A process for the preparation of the valproic acid intermediate dipropyl malonic acid diethyl ester

Abstract

The application discloses a method for preparing a valproic acid intermediate, diethyl dipropylmalonate, and belongs to the technical field of medicines. The method comprises the following steps: adding a compound shown in formula III, a compound shown in formula A, a base and a phase transfer catalyst into an amide solvent to react, so as to obtain a compound shown in formula I. The method can significantly reduce the content of a propylmalonic acid diethyl ester impurity in the product, and the content of the propylmalonic acid diethyl ester impurity is controlled to be less than or equal to 0.17%. The diethyl dipropylmalonate prepared by the method has a purity of greater than or equal to 98.16% and a yield of greater than or equal to 85%. The method is economical and environment-friendly, simple and convenient to operate, low in cost, safe and controllable, and suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a method for preparing diethyl dipropylmalonate, an intermediate of valproic acid, and a method for preparing valproic acid and its salts. Background Technology

[0002] Valproic acid (VPA) is a first-line, broad-spectrum antiepileptic drug used to treat various types of epilepsy, including petit mal seizures, myoclonic seizures, generalized seizures, partial motor seizures, absence seizures, and infantile spasms. In addition to its antiepileptic effects, valproic acid is also used to treat manic episodes associated with bipolar disorder. With advancements in valproic acid research, more effective valproate-containing drugs with fewer adverse reactions have been developed, such as sodium valproate and magnesium valproate.

[0003] Currently, numerous publications report methods for preparing valproic acid and its salts. For example, US Patent Document US5101070 discloses a process for preparing sodium valproate, with the following reaction route:

[0004]

[0005] This route uses methyl acetoacetate as a raw material, and proceeds through chloropropylene alkylation, Raney nickel reduction, deacetylation, and ester hydrolysis to prepare valproic acid, followed by salt formation to prepare sodium valproate. This process uses Raney nickel reduction, which is flammable, posing a significant risk for industrial production. Furthermore, the route is lengthy and unsuitable for industrial application.

[0006] Chinese patent application number 201310018398.7 discloses a method for preparing sodium valproate, the reaction route of which is as follows:

[0007]

[0008] This process uses diethyl malonate and 1-bromopropane as raw materials, and produces sodium valproate through a four-step reaction involving alkylation, hydrolysis, decarboxylation, and salt formation. This process avoids the use of Raney nickel reduction, reducing the risks associated with industrial production. However, this process easily generates a monoalkylated substitution impurity: diethyl propyl malonate. This impurity is transferred to the target product in subsequent reactions, forming a new impurity in the target product: valproic acid and its salts. This affects the quality of the target product, valproic acid and its salts, thus impacting the efficacy and safety of the drug. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines on impurity studies for new active pharmaceutical ingredients stipulate that for drugs with a maximum daily dose of the main ingredient of 2g or less, the limit for any single non-specific impurity in the active pharmaceutical ingredient quality standard must not exceed the identification limit (0.1%). According to ICH requirements, valproic acid, as a non-specific impurity, cannot exceed 0.1% in valproic acid drugs.

[0009] In the above methods, diethyl dipropylmalonate is a key intermediate in the preparation of valproic acid and its salts. Developing a new method for preparing diethyl dipropylmalonate, reducing the content of diethyl dipropylmalonate impurities in the product, is of great significance for improving the efficacy and safety of valproic acid and its salts in pharmaceuticals. Summary of the Invention

[0010] One object of the present invention is to provide a novel method for preparing the intermediate dipropylmalonate diethyl ester, which can significantly reduce the content of dipropylmalonate diethyl ester impurities in the product.

[0011] Another objective of this invention is to provide a novel method for preparing valproic acid and its salts, which can significantly reduce the content of valproic acid impurities in the product and improve the efficacy and safety of the drug.

[0012] This invention provides a method for preparing the compound shown in Formula I, the method comprising the following steps:

[0013]

[0014] The compound shown in Formula III, the compound shown in Formula A, a base, and a phase transfer catalyst were added to an amide solvent and reacted to obtain the compound shown in Formula I.

[0015] In formula A, X is a halogen.

[0016] Furthermore, the molar ratio of the compound shown in Formula III to the compound shown in Formula A is 1:(2-3); the molar ratio of the compound shown in Formula III to the base is 1:(2-5); the molar ratio of the compound shown in Formula III to the phase transfer catalyst is 1:(0.001-0.100); and the mass-volume ratio of the compound shown in Formula III to the amide solvent is 1:(3-20) g / mL.

[0017] And / or, in the compound represented by formula A, X is bromine; the base is a hydroxide; the phase transfer catalyst is selected from one or more of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, tetrabutylammonium iodide, benzyltriethylammonium chloride, and trioctylmethylammonium chloride; the amide solvent is one or two of N,N-dimethylformamide and N,N-dimethylacetamide.

[0018] Further, the molar ratio of the compound shown in Formula III to the compound shown in Formula A is 1:(2.1 to 2.5), preferably 1:2.2; the molar ratio of the compound shown in Formula III to the base is 1:(2.0 to 3.0), preferably 1:2.4; the molar ratio of the compound shown in Formula III to the phase transfer catalyst is 1:(0.005 to 0.019), preferably 1:0.010; the mass-volume ratio of the compound shown in Formula III to the amide solvent is 1:(5 to 10) g / mL, preferably 1:7 g / mL;

[0019] And / or, the hydroxide is selected from one or more of potassium hydroxide, lithium hydroxide, and sodium hydroxide.

[0020] Furthermore, the reaction temperature is 0–45°C, and the time is 1–24 hours.

[0021] Furthermore, the reaction temperature is 10–25°C, preferably 20°C.

[0022] Furthermore, the reaction includes the following post-processing steps: filtering the reaction solution to remove the amide solvent in the filtrate, adding water to the residue, extracting, separating, retaining the organic layer, and obtaining the compound shown in Formula I.

[0023] The present invention also provides a method for preparing valproic acid, the method comprising the following steps:

[0024]

[0025] (1) The compound shown in Formula I was prepared according to the method described above;

[0026] (2) The compound shown in Formula I is obtained by ester hydrolysis to give the compound shown in Formula IV;

[0027] (3) The compound shown in Formula IV undergoes a decarboxylation reaction to yield valproic acid.

[0028] Further, in step (2), the operation of the ester hydrolysis reaction is as follows: the compound shown in formula I is added to an alcohol solvent containing an alkaline aqueous solution to carry out the ester hydrolysis reaction to obtain the salt of the compound shown in formula IV, and then acidified to obtain the compound shown in formula IV.

[0029] In step (3), the decarboxylation reaction is carried out at a temperature of 170–180 °C for a time of 0.3–1 h.

[0030] Further, in step (2), the alkaline aqueous solution is selected from one or more of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, and lithium hydroxide aqueous solution;

[0031] The concentration of the alkaline aqueous solution is 0.5–2 g / mL;

[0032] The mass-to-volume ratio of the compound shown in Formula I to the alkaline aqueous solution is 1:(0.5~5)g / mL;

[0033] The alcohol solvent is selected from one or more of methanol, ethanol, and isopropanol;

[0034] The mass-to-volume ratio of the compound shown in Formula I to the alcohol solvent is 1:(1~10)g / mL;

[0035] The ester hydrolysis reaction is carried out at a temperature of 80–90°C for a time of 0.5–3 hours.

[0036] The pH value of the acidification is 2 to 3.

[0037] The present invention also provides a method for preparing a salt of valproic acid, the method comprising the following steps:

[0038] (i) Valproic acid was prepared according to the method described above;

[0039] (ii) The valproic acid is subjected to a salt formation reaction to obtain the salt of valproic acid;

[0040] Preferably, the salt of valproic acid is sodium valproate or magnesium valproate.

[0041] The structure of diethyl propyl malonate is shown in Formula II, and the structure of valeric acid is shown in Formula II':

[0042]

[0043] Compared with the prior art, the method for preparing the intermediate dipropylmalonate of the present invention has achieved the following beneficial effects: the method of the present invention can significantly reduce the content of dipropylmalonate impurity (Formula II) in the product, and control the content of dipropylmalonate impurity ≤0.17%; the purity of dipropylmalonate obtained by the method of the present invention is ≥98.16%, and the yield is ≥85%.

[0044] Compared with the prior art, the method for preparing valproic acid of the present invention has the following beneficial effects: the method of the present invention can significantly reduce the content of valproic acid impurity (Formula II') in the product, control the content of valproic acid impurity to as low as 0.01%, and the residual amount of bromopropane to as low as 0.01 ppm; the purity of valproic acid obtained by the method of the present invention is as high as 99.97%.

[0045] The method of the present invention can recover and reuse solvents. This method is economical, environmentally friendly, easy to operate, low in cost, safe and controllable, and suitable for large-scale industrial production.

[0046] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions, or alterations can be made without departing from the basic technical concept of the present invention.

[0047] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Detailed Implementation

[0048] The raw materials and equipment used in this invention are all known products, obtained by purchasing commercially available products.

[0049] Example 1: Preparation of Compound I

[0050]

[0051] Add 240 mL of N,N-dimethylformamide, 1.0 g (3.6 mmol) of tetrabutylammonium chloride, and 21.0 g (374.3 mmol) of potassium hydroxide solid to a reaction flask. Stir rapidly and cool to 10–15 °C. Add 30.0 g (187.3 mmol) of compound III dropwise. After the addition is complete, react for 30 minutes, then add 55.3 g (449.6 mmol) of bromopropane dropwise. After the addition is complete, maintain the reaction temperature at 25 °C for 24 hours. Filter the reaction solution and concentrate the filtrate at -0.095 MPa and 85–100 °C to remove N,N-dimethylformamide. Recover the N,N-dimethylformamide from the distillate. Add 45 mL of water to the concentrated residue, extract, separate the layers, and collect the organic layer to obtain 39.0 g of compound I, with a yield of 85%. Gas chromatography was used to determine the purity of compound I, which was 98.45%, and the impurity content of compound II was 0.15%.

[0052] Example 2: Preparation of Compound I

[0053] Add 210 mL of N,N-dimethylformamide, 0.6 g (1.9 mmol) of tetrabutylammonium bromide, and 18.0 g (450.0 mmol) of sodium hydroxide solid to a reaction flask. Stir rapidly and cool to 10–15 °C. Add 30.0 g (187.3 mmol) of compound III dropwise. After the addition is complete, react for 30 minutes, then add 51.0 g (414.7 mmol) of bromopropane dropwise. After the addition is complete, maintain the temperature at 20 °C for 24 hours. Filter the reaction solution and concentrate the filtrate at -0.095 MPa and 85–100 °C until N,N-dimethylformamide is removed. Recover the N,N-dimethylformamide from the distillate. Add 45 mL of water to the concentrated residue, extract, separate the layers, and collect the organic layer to obtain 40.3 g of compound I, with a yield of 88%. Gas chromatography was used to determine the purity of compound I, which was 98.50%, and the impurity content of compound II was 0.10%.

[0054] Example 3: Preparation of Compound I

[0055] Add 150 mL of N,N-dimethylacetamide, 0.4 g (1.1 mmol) of tetrabutylammonium iodide, and 10.3 g (430.1 mmol) of lithium hydroxide solid to a reaction flask. Stir rapidly and cool to 10–15 °C. Add 30.0 g (187.3 mmol) of compound III dropwise. After the addition is complete, react for 30 minutes, then add 57.6 g (468.3 mmol) of bromopropane. After the addition is complete, maintain the reaction temperature at 10 °C for 24 hours. Filter the reaction solution and concentrate the filtrate at -0.095 MPa and 85–100 °C to remove N,N-dimethylacetamide. Recover the distillate containing N,N-dimethylacetamide. Add 45 mL of water to the concentrated residue, extract, separate the layers, and collect the organic layer to obtain 39.0 g of compound I, with a yield of 85%. Gas chromatography was used to determine the purity of compound I, which was 98.25%, and the impurity content of compound II was 0.15%.

[0056] Example 4: Preparation of Compound I

[0057] Add 150 mL of N,N-dimethylacetamide, 0.6 g (1.8 mmol) of tetrabutylammonium hydrogen sulfate, and 18.7 g (467.5 mmol) of sodium hydroxide solid to a reaction flask. Stir rapidly and cool to 10–15 °C. Add 30.0 g (187.3 mmol) of compound III dropwise. After the addition is complete, react for 30 minutes, then add 57.6 g of bromopropane (468.3 mmol). After the addition is complete, maintain the reaction temperature at 15 °C for 24 hours. Filter the reaction solution and concentrate the filtrate at -0.095 MPa and 85–100 °C to remove N,N-dimethylacetamide. Recover the distillate containing N,N-dimethylacetamide. Add 45 mL of water to the concentrated residue, extract, separate the layers, and collect the organic layer to obtain 39.8 g of compound I, with a yield of 87%. Gas chromatography was used to determine the purity of compound I, which was 98.38%, and the impurity content of compound II was 0.14%.

[0058] Example 5: Preparation of Compound I

[0059] Add 300 mL of N,N-dimethylformamide, 0.6 g (2.6 mmol) of benzyltriethylammonium chloride, and 22.5 g (562.5 mmol) of sodium hydroxide solid to a reaction flask. Stir rapidly and cool to 10–15 °C. Add 30.0 g (187.3 mmol) of compound III dropwise. After the addition is complete, react for 30 minutes, then add 48.4 g of bromopropane (393.5 mmol). After the addition is complete, maintain the temperature at 20 °C for 24 hours. Filter the reaction solution and concentrate the filtrate at -0.095 MPa and 85–100 °C to remove N,N-dimethylformamide. Recover the N,N-dimethylformamide from the distillate. Add 45 mL of water to the concentrated residue, extract, separate the layers, and collect the organic layer to obtain 39.4 g of compound I, with a yield of 86%. Gas chromatography was used to determine the purity of compound I, which was 98.16%, and the impurity content of compound II was 0.17%.

[0060] Example 6: Preparation of valproic acid

[0061]

[0062] Add 15 mL of sodium hydroxide aqueous solution (concentration 1 g / mL) and 50 mL of ethanol to the reaction flask, heat to 85 °C, and slowly add 15.4 g of the compound of formula I prepared in Example 1. After the addition is complete, reflux at 86 °C for 1.5 h. Add 45 mL of water to dissolve the precipitate completely, and continue heating for 20 min to obtain a sodium salt solution of compound of formula IV. Cool naturally, acidify with concentrated hydrochloric acid to pH 2-3, and extract the solution three times with 15 mL of anhydrous diethyl ether each time. Combine the ether layers, dry with anhydrous magnesium sulfate, and remove the ether by distillation under normal pressure. The remaining liquid is 10.5 g of compound of formula IV, with a yield of 89%.

[0063] 10.5 g of the prepared compound IV was placed in a reaction flask and heated to 175 °C for decarboxylation reaction for 20 min. Then, it was distilled under reduced pressure, and the fraction collected at 112–114 °C / 1.067 kPa was used to obtain 6.7 g of valproic acid, with a yield of 83%. Gas chromatography analysis showed that the purity of valproic acid was 99.97%, containing 0.01% valeric acid (i.e., impurity of formula II') and 0.01 ppm of bromopropane residue.

[0064] Preparation of Compound I in Comparative Example 1

[0065] Add 210 mL of ethanol, 0.6 g (1.9 mmol) of tetrabutylammonium bromide, and 18.0 g (450.0 mmol) of sodium hydroxide solid to a reaction flask, stir rapidly, and cool to 10–15 °C. Add 30.0 g (187.3 mmol) of compound III dropwise. After the addition is complete, react for 30 minutes, then add 51.0 g (414.7 mmol) of bromopropane dropwise. After the addition is complete, maintain the temperature at 20 °C for 24 hours. Filter the reaction solution, and concentrate the filtrate at -0.095 MPa and 85–100 °C to remove ethanol. Add 45 mL of water to the concentrated residue, extract, separate the layers, and collect the organic layer to obtain 30.0 g of oily liquid. Gas chromatography analysis showed that the purity of compound I was 65.56%, the impurity content of compound II was 5.44%, and the remaining starting material compound III was 27.54%.

[0066] Preparation of Compound I in Comparative Example 2

[0067] Add 210 mL of toluene, 0.6 g (1.9 mmol) of tetrabutylammonium bromide, and 18.0 g (450.0 mmol) of sodium hydroxide solid to a reaction flask, stir rapidly, and cool to 10–15 °C. Add 30.0 g (187.3 mmol) of compound III dropwise. After the addition is complete, react for 30 minutes, then add 51.0 g (414.7 mmol) of bromopropane dropwise. After the addition is complete, maintain the temperature at 20 °C for 24 hours. Filter the reaction solution, and concentrate the filtrate at -0.095 MPa and 85–100 °C to remove toluene. Add 45 mL of water to the concentrated residue, extract, separate the layers, and collect the organic layer to obtain 31.0 g of oily liquid. Gas chromatography analysis showed that the purity of compound I was 20.48%, the impurity content of compound II was 5.98%, and the remaining starting material compound III accounted for 71.54%.

[0068] Preparation of Compound I in Comparative Example 3

[0069] In a 500 mL three-necked flask equipped with a sealed stirrer, a pressure dropping funnel, and a reflux condenser (with a calcium chloride drying tube), 110 mL of sodium ethoxide solution was added. The mixture was heated to 80 °C with stirring in an external bath. 19.2 g (119.9 mmol) of compound III was then added dropwise. After the addition was complete, the mixture was stirred for 10 minutes, followed by the addition of 33.5 g (272.4 mmol) of bromopropane over approximately 30 minutes. The mixture was then stirred and refluxed for 2 hours. The mixture was allowed to stand at room temperature for 2 hours. Sodium bromide was removed by filtration, and the filter cake was washed with a small amount of anhydrous ethanol. The filtrate and washings were combined, and the ethanol was recovered by atmospheric distillation, yielding 28.0 g of crude dipropylmalonate. After drying with anhydrous sodium sulfate, the product was subjected to vacuum distillation, collecting the fraction at 110–124 °C / 7–8 mmHg, yielding 26.0 g of a colorless oily liquid, with a yield of 90%. Gas chromatography was used to determine the purity of compound I, which was 95.68%, and the impurity content of compound II was 2.66%.

[0070] Comparative Example 4: Preparation of Valproic Acid

[0071] Add 15 mL of sodium hydroxide aqueous solution (concentration 1 g / mL) and 50 mL of ethanol to the reaction flask, heat to 85 °C, and slowly add 15.4 g of compound I prepared in Comparative Example 3. After the addition is complete, reflux at 86 °C for 1.5 h. Add 45 mL of water to dissolve the precipitate completely, and continue heating for 20 min to obtain a sodium salt solution of compound IV. Allow it to cool naturally, and acidify with concentrated hydrochloric acid to a pH of 2–3. Extract the solution three times with 15 mL of anhydrous diethyl ether each time. Combine the ether layers, dry with anhydrous magnesium sulfate, and remove the ether by distillation under normal pressure. The remaining liquid is 10.5 g of compound IV, with a yield of 89%.

[0072] 10.5 g of the prepared compound IV was placed in a reaction flask and heated to 175 °C for decarboxylation reaction for 20 min. Then, the mixture was distilled under reduced pressure, and the fraction collected at 112–114 °C / 1.067 kPa yielded 6.4 g of valproic acid, with a yield of 80%. Gas chromatography analysis showed that the purity of valproic acid was 99.18%, containing 0.54% valeric acid (i.e., impurity II').

Claims

1. A method for preparing the compound shown in Formula I, characterized in that: The method includes the following steps: The compound shown in Formula III, the compound shown in Formula A, a base, and a phase transfer catalyst were added to an amide solvent and reacted to obtain the compound shown in Formula I. In formula A, X is a halogen; The molar ratio of the compound shown in Formula III to the compound shown in Formula A is 1:(2.1~2.5); the molar ratio of the compound shown in Formula III to the base is 1:(2.0~3.0); the molar ratio of the compound shown in Formula III to the phase transfer catalyst is 1:(0.005~0.019); the mass-volume ratio of the compound shown in Formula III to the amide solvent is 1:(5~10) g / mL; The amide solvent is one or both of N,N-dimethylformamide and N,N-dimethylacetamide; The phase transfer catalyst is selected from one or more of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium hydrogen sulfate, tetrabutylammonium iodide, benzyltriethylammonium chloride, and trioctylmethylammonium chloride.

2. The method according to claim 1, characterized in that: In the compound represented by formula A, X is bromine; the base is a hydroxide.

3. The method according to claim 2, characterized in that: The hydroxide is selected from one or more of potassium hydroxide, lithium hydroxide, and sodium hydroxide.

4. The method according to claim 1, characterized in that: The molar ratio of the compound shown in Formula III to the compound shown in Formula A is 1:2.2; the molar ratio of the compound shown in Formula III to the base is 1:2.4; the molar ratio of the compound shown in Formula III to the phase transfer catalyst is 1:0.010; and the mass-volume ratio of the compound shown in Formula III to the amide solvent is 1:7 g / mL.

5. The method according to claim 1, characterized in that: The reaction is carried out at a temperature of 0-45°C for 1-24 hours.

6. The method according to claim 5, characterized in that: The reaction temperature is 10~25℃.

7. The method according to claim 6, characterized in that: The reaction was carried out at a temperature of 20°C.

8. The method according to any one of claims 1 to 7, characterized in that: The reaction also includes the following post-processing steps: filtering the reaction solution to remove the amide solvent in the filtrate, adding water to the residue, extracting, separating the liquid, retaining the organic layer, and obtaining the compound shown in Formula I.

9. A method for preparing valproic acid, characterized in that: The method includes the following steps: (1) The compound of formula I is prepared by the method according to any one of claims 1 to 8; (2) The compound shown in Formula I is obtained by ester hydrolysis to give the compound shown in Formula IV; (3) The compound shown in Formula IV is decarboxylated to obtain valproic acid.

10. The method according to claim 9, characterized in that: In step (2), the operation of the ester hydrolysis reaction is as follows: the compound shown in formula I is added to an alcohol solvent containing an alkaline aqueous solution to carry out the ester hydrolysis reaction to obtain the salt of the compound shown in formula IV, and then acidified to obtain the compound shown in formula IV; in step (3), the temperature of the decarboxylation reaction is 170~180℃ and the time is 0.3~1h.

11. The method according to claim 10, characterized in that: In step (2), the alkaline aqueous solution is selected from one or more of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, and lithium hydroxide aqueous solution; The concentration of the alkaline aqueous solution is 0.5~2g / mL; The mass-to-volume ratio of the compound shown in Formula I to the alkaline aqueous solution is 1:(0.5~5) g / mL; The alcohol solvent is selected from one or more of methanol, ethanol, and isopropanol; The mass-to-volume ratio of the compound shown in Formula I to the alcohol solvent is 1:(1~10)g / mL; The ester hydrolysis reaction is carried out at a temperature of 80-90°C for a time of 0.5-3 hours. The pH value of the acidification is 2~3.

12. A method for preparing a salt of valproic acid, characterized in that: The method includes the following steps: (i) Valproic acid is prepared according to the method of any one of claims 9 to 11; (ii) The valproic acid is subjected to a salt formation reaction to obtain the salt of valproic acid.

13. The method according to claim 12, characterized in that: The method includes the following steps: the salt of valproic acid is sodium valproate or magnesium valproate.

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