were collected under normal pressure until the internal temperature was 210°C without distillate, and then the pressure was reduced (gradually increasing the vacuum degree, -0.085MPa) and collected until the internal temperature was 210°C. No distillate was distilled out as the collection end point.

[0121] 113.3 g of colorless transparent liquid was obtained with a yield of 90.5% (based on methyl cyanoacetate) and a GC purity of 98.03%.

[0122] Example 4 Preparation of 2-propylvaleronitrile

[0123] The difference from Example 3 is that the 2-cyano-2-propylpentanoic acid prepared in Example 2 is used, and the other steps are the same.

[0124] 115.32 g of colorless transparent liquid was obtained, with a yield of 92.10% (based on ethyl cyanoacetate) and a GC purity of 98.23%. Figure 3 Gas chromatogram of 2-propylvaleronitrile.

[0125] 2-Propylvaleronitrile: 1 HNMR (400MHz, DMSO-d6) δ: 2.78 (s, 1H, CH), 1.54-1.37 (m, 4H, CH2×2), 1.34-1.28 (m, 4H, CH2×2), 0.89 (t, J=7.2Hz, 6H, CH3×2).

[0126] Example 5 Preparation of 2-propylvaleric acid

[0127]

[0128] 86 g of water was added to a 500 mL reaction bottle, 170 g (1.7 mol) of 98% concentrated sulfuric acid was slowly added while cooling, the internal temperature was controlled below 60° C., 100 g of 2-propylvaleronitrile (0.7987 mol, prepared by the ethyl cyanoacetate method) obtained in Example 4 was added, the temperature was slowly raised to 130±4° C., and kept warm for 24±2 h. During this period, the reaction endpoint was monitored by HPLC. When valproamide ≤0.5%, the reaction was considered complete.

[0129] After the reaction, cool to 40°C, slowly add 100g water, separate layers, discard the water layer, wash the organic layer once with 50g water; transfer the washed organic layer to a reaction bottle, slowly add 25% sodium hydroxide aqueous solution (1.15eq sodium hydroxide), keep warm at 60°C for 0.5h, the reaction is completed, and a sodium valproate aqueous solution is generated. The solution is cooled to 30°C, extracted twice with 100mL of dichloromethane, and 56g of concentrated sulfuric acid (concentration 98%) is slowly added to the water layer to neutralize to pH = 1, separate layers, and discard the water layer to obtain crude valproic acid.

[0130] 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 250 mL reaction bottle, and then heated to 140° C., and low-boiling substances were distilled off under reduced pressure, and then valproic acid was collected. After the distillation was complete, the distillation was stopped to obtain 108.27 g of valproic acid, with a yield of 94% and a GC purity of 99.97%. Figure 4 Gas chromatogram of 2-propylvaleric acid (ethyl cyanoacetate method).

[0131] Among them, GC purity is detected according to the method of Example 15 in the Chinese patent with application number "202311045024.9" and name "A method for detecting impurities in preparing valproic acid by methyl cyanoacetate method".

[0132] 2-Propylvaleric acid: 1 HNMR (400MHz, DMSO-d6) δ: 11.99 (s, 1H, COOH), 2.24-2.18 (m, 1H, CH), 1.54-1.44 (m, 2H , CH2), 1.39-1.34 (m, 2H, CH2), 1.32-1.22 (m, 4H, CH2×2), 0.86 (t, J=7.2Hz, 6H, CH3×2).

[0133] Example 6 Preparation of 2-propylvaleric acid

[0134] 43 g of water was added to a 250 mL reaction bottle. Under oil bath cooling, 85 g (0.84 mol) of 98% concentrated sulfuric acid was slowly added to control the internal temperature below 60°C. Then 50 g (0.4 mol, prepared by the methyl cyanoacetate method) of 2-propylvaleronitrile obtained in Example 3 was added. The temperature was slowly raised to 130±4°C and kept warm for 24±2 h. During this period, the reaction endpoint was monitored by HPLC. When valproamide ≤0.5%, the reaction was considered complete.

[0135] After the reaction is completed, the temperature is lowered to 40°C, 50g of water is slowly added, the layers are separated, the water layer is discarded, and the organic layer is washed once with 50g of water; the washed organic layer is transferred to a reaction bottle, 73.33g of a 25% sodium hydroxide aqueous solution (1.15eq of sodium hydroxide) is slowly added, and the temperature is kept at 60°C for 0.5h, and the reaction is completed to generate a sodium valproate aqueous solution. The solution is cooled to 30°C, extracted twice with 50mL of dichloromethane, the organic layer is collected for treatment, 28g of concentrated sulfuric acid (98%) is slowly added to the water layer to neutralize to pH = 1, the layers are separated, and the water layer is discarded to obtain a crude valproic acid.

[0136] 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 bottle, heated to 140°C, and low-boiling substances were distilled off under reduced pressure, and valproic acid was collected. After distillation was complete, the distillation was stopped to obtain 53.55 g of valproic acid, with a yield of 93% and a GC purity of 99.91%. Figure 5 Gas chromatogram of 2-propylvaleric acid (methyl cyanoacetate method).

[0137] The detection was performed according to the method of Example 15 in the Chinese patent with application number "202311045024.9" and titled "A method for detecting impurities in preparing valproic acid by the methyl cyanoacetate method".

[0138] In the following Comparative Examples 1, 3 and 6, valproic acid (2-propyl valeric acid) is prepared according to the original methyl cyanoacetate method. When the dipropylation reaction (preparation of methyl 2-cyano-2-propyl valeric acid) is carried out, transesterification is easily carried out to generate 2-cyano-2-methyl propyl valerate, and then generate 2-methyl valeric acid, which exists in 2-propyl valeric acid. The reaction formula is shown below:

[0139]

[0140] In the following Comparative Examples 2, 4 and 5, valproic acid (2-propyl valeric acid) is prepared according to the ethyl cyanoacetate method. When the dipropylation reaction (preparation of ethyl 2-cyano-2-propyl valeric acid) is carried out, transesterification is easily carried out to generate 2-cyano-2-ethyl valeric acid propyl ester, and then generate 2-ethyl valeric acid, which exists in 2-propyl valeric acid. The reaction formula is shown below:

[0141]

[0142] Comparative Example 1 Preparation of 2-cyano-2-propylvaleric acid methyl ester and 2-cyano-2-propylvaleric acid

[0143]

[0144] In a 2L reactor, add 99.1g (1.0mol) methyl cyanoacetate, 6g TBAB, 1.18g potassium bromide, 263.2g (1.9mol) K2CO3 (300 mesh), 400mL (377.6g) DMF, 180g (2.29mol) 1-chloropropane (the content of 2-chloropropane and 1-chlorobutane is less than 0.03%). After the addition, set the oil bath temperature to 75°C and react for 2h under stirring. The color of the reaction liquid gradually darkens, and then stir and react at 95°C (oil bath) for 3h (LC monitors the reaction endpoint, monosubstituted product ≤3%); after the reaction, cool to below 45°C, filter, wash the filter cake until it is white, and drain. The filtrate was recovered under reduced pressure until almost no distillation was produced, the temperature was lowered to below 30° C., 300 mL of petroleum ether was added, the organic phase was washed with 10% NaOH solution and then with water, the petroleum ether was recovered under normal pressure, and then distilled under reduced pressure to obtain 164.93 g of methyl 2-cyano-2-propylpentanoate as a colorless transparent liquid with a yield of 90% (based on methyl cyanoacetate) and a purity of 97.36% (GC).

[0145] 10 wt% KOH solution was added to methyl 2-cyano-2-propylpentanoate, and the mixture was hydrolyzed at 60°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, and the mixture was filtered and dried to obtain 162.9 g of monohydrated 2-cyano-2-propylpentanoic acid as a white solid. The yield was 96.67%, and the HPLC purity was 99.62%. Figure 6 HPLC chromatogram of 2-cyano-2-propylpentanoic acid (methyl cyanoacetate method).

[0146] Comparative Example 2 Preparation of 2-cyano-2-propylvaleric acid ethyl ester and 2-cyano-2-propylvaleric acid

[0147]

[0148] In a 2L reactor, add 113.1g (1.0mol) ethyl cyanoacetate, 6g TEAB, 1.18g potassium bromide, 207g (1.5mol) K2CO3 (300 mesh), 283g DMF, and 172.7g (2.2mol) 1-chloropropane in sequence. After the addition, stir and react at 85°C (oil bath) for 2h, then heat to 100°C (oil bath) and stir and react for 3h (LC monitors the reaction endpoint). After the reaction, cool to below 45°C, filter, wash the filter cake with recovered DMF until it turns white, and drain. The filtrate was recovered under reduced pressure until almost no distillation was produced, the temperature was lowered to below 30° C., petroleum ether was added, the organic phase was washed with 10% NaOH solution and then with water, the petroleum ether was recovered under normal pressure, and then distilled under reduced pressure to obtain 180.01 g of ethyl 2-cyano-2-propylpentanoate as a colorless transparent liquid with a yield of 91.25% (based on ethyl cyanoacetate) and a purity of 97.98% (GC).

[0149] 10 wt% NaOH solution was added to ethyl 2-cyano-2-propylpentanoate, and the mixture was hydrolyzed at 60°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, and the mixture was filtered and dried to obtain 166.53 g of monohydrated 2-cyano-2-propylpentanoic acid as a white solid. The yield was 97.47%, and the HPLC purity was 99.76%. Figure 7 .

[0150] Comparative Example 3 Preparation of 2-propylvaleronitrile

[0151]

[0152] 180g (wet weight) of 2-cyano-2-propylpentanoic acid prepared in Comparative Example 1 was added to a decarboxylation distillation flask, and the oil bath temperature was adjusted to 140°C. After the water was evaporated, the internal temperature was raised to 130°C for decarboxylation and heat preservation reaction for 3 hours. After the decarboxylation was completed, low boiling products were collected until the internal temperature was 180°C, and normal boiling products were collected instead. Normal boiling products were collected under normal pressure until the internal temperature was 210°C and no distillate was produced. The pressure was reduced again (the vacuum degree was gradually increased, -0.085MPa) and the products were collected until the internal temperature was 210°C. No distillate was produced, which was the end point of the collection.

[0153] 107.3 g of colorless transparent liquid was obtained with a yield of 85.7% (based on methyl cyanoacetate) and a GC purity of 93.34%.

[0154] Comparative Example 4

[0155] The difference from Comparative Example 3 is that 2-cyano-2-propylpentanoic acid prepared in Comparative Example 2 is used, and the remaining steps are the same.

[0156] 112.54 g of colorless transparent liquid was obtained, with a yield of 89.09% (based on ethyl cyanoacetate) and a GC purity of 93.34%. Figure 8 .

[0157] Comparative Example 5 Preparation of Valproic Acid

[0158]

[0159] The difference from Example 6 is that 2-propylvaleronitrile (prepared by the ethyl orthocyanoacetate method) prepared in Comparative Example 4 is used, and the remaining steps are the same.

[0160] 52.98 g of valproic acid was obtained with a yield of 92% and a GC purity of 99.93%. Fig. 9 .

[0161] Comparative Example 6 Preparation of Valproic Acid

[0162] The difference from Example 6 is that 2-propylvaleronitrile (prepared by the methyl cyanoacetate method) obtained in Comparative Example 3 is used, and the remaining steps are the same.

[0163] 53 g of valproic acid was obtained with a yield of 92% and a GC purity of 99.89%. Fig.10 .

[0164] Fig.11 The gas chromatogram of ethyl 2-cyano-2-propylpentanoate (unmodified) of Comparative Example 2; Fig.12 The gas chromatogram of ethyl 2-cyano-2-propyl valerate (after improvement) of Example 2. After improvement, the purity of ethyl 2-cyano-2-propyl valerate is 99.54%, while the purity of the unimproved one is only 97.98%, and the number of impurities is reduced from 18 in the unimproved one to 3, and the maximum single impurity is reduced from 1.18% in the unimproved one to 0.23%, and the product quality is significantly improved.

[0165] Table 1 is a summary table of the results of the embodiments and comparative examples:

[0166] Table 1 Summary of results of examples and comparative examples

[0167]

[0168]

[0169] It can be seen from Table 1 above that the valproic acid intermediate (2-cyano-2-propyl valeric acid) and valproic acid prepared by the improved method not only have better quality, lower impurity content, fewer impurity types, but also higher yield. Taking the ethyl cyanoacetate method as an example, the total yield reached 86.57%, which is significantly improved compared to the total yield of 81.96% of the original method.

[0170] Comparative Example 7 Preparation of 2-cyano-2-propylpentanoic acid

[0171] In a dry and clean 500mL three-necked flask, add 29.7g (0.3mol) methyl cyanoacetate (anhydrous), 1.6g (6mmol) TPAB (anhydrous), 91.2g (0.66mol) K2CO3 (300 mesh), 120g DMF (anhydrous), 54.2g (0.69mol) 1-chloropropane, stirred and heated to 70℃ for 2h, the reaction solution gradually darkened in color, and then stirred at 105℃ (oil bath) for 3h (LC monitoring reaction end point, when the monosubstituted product ≤3%, the reaction was considered complete), after the reaction, cooled, added 600mL of water to dissolve the solid inorganic salt, extracted with petroleum ether (150mL×3), washed with water until the organic phase was light yellow, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to recover petroleum ether to obtain 49.48g of light yellow transparent liquid 2-cyano-2-propyl valeric acid methyl ester, with a yield of 90%, HPLC purity of 70.93%, and an impurity 2-cyano-2-methyl valeric acid ester content of 9.19%, see Fig.13 .

[0172] 10% NaOH solution (140 g) was added to the crude product of methyl 2-cyano-2-propylpentanoate, and the mixture was hydrolyzed at 60°C for 3 h. Methanol was recovered by rotary evaporation, and 90 mL of water was added. Concentrated hydrochloric acid was added under ice bath to neutralize the mixture to pH 1. A white solid was precipitated, and the mixture was filtered and dried to obtain 50.55 g of 2-cyano-2-propylpentanoic acid monohydrate as a white solid with a yield of 90% and a HPLC purity of 92.27%. The content of 2-cyano-2-methylpentanoic acid was 6.22%. Fig.14 .

[0173] Compared with Comparative Example 1, the dipropylation temperature in Comparative Example 7 is increased, and the content of the impurity 2-cyano-2-methylvaleric acid ester is increased, which in turn increases the content of the impurity 2-cyano-2-methylvaleric acid in 2-cyano-2-propyl valeric acid.

[0174] Although the above-mentioned embodiments have made a detailed description of the present invention, they are only some embodiments of the present invention, rather than all embodiments. People can also obtain other embodiments based on the embodiments of the present invention without creative work, and these embodiments all fall within the scope of protection of the present invention.

Claims

1. A method for preparing 2-cyano-2-propyl valerate, characterized in that: The following steps are involved: Mixing cyanoacetate, a first 1-halopropane, a first propylation catalyst and a first organic solvent to perform a first propylation reaction to obtain 2-cyanovaleric acid ester; the first organic solvent is an aprotic solvent; The 2-cyanovaleric acid ester, the second 1-halopropane, the second propylation catalyst and the second organic solvent are mixed to carry out a second propylation reaction to obtain 2-cyano-2-propyl valeric acid ester; the second organic solvent is a protic solvent, and the temperature of the second propylation reaction is 80-90° C.; The first propylation catalyst and the second propylation catalyst independently include a heteropolyacid salt, a phase transfer catalyst and a surfactant.

2. The preparation method according to claim 1, characterized in that: The aprotic solvent includes toluene and / or xylene.

3. The preparation method according to claim 1, characterized in that: The protic solvent includes one or more of N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide.

4. The preparation method according to claim 1, characterized in that: The mass ratio of the heteropolyacid salt to the phase transfer catalyst is 0.01-0.03:1; the mass ratio of the sum of the mass of the heteropolyacid salt and the phase transfer catalyst to the surfactant is (0.9-1.2):(0.3-0.6).

5. The preparation method according to claim 1 or 4, characterized in that: The heteropolyacid salt includes one or more of ammonium phosphomolybdate, sodium phosphomolybdate, ammonium phosphotungstate and sodium phosphotungstate; the phase transfer catalyst includes one or more of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium iodide, dodecyltrimethylammonium chloride, dodecyltrimethylammonium bromide, dodecyltrimethylammonium iodide, hexadecyltrimethylammonium chloride, hexadecyltrimethylammonium bromide and hexadecyltrimethylammonium iodide.

6. The preparation method according to claim 1 or 4, characterized in that: The surfactant includes polyethylene glycol, and the polyethylene glycol includes PEG400, PEG600 or PEG1000.

7. The preparation method according to claim 1, characterized in that: The temperature of the first propylation reaction is 60-120° C., and the reaction time is 4-8 hours.

8. The preparation method according to claim 1, characterized in that: The first 1-halopropane and the second 1-halopropane are both 1-chloropropane.

9. A method for preparing valproic acid, characterized in that: The following steps are involved: 2-Cyano-2-propyl valerate is obtained by the preparation method of 2-cyano-2-propyl valerate according to any one of claims 1 to 8; The 2-cyano-2-propyl valeric acid ester is subjected to ester hydrolysis to obtain 2-cyano-2-propyl valeric acid; Decarboxylating the 2-cyano-2-propylpentanoic acid to obtain 2-propylpentanenitrile; The 2-propylvaleronitrile is subjected to nitrile hydrolysis to obtain valproic acid.

10. The method for preparing valproic acid according to claim 9, characterized in that: The decarboxylation comprises: mixing and heating the 2-cyano-2-propylpentanoic acid, toluene and 4-dimethylaminopyridine; the heating temperature is 110-130° C. and the heating time is 5 hours.

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