A preparation method and product of ethosuximide

Abstract

The present invention relates to the field of pharmaceutical synthesis technology, and in particular to a preparation method and product of ethosuximide. The method comprises the following steps: subjecting 2-methyl-2-ethyl-4-pentenoic acid to an oxidation reaction under the action of acidic potassium permanganate to obtain 2-methyl-2-ethylsuccinic acid; and subjecting 2-methyl-2-ethylsuccinic acid to a cyclization reaction with NH3 to form ethosuximide. The synthetic route of ethosuximide proposed by the present invention has short steps, simple operation, low preparation cost, easy availability of raw materials, no need to use expensive catalysts, high reaction efficiency, and is suitable for industrial application. The prepared ethosuximide product has high purity and low impurity level, and can meet the requirements of pharmaceutical grade.

Description

Technical Field

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

[0002] Ethosuximide is a succinamide antiepileptic drug with rapid and complete oral absorption, reaching peak absorption within 1 to 4 hours. It has low plasma protein binding, with a half-life of approximately 60 hours in adults and approximately 30 hours in children. It is extensively metabolized in the liver through hydroxylation to inactive metabolites. Ethosuximide is primarily used for absence and clonic seizures, but is ineffective against tonic-clonic and partial-onset seizures. It can be used in combination with other antiepileptic drugs for mixed seizures. Ethosuximide can raise the seizure threshold and reduce seizure frequency, and is effective in treating absence status epilepticus. Ethosuximide is safe, effective, and non-sedative, with a long elimination half-life. A single daily dose is sufficient to control seizures, making it the preferred treatment for minor seizures.

[0003] The synthetic route for ethosuximide reported in the literature (Organic Syntheses, 1964, 44, 59-61) uses 2-butanone and ethyl 2-cyanoacetate as raw materials, and proceeds through the intermediate ethyl 2,3-dicyano-3-methylvalerate, but this intermediate is not isolated. The cyano and ester groups are hydrolyzed under acidic conditions provided by hydrochloric acid, and then heated for decarboxylation 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, which places high requirements on the qualifications of the production enterprises, creates great pressure on production safety, and imposes high regulatory requirements, making it difficult to achieve independent and controllable production of raw materials.

[0006] The existing technology has also reported a synthetic route using N-substituted vinyl-α-chloro-α-methylthioacetamide as a key intermediate, and the reaction process is as follows:

[0007]

[0008] This route uses intermediate 1 as the raw material and undergoes five steps of reaction with a total yield of 5.76%, which is relatively low. In addition, each step requires column chromatography for separation and purification. Heavy metal reagents such as chromium trioxide pyridine hydrochloride (PCC) are also used in the reaction process, which is a key environmental concern. This puts great pressure on the environment and is therefore not suitable for large-scale production of raw materials.

[0009] The literature has also reported a synthetic route with copper-catalyzed O2 oxidative C=C cleavage to construct an imide ring as the key step. The reaction process is as follows:

[0010]

[0011] However, this route still has the disadvantages of low yield, complex impurity types, high impurity content, and the need for column chromatography purification. It also requires the use of precious metal catalysts, and is therefore not suitable for large-scale production of raw materials.

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

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

[0014] The present invention provides a method for synthesizing ethosuximide, which comprises at least the following steps:

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

[0016] S2. cyclizing 2-methyl-2-ethylsuccinic acid with NH3 to form ethosuximide.

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

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

[0019] Optionally, in S1, potassium permanganate is added by continuously or batchwise adding solid potassium permanganate or by dropwise adding 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 potassium permanganate solution, the concentration of sulfuric acid is 12 to 18 mol / L.

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

[0021] Optionally, in S1, after the oxidation reaction is completed, a post-treatment step is further included, including: filtering the reaction product, washing the obtained filtrate with organic solvent A, and extracting with organic solvent B to obtain an organic phase; the organic phase is washed with saturated sodium chloride solution and dried 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, and 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 is completed, a post-treatment step is further included, including: extracting the crude product solution obtained from the cyclization reaction with an organic solvent, washing and drying to obtain the ethosuximide product. 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 liquid includes: a sodium bicarbonate aqueous solution with a mass percentage concentration of 3% to 5% and pure water. Preferably, each washing liquid is used for washing 1 to 2 times. Preferably, the volume of the washing liquid used for each gram of 2-methyl-2-ethylsuccinic acid during each washing 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 existing technology:

[0027] The synthetic route of ethosuximide proposed by the present invention has short steps, simple operation, low preparation cost, readily available raw materials, no need to use expensive catalysts, no need for special reaction conditions such as high pressure, high reaction efficiency, no need to use 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 pharmaceutical grade. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 2-Methyl-2-ethylsuccinate 1 H-NMR spectrum;

[0030] Figure 2 Ethosuximide 1 H-NMR spectrum;

[0031] Figure 3 Ethosuximide 1 Enlarged view of the H-NMR spectrum;

[0032] Figure 4 Ethosuximide 13 C-NMR spectrum;

[0033] Figure 5 This is the ESI-MS spectrum of ethosuximide. DETAILED DESCRIPTION

[0034] In order to more clearly understand the above-mentioned objectives, features and advantages of the present invention, the scheme of the present invention will be further described below. It should be noted that, in the absence of conflict, the embodiments of the present invention and the features therein can be combined with each other.

[0035] In the following description, many specific details are set forth to facilitate a full understanding of the present invention, but the present invention may also be implemented in other ways different from those described herein; it is obvious that the embodiments in the specification are only part of the embodiments of the present invention, rather than all 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: carbon nuclear magnetic resonance.

[0043] The present invention provides a method for preparing ethosuximide, which uses a synthetic route of oxidizing 2-methyl-2-ethyl-4-pentenoic acid to 2-methyl-2-ethylsuccinic acid. This method does not require the use of precious metal catalysts, and the intermediate product is easily purified, eliminating the need for separation and purification using a chromatography column. The method is particularly suitable for the industrial production of bulk drugs. Furthermore, through in-depth research, potassium permanganate was used as an oxidant for the oxidation reaction, resulting in low cost and high reaction efficiency. Specifically, the method comprises the following steps:

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

[0045]

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

[0047]

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

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

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

[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 1:2-4, and the molar ratio of 2-methyl-2-ethyl-4-pentenoic acid to potassium permanganate is 1:2-4, the oxidation reaction is efficient and complete, the yield can meet production needs, and the generated impurities can be separated through simple post-treatment and refining steps, without the need for purification using a chromatography column, making it suitable for industrial application.

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

[0053] Finally, because potassium permanganate has strong oxidizing properties, if potassium permanganate solid is all added at once, the reaction will be violent, and the reaction will be incomplete and side reactions will increase. Therefore, it is preferred to continuously add or add potassium permanganate solid or drip potassium permanganate solution in batches to control the reaction rate and reduce side reactions.

[0054] The specific addition method is: solid potassium permanganate is added in a continuous flow control feeding method or in batches, and the addition rate is based on controlling the reaction temperature of the reaction system to not exceed 60°C. For example, the reaction temperature can be controlled within the range of 20°C to 60°C by the addition rate of solid potassium permanganate. If the addition rate of solid potassium permanganate is too fast, the reaction temperature rises too quickly or the temperature is too high, which may result in a decrease in yield due to an increase in by-products. When adding solid potassium permanganate, sulfuric acid with a concentration of 1 to 2 mol / L can be used. In order to make the reaction system easier to stir, sulfuric acid with a concentration of 1 to 1.5 mol / L can also be used.

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

[0056] As an improvement to the embodiment of the present invention, after the potassium permanganate is added, the mixture is kept warm and stirred for 0.5 to 1.5 hours to ensure complete reaction and improve the yield.

[0057] After the oxidation reaction in S1 is completed, the 2-methyl-2-ethylsuccinic acid is purified and dried before being used in the next cyclization reaction. Specifically, the oxidized reaction product is filtered, the resulting filtrate is washed 1 to 3 times with organic solvent A, and extracted 1 to 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, and n-pentanol. Drying can be performed in various ways, such as by adding anhydrous sodium sulfate. Concentration can be performed under reduced pressure, specifically at a temperature of 40°C to 50°C.

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

[0059] As a specific implementation of the post-treatment of S1: the reaction product is filtered, the filter cake is washed with water, the filtrate is combined, the filtrate is washed with n-heptane, the organic phase is discarded, the aqueous phase is extracted with ethyl acetate, the organic phases are combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, rinsed with ethyl acetate, and concentrated under reduced pressure at 42°C to 45°C to obtain the product.

[0060] As an improvement to an embodiment of the present invention, in S2, 2-methyl-2-ethylsuccinic acid and NH3 undergo a cyclization reaction. The molar ratio of 2-methyl-2-ethylsuccinic acid to NH3 can be 1:1 to 3. Further research has 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 unsatisfactory. Therefore, using an excess of 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 can further be 1:2.0 to 2.4, for example 1:2.1, 1:2.2, or 1:2.3.

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

[0062] As an improvement to an embodiment of the present invention, the reaction conditions of the cyclization reaction are to raise the temperature to 120°C to 180°C and react for 2 to 6 hours after fractional distillation and water removal. Specifically, during the actual reaction, the temperature can be controlled in the range of 120°C to 125°C, 125°C to 135°C, 135°C to 145°C, 145°C to 155°C, and 155°C to 165°C. The cyclization reaction time can be 3 hours, 4 hours, or 5 hours. For example, the temperature can be raised to 140°C to 160°C and reacted 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 S2 reaction, 2-methyl-2-ethylsuccinic acid is added to 12% to 14% ammonia water by weight, stirred to dissolve, heated to 145° C. to 155° C., reacted for 4 to 5 hours, and then stopped heating. After the reaction, water is added, and the solution is decolorized and washed to obtain a crude product solution. The volume of water added is 3 to 6 mL, preferably 4 to 5 mL, per gram of 2-methyl-2-ethylsuccinic acid.

[0064] In S2, after the reaction is completed, a post-treatment step is further included, including: extracting, washing and drying the crude product solution to obtain the ethosuximide product.

[0065] The organic solvent for extraction can be, for example, dichloromethane, ethyl acetate, chloroform, dichloroethane, or isopropyl ether, with chloroform being particularly preferred. The extraction can be repeated multiple times to ensure yield, for example, 1 to 4 times, and specifically 2, 3, or 4 times. The organic phase obtained by extraction is collected and washed, specifically by first washing 1 to 2 times with a 3% to 5% by mass sodium bicarbonate aqueous solution to remove unreacted 2-methyl-2-ethylsuccinic acid, and then washing 1 to 2 times with pure water.

[0066] In each washing, the volume of washing solution used per gram of ethyl-2-methylsuccinic acid is 2 to 4 mL, specifically 2 mL, 2.5 mL, 3 mL, or 3.5 mL. After washing, the product is dried and concentrated to obtain the ethosuximide product.

[0067] As a specific embodiment of post-treatment S2: After the reaction is completed, the reaction solution is cooled, decolorized with water and activated carbon, filtered, the filter cake washed with water, and the filtrate extracted 2-4 times with chloroform. The organic phases are combined. The organic phases are first washed 1-2 times with a 3% to 5% by weight aqueous sodium bicarbonate solution, then 1-2 times with pure water, dried, and concentrated to obtain the ethosuximide product. Concentration can be performed by vacuum distillation at 30°C to 35°C.

[0068] Because acidic potassium permanganate is as oxidant, the reaction is violent, the side reaction is many, and the yield is relatively low. Therefore, in the field of drug synthesis, a novel oxidation catalyst is generally adopted, or other reaction routes are adopted. And the embodiment of the present invention is found by studying unexpectedly that the double bond in 2-methyl-2-ethyl-4-pentenoic acid is directly oxidized with acidic potassium permanganate, not only with the technical advantage of short reaction circuit, and by the control of conditions, the intermediate product that yield and purity all meet preparation requirements can be obtained. In the starting material of the embodiment of the present invention, 2-methyl-2-ethyl-4-pentenoic acid is easy to prepare and moderate in price, and potassium permanganate and sulfuric acid are cheap and material is easy to obtain. The synthetic route of the embodiment of the present invention does not need to use highly toxic reagents (such as cyanide), nor does it need to use expensive metal catalysts. Most importantly, the product after the embodiment of the present invention oxidation reaction and cyclization reaction does not need to be purified using a chromatography column, which not only greatly reduces the cost of separation and purification, but is also particularly suitable for the production of pharmaceutical raw materials.

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

[0070] pS1. Ethyl 2-methylbutyrate and allyl bromide are reacted in the presence of a non-nucleophilic strong base to produce ethyl 2-methyl-2-ethyl-4-pentenoate. The reaction equation is as follows:

[0071]

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

[0073]

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

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

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

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

[0078] As an improvement to an embodiment of the present invention, in pS1, ethyl 2-methylbutyrate and allyl bromide are both dissolved in an organic solvent and then 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 used.

[0079] As an improvement to an embodiment of the present invention, 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 sequentially to pS1; while ensuring that the reaction temperature during the raw material addition process is within the range of -60°C to -10°C to control the reaction progress and the occurrence of side reactions.

[0080] As an improvement to an embodiment of the present invention, in pS1, a non-nucleophilic strong base in an organic solvent is first added, followed by ethyl 2-methylbutyrate dissolved in an organic solvent. After the additions are complete, the reaction temperature is maintained within the range of -60°C to -10°C for a period of time, for example, 20 to 40 minutes, specifically 30 minutes, to ensure sufficient reaction. Allyl bromide dissolved in an organic solvent is then added, and the reaction temperature is maintained within the range of -60°C to -10°C for 20 to 40 minutes, specifically 30 minutes.

[0081] As an improvement to the embodiment of the present invention, in pS1, after the reaction is complete, a mineral acid is added to adjust the pH to 5-6 to terminate the reaction. Specifically, dilute hydrochloric acid can be used. Meanwhile, the temperature during the addition is maintained below 5°C, for example, within a range of -10°C to 5°C, to control side reactions.

[0082] The embodiment of the present invention also proposes a specific implementation method of pS1: under anhydrous and oxygen-free 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, and the temperature is maintained at -60°C to -10°C during the addition process, and the temperature is maintained for 20 to 30 minutes after the addition is completed; allyl bromide dissolved in a dry organic solvent is added dropwise, and the temperature is maintained at -60°C to -10°C during the addition process, and the temperature is maintained for 25 to 35 minutes after the addition is completed; dilute hydrochloric acid is added dropwise to adjust the pH to 5 to 6 to terminate the reaction, and the temperature is maintained at -50°C to 5°C during the addition process.

[0083] As an improvement to the embodiment of the present invention, in pS1, a post-treatment step is further included after the reaction is completed, 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] More preferably, the post-treatment step comprises discarding the aqueous phase of the reaction solution, washing the organic phase with dilute hydrochloric acid, saturated aqueous NaHCO₃, and saturated aqueous NaCl, sequentially, drying, filtering, and washing the filter cake with an organic solvent, preferably 2 to 4 times. The product is obtained after concentration. The organic solvent used to wash the filter cake is at least one of dichloromethane, ethyl acetate, chloroform, and dichloroethane. Concentration can be performed under reduced pressure at 40 to 45°C.

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

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

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

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

[0089] As an improvement to an 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 to 6, and can further be 1:4 to 5, specifically 1:4, 1:4.5 or 1:5.

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

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

[0092] As an improvement to the embodiment of the present invention, in pS2, after the hydrolysis reaction is completed, a post-treatment step is further included, specifically including:

[0093] pS21. Remove the alcoholic organic solvent from the reaction system and wash with an organic solvent. Adjust the pH to 2-4 by adding an inorganic acid to the aqueous phase, while maintaining the temperature of the reactants within the range of 0-20°C. The organic solvent for washing can be n-heptane, n-hexane, or petroleum ether, or a mixture thereof.

[0094] pS22, extracting with an organic solvent to obtain an organic phase, 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 extractions can be 1 to 3 times;

[0095] The organic phase was washed with a saturated aqueous solution of NaCl and the product was obtained.

[0096] As a specific embodiment of pS2: ethanol and sodium hydroxide solution are added to 2-methyl-2-ethyl-4-pentenoic acid ethyl ester, with 6-12 mL of ethanol added per gram of 2-methyl-2-ethyl-4-pentenoic acid ethyl ester, and the molar ratio of 2-methyl-2-ethyl-4-pentenoic acid ethyl ester to NaOH being 1:4; reflux reaction for 6-12 hours, and after the reaction, the ethanol is removed by vacuum rotary evaporation and diluted with water. Wash twice with n-heptane, discard the organic phase, add hydrochloric acid dropwise to the aqueous phase to adjust the pH to 2-4, extract with ethyl acetate, combine the organic phases, wash with saturated NaCl aqueous solution, dry, filter, rinse the filter cake with ethyl acetate, and concentrate under reduced pressure to obtain the product.

[0097] The present invention also provides an ethosuximide product obtained by the above-mentioned synthesis method. The ethosuximide of the present invention has a high purity of 99.80% and a low impurity level, which can meet the requirements of pharmaceutical grade.

[0098] Example 1

[0099] This example proposes a method for synthesizing ethosuximide:

[0100] S1: 2-methyl-2-ethyl-4-pentenoic acid is oxidized in the presence of acidic potassium permanganate to obtain 2-methyl-2-ethylsuccinic acid;

[0101] Take 297.25g (1.0eq) of 2-methyl-2-ethyl-4-pentenoic acid and add it to the reaction vessel. Add 3902mL (2.8eq) of 1.5M sulfuric acid solution and stir. Add KMnO4991.2g (3.0eq) continuously. Control the addition rate and the temperature of the reaction system at 50°C. After the addition is completed, record the total time of adding potassium permanganate and continue stirring for 60min.

[0102] Post-treatment: After completion of the reaction, the reaction mixture was filtered, and the filter cake was washed twice with water. The resulting filtrate was combined to obtain 270 mL of filtrate, which was then washed twice with n-heptane (1080 mL). The organic phase was discarded. The aqueous phase was extracted with EA (1620 mL twice). The combined organic phases were washed once with saturated sodium chloride solution (1080 mL once). The organic phase was dried over anhydrous sodium sulfate, filtered, and the sides and filter cake were rinsed twice with EA. The product 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 aqueous ammonia to form ethosuximide.

[0104] Take 170g (1.0eq) of 2-methyl-2-ethylsuccinic acid, add 166.6mL of water, and add 166.6mL (2.2eq) of aqueous ammonia (25% by mass) with stirring, stirring to dissolve. Heat the reaction solution and remove water by fractional distillation. The reaction temperature is raised to 150°C and the reaction is carried out for 4 hours. After the reaction is completed, the heating is stopped, the reaction solution is cooled to 80°C, 680mL of water is added, and 17g of activated carbon is added for decolorization. The solution is filtered while hot, and the filter cake is washed with water twice to obtain a crude product solution.

[0105] Post-treatment: The crude product solution was extracted with chloroform (3 x 510 mL), and the chloroform phases were combined. The chloroform phase was washed once with 510 mL of 3% sodium bicarbonate aqueous solution and once with 510 mL of purified water. The mixture was dried over anhydrous sodium sulfate and filtered. The flask wall and filter cake were rinsed with chloroform. The filtrates were combined and concentrated under reduced pressure at 30-35°C until there were no droplets. The mixture was then dried under vacuum at 30-35°C to obtain 127.4 g of ethosuximide, with a yield of 85.1% and a purity of 99.59%.

[0106] 2-Methyl-2-ethyl-4-pentenoic acid after further purification 1 H-NMR spectrum Figure 1 (Take 10g of white waxy solid, add 1mol / L sodium hydroxide to adjust the pH to 10, add EA to wash twice × 90mL, then add 1mol / L hydrochloric acid dropwise to adjust the pH to 1, extract the aqueous phase with EA twice × 90mL, combine the organic phases, dry and concentrate, the purity is 95.23%.) 1 H-NMR, 13 C-NMR and ESI-MS spectra are shown in Figures 2 to 5 shown.

[0107] Example 2

[0108] 29.7 g (1.0 eq) of 2-methyl-2-ethyl-4-pentenoic acid was added to a reaction vessel, 390.2 mL of 1.5 M sulfuric acid solution was added, and the mixture was stirred. 1.6 L of a 6% by mass aqueous solution of potassium permanganate was added dropwise to the reaction system over the same total time as in Example 1. The temperature of the reaction system was controlled at 50° C. After the addition was completed, stirring was continued for 60 min.

[0109] After the reaction is complete, filter the mixture, wash the filter cake twice with appropriate amounts 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, rinse the flask walls and the filter cake twice with EA, and concentrate under reduced pressure at 42°C. The calculated yield of 2-methyl-2-ethylsuccinic acid is 84.5%, and the purity is 86.4%.

[0110] Example 3

[0111] 1. The method of Example 1 was used for preparation, except that the concentration of sulfuric acid in S1 was changed, as shown in Table 1. After the reaction was completed, the product yield was calculated by weighing and the product purity was tested. The results are shown in Table 1.

[0112] Table 1

[0113] serial number sulfuric acid concentration Sulfuric acid dosage Potassium permanganate dosage 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] According to the above examples, it can be found that when the concentration of sulfuric acid is low, the yield of the product is low and the purity is relatively low. After increasing the concentration of sulfuric acid, the yield is significantly improved.

[0115] 2. The method of Example 1 was used for preparation, except that the amount of sulfuric acid in S1 was changed, as shown in Table 2. After the reaction was completed, the product yield was calculated by weighing and the product purity was tested. The results are shown in Table 2.

[0116] Table 2

[0117]

[0118]

[0119] According to the above examples, it can be found that when the amount of sulfuric acid is too small, the yield of the product is low and the purity is relatively low. When the amount of sulfuric acid is too large, the yield tends to decrease.

[0120] 3. The method of Example 1 was used for preparation, except that the amount of potassium permanganate in S1 was changed, as shown in Table 3. After the reaction was completed, the product yield was calculated by weighing and the product purity was tested. The results are shown in Table 3.

[0121] Table 3

[0122]

[0123] Can find according to above-described embodiment, when the consumption of potassium permanganate was less, the yield of product was on the low side, and purity was also relatively on the low side.Along with the increase of potassium permanganate consumption, yield and purity all have certain raising.But when potassium permanganate consumption further increases, yield and purity do not have the trend of further improving.

[0124] Example 4

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

[0126] Table 4

[0127] serial number Potassium permanganate addition method Yield (%) purity(%) 1 Potassium permanganate was added directly to the reaction system without controlling the internal temperature. 28.6 70.53 2 Potassium permanganate was added in batches and the internal temperature was controlled at 15°C 40.3 75.35 3 Potassium permanganate was added in batches and the internal temperature was controlled at 70°C. 58.4 70.24

[0128] According to the above examples, it can be found that when all 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 are significantly increased, so the yield is significantly reduced.

[0129] If the reaction temperature is not properly controlled, it will also have a significant impact on the yield and purity.

[0130] Example 5

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

[0132] Table 5

[0133] serial number Organic solvent for washing the filtrate Extraction solvent 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] According to this example, it can be found that changing the type of organic solvent used in the post-treatment has a certain impact on the yield and purity of the product.

[0135] Example 6

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

[0137] Table 6

[0138]

[0139] According to this embodiment, it can be found that the purity and yield of the product can be ensured by selecting the volume of the solvent used in the post-treatment within the scope of the embodiment of the present invention.

[0140] Example 7

[0141] The preparation was carried out using the method of Example 1, except that the amount of ammonia added in S2 and the conditions of the cyclization reaction were changed, as shown in Table 7. After the reaction was completed, the product yield was calculated by weighing and the product purity was tested, and the results are shown in Table 7.

[0142] Table 7

[0143] serial number Ammonia addition amount Cyclization reaction conditions purity(%) Yield (%) 1 1.0eq Heat at 150°C for 4 hours 98.15 54.8 2 1.0eq Heat at 160℃ for 12 hours 97.20 55.7 3 1.5eq Heat at 180°C for 6 hours 97.61 68.6 4 1.5eq Heat at 160℃ for 12 hours 97.22 65.3 5 2.0eq Heat at 150°C for 4 hours 99.24 84.2 6 2.4eq Heat at 140°C for 4 hours 99.98 85.5 7 3.0eq Heat at 150°C for 4 hours 98.86 79.4 8 3.2eq Heat at 150°C for 4 hours 97.94 78.2

[0144] According to Examples 1 to 4, when NH3 is used in an amount less than 2 times the equivalent, 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] As shown in Examples 5 to 8, increasing the amount of NH3 and properly controlling the reaction temperature and time can help increase the reaction rate, reduce side reactions, and improve both yield and purity. Further increases in the amount of NH3 did not show any further improvement in yield or purity.

[0146] Example 8

[0147] The preparation was carried out using the method of Example 1, except that only the cyclization reaction conditions in S2 were changed, as shown in Table 8. After the reaction was completed, the product yield was calculated by weighing and the product purity was tested, and the results are shown in Table 8.

[0148] Table 8

[0149] serial number Ammonia addition amount Cyclization reaction temperature (℃) 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 had a certain influence on the yield. When the temperature was low, the yield was still low after extending the reaction time. When the temperature was high, the yield and purity did not increase further.

[0151] Example 9

[0152] The preparation was carried out using the method of Example 1, except that the washing conditions of the chloroform phase in S2 were changed (the volume of the washing liquid was based on the volume of the washing liquid used per gram of 2-methyl-2-ethylsuccinic acid). After the reaction was completed, the product yield was calculated by weighing, and the product purity and content were tested. The results are shown in Table 9:

[0153] Table 9

[0154]

[0155] According to Examples No. 1 to 3, it is known that ethyl-2-methylsuccinic acid cannot be completely removed by washing with saturated sodium chloride and pure water.

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

[0157] According to Examples No. 5 to 9, the use of a sodium bicarbonate solution and pure water for washing can improve the purity and yield of the product.

[0158] Example 10

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

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

[0161] Under anhydrous and anaerobic conditions, 1265 mL (1.1 eq) of a 2 mol / L solution of lithium diisopropylamide (LDA) in THF + n-hexane (v:v = 12:25) was added to the reaction vessel, 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 kept below -10°C during the addition, and the temperature was maintained for 30 minutes after the addition; 306.1 g (1.1 eq) of allyl bromide dissolved in THF was added, and the internal temperature was kept below -10°C during the addition, and the temperature was maintained for 30 minutes after the addition; 2 M hydrochloric acid solution was added dropwise, and the internal temperature was kept below 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: 2-methyl-2-ethyl-4-pentenoic acid ethyl ester is hydrolyzed under alkaline conditions to give 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 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, the mixture was evaporated under reduced pressure, diluted with 1200 mL of water, and transferred to a separatory funnel and washed three times with n-heptane.

[0165] The organic phase was discarded, 6 M hydrochloric acid was added dropwise to the aqueous phase to adjust the pH to 3, the aqueous phase was extracted twice with EA, the combined organic phases were washed with saturated aqueous NaCl solution, dried over anhydrous NaSO4, filtered, and concentrated under reduced pressure to obtain 283.6 g of 2-methyl-2-ethyl-4-pentenoic acid (brown-red 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, except that:

[0168] 297.25 g (1.0 eq) of 2-methyl-2-ethyl-4-pentenoic acid and 3902 mL of water were stirred. KMnO (4991.2 g) (3.0 eq) was added continuously over the same total time as in Example 1. The reaction temperature was maintained at 50°C, and stirring was continued for 60 minutes after the addition was complete. After the reaction was complete, 1.5 M sulfuric acid was added to adjust the pH of the reaction system to 1. The same post-processing steps as in Example 1 were then performed. The calculated yield was 38.7%, and the purity was 80.5%.

[0169] It can be seen from this comparative example that if no acid is added during the oxidation process, the oxidation rate will be slow, the reaction will be incomplete, the yield of the product will be low, and the purity will be poor.

[0170] The foregoing description is intended only to provide specific embodiments of the present invention, which will enable those skilled in the art to understand and implement the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the general principles defined herein may be implemented in other embodiments without departing from the spirit or scope of the present invention. Therefore, the present invention is not intended to be limited to the embodiments described herein, but is to be construed in the widest manner consistent with the principles and novel features disclosed herein.

Claims

1. A method for synthesizing ethosuximide, characterized in that: At least the following steps are included: S1, oxidizing 2-methyl-2-ethyl-4-pentenoic acid under the action of acidic potassium permanganate to obtain 2-methyl-2-ethylsuccinic acid; The molar ratio of 2-methyl-2-ethyl-4-pentenoic acid to sulfuric acid is 1:2-4, and the molar ratio of 2-methyl-2-ethyl-4-pentenoic acid to potassium permanganate is 1:2-4; The potassium permanganate is added by continuously or batchwise adding solid potassium permanganate or by dropwise adding a potassium permanganate solution; in the continuous or batchwise adding of solid potassium permanganate, the concentration of sulfuric acid is 1 to 2 mol / L; in the dropwise adding of the potassium permanganate solution, the concentration of sulfuric acid is 12 to 18 mol / L; When adding potassium permanganate, the reaction temperature in the reaction system is controlled at 20°C to 60°C; S2. cyclizing 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 1:2.4-3.

6.

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

6.

4. The synthesis method according to claim 1, characterized in that In S1, the reaction temperature in the reaction system is controlled to be 30°C to 50°C when potassium permanganate is added.

5. The synthesis method according to claim 1, characterized in that In S1, after the oxidation reaction is completed, a post-treatment step is further included, 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 one or more of n-heptane, n-hexane or petroleum ether; the organic solvent B is one or more of ethyl acetate, n-butanol and n-pentanol.

6. The synthesis method according to claim 1, characterized in that In S2, the molar ratio of 2-methyl-2-ethylsuccinic acid to NH3 is 1:1-3.

7. The synthesis method according to claim 1, characterized in that In S2, the reaction temperature of the cyclization reaction is 120° C. to 180° C., and the reaction time is 2 to 6 hours.

8. The synthesis method according to claim 1, characterized in that In S2, after the cyclization reaction is completed, a post-treatment step is further included, including: extracting the crude product solution obtained by the cyclization reaction with an organic solvent, washing and drying to obtain the ethosuximide product.

9. The synthesis method according to claim 8, characterized in that The organic solvent used in the extraction is selected from one or more of dichloromethane, ethyl acetate, chloroform, dichloroethane and isopropyl ether.

10. The synthesis method according to claim 8, characterized in that The washing solution comprises: a sodium bicarbonate aqueous solution with a mass percentage concentration of 3% to 5% and pure water.

11. The synthesis method according to claim 8, characterized in that Wash 1 to 2 times with each washing solution.

12. The synthesis method according to claim 8, characterized in that In each washing, the volume of the washing solution used is 2 to 4 mL per gram of 2-methyl-2-ethylsuccinic acid.

13. The synthesis method according to any one of claims 1 to 3, characterized in that 2-Methyl-2-ethyl-4-pentenoic acid was prepared by the following method: Ethyl 2-methylbutyrate and allyl bromide are used as raw materials and reacted in the presence of a non-nucleophilic strong base to obtain ethyl 2-methyl-2-ethyl-4-pentenoate; and ethyl 2-methyl-2-ethyl-4-pentenoate is hydrolyzed under alkaline conditions to obtain 2-methyl-2-ethyl-4-pentenoic acid.

14. The synthesis method according to claim 13, characterized in that The non-nucleophilic strong base is selected from lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, trityl lithium, trityl sodium, and trityl potassium.

15. The synthesis method according to claim 13, characterized in that A non-nucleophilic strong base in an organic solvent, ethyl 2-methylbutyrate in an organic solvent, and allyl bromide in an organic solvent are added in sequence.

16. The synthesis method according to claim 13, characterized in that During the hydrolysis reaction, an aqueous solution of an inorganic base and an alcohol organic solvent are added to the reaction system.

17. The synthesis method according to claim 16, characterized in that The inorganic base is selected from one of sodium hydroxide and potassium hydroxide.

18. The synthesis method according to claim 17, characterized in that The molar ratio of ethyl 2-methyl-2-ethyl-4-pentenoate to the hydroxide ions in the inorganic base is 1:3-6.

19. The synthesis method according to claim 16, characterized in that The volume of the alcohol organic solvent added per gram of ethyl 2-methyl-2-ethyl-4-pentenoate is 5 to 10 mL.

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