Preparation method of valproic acid

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of valproic acid. The invention provides a valproic acid preparation method. The valproic acid preparation method comprises the following steps: carrying out first mixing on malonic acid diester, allyl halide, an alkaline solution and a first catalyst, and then carrying out allylation reaction to obtain diallyl malonic acid diester; the structural formula of the malonic acid diester is shown in the specification, wherein R is C1-C4 straight-chain alkyl or C3-C4 branched-chain alkyl; carrying out second mixing on the diallyl malonic acid diester, hydrogen, an organic solvent and a second catalyst, and then carrying out hydrogenation reaction to obtain dipropyl malonic acid diester; and hydrolyzing the dipropyl malonic acid diester, and then carrying out decarboxylation to obtain the valproic acid. According to the preparation method provided by the invention, the used preparation raw materials are high in safety, harm to a human body and the environment is reduced, meanwhile, the preparation process is simple and easy to operate, the production safety is greatly improved, the production time is shortened, and the production efficiency is improved.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing valproic acid. Background Technology

[0002] Valproic acid, chemically known as 2-propylvaleric acid, with CAS registration number 99-66-1, is an important pharmaceutical intermediate that can be used to prepare antiepileptic drugs sodium valproate and magnesium valproate, and has broad application prospects in the pharmaceutical industry.

[0003] Valproic acid, as a precursor for the preparation of antiepileptic drugs, has been extensively studied in its preparation methods. For example, in patent US4127604, methyl 2-cyano-2-propylvalerate is prepared using cyanoacetate and bromopropane as starting materials and sodium alkoxide as a base reagent for catalytic reaction. After hydrolysis, acidification, and high-temperature deacidification, valproic acid is obtained. Valproic acid is then hydrolyzed with 80% sulfuric acid to valproamide, and further oxidized by adding nitrous acid to the reaction system to obtain valproic acid. During the reaction, sodium nitrite reacts with an acid, such as sulfuric acid, to generate nitrous acid, which then further decomposes into nitric oxide and nitrogen dioxide. Nitric oxide and nitrogen dioxide are acidic and toxic oxides that not only corrode metal equipment but also cause significant environmental pollution and pose certain risks from an operational perspective. For example, in patent CN111349003A, ethyl valerate is used as the starting material, and a pyrrole metal catalyst is used in an ether solution to produce ethyl 2-propyl-valerate. Then, ethyl 2-propyl-valerate is hydrolyzed with sodium hydroxide to obtain crude sodium valerate. After distillation to remove ethanol and acidification to remove salt, valproic acid is obtained. However, this method uses ether as a solvent, which is somewhat dangerous for industrial application. At the same time, it uses pyrrole metal as a catalyst, which is not common in industry and is also somewhat dangerous.

[0004] In summary, there is an urgent need for a safe production method for valproic acid. Summary of the Invention

[0005] In view of this, the present invention provides a method for preparing valproic acid. The preparation method provided by the present invention has high safety of raw materials, simple and easy-to-operate preparation process, and greatly improves production safety.

[0006] To address the aforementioned technical problems, this invention provides a method for preparing valproic acid, comprising the following steps: Malonate diester, allyl halide, alkaline solution, and a first catalyst are mixed and then subjected to an allylation reaction to obtain diallyl malonate diester; the structural formula of the malonate diester is as follows. , wherein R is a C1~C4 straight-chain alkyl or a C3~C4 branched alkyl; The diallyl malonate, hydrogen, organic solvent, and second catalyst are mixed and then subjected to a hydrogenation reaction to obtain dipropyl malonate. The dipropylmalonic acid diester was hydrolyzed and then decarboxylated to obtain valproic acid.

[0007] Preferably, the allyl halide includes allyl chloride, allyl bromide, or allyl iodide; the molar ratio of the malonate diester to the allyl halide is 1:2 to 20.

[0008] Preferably, the alkaline compound in the alkaline solution includes sodium methoxide, sodium ethoxide, sodium propoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, or potassium carbonate. The solvent in the alkaline solution includes water, methanol, or ethanol; The molar ratio of the malonate diester to the alkaline compound in the alkaline solution is 1:1 to 4.

[0009] Preferably, the first catalyst comprises one or more of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium iodide, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium iodide, tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide, polyethylene glycol, and triethylamine; The molar ratio of the malondiol diester to the first catalyst is 1:0~0.5.

[0010] Preferably, the allylation reaction is carried out in a dynamic tubular reactor; The allylation reaction is carried out at a temperature of 20~140℃, a pressure of 0~10MPa, and a time of 1~60min.

[0011] Preferably, the organic solvent includes methanol, ethanol, acetic acid, tetrahydrofuran, or ethyl acetate; The second catalyst includes palladium on carbon, palladium-silica, palladium-alumina, platinum on carbon, Raney nickel, nickel-silica, or nickel on carbon.

[0012] Preferably, the molar ratio of diallyl malonate to hydrogen is 1:2 to 6.

[0013] Preferably, the hydrogenation reaction is carried out in a fixed bed; The hydrogenation reaction is carried out at a temperature of 20–180 °C, a pressure of 0–10 MPa, and a mass hourly space velocity of 0.1–10 h⁻¹. -1 The stay time is 1 to 60 minutes.

[0014] Preferably, the hydrolysis step may include the following steps: mixing the system after hydrogenation reaction with an alkaline solution in the third step and then refluxing the mixture; concentrating the system after reflux reaction and mixing it with water in the fourth step; adjusting the pH value to ≤1.5 and then filtering the mixture; and washing the obtained solid with water to obtain dipropylmalonic acid.

[0015] Preferably, the decarboxylation temperature is 160~180℃ and the time is 1~3h.

[0016] This invention provides a method for preparing valproic acid, comprising the following steps: mixing malonate diester, allyl halide, alkaline solution, and a first catalyst, followed by an allylation reaction to obtain diallyl malonate diester; the structural formula of the malonate diester is as follows: R is a C1-C4 straight-chain alkyl group or a C3-C4 branched alkyl group. The diallyl malonate, hydrogen, an organic solvent, and a second catalyst are mixed and then subjected to a hydrogenation reaction to obtain dipropyl malonate. The dipropyl malonate is then hydrolyzed and decarboxylated to obtain valproic acid. The preparation method provided by this invention uses highly safe raw materials, reducing harm to human health and the environment. Simultaneously, the preparation process is simple and easy to operate, significantly improving production safety, shortening production time, and increasing production efficiency. Attached Figure Description

[0017] Figure 1 This is a schematic diagram of the reaction process of the preparation method provided by the present invention, wherein R is a C1~C4 straight-chain alkane or a C3~C4 branched-chain alkane; X is Cl, Br or I; Figure 2 The gas chromatogram of valproic acid prepared in Example 1; Figure 3 The gas chromatogram of valproic acid prepared in Example 2 is shown. Figure 4 The gas chromatogram of valproic acid prepared in Example 3; Figure 5 The image shows the gas chromatogram of valproic acid prepared in Example 4. Detailed Implementation

[0018] This invention provides a method for preparing valproic acid, comprising the following steps: Malonate diester, allyl halide, alkaline solution, and a first catalyst are mixed and then subjected to an allylation reaction to obtain diallyl malonate diester; the structural formula of the malonate diester is as follows. , wherein R is a C1~C4 straight-chain alkyl or a C3~C4 branched alkyl; The diallyl malonate, hydrogen, organic solvent, and second catalyst are mixed and then subjected to a hydrogenation reaction to obtain dipropyl malonate. The dipropylmalonic acid diester was hydrolyzed and then decarboxylated to obtain valproic acid.

[0019] Dimalonate, allyl halide, alkaline solution, and a first catalyst are mixed and then subjected to an allylation reaction to obtain diallyl malonate. In this invention, the structural formula of the malonate is as follows: R is a C1-C4 straight-chain alkyl group or a C3-C4 branched alkyl group, specifically methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, or tert-butyl. In embodiments of the present invention, the malonate diester is diethyl malonate.

[0020] In this invention, the allyl halide may include allyl chloride, allyl bromide or allyl iodide; the molar ratio of the malonate diester to the allyl halide may be 1:2 to 20, specifically 1:2.2, 1:3, 1:5, 1:10 or 1:15.

[0021] In this invention, the alkaline compound in the alkaline solution may include sodium methoxide, sodium ethoxide, sodium propoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, or potassium carbonate; the solvent in the alkaline solution may include water, methanol, or ethanol, specifically water or ethanol; the mass concentration of the alkaline solution may be 10-50%, specifically 15%, 20%, 25%, 30%, 35%, 40%, or 45%. In embodiments of this invention, the alkaline solution is an ethanol solution of sodium ethoxide or a methanol solution of sodium methoxide. In this invention, the molar ratio of the malonate diester to the alkaline compound in the alkaline solution may be 1:1-4, specifically 1:1.5, 1:2, 1:2.1, 1:2.3, 1:2.5, 1:3, or 1:3.5.

[0022] In this invention, the first catalyst may include one or more of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium iodide, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium iodide, tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide, polyethylene glycol, and triethylamine, specifically tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium iodide, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium iodide, tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide, polyethylene glycol, or triethylamine; the molar ratio of the malonate diester to the first catalyst may be 1:0~0.5, specifically 1:0.01, 1:0.1, 1:0.15, 1:0.2, 1:0.3, or 1:0.4. In this invention, when the alkaline compound in the alkaline solution is sodium methoxide or sodium ethoxide, a small amount of the first catalyst may be added or no first catalyst may be added.

[0023] In this invention, the allylation reaction is carried out in a dynamic tubular reactor. The first mixing may include the following steps: mixing malonate diester, allyl halide, and a first catalyst to obtain a first mixed solution; and then introducing the first mixed solution and an alkaline solution into the dynamic tubular reactor via a liquid plunger pump. In this invention, the temperature of the allylation reaction can be 20-140°C, or 40-100°C, specifically 30°C, 45°C, 60°C, 70°C, 85°C, 95°C, 110°C, or 130°C; the pressure of the allylation reaction can be 0-10 MPa, specifically 1 MPa, 3 MPa, 5 MPa, or 8 MPa; and the time of the allylation reaction can be 1-60 min, specifically 5 min, 10 min, 15 min, 25 min, 35 min, or 50 min. This invention, by conducting the allylation reaction in a dynamic tubular reactor, enables continuous operation and improves the degree of process automation.

[0024] In this invention, the allylation reaction may further include: filtering the system after the allylation reaction, and subjecting the filtrate to vacuum distillation to obtain the diallyl malonate. This invention does not impose special requirements on the filtration and vacuum distillation; conventional methods in the art can be used.

[0025] After obtaining diallyl malonate, the present invention further involves mixing the diallyl malonate, hydrogen, an organic solvent, and a second catalyst, and then subjecting the mixture to a hydrogenation reaction to obtain dipropyl malonate. In this invention, the organic solvent may include methanol, ethanol, acetic acid, tetrahydrofuran, or ethyl acetate; the second catalyst may include a palladium-on-carbon catalyst, palladium-silica, palladium-alumina, platinum-on-carbon catalyst, Raney nickel, nickel-silica, or nickel-on-carbon catalyst. In the embodiments of this invention, the second catalyst is a 5% palladium-on-carbon catalyst. In this invention, the molar ratio of diallyl malonate to hydrogen can be 1:2 to 6, specifically 1:2.2, 1:3, 1:4, or 1:5.

[0026] In this invention, the hydrogenation reaction is carried out in a fixed bed; the fixed bed can be a fully automated fixed bed hydrogenation device, purchased from Ousheng Beijing Technology Co., Ltd. H-Flow-S10, with a reactor volume of approximately 5.6 mL; the second mixing may include the following steps: filling a second catalyst into the fixed bed, mixing the diallyl malonate and an organic solvent to obtain a diallyl malonate solution; and separately introducing the diallyl malonate solution and hydrogen into the fixed bed for mixing.

[0027] In this invention, the temperature of the hydrogenation reaction can be 20~180℃, or 60~160℃, specifically 50℃, 90℃, 100℃, or 130℃; the pressure of the hydrogenation reaction can be 0~10MPa, specifically 2MPa, 4MPa, 5MPa, or 8MPa; and the mass hourly space velocity of the fixed bed can be 0.1~10h. -1 Specifically, 1 hour -1 2h -1 2.5h -1 4h -1 5h -1 or 8h -1 The residence time in the fixed bed can be 1~60 min, or 5~20 min, specifically 5 min, 10 min, 15 min, or 20 min. In this invention, the mass hourly space velocity (MHV) is the ratio of the feed mass flow rate (kg·h) to the catalyst mass (kg).

[0028] After obtaining dipropylmalonate diester, the present invention hydrolyzes the dipropylmalonate diester and then decarboxylates it to obtain valproic acid. In the present invention, the hydrolysis step may include the following steps: mixing the system after hydrogenation reaction with an alkaline solution in a third step and then refluxing the mixture; concentrating the refluxed system and mixing it with water in a fourth step; adjusting the pH value to ≤1.5 and then filtering; washing the obtained solid with water to obtain dipropylmalonate. In the present invention, the alkaline solution may include potassium hydroxide solution or sodium hydroxide solution; the mass concentration of the alkaline solution may be 10-50%, specifically 20%, 30%, 40%, or 45%; the molar ratio of the alkaline substance to dipropylmalonate diester in the alkaline solution may be 2-4:1, specifically 2.2:1, 2.5:1, or 3:1. In the present invention, the reflux reaction time may be 3-5 hours, specifically 4 hours.

[0029] This invention does not impose any particular limitation on the concentration method; conventional methods in the art can be used. This invention also does not impose any particular limitation on the fourth mixture, as long as complete dissolution is achieved. This invention can adjust the pH value to ≤1.5 (specifically 1) by adding an acidic solution. The acidic solution may include hydrochloric acid solution, and the mass concentration of the acidic solution can be 20-36%, specifically 25%, 30%, or 35%. This invention does not impose any particular limitation on the amount of the acidic solution used, as long as the desired pH value is achieved.

[0030] In this invention, the decarboxylation temperature can be 160~180℃, specifically 165℃, 170℃ or 175℃; the decarboxylation time can be 1~3h, specifically 1h, 1.5h, 2h or 2.5h.

[0031] This invention employs a dynamic tubular reactor for alkylation and a fully automated fixed-bed hydrogenation device for hydrogenation, achieving continuous production, effectively avoiding the safety risks of these two hazardous chemical processes, shortening reaction time, and greatly improving production efficiency.

[0032] Figure 1 This is a schematic diagram of the reaction process of the preparation method provided by the present invention, in which R is a C1~C4 straight-chain alkane or a C3~C4 branched-chain alkane; X is Cl, Br or I.

[0033] In this invention, the decarboxylation process may further include: distilling the decarboxylation system to obtain valproic acid; the distillation temperature may be 120~170℃, specifically 130℃, 140℃, 150℃ or 160℃.

[0034] The preparation method provided by this invention has the advantages of high safety factor, high production efficiency and high product purity, and is suitable for industrial production.

[0035] To further illustrate the present invention, the technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention.

[0036] Example 1 Diethyl malonate, 3-chloropropene, and tetrabutylammonium bromide were mixed thoroughly in a molar ratio of 1:2.2:0.01 to obtain a mixed solution. A dynamic tubular reactor (Huasi Instruments DTR3600, 100 mL capacity) was set at 85℃, a back pressure valve pressure of 1.0 MPa, and a rotation speed of 500 rpm. The mixed solution and a 20% sodium ethoxide ethanol solution (diethyl malonate to sodium ethoxide molar ratio of 1:2.3) were separately introduced into the dynamic tubular reactor via liquid plunger pumps for allylation reaction. The reaction time was approximately 15 min. The outflowing liquid was filtered and distilled under reduced pressure to obtain diallyl diethyl malonate.

[0037] A 5% palladium-on-carbon catalyst was pre-loaded into a fully automated fixed-bed hydrogenation unit (H-Flow-S10, Beijing Oushang Technology Co., Ltd., reactor volume approximately 5.6 mL). The preheater temperature was set at 80℃, the fixed-bed reaction temperature at 90℃, and the reaction pressure at 2 MPa. Diallyl malonate and anhydrous ethanol were mixed at a mass ratio of 1:2.0. The mixed solution was then pumped into the fully automated fixed-bed hydrogenation unit (hydrogenation reactor) via a liquid plunger pump and mixed with hydrogen (molar ratio of diallyl malonate to hydrogen 1:3.0, reaction time 5 min, mass hourly space velocity 2.5 h⁻¹). -1 The hydrogenation reaction is carried out to obtain diethyl dipropylmalonate.

[0038] 3.00 kg of an ethanolic solution of diethyl dipropylmalonate obtained from the hydrogenation reaction (the system after the hydrogenation reaction) and 1.31 kg of a 45% potassium hydroxide solution (the molar ratio of potassium hydroxide to diethyl dipropylmalonate is 2.5:1) were added to a reaction vessel and refluxed for 4 h. The mixture was then concentrated to near dryness under normal pressure, and 3.50 kg of water was added. The pH was adjusted to 1 with a 30% hydrochloric acid solution. The mixture was filtered, and the solid obtained from the filtration was washed with an appropriate amount of water to obtain dipropylmalonic acid. The dipropylmalonic acid was added to a reaction vessel, heated to 175 °C, and kept at this temperature for 1 h (decarboxylation). The mixture was then distilled at 140–60 °C to obtain valproic acid.

[0039] The chromatogram of valproic acid prepared by gas chromatography is shown below. Figure 2 As shown, the specific results are listed in Table 1.

[0040] Table 1. Gas chromatographic detection results of valproic acid prepared in Example 1

[0041] In Example 1, the total yield of valproic acid was 85.5%, and the purity was 99.984%.

[0042] Example 2 Valproic acid was prepared according to the method of Example 1, except that the 5% palladium on carbon catalyst in the hydrogenation reaction was replaced with 5% palladium-silica; the total yield of valproic acid obtained was 84%, and the purity was 99.978%.

[0043] The chromatogram of valproic acid prepared by gas chromatography is shown below. Figure 3 As shown, the specific results are listed in Table 2.

[0044] Table 2. Gas chromatographic detection results of valproic acid prepared in Example 2

[0045] Example 3 Valproic acid was prepared according to the method of Example 1, except that diethyl malonate was replaced with dimethyl malonate in the allylation reaction process, and the ethanol solution of sodium ethoxide with a mass concentration of 20% was replaced with the methanol solution of sodium methoxide with a mass concentration of 30%. The total yield of valproic acid obtained was 82%, and the purity was 99.966%.

[0046] The chromatogram of valproic acid prepared by gas chromatography is shown below. Figure 4 As shown, the specific results are listed in Table 3.

[0047] Table 3. Gas chromatographic detection results of valproic acid prepared in Example 3

[0048] Example 4 Valproic acid was prepared according to the method of Example 1, except that the 5% palladium on carbon catalyst in the hydrogenation reaction was replaced with 15% nickel-silica; the preheater temperature was set to 115°C, the fixed bed reaction temperature to 120°C, and the mass hourly space velocity to 1.2; the total yield of valproic acid obtained was 75%, and the purity was 99.982%.

[0049] The chromatogram of valproic acid prepared by gas chromatography is shown below. Figure 5 As shown, the specific results are listed in Table 4.

[0050] Table 4. Gas chromatographic detection results of valproic acid prepared in Example 4

[0051] As can be seen from the gas chromatography detection results of Examples 1-4, valproic acid can be prepared according to the preparation method provided by the present invention, and it has high purity and yield.

[0052] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for preparing valproic acid, characterized in that, Includes the following steps: Malonate diester, allyl halide, alkaline solution, and a first catalyst are mixed and then subjected to an allylation reaction to obtain diallyl malonate diester; the structural formula of the malonate diester is as follows. , wherein R is a C1~C4 straight-chain alkyl or a C3~C4 branched alkyl; The diallyl malonate, hydrogen, organic solvent, and second catalyst are mixed and then subjected to a hydrogenation reaction to obtain dipropyl malonate. The dipropylmalonic acid diester was hydrolyzed and then decarboxylated to obtain valproic acid.

2. The preparation method according to claim 1, characterized in that, The allyl halide includes allyl chloride, allyl bromide, or allyl iodide; the molar ratio of the malonate diester to the allyl halide is 1:2 to 20.

3. The preparation method according to claim 1, characterized in that, The alkaline compounds in the alkaline solution include sodium methoxide, sodium ethoxide, sodium propoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydroxide, potassium hydroxide, or potassium carbonate. The solvent in the alkaline solution includes water, methanol, or ethanol; The molar ratio of the malonate diester to the alkaline compound in the alkaline solution is 1:1 to 4.

4. The preparation method according to claim 1, characterized in that, The first catalyst comprises one or more of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium iodide, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium iodide, tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide, polyethylene glycol, and triethylamine; The molar ratio of the malondiol diester to the first catalyst is 1:0~0.

5.

5. The preparation method according to any one of claims 1 to 4, characterized in that, The allylation reaction is carried out in a dynamic tubular reactor; The allylation reaction is carried out at a temperature of 20~140℃, a pressure of 0~10MPa, and a time of 1~60min.

6. The preparation method according to claim 1, characterized in that, The organic solvent includes methanol, ethanol, acetic acid, tetrahydrofuran, or ethyl acetate; The second catalyst includes palladium on carbon, palladium-silica, palladium-alumina, platinum on carbon, Raney nickel, nickel-silica, or nickel on carbon.

7. The preparation method according to claim 1, characterized in that, The molar ratio of diallyl malonate to hydrogen is 1:2~6.

8. The preparation method according to claim 1, 6, or 7, characterized in that, The hydrogenation reaction is carried out in a fixed bed; The hydrogenation reaction is carried out at a temperature of 20–180 °C, a pressure of 0–10 MPa, and a mass hourly space velocity of 0.1–10 h⁻¹. -1 The stay time is 1 to 60 minutes.

9. The preparation method according to claim 1, characterized in that, The hydrolysis step may include the following steps: mixing the system after hydrogenation reaction with an alkaline solution in the third step and then refluxing the mixture; concentrating the system after reflux reaction and mixing it with water in the fourth step; adjusting the pH value to ≤1.5 and then filtering the mixture; and washing the obtained solid with water to obtain dipropylmalonic acid.

10. The preparation method according to claim 1, characterized in that, The decarboxylation temperature is 160~180℃, and the time is 1~3h.

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