Preparation method and product of ethosuximide

Abstract

The invention relates to the technical field of medicine synthesis, in particular to a preparation method of ethosuximide and a product. Comprising the following steps: carrying out oxidation reaction on 2-methyl-2-ethyl-4-pentenoic acid under the action of acidic potassium permanganate to obtain 2-methyl-2-ethyl succinic acid; the method comprises the following steps: carrying out cyclization reaction on 2-methyl-2-ethyl succinic acid and NH3 to form ethosuximide. The ethosuximide synthesis route provided by the invention has the advantages of short steps, simple operation, low preparation cost, easily available raw materials, no need of expensive catalyst, high reaction efficiency, and suitableness for industrial application. The prepared ethosuximide product is high in purity and low in impurity level, and can meet the requirements of medicinal level.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and particularly relates to a preparation method and product of ethosuximide. Background Art

[0002] Ethosuximide is a succinimide anti-epileptic drug. It is rapidly and completely absorbed orally, with a peak time of 1 - 4 hours, a low plasma protein binding rate, a half-life of about 60 hours in adults and about 30 hours in children. It is extensively metabolized in the liver by hydroxylation into inactive metabolites. Ethosuximide is mainly used for absence seizures and clonic seizures, and is ineffective against tonic-clonic and partial seizures. It can be used with other anti-epileptic drugs for mixed epileptic seizures. Ethosuximide can increase the seizure threshold and slow down the seizure frequency, and has good efficacy in treating absence status epilepticus. The advantages of ethosuximide are safety, effectiveness, no sedative effect, a relatively long elimination half-life, and single daily dosing can control seizures. It is mainly used as the first choice drug for petit mal seizures.

[0003] The currently reported synthetic route of ethosuximide (Organic Syntheses, 1964, 44, 59 - 61) uses 2-butanone and ethyl 2-cyanoacetate as raw materials, goes through the intermediate ethyl 2,3-dicyano-3-methylvalerate, but this intermediate is not separated. Under the acidic condition provided by hydrochloric acid, the cyano group and ester group are hydrolyzed, and decarboxylation is carried out by heating to obtain 2-methyl-2-ethylsuccinic acid.

[0004]

[0005] This route inevitably requires the use of highly toxic reagents such as potassium cyanide or sodium cyanide, has high requirements for the qualifications of production enterprises, great production safety pressure, high regulatory requirements, and it is difficult to achieve self-controlled production of bulk drugs.

[0006] The currently existing technologies also report a synthetic route with N-substituted vinyl-α-chloro-α-methylthioacetamide as the key intermediate. The reaction process is as follows:

[0007]

[0008] This route uses intermediate 1 as the raw material and undergoes five-step reactions, with a total yield of 5.76%, which is relatively low. And each step requires column chromatography for separation and purification. During the reaction process, environmentally key-concerned reagents such as pyridinium chlorochromate (PCC) are also used, resulting in great environmental pressure. Therefore, it is not suitable for large-scale production of bulk drugs.

[0009] The currently existing literature also reports a synthetic route with the key step of constructing an imide ring by copper-catalyzed O2 oxidation of C = C cleavage. The reaction process is as follows:

[0010]

[0011] However, this route still has the defects of low yield, complex impurity types, high impurity content, and the need for column chromatography for purification. In addition, precious metal catalysts need to be used, so it is not suitable for large-scale production for the preparation of bulk drugs either.

[0012] In view of this, there is currently a need for a synthesis method of ethosuximide that has few steps, low cost, high efficiency, and is suitable for industrial application. Summary of the Invention

[0013] To solve the above technical problems, the present invention provides a preparation method and product of ethosuximide.

[0014] The present invention provides a synthesis method of ethosuximide, which at least includes the following steps:

[0015] S1. Oxidize 2-methyl-2-ethyl-4-pentenoic acid under the action of acidic potassium permanganate to obtain 2-methyl-2-ethylsuccinic acid;

[0016] S2. Perform a cyclization reaction on 2-methyl-2-ethylsuccinic acid and NH3 to form ethosuximide.

[0017] Optionally, in S1, the molar ratio of 2-methyl-2-ethyl-4-pentenoic acid to sulfuric acid is 1:2 to 4; preferably 1:2.4 to 3.6.

[0018] Optionally, in S1, the molar ratio of 2-methyl-2-ethyl-4-pentenoic acid to potassium permanganate is 1:2 to 4, preferably 1:2.4 to 3.6.

[0019] Optionally, in S1, the addition method of potassium permanganate is to continuously or batchwise add solid potassium permanganate or dropwise add a potassium permanganate solution; in the method of continuously or batchwise adding solid potassium permanganate, the concentration of sulfuric acid is 1 to 2 mol / L; in the method of dropwise adding a potassium permanganate solution, the concentration of sulfuric acid is 12 to 18 mol / L.

[0020] Optionally, in S1, when adding potassium permanganate, the reaction temperature in the reaction system is controlled at 20°C to 60°C, preferably 30°C to 50°C.

[0021] Optionally, in S1, after the oxidation reaction is completed, it further includes a post-treatment step, including: filtering the reaction product, washing the obtained filtrate with organic solvent A and extracting with organic solvent B to obtain an organic phase; washing the organic phase with saturated sodium chloride solution and drying to obtain a crude product; organic solvent A is preferably one or more of n-heptane, n-hexane, or petroleum ether; organic solvent B is one or more of ethyl acetate, n-butanol, or n-pentanol.

[0022] Optionally, in S2, the molar ratio of 2-methyl-2-ethylsuccinic acid to NH3 is 1:1 to 3.

[0023] Optionally, the reaction temperature of the cyclization reaction is 120 °C to 180 °C, and the reaction time is 2 to 6 hours.

[0024] Optionally, in S2, after the cyclization reaction, a post-treatment step is further included, including: extracting the crude product solution obtained from the cyclization reaction with an organic solvent, and obtaining the ethosuximide product through washing and drying. Optionally, the organic solvent used for extraction is selected from one or more of dichloromethane, ethyl acetate, chloroform, dichloroethane, and isopropyl ether. Optionally, the washing solution for washing includes: an aqueous sodium bicarbonate solution with a mass percentage concentration of 3% to 5% and pure water. Preferably, each washing solution is used for washing 1 to 2 times. Preferably, each time of washing, the volume of the washing solution used per gram of 2-methyl-2-ethylsuccinic acid is 2 to 4 mL.

[0025] The present invention also provides an ethosuximide product obtained by the above synthesis method.

[0026] The technical solution provided by the embodiment of the present invention has the following advantages compared with the prior art:

[0027] The synthesis route of ethosuximide proposed by the present invention has short steps, simple operation, low preparation cost, easily available raw materials, does not require the use of expensive catalysts, does not require special reaction conditions such as high pressure, and has high reaction efficiency. It does not require the use of a chromatography column for separation and purification, and is suitable for industrial application.

[0028] The ethosuximide product prepared by the present invention has high purity and low impurity level, and can meet the requirements of the pharmaceutical grade. Description of the Drawings

[0029] Figure 1 is the 1 H-NMR spectrum of 2-methyl-2-ethylsuccinic acid;

[0030] Figure 2 is the 1 H-NMR spectrum of ethosuximide;

[0031] Figure 3 is the 1 magnified view of the H-NMR spectrum of ethosuximide;

[0032] Figure 4 is the 13 C-NMR spectrum of ethosuximide;

[0033] Figure 5 is the ESI-MS spectrum of ethosuximide. Detailed Embodiments

[0034] In order to more clearly understand the above-mentioned objects, features and advantages of the present invention, the solutions of the present invention will be further described below. It should be noted that, without conflict, the embodiments of the present invention and the features in the embodiments can be combined with each other.

[0035] In the following description, many specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways different from those described herein; obviously, the embodiments in the specification are only a part of the embodiments of the present invention, rather than all of the embodiments.

[0036] The abbreviations used in this application are as follows:

[0037] EA: ethyl acetate;

[0038] THF: tetrahydrofuran;

[0039] DCM: dichloromethane;

[0040] HRMS: high resolution mass spectrometry;

[0041] 1 H-NMR: nuclear magnetic resonance hydrogen spectrum;

[0042] 13 C-NMR: nuclear magnetic resonance carbon spectrum.

[0043] An embodiment of the present invention provides a method for preparing ethosuximide, adopting a synthetic route of oxidizing 2-methyl-2-ethyl-4-pentenoic acid to 2-methyl-2-ethylsuccinic acid, without the need to use noble metal catalysts, the intermediate products are easy to purify, and there is no need to use chromatography columns for separation and purification, which is particularly suitable for the industrial production of bulk drugs. Moreover, through in-depth research, potassium permanganate is used as an oxidant for the oxidation reaction, which has the advantages of low cost and high reaction efficiency. Specifically, the method includes the following steps:

[0044] S1. Oxidize 2-methyl-2-ethyl-4-pentenoic acid under the action of acidic potassium permanganate to oxidize the double bond to a carboxyl group, obtaining 2-methyl-2-ethylsuccinic acid; the reaction equation is as follows:

[0045]

[0046] S2. Perform a cyclization reaction on 2-methyl-2-ethylsuccinic acid and NH3 to form ethosuximide; the reaction equation is as follows:

[0047]

[0048] In step S1 of the embodiment of the present invention, acidic potassium permanganate is used as an oxidant. Using 2-methyl-2-ethyl-4-pentenoic acid as a raw material, its double bond is oxidized to a carboxyl group to obtain 2-methyl-2-ethylsuccinic acid. Since acidic potassium permanganate has strong oxidizing properties, it is necessary to control the reaction conditions to reduce the occurrence of side reactions and improve the yield.

[0049] First of all, in the reaction system, applying sulfuric acid and potassium permanganate in a suitable ratio can reduce the occurrence of side reactions.

[0050] Secondly, the addition amount of potassium permanganate has an impact on the yield. If the addition amount of potassium permanganate is less, the product yield is low and the oxidation reaction is incomplete. If the addition amount of potassium permanganate is too much, the increase in side reactions will also cause the yield to decrease.

[0051] After a large number of experiments, the inventors found that when the molar ratio of 2-methyl-2-ethyl-4-pentenoic acid to sulfuric acid is 1:2 to 4, and the molar ratio of 2-methyl-2-ethyl-4-pentenoic acid to potassium permanganate is 1:2 to 4, the oxidation reaction efficiency is high, the reaction is complete, the yield can meet the production requirements, and the impurities generated can be separated through simple post-treatment and refining steps, without the need to use a chromatography column for purification, which is suitable for industrial application.

[0052] Specifically, the molar ratio of 2-methyl-2-ethyl-4-pentenoic acid to sulfuric acid can further be 1:2.4 to 3.6. For example, it can be 1:2.4 to 2.8, 1:2.6 to 3.0, 1:2.8 to 3.2 or 1:3.0 to 3.6. Specifically, it can be 1:2.5, 1:2.7, 1:2.8, 1:2.9, 1:3.0, 1:3.2, 1:3.4 or 1:3.5; the molar ratio of 2-methyl-2-ethyl-4-pentenoic acid to potassium permanganate can be 1:2.4 to 3.6. For example, it can be 1:2.4 to 2.8, 1:2.6 to 3.0 or 1:2.8 to 3.2. For example, specifically, it can be 1:2.5, 1:2.6, 1:2.7, 1:2.9, 1:3.0 or 1:3.1.

[0053] Finally, since potassium permanganate has strong oxidizing properties, if all the potassium permanganate solid is added at once, the reaction is violent, and it will also cause incomplete reaction and more side reactions. Therefore, it is preferably to continuously add or add potassium permanganate solid in batches or dropwise add potassium permanganate solution, so as to control the reaction rate and reduce side reactions.

[0054] The specific addition method is as follows: Solid potassium permanganate is added in a continuous controlled-flow feeding manner or in batches, and the addition rate is controlled so that the reaction temperature of the reaction system does not exceed 60°C. For example, the reaction temperature can be controlled within the range of 20°C to 60°C by adjusting the addition rate of solid potassium permanganate. If the addition rate of solid potassium permanganate is too fast, the reaction temperature will rise too quickly and become too high, which may lead to a decrease in the yield due to an increase in by-products. When adding solid potassium permanganate, sulfuric acid with a concentration of 1 - 2 mol / L can be used. To make the reaction system easier to stir, sulfuric acid with a concentration of 1 - 1.5 mol / L can also be used.

[0055] The method of dropping the potassium permanganate solution is as follows: Potassium permanganate is prepared into an aqueous solution with a mass percentage concentration of 5% - 6%, and then dropped into the reaction system, and the dropping is completed within 1 - 3 hours, controlling the reaction temperature of the reaction system not to exceed 60°C, for example, within the range of 20°C - 60°C, and further within the range of 30°C - 50°C. When adding liquid potassium permanganate, to reduce the solvent volume of the reaction system, sulfuric acid with a higher concentration can be used, such as 12 - 18 mol / L. The reaction conditions of this method are milder and easier to control.

[0056] As an improvement of the embodiment of the present invention, after the addition of potassium permanganate is completed, keep warm and stir for 0.5 - 1.5 hours to ensure complete reaction and improve the yield.

[0057] After the oxidation reaction in S1 is completed, 2-methyl-2-ethylsuccinic acid is purified and dried for use in the next cyclization reaction. Specifically: The oxidized reaction product is filtered, and the obtained filtrate is washed 1 - 3 times with organic solvent A and extracted 1 - 3 times with organic solvent B to obtain an organic phase; the organic phase is washed with saturated sodium chloride solution, dried, and concentrated to obtain the product. Organic solvent A can be one or more of n-heptane, n-hexane, or petroleum ether; organic solvent B can be one or more of ethyl acetate, n-butanol, or n-pentanol. Among them, drying can be carried out in various ways, for example, by adding anhydrous sodium sulfate. Concentration can be carried out by vacuum concentration, specifically at a temperature condition of 40°C - 50°C.

[0058] As an improvement of the embodiment of the present invention, the dosage of organic solvent A is: 3 - 6 mL of organic solvent A is added per gram of 2-methyl-2-ethyl-4-pentenoic acid, preferably 4 - 5 mL. The dosage of organic solvent B is: 5 - 8 mL of organic solvent B is added per gram of 2-methyl-2-ethyl-4-pentenoic acid, preferably 6 - 7 mL. The dosage of saturated sodium chloride solution is: 3 - 6 mL of saturated sodium chloride solution is added per gram of 2-methyl-2-ethyl-4-pentenoic acid, preferably 4 - 5 mL.

[0059] As a specific embodiment of the post-treatment of S1: Filter the reaction product, wash the filter cake with water, combine the filtrates, wash the filtrates with n-heptane, discard the organic phase, extract the aqueous phase with ethyl acetate, combine the organic phases, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, filter, wash with ethyl acetate, and concentrate under reduced pressure at 42 °C to 45 °C to obtain the product.

[0060] As an improvement of the embodiment of the present invention, in S2, 2-methyl-2-ethylsuccinic acid undergoes a cyclization reaction with NH3. The molar ratio of 2-methyl-2-ethylsuccinic acid to NH3 can be 1:1 to 3; through further research, it is found that when the molar ratio of 2-methyl-2-ethylsuccinic acid to NH3 is less than 1:2, the reaction rate is slow and the yield is not ideal. Therefore, the condition of excessive ammonia water can ensure the reaction rate and improve the yield. The molar ratio of 2-methyl-2-ethylsuccinic acid to ammonia water can specifically be 1:2 to 3, and further can be selected as 1:2.0 to 2.4, such as 1:2.1, 1:2.2, 1:2.3.

[0061] As an improvement of the embodiment of the present invention, 2-methyl-2-ethylsuccinic acid is mixed with ammonia water, and the ammonia water can be prepared by mixing concentrated ammonia water with a mass percentage concentration of 25% to 28% and water in a certain ratio, for example, ammonia water with a mass percentage concentration of 10% to 15% can be used.

[0062] As an improvement of the embodiment of the present invention, the reaction conditions for the cyclization reaction are to raise the temperature to 120 °C to 180 °C and react for 2 to 6 hours after fractionally removing water. Specifically, during the actual reaction, the temperature can be controlled within the range of 120 °C to 125 °C, 125 °C to 135 °C, 135 °C to 145 °C, 145 °C to 155 °C, 155 °C to 165 °C. The reaction time for the cyclization reaction can be 3 hours, 4 hours, or 5 hours. For example, the temperature can be raised to 140 °C to 160 °C and react for 3 to 5 hours. After the reaction is completed, water is added to obtain a crude product solution.

[0063] As a specific embodiment of the reaction part of S2: Add 2-methyl-2-ethylsuccinic acid to ammonia water with a mass percentage concentration of 12% to 14%, stir to dissolve, raise the temperature to 145 °C to 155 °C, react for 4 to 5 hours, stop heating, after the reaction is completed, add water, and then obtain a crude product solution through decolorization and washing. Among them, the volume of water added is 3 to 6 mL of water per gram of 2-methyl-2-ethylsuccinic acid, preferably 4 to 5 mL.

[0064] In S2, after the reaction is completed, it also includes a post-treatment step, including: The crude product solution is subjected to extraction, washing, and drying to obtain the ethosuximide product.

[0065] Among them, the organic solvent for extraction can be, for example, dichloromethane, ethyl acetate, chloroform, dichloroethane, isopropyl ether, and specifically chloroform can be used. Extraction can be carried out multiple times to ensure the yield, for example, 1 to 4 times, and specifically 2, 3, or 4 times can be used. The organic phase obtained by extraction is collected and washed. The specific washing method is as follows: first, wash with an aqueous sodium bicarbonate solution with a mass percentage concentration of 3% to 5% for 1 to 2 times to remove the unreacted 2-methyl-2-ethylsuccinic acid, and then wash with pure water for 1 to 2 times.

[0066] Each time during washing, the volume of the washing solution used per gram of ethyl-2-methylsuccinic acid is 2 to 4 mL, and specifically 2 mL, 2.5 mL, 3 mL, or 3.5 mL can be used. After washing with water, the product ethosuximide is obtained through drying and concentration.

[0067] As a specific implementation manner of the post-treatment of S2: after the reaction is completed, the reaction solution is cooled, water and activated carbon are added for decolorization, filtered, the filter cake is washed with water, and the filtrate is extracted with chloroform 2 to 4 times, and the organic phases are combined. The organic phase is first washed with an aqueous sodium bicarbonate solution with a mass percentage concentration of 3% to 5% for 1 to 2 times, and then washed with pure water for 1 to 2 times. After drying and concentration, the product ethosuximide is obtained. Concentration can be carried out by vacuum distillation at 30°C to 35°C.

[0068] Since the reaction of acidic potassium permanganate as an oxidant is violent, has many side reactions, and the yield is relatively low. Therefore, in the field of drug synthesis, a new type of oxidation catalyst is generally used, or other reaction routes are adopted. However, through accidental research, it is found that in the examples of the present invention, the double bond in 2-methyl-2-ethyl-4-pentenoic acid is directly oxidized with acidic potassium permanganate, which not only has the technical advantage of a short reaction route, but also through the control of conditions, an intermediate product with a yield and purity both meeting the preparation requirements can be obtained. In the starting materials of the examples of the present invention, 2-methyl-2-ethyl-4-pentenoic acid is easy to prepare and has a moderate price, and potassium permanganate and sulfuric acid are inexpensive and the materials are easily available. The synthesis route of the examples of the present invention does not require the use of highly toxic reagents (such as cyanides), nor does it require the use of expensive metal catalysts. Most importantly, the products after the oxidation reaction and cyclization reaction in the examples of the present invention do not need to be purified using a chromatography column, which not only greatly reduces the cost of separation and purification, but also is particularly suitable for the production of drug raw materials.

[0069] As an improvement of the examples of the present invention, ethyl 2-methyl-2-ethyl-4-pentenoate in the examples of the present invention can be commercially purchased or can be prepared through the following steps:

[0070] pS1. Using ethyl 2-methylbutyrate and allyl bromide as raw materials, reacting in the presence of a non-nucleophilic strong base to generate ethyl 2-methyl-2-ethyl-4-pentenoate, and the reaction equation is as follows:

[0071]

[0072] pS2. Ethyl 2-methyl-2-ethyl-4-pentenoate is hydrolyzed under alkaline conditions to obtain 2-methyl-2-ethyl-4-pentenoic acid. The reaction equation is as follows:

[0073]

[0074] As an improvement of the embodiment of the present invention, the process conditions of pS1 are as follows: using a non-nucleophilic strong base as a catalyst, using ethyl 2-methylbutyrate and allyl bromide as raw materials, and carrying out the reaction in an anhydrous and oxygen-free organic solvent; after the reaction is completed, the reaction is terminated by adjusting the pH of the reaction system to obtain ethyl 2-methyl-2-ethyl-4-pentenoate.

[0075] As an improvement of the embodiment of the present invention, in pS1, the non-nucleophilic strong base can be selected from one of lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, trityllithium, tritylsodium, and tritylpotassium. The reaction temperature can be -60°C to -10°C.

[0076] As an improvement of the embodiment of the present invention, in pS1, the molar ratio of ethyl 2-methylbutyrate to allyl bromide is 1:1.0 to 1.2, for example, 1:0.9, 1:1, 1:1.05, 1:1.1, 1:1.15, 1:1.2 can be adopted.

[0077] As an improvement of the embodiment of the present invention, in pS1, the molar ratio of ethyl 2-methylbutyrate to lithium diisopropylamide is 1:1.0 to 1.2, for example, 1:0.9, 1:1, 1:1.05, 1:1.1, 1:1.15, 1:1.2 can be adopted.

[0078] As an improvement of the embodiment of the present invention, in pS1, after both ethyl 2-methylbutyrate and allyl bromide are dissolved in an organic solvent, they are added to the reaction system. The organic solvent can be selected from one of tetrahydrofuran, methyl tert-butyl ether, diethyl ether, and diisopropyl ether, for example, tetrahydrofuran can be adopted.

[0079] As an improvement of the embodiment of the present invention, in pS1, a non-nucleophilic strong base placed in an organic solvent, ethyl 2-methylbutyrate dissolved in an organic solvent, and allyl bromide dissolved in an organic solvent are added in sequence; at the same time, ensure that the reaction temperature during the addition of raw materials is within the range of -60°C to -10°C to control the reaction process and the occurrence of side reactions.

[0080] As an improvement of the embodiment of the present invention, in pS1, a non-nucleophilic strong base placed in an organic solvent is first added, and then ethyl 2-methylbutyrate dissolved in the organic solvent is added. After adding, the reaction temperature is maintained within the range of -60°C to -10°C for a period of time, such as 20 to 40 minutes, specifically 30 minutes can be adopted to ensure the full progress of the reaction. Allyl bromide dissolved in the organic solvent is added, and the reaction temperature is maintained within the range of -60°C to -10°C for reaction for 20 to 40 minutes, specifically 30 minutes can be adopted.

[0081] As an improvement of the embodiment of the present invention, in pS1, after the reaction is completed, an inorganic acid is added to adjust the pH to 5 to 6 to end the reaction, and dilute hydrochloric acid can be specifically adopted. At the same time, ensure that the temperature during the dropping process does not exceed 5°C, for example, within the range of -10°C to 5°C, to control the occurrence of side reactions.

[0082] The embodiment of the present invention also proposes a specific implementation manner of pS1: under anhydrous and anaerobic conditions, a non-nucleophilic strong base stored in an organic solvent is added, the temperature is lowered to -60°C to -10°C, and ethyl 2-methylbutyrate dissolved in a dry organic solvent is added dropwise. During the dropping process, the temperature is maintained at -60°C to -10°C. After adding, the temperature is maintained for 20 to 30 minutes; allyl bromide dissolved in a dry organic solvent is added dropwise. During the dropping process, the temperature is maintained at -60°C to -10°C. After adding, the temperature is maintained for 25 to 35 minutes; dilute hydrochloric acid is added dropwise to adjust the pH to 5 to 6 to terminate the reaction. During the dropping process, the temperature is maintained at -50°C to 5°C.

[0083] As an improvement of the embodiment of the present invention, in pS1, after the reaction ends, it also includes a post-treatment step, specifically including: discarding the aqueous phase of the reaction solution, washing, drying, and concentrating the organic phase to obtain a product for the next reaction.

[0084] Further preferably, the post-treatment step is: discarding the aqueous phase of the reaction solution, washing the organic phase successively with dilute hydrochloric acid, saturated NaHCO3 aqueous solution, and saturated NaCl aqueous solution, drying, filtering, washing the filter cake with an organic solvent, preferably washing 2 to 4 times. The product is obtained after concentration. The organic solvent used for washing the filter cake is at least one of dichloromethane, ethyl acetate, chloroform, and dichloroethane. Concentration can be carried out by vacuum concentration at 40 to 45°C.

[0085] As an improvement of the embodiment of the present invention, in pS1, during washing, the dosage of dilute hydrochloric acid per gram of ethyl 2-methylbutyrate is 2 to 5 mL, the dosage of saturated NaHCO3 aqueous solution per gram of ethyl 2-methylbutyrate is 2 to 5 mL, and the dosage of saturated NaCl aqueous solution per gram of ethyl 2-methylbutyrate is 2 to 5 mL.

[0086] As a specific embodiment of the post-treatment step of pS1: Discard the aqueous phase of the reaction solution. The organic phase is washed successively with 1 mol / L hydrochloric acid, saturated aqueous NaHCO3 solution, and saturated aqueous NaCl solution, dried over anhydrous Na2SO4, filtered, and the filter cake is rinsed twice with dichloromethane. The filtrates are combined and concentrated under reduced pressure to obtain the product.

[0087] As an improvement of the embodiment of the present invention, an alcohol organic solvent and an aqueous inorganic base solution are added to the reaction system of pS2 for reaction. The addition of the alcohol organic solvent can promote the reaction. Specifically, the alcohol organic solvent can be methanol, ethanol, isopropanol, etc., and the inorganic base can be selected from one of sodium hydroxide and potassium hydroxide.

[0088] As an improvement of the embodiment of the present invention, in pS2, the hydrolysis temperature can be the reflux temperature, and the hydrolysis time can be 8 - 14 hours, for example, 9 hours, 10 hours, 11 hours, or 12 hours.

[0089] As an improvement of the embodiment of the present invention, in pS2, the molar ratio of ethyl 2 - methyl - 2 - ethyl - 4 - pentenoate to hydroxide ions in the inorganic base is 1:3 - 6, and further can be 1:4 - 5, specifically can be 1:4, 1:4.5, or 1:5.

[0090] As an improvement of the embodiment of the present invention, in the reaction system of pS2, the mass - to - volume ratio of ethyl 2 - methyl - 2 - ethyl - 4 - pentenoate to the alcohol organic solvent is 1:5 - 9, where the unit of mass is g and the unit of volume is mL. The volume ratio of the aqueous inorganic base solution to the alcohol organic solvent is 1:0.8 - 1.2, and specifically can be 1:0.9, 1:1, or 1:1.1.

[0091] As an improvement of the embodiment of the present invention, in the reaction system of pS2, the mass - to - volume ratio of ethyl 2 - methyl - 2 - ethyl - 4 - pentenoate to water is 1:4 - 8, specifically can be 1:4, 1:5, or 1:6, where the unit of mass is g and the unit of volume is mL.

[0092] As an improvement of the embodiment of the present invention, in pS2, after the hydrolysis reaction, there is also a post - treatment step, which specifically includes:

[0093] pS21: First, remove the alcohol organic solvent from the reaction system and wash it with an organic solvent; take the aqueous phase and adjust the pH value to 2 - 4 with an inorganic acid, while maintaining the temperature of the reactants within the range of 0 - 20°C. The organic solvent for washing can be one of n - heptane, n - hexane, or petroleum ether or a mixed solvent.

[0094] pS22. The organic phase is obtained by extraction with an organic solvent. The organic solvent used for extraction can be selected from at least one of ethyl acetate, n-butanol, and n-pentanol. For example, ethyl acetate can be used, and the number of extraction times can be 1 to 3 times.

[0095] pS23. The obtained organic phase is washed and dried to obtain the product. The organic phase is washed with saturated NaCl aqueous solution.

[0096] As a specific embodiment of pS2: Ethanol and an aqueous sodium hydroxide solution are added to ethyl 2-methyl-2-ethyl-4-pentenoate. 6 - 12 mL of ethanol is added per gram of ethyl 2-methyl-2-ethyl-4-pentenoate, and the molar ratio of ethyl 2-methyl-2-ethyl-4-pentenoate to NaOH is 1:4. The reaction is refluxed for 6 - 12 hours. After the reaction is completed, ethanol is removed by rotary evaporation under reduced pressure, and water is added for dilution. It is washed twice with n-heptane, and the organic phase is discarded. Hydrochloric acid is added dropwise to the aqueous phase to adjust the pH value to 2 - 4, and then extracted with ethyl acetate. After combining the organic phases, they are washed with saturated NaCl aqueous solution, dried, filtered, the filter cake is rinsed with ethyl acetate, and concentrated under reduced pressure to obtain the product.

[0097] The embodiments of the present invention also propose an ethosuximide product obtained by the above synthesis method. The ethosuximide in the embodiments of the present invention has high purity, which can reach 99.80%, and low impurity level, meeting the requirements of the pharmaceutical grade.

[0098] Example 1

[0099] The synthesis method of ethosuximide proposed in this example:

[0100] S1: 2-Methyl-2-ethyl-4-pentenoic acid undergoes an oxidation reaction under the action of acidic potassium permanganate to obtain 2-methyl-2-ethylsuccinic acid;

[0101] Take 297.25 g (1.0 eq) of 2-methyl-2-ethyl-4-pentenoic acid and add it to the reaction vessel. Add 3902 mL (2.8 eq) of 1.5 M sulfuric acid solution, stir, and continuously add 991.2 g (3.0 eq) of KMnO4 while controlling the addition rate. The temperature of the reaction system is controlled at 50 °C. After the addition is completed, record the total duration of adding potassium permanganate, and continue stirring for 60 min.

[0102] Work-up: After the reaction was completed, the mixture was filtered, and the filter cake was washed twice with water. The filtrates were combined to obtain 270 mL of filtrate, which was washed twice with n-heptane (2×1080 mL), and the organic phase was discarded. The aqueous phase was extracted twice with EA (2×1620 mL), and the organic phases were combined, washed once with saturated sodium chloride solution (1×1080 mL), dried over anhydrous sodium sulfate, filtered, and the filter cake was rinsed with EA twice after rinsing the bottle wall with EA. The filtrate was concentrated under reduced pressure at 42 °C to obtain 285.3 g of a white waxy solid. The yield of 2-methyl-2-ethylsuccinic acid was 85.2%, and the purity was 88.54%.

[0103] S2: 2-Methyl-2-ethylsuccinic acid undergoes a cyclization reaction with ammonia water to form ethosuximide.

[0104] 170 g (1.0 eq) of 2-methyl-2-ethylsuccinic acid was taken, 166.6 mL of water was added, and 166.6 mL (2.2 eq) of ammonia water (mass percentage concentration of 25%) was added with stirring. The mixture was stirred until dissolved. The temperature was raised for heating, and the water in the reaction solution was removed by fractional distillation. When the reaction temperature reached 150 °C, the reaction was carried out for 4 hours. After the reaction was completed, heating was stopped, and the reaction solution was cooled to 80 °C. 680 mL of water was added, and 17 g of activated carbon was added for decolorization. The mixture was filtered while hot, and the filter cake was washed twice with water to obtain a crude product solution.

[0105] Work-up: The crude product solution was extracted three times with chloroform (3×510 mL), and the chloroform phases were combined. 510 mL of 3% aqueous sodium bicarbonate solution was added to the chloroform phase for washing once, 510 mL of purified water was added for washing once, dried over anhydrous sodium sulfate, filtered, and the bottle wall and the filter cake were rinsed with chloroform. The filtrates were combined, concentrated under reduced pressure at 30-35 °C until no droplets were present, and dried in vacuo at 30-35 °C to obtain 127.4 g of ethosuximide. The yield was 85.1%, and the purity was 99.59%.

[0106] After further purification of 2-methyl-2-ethyl-4-pentenoic acid 1 The H-NMR spectrum is as Figure 1 shown. (10 g of the white waxy solid was taken, the pH was adjusted to 10 with 1 mol / L sodium hydroxide, washed twice with EA (2×90 mL), then the pH was adjusted to 1 by dropwise addition of 1 mol / L hydrochloric acid, the aqueous phase was extracted twice with EA (2×90 mL), the organic phases were combined, dried and concentrated, and the purity was 95.23%.) The 1 H-NMR, 13 C-NMR, and ESI-MS spectra of ethosuximide are respectively as Figures 2 - 5 shown.

[0107] Example 2

[0108] Take 29.7 g (1.0 eq) of 2-methyl-2-ethyl-4-pentenoic acid and add it to a reaction vessel. Then add 390.2 mL of 1.5 M sulfuric acid solution and stir. Add 1.6 L of an aqueous potassium permanganate solution with a mass percentage concentration of 6% dropwise to the reaction system over the same total duration as in Example 1, control the temperature of the reaction system at 50 °C, and continue stirring for 60 min after the addition is complete.

[0109] After the reaction is completed, filter, wash the filter cake twice with an appropriate amount of water, and combine the filtrates. Wash the filtrate twice with n-heptane and discard the organic phase. Extract the aqueous phase twice with EA, combine the organic phases, wash with saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter, wash the bottle wall with EA and then wash the filter cake, twice in total, and concentrate under reduced pressure at 42 °C. Calculate the yield of 2-methyl-2-ethylsuccinic acid to be 84.5% and the purity to be 86.4%.

[0110] Example 3

[0111] 1. Prepare using the method of Example 1, with the difference that the concentration of sulfuric acid in S1 is changed, as shown in Table 1 specifically. After the reaction is completed, weigh and calculate the product yield, and detect the product purity. The results are shown in Table 1.

[0112] Table 1

[0113] Number Sulfuric acid concentration Dosage of sulfuric acid Dosage of potassium permanganate Yield (%) Purity (%) 1 0.5M 2.8eq 3.0eq 50.1 81.72 2 1.0M 2.8eq 3.0eq 81.6 88.32 3 2M 2.8eq 3.0eq 85.5 88.48

[0114] It can be found from the above examples that when the concentration of sulfuric acid is low, the product yield is low and the purity is also relatively low. After increasing the concentration of sulfuric acid, the yield is significantly improved.

[0115] 2. Prepare using the method of Example 1, with the difference that the amount of sulfuric acid in S1 is changed, as shown in Table 2 specifically. After the reaction is completed, weigh and calculate the product yield, and detect the product purity. The results are shown in Table 2.

[0116] Table 2

[0117]

[0118]

[0119] It can be found from the above examples that when the amount of sulfuric acid is too small, the product yield is low and the purity is also relatively low. When the amount of sulfuric acid is too large, the yield shows a downward trend.

[0120] 3. Prepare using the method of Example 1, with the difference that the amount of potassium permanganate in S1 is changed, as shown in Table 3 specifically. After the reaction is completed, weigh and calculate the product yield, and detect the product purity. The results are shown in Table 3.

[0121] Table 3

[0122]

[0123] It can be found from the above embodiments that when the amount of potassium permanganate used is small, the yield of the product is low and the purity is also relatively low. As the amount of potassium permanganate used increases, both the yield and the purity increase to a certain extent. However, when the amount of potassium permanganate used further increases, there is no tendency for further improvement in the yield and purity.

[0124] Example 4

[0125] The preparation was carried out by the method of Example 1, except that the addition method of potassium permanganate in S1 and the controlled temperature of the internal temperature were changed. After the reaction was completed, the yield of the product was weighed and calculated, and the purity of the product was detected. The results are shown in Table 4.

[0126] Table 4

[0127] Number Adding method of potassium permanganate Yield (%) Purity (%) 1 All potassium permanganate is directly added to the reaction system without controlling the internal temperature 28.6 70.53 2 Potassium permanganate is added in batches with the internal temperature controlled at 15°C 40.3 75.35 3 Potassium permanganate is added in batches with the internal temperature controlled at 70°C 58.4 70.24

[0128] It can be found from the above embodiments that when all the potassium permanganate is directly added to the reaction system, the reaction is violent, the heating rate is fast and the temperature is high, and the side reactions increase significantly, so the yield is significantly reduced.

[0129] If the control of the internal temperature of the reaction is improper, it will also have a significant impact on the yield and purity.

[0130] Example 5

[0131] The preparation was carried out by the method of Example 1, except that the organic solvent for the post-treatment in S1 was changed. After the reaction was completed, the yield of the product was weighed and calculated, and the purity of the product was detected. The results are shown in Table 5.

[0132] Table 5

[0133] Number Organic solvent for filtrate washing Solvent for extraction Yield (%) Purity (%) 1 n - Hexane EA 85.4 79.32 2 Petroleum ether EA 84.8 77.15 3 n - Heptane n - Butanol 86.6 75.54

[0134] It can be found from this embodiment that changing the type of the organic solvent used for the post-treatment has a certain impact on both the yield and the purity of the product.

[0135] Example 6

[0136] The preparation was carried out by the method of Example 1, except that the volume of the solvent for the post-treatment in S1 was changed. After the reaction was completed, the yield of the product was weighed and calculated, and the purity of the product was detected. The results are shown in Table 6.

[0137] Table 6

[0138]

[0139] It can be found from this embodiment that within the scope of the embodiments of the present invention, selecting the volume of the solvent used for the post-treatment can ensure the purity and yield of the product.

[0140] Example 7

[0141] It was prepared by the method of Example 1, except that the addition amount of ammonia water in S2 and the conditions of the cyclization reaction were changed, as specifically shown in Table 7. After the reaction was completed, the product yield was weighed and calculated, and the product purity was detected, and the results are shown in Table 7.

[0142] Table 7

[0143] Number Dosage of ammonia water Cyclization reaction conditions Purity (%) Yield (%) 1 1.0eq Heated at 150°C for 4 hours 98.15 54.8 2 1.0eq Heated at 160°C for 12 hours 97.20 55.7 3 1.5eq Heated at 180°C for 6 hours 97.61 68.6 4 1.5eq Heated at 160°C for 12 hours 97.22 65.3 5 2.0eq Heated at 150°C for 4 hours 99.24 84.2 6 2.4eq Heated at 140°C for 4 hours 99.98 85.5 7 3.0eq Heated at 150°C for 4 hours 98.86 79.4 8 3.2eq Heated at 150°C for 4 hours 97.94 78.2

[0144] According to the examples numbered 1 to 4, it can be seen that when the amount of NH3 used is less than 2 equivalents, the product yield is poor. Even by increasing the reaction temperature and prolonging the reaction time, there are still problems of low reaction rate and poor yield.

[0145] According to the examples numbered 5 to 8, it can be seen that increasing the amount of NH3 used and reasonably controlling the reaction temperature and time are beneficial to improving the reaction rate, reducing side reactions, and both the yield and purity are improved. Further increasing the amount of NH3 used shows no further increase in the yield and purity.

[0146] Example 8

[0147] It was prepared by the method of Example 1, except that only the cyclization reaction conditions in S2 were changed, as specifically shown in Table 8. After the reaction was completed, the product yield was weighed and calculated, and the product purity was detected, and the results are shown in Table 8.

[0148] Table 8

[0149] Number Dosage of ammonia water Cyclization reaction temperature (°C) Cyclization reaction time (h) Purity (%) Yield (%) 1 2.2eq 120 6 96.33 52.8 2 2.2eq 140 4 99.54 85.9 3 2.2eq 160 3 99.49 83.5 4 2.2eq 180 2 96.76 78.3

[0150] According to the above examples, it was found that the time and temperature of the cyclization reaction have a certain influence on the yield. When the temperature is low, the yield is still low after prolonging the reaction time. When the temperature is high, there is no further increase in the yield and purity.

[0151] Example 9

[0152] It was prepared by the method of Example 1, except that the washing conditions of the chloroform phase in S2 were changed (the volume of the washing solution is calculated based on the volume of the washing solution used per gram of 2-methyl-2-ethylsuccinic acid). After the reaction was completed, the product yield was weighed and calculated, and the product purity and content were detected, and the results are shown in Table 9:

[0153] Table 9

[0154]

[0155] According to the examples numbered 1 to 3, it can be seen that using saturated sodium chloride and pure water for washing cannot completely remove ethyl-2-methylsuccinic acid.

[0156] According to the embodiment No. 4, it is known that by washing with sodium bicarbonate solution, the diacid can be completely removed, but it has a certain impact on the yield.

[0157] According to the embodiments No. 5 - 9, it is known that by washing with a combination of sodium bicarbonate solution and pure water, both the purity and the yield of the product are improved.

[0158] Example 10

[0159] This example provides a preparation method of 2 - methyl - 2 - ethyl - 4 - pentenoic acid for the preparation in Example 1:

[0160] pS1: Using ethyl 2 - methylbutyrate and allyl bromide as raw materials to produce ethyl 2 - methyl - 2 - ethyl - 4 - pentenoate;

[0161] Under anhydrous and anaerobic conditions, 1265 mL (1.1 eq) of a solution of lithium diisopropylamide (LDA) in THF + n - hexane (v:v = 12:25) with a concentration of 2 mol / L was added to the reaction vessel, and the temperature was lowered to - 20 °C. 300 g (1.0 eq) of ethyl 2 - methylbutyrate dissolved in THF was added, and the internal temperature was maintained not higher than - 10 °C during the addition. After the addition, the temperature was maintained for 30 min; 306.1 g (1.1 eq) of allyl bromide dissolved in THF was added, and the internal temperature was maintained not higher than - 10 °C during the addition. After the addition, the temperature was maintained for 30 min; 2M hydrochloric acid solution was added dropwise, and the internal temperature was maintained not higher than 5 °C during the addition, and the pH was adjusted to 5.

[0162] The aqueous phase of the reaction solution was discarded, and the organic phase was washed with 600 mL of 1 mol / L hydrochloric acid, 600 mL of saturated aqueous NaHCO3 solution, and 600 mL of saturated aqueous NaCl solution respectively. The organic phase was concentrated under reduced pressure to obtain the product.

[0163] pS2: Hydrolyzing ethyl 2 - methyl - 2 - ethyl - 4 - pentenoate under alkaline conditions to obtain 2 - methyl - 2 - ethyl - 4 - pentenoic acid;

[0164] To the product of step pS1, sodium hydroxide solution (350.3 g (4.0 eq) of sodium hydroxide was taken and dissolved in 1200 mL of water) and 2400 mL of 95% ethanol solution were added, and the mixture was heated under reflux for 8 hours. After the reaction was completed, it was distilled under reduced pressure, diluted with 1200 mL of water and transferred to a separatory funnel, and washed 3 times with n - heptane.

[0165] Discard the organic phase, add 6M hydrochloric acid dropwise to the aqueous phase to adjust the pH value to 3. Extract the aqueous phase with EA twice, combine the organic phases, wash with saturated NaCl aqueous solution, dry with anhydrous NaSO4, filter, and concentrate under reduced pressure to obtain 283.6 g of 2-methyl-2-ethyl-4-pentenoic acid (reddish-brown oil), with a yield of 86.7% and a purity of 96.20%.

[0166] Comparative Example 1

[0167] Prepared according to the method of Example 1, with the difference that:

[0168] Take 297.25 g (1.0 eq) of 2-methyl-2-ethyl-4-pentenoic acid and 3902 mL of water, stir, and continuously add 991.2 g (3.0 eq) of KMnO4 in the same total duration as in Example 1. Control the temperature of the reaction system at 50 °C, and continue to stir for 60 min after the addition is complete. After the reaction is complete, add 1.5M sulfuric acid to adjust the pH of the reaction system to 1. Then perform the same post-treatment steps as in Example 1. Weigh and calculate the yield to be 38.7% and the purity to be 80.5%.

[0169] It can be seen from this comparative example that without adding acid during the oxidation process, the oxidation rate is slow, the reaction is incomplete, the yield of the product is low, and the purity is also poor.

[0170] The above are only specific embodiments of the present invention, enabling those skilled in the art to understand or implement the present invention. Various modifications to these embodiments will be obvious to those skilled in the art. The general principles defined herein can be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention will not be limited to these embodiments described herein, but rather will conform to the broadest scope consistent with the principles and novel features disclosed herein.

Claims

1. A method for synthesizing ethosuximide, characterized in that, It includes at least the following steps: S1. Oxidize 2-methyl-2-ethyl-4-pentenoic acid under the action of acidic potassium permanganate to obtain 2-methyl-2-ethylsuccinic acid; S2. Perform a cyclization reaction on 2-methyl-2-ethylsuccinic acid with NH3 to form ethosuximide.

2. The synthesis method according to claim 1, wherein In S1, the molar ratio of 2-methyl-2-ethyl-4-pentenoic acid to sulfuric acid is 1:2 - 4, preferably 1:2.4 - 3.6; Optionally, the molar ratio of 2-methyl-2-ethyl-4-pentenoic acid to potassium permanganate is 1:2 - 4, preferably 1:2.4 - 3.

6.

3. The synthesis method according to claim 1 or 2, characterized in that, In S1, the addition method of potassium permanganate is to continuously or batchwise add solid potassium permanganate or dropwise add a potassium permanganate solution; in the method of continuously or batchwise adding solid potassium permanganate, the concentration of sulfuric acid is 1 - 2 mol / L; in the method of dropwise adding a potassium permanganate solution, the concentration of sulfuric acid is 12 - 18 mol / L; Optionally, when adding potassium permanganate, control the reaction temperature in the reaction system at 20°C - 60°C, preferably 30°C - 50°C.

4. The synthesis method according to claim 1, characterized in that, In S1, after the oxidation reaction is completed, it also includes a post-treatment step, including: filtering the reaction product, washing the obtained filtrate with organic solvent A and extracting with organic solvent B to obtain an organic phase; washing the organic phase with saturated sodium chloride solution and drying to obtain a crude product; The organic solvent A is preferably one or more of n-heptane, n-hexane or petroleum ether; the organic solvent B is one or more of ethyl acetate, n-butanol, n-pentanol.

5. The synthesis method according to claim 1, wherein, In S2, the molar ratio of 2-methyl-2-ethylsuccinic acid to NH3 is 1:1 - 3; Optionally, the reaction temperature of the cyclization reaction is 120°C - 180°C, and the reaction time is 2 - 6 hours.

6. The synthesis method according to claim 1, characterized in that In S2, after the cyclization reaction is completed, it also includes a post-treatment step, including: extracting the crude product solution obtained from the cyclization reaction with an organic solvent, and washing and drying to obtain an ethosuximide product; Optionally, the organic solvent used for extraction is selected from one or more of dichloromethane, ethyl acetate, chloroform, dichloroethane, isopropyl ether.

7. The synthesis method according to claim 6, characterized in that, The washing liquid for washing includes: an aqueous sodium bicarbonate solution with a mass percentage concentration of 3% - 5% and pure water; Optionally, each washing liquid is washed 1 - 2 times; Optionally, each time of washing, the volume of the washing liquid used per gram of 2-methyl-2-ethylsuccinic acid is 2 - 4 mL.

8. The synthesis method according to claim 1 or 2, characterized in that, 2-Methyl-2-ethyl-4-pentenoic acid is prepared by the following method: Using ethyl 2-methylbutyrate and allyl bromide as raw materials, react under the condition of the presence of a non-nucleophilic strong base to obtain ethyl 2-methyl-2-ethyl-4-pentenoate; perform a hydrolysis reaction on ethyl 2-methyl-2-ethyl-4-pentenoate under alkaline conditions to obtain 2-methyl-2-ethyl-4-pentenoic acid; Optionally, the non-nucleophilic strong base is selected from lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, trityllithium, tritylsodium, tritylpotassium; Optionally, a non-nucleophilic strong base in an organic solvent, ethyl 2-methylbutyrate dissolved in an organic solvent, and allyl bromide dissolved in an organic solvent are added successively.

9. The synthesis method according to claim 8, characterized in that, During the hydrolysis reaction, an aqueous solution of an inorganic base and an alcoholic organic solvent are added to the reaction system; Optionally, the inorganic base is selected from one of sodium hydroxide and potassium hydroxide; Optionally, the molar ratio of ethyl 2-methyl-2-ethyl-4-pentenoate to the hydroxide ions in the inorganic base is 1:3 to 6; Optionally, the volume of the alcoholic organic solvent added per gram of ethyl 2-methyl-2-ethyl-4-pentenoate is 5 to 10 mL.

10. The ethosuximide product obtained by the synthesis method according to any one of claims 1 to 9.

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