A method for preparing an antiepileptic drug, magnesium valproate

Abstract

The present application relates to the preparation method of magnesium valproate shown in chemical structural formula I: under the action of potassium carbonate and PTC, dimethyl malonate is subjected to dipropylization with 1-chloropropane in DMF solvent to prepare dimethyl dipropyl malonate shown in formula III; III is subjected to hydrolysis reaction to prepare dipropyl malonic acid shown in formula II; II is uniformly mixed with magnesium oxide, and heated to prepare magnesium valproate shown in formula I by decarboxylation, and the total yield of magnesium valproate is not less than 90.0%; the preparation reaction is as follows: wherein, the PTC for dipropylization is selected from quaternary ammonium salt, the reaction temperature is 50-140 DEG C, the reaction time is 4.0-14.0 h; the hydrolysis temperature is 70-95 DEG C, the time is 2.0-4.0 h; the decarboxylation temperature is 140-158 DEG C, and the time is 3.0-5.0 h.

Description

Technical Field

[0001] This invention relates to the pharmaceutical industry, specifically to the preparation of the antiepileptic drug magnesium valproate using the dimethyl malonate method. Background Technology

[0002] Jiujiang Desi Optoelectronic Materials Co., Ltd. [Wang Feiqiang, Fan Yunlong. A method for preparing dialkyl dimethyl malonate, CN115304481A, 2022.11.08] describes the reaction of dimethyl malonate with 1-bromohexane, 1-bromoheptane and 1-bromooctane in tert-butanol under the action of potassium tert-butoxide to prepare dihexyl dimethyl malonate, diheptyl dimethyl malonate and dioctyl dimethyl malonate, respectively, with a crude yield of 91% to 92%.

[0003]

[0004] The dimethyl malonate method for preparing valproic acid currently mainly uses 1-bromopropane as an alkylating agent and sodium alkoxide as a base to undergo dipropylation in alcohols; however, 1-bromopropane is expensive, and sodium alkoxide is a strong base.

[0005] Fu Jinguang [Improvement of the synthesis process of sodium valproate. Shandong Chemical Industry, 2012, 41(10):3-4] selected dimethyl malonate, reacted with 1-bromopropane under the catalysis of PEG-400 and the action of sodium methoxide, and then hydrolyzed with sodium hydroxide to prepare dipropylmalonic acid. The latter was heated to decarboxylate and finally formed into salt to obtain sodium valproate.

[0006]

[0007] Tao Jing et al. [Preparation method of dipropylmalonate. Chinese Invention Patent CN103183612A, 2013-07-03; A method for preparing 2-propylvaleric acid, CN103183599B, ​​2015-04-01] describe a method for preparing valeric acid; they describe the reaction of dimethyl malonate and 1-bromopropane in tert-butanol under the action of potassium tert-butoxide to prepare dimethyl dipropylmalonate, with a crude yield of 90.5%.

[0008]

[0009] One method was selected to prepare valproic acid using methyl malonate propyl ester and 1-chloropropane as raw materials. In this method, dipropyl methyl malonate propyl ester was prepared by dipropylation reaction with 1-chloropropane as an alkylating agent. The crude product yield was 70.5%.

[0010]

[0011] Valproic acid is prepared from 1-chloropropane. However, due to the low reactivity of 1-chloropropane, the dipropylation reaction to prepare dipropylmalonic acid diester has a low yield (70.5%), which is a technical challenge in the production process.

[0012] The decarboxylation of dipropylmalonic acid to valproic acid at high temperature is one of the key steps in the process. This method requires decarboxylation at high temperatures of 160-190°C, which results in high energy consumption, low safety, and the production of byproducts such as valproic anhydride at high temperatures.

[0013] In 1984, Li Xinyuan et al. [Synthesis of valproic acid antiepileptic drugs by solid-liquid phase transfer catalytic reaction. Pharmaceutical Industry, 1984, 5: 4-6] selected methyl cyanoacetate, 1-bromopropane and solid potassium carbonate, and dipropylated them under quaternary ammonium salt catalysis, followed by hydrolysis, decarboxylation and salt formation to prepare sodium / magnesium valproate or valproamide.

[0014]

[0015] Hunan University [Preparation, Hydrolysis and Application of Dimethyl Dipropylmalonate, CN118373737A, published 2024.7.23] selected dimethyl malonate to undergo dipropylation with 1-chloropropane to prepare dimethyl dipropylmalonate of formula III; formula III was hydrolyzed by potassium hydroxide catalysis to prepare dipropylmalonic acid of formula II; and formula II was decarboxylated at 160-180℃ to prepare valproic acid.

[0016]

[0017] Magnesium valproate is mainly used as an antiepileptic and antimanic drug. Magnesium valproate itself has certain toxic side effects, which mainly manifest as gastrointestinal symptoms such as nausea, vomiting, diarrhea, and loss of appetite, followed by adverse reactions such as muscle weakness, limb tremors, ataxia, drowsiness, confusion, or coma.

[0018] Hunan Xiangzhong Pharmaceutical Co., Ltd. [a magnesium valproate sustained-release tablet and its preparation process, CN201711306377X; magnesium valproate injection and its preparation process, CN201110130586X; magnesium valproate sustained-release tablet and its preparation process, ZL001133403] has successfully developed magnesium valproate sustained-release tablets and magnesium valproate injection. Summary of the Invention

[0019] The purpose of this invention is to provide a method for preparing magnesium valproate as shown in chemical structural formula I: characterized in that, in DMF solvent, under the action of potassium carbonate and PTC, dimethyl malonate reacts with 1-chloropropane to undergo dipropylation to prepare dimethyl dipropylmalonate as shown in formula III; formula III is then hydrolyzed to prepare dipropylmalonic acid as shown in formula II; formula II is mixed uniformly with magnesium oxide and heated for decarboxylation to prepare magnesium valproate as shown in formula I, with a total yield of magnesium valproate not less than 90.0% (based on dimethyl malonate); the preparation reaction is as follows:

[0020]

[0021] The PTC used for dipropylation is selected from quaternary ammonium salts; the amount of PTC catalyst used for dipropylation is selected from a molar ratio of dimethyl malonate to PTC catalyst of 1:0.001 to 0.05; the reaction temperature for dipropylation is selected from 50℃ to 140℃; the reaction time for dipropylation is selected from 4.0h to 14.0h; the amount of feed used for dipropylation is selected from a molar ratio of dimethyl malonate to 1-chloropropane of 1:2.0 to 2.5; and the amount of potassium carbonate used for dipropylation is selected from a molar ratio of dimethyl malonate to potassium carbonate of 1:1.10 to 1.90.

[0022] The hydrolysis temperature was selected from 70℃ to 95℃; the hydrolysis reaction time was selected from 2.0h to 4.0h.

[0023] The decarboxylation temperature is selected from 140℃ to 158℃; the decarboxylation reaction time is selected from 3.0h to 5.0h.

[0024] This invention also provides a method for processing magnesium valproate as shown in chemical formula I, the process flow of which is as follows: Figure 1 As shown.

[0025] Figure 1 The middle filtrate 1 was distilled under reduced pressure to recover DMF and recycled; the inorganic salts were combined with filtrate 3 and then concentrated, crystallized and dried to recover potassium chloride. Attached Figure Description

[0026] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0027] Figure 1 Process flow for preparing magnesium valproate

[0028] Compared with the prior art, the present invention has the following advantages:

[0029] (1) Magnesium valproate was prepared by a dimethyl malonate phase transfer catalyst, and the preparation reaction is as follows:

[0030]

[0031] Among them, the first one-pot method was used to achieve decarboxylation and salt formation.

[0032] (2) Magnesium oxide was selected as the catalyst for the decarboxylation of dipropylmalonic acid for the first time; the decarboxylation reaction was carried out at 140℃~158℃; the decarboxylation byproduct valproic anhydride could be avoided at high temperature (160℃~180℃).

[0033] Detailed Implementation

[0034] The present invention will be further described in detail below with reference to the embodiments.

[0035] Example 1

[0036] Preparation of dipropylmalonic acid

[0037] (1) Add 3.0 mmol TBAB and 50 mL DMF to a three-necked flask and stir with an electric stirrer. Then add 0.15 mol potassium carbonate (200 mesh) and 13.2 g (0.10 mol) dimethyl malonate. Add 19.64 g (0.25 mol) 1-chloropropane dropwise. Stir the reaction at 75℃~130℃ for 12.0 h and recover the excess 1-chloropropane (to be reused next time). After the reaction is complete, cool to room temperature and filter. The filter cake is an inorganic base salt (KCl and KHCO3). Filtrate 1 is a pale yellow liquid. Add 60 mL methanol to the filter cake and reflux to slurry the inorganic salt (1-2 times). Filter to obtain filtrate 2. Use the filter cake to recover potassium chloride. Combine filtrate 2 and filtrate 1, and recover methanol by atmospheric distillation. Then recover DMF by vacuum distillation at 80℃~90℃ (to be recycled). The residue is then subjected to hydrolysis of dimethyl dipropyl malonate.

[0038] (2) Add potassium hydroxide aqueous solution (KOH 16g, H2O 16mL) and 10mL methanol to dimethyl dipropylmalonic acid, heat to 90℃ for 3h, and hydrolyze to obtain solid by rotary evaporation. Add 50mL of water to dissolve the solid, adjust the pH to 1-1.5 with concentrated hydrochloric acid, and solid precipitates out. Filter, combine the filtrate with the filter cake from (1), concentrate, crystallize and dry to recover KCl; the solid is dimethylmalonic acid with a melting point of 157-158℃.

[0039] Example 2

[0040] Preparation of magnesium valproate

[0041]

[0042] The dipropylmalonic acid obtained in Example 1 was mixed evenly with 2.0 g of magnesium oxide and added to a round-bottom flask. The mixture was decarboxylated at 140–158 °C for 3 h to obtain 14 g of magnesium valproate, with a total yield of 90.0% (based on dimethyl malonate).

[0043] In this specification, the invention has been described with reference to specific embodiments thereof. However, it will be apparent that various modifications and variations can be made without departing from the spirit and scope of the invention. Therefore, this specification should be considered illustrative rather than restrictive.

Claims

1. A method for preparing a compound represented by chemical structural formula I, characterized in that... In DMF solvent, dimethyl malonate undergoes a dipropylation reaction with 1-chloropropane in the presence of potassium carbonate and PTC to prepare dimethyl dipropylmalonate; dimethyl dipropylmalonate is then hydrolyzed to prepare dipropylmalonic acid; dipropylmalonic acid is then mixed with magnesium oxide and heated for decarboxylation to prepare the compound shown in Formula I; the preparation reaction is as follows: Among them, PTC is selected from quaternary ammonium salts; the dipropylation reaction temperature is selected from 50℃ to 140℃; the dipropylation reaction time is selected from 4.0h to 14.0h; the hydrolysis temperature is selected from 70℃ to 95℃; the hydrolysis reaction time is selected from 2.0h to 4.0h; the decarboxylation temperature is selected from 140℃ to 158℃; and the decarboxylation reaction time is selected from 3.0h to 5.0h.

2. The method for preparing the compound represented by Formula I as described in claim 1, characterized in that... The specific steps are as follows: (1) Add 3.0 mmol tetrabutylammonium bromide and 50 mL DMF to a three-necked flask and stir with an electric stirrer. Then add 0.15 mol 200 mesh potassium carbonate, 13.2 g dimethyl malonate, and 19.64 g 1-chloropropane. Stir the reaction at 75℃~130℃ for 12.0 h and recover excess 1-chloropropane. After the reaction is complete, cool to room temperature and filter. The filter cake is an inorganic alkali salt. Filtrate 1 is a pale yellow liquid. Add 60 mL methanol to the filter cake and reflux to remove inorganic salts. Filter to obtain filtrate 2. Use the filter cake to recover potassium chloride. Combine filtrate 2 with filtrate 1 and distill at atmospheric pressure to recover methanol. Then recover DMF under reduced pressure at 80℃~90℃ and reuse. The residue is used for subsequent hydrolysis of dimethyl dipropyl malonate. (2) Add 32g of 50% potassium hydroxide aqueous solution and 10 mL of methanol to the pale yellow liquid of dipropylmalonic acid, heat to 90℃ for 3 h for hydrolysis, and rotary evaporate to obtain solid; add 50 mL of water to dissolve the solid, adjust the pH to 1~1.5 with concentrated hydrochloric acid, and solid precipitates out, filter; combine the filtrate with the filter cake in (1), concentrate, crystallize and dry to recover KCl; the solid is dipropylmalonic acid; (3) Mix the dipropylmalonic acid obtained in step (2) with 2.0 g of magnesium oxide, add it to a round-bottom flask, and decarboxylate at 140~158℃ for 3 h to obtain 14 g of the compound shown in Formula I.

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