An intermediate, its preparation method and application

Abstract

The present invention discloses an intermediate, a preparation method thereof and an application. In particular, the present invention discloses a method for preparing a compound of formula IA, wherein R1 and R2 are independently selected from C 1‑6 alkyl. By using the method of the present invention to synthesize ethosuximide, the use of highly toxic cyanide as a raw material can be avoided, the reaction conditions are mild, the yield is relatively high, the product quality is good, and there are few impurities, which is suitable for industrial production. #imgabs0#

Description

Technical Field

[0001] The present invention relates to a method for synthesizing ethosuximide and its analogs. The present invention also relates to an intermediate for synthesizing ethosuximide and its analogs, and a preparation method of the intermediate. The present invention further relates to the application of the intermediate in the synthesis of ethosuximide and its analogs. Background Art

[0002] As an antiepileptic drug, ethosuximide is mainly used for the treatment of petit mal epilepsy, that is, the treatment of absence seizures and clonic seizures, and is ineffective against tonic-clonic and partial seizures. It can be used together with other antiepileptic drugs for mixed epileptic seizures. The advantages of ethosuximide are safety, effectiveness, no sedative effect, and a relatively long elimination half-life, and single daily dosing can control seizures. There is a chiral carbon atom in the structure of ethosuximide, but the marketed drug is a racemic mixture, not an optically pure enantiomer.

[0003] Currently, the reported synthetic methods of ethosuximide in the literature mainly have the following three routes:

[0004] 1. A synthetic route with 2-methyl-2-ethylsuccinic acid as the key intermediate

[0005]

[0006] This route was first reported in two papers in 1927. According to the brief description in the literature, it uses the ammonium salt of 2-methyl-2-ethylsuccinic acid as the raw material and is obtained by atmospheric distillation (J Chem Soc, 1927, 600 - 605; J Chem Soc, 1927, 1252 - 1256). The US patent US2993835 for a pharmaceutical composition for treating petit mal epilepsy with ethosuximide as the active ingredient also cites the synthetic methods of these two papers for the preparation of ethosuximide. Hill RK et al. described in detail in the literature (J OrgChem, 1981, 46, 2757 - 2764) the method of reacting 2-methyl-2-ethylsuccinic acid with ammonia and then performing vacuum distillation to prepare ethosuximide; Hine J et al. based on the paper of Hill RK, reacted 2-methyl-2-ethylsuccinic acid with ammonium hydroxide and then performed vacuum distillation to prepare ethosuximide (J Org Chem, 1988, 53, 884 - 887).

[0007] The synthesis of the raw material 2-methyl-2-ethylsuccinic acid used in this route is mainly carried out through the following route (OrganicSyntheses, 1964, 44, 59 - 61). Using 2-butanone and ethyl 2-cyanoacetate as raw materials, passing through the intermediate ethyl 2,3-dicyano-3-methylvalerate, but this intermediate is not separated, and the cyano group and ester group are hydrolyzed under the acidic condition provided by hydrochloric acid, and decarboxylation is carried out by heating to obtain 2-methyl-2-ethylsuccinic acid.

[0008]

[0009] 2. Synthetic route with N-substituted vinyl-α-chloro-α-methylthioacetamide as the key intermediate (2)

[0010]

[0011] Ishibashi H et al. reported in the literature (Tetrahedron, 1995, 51(10), 2929-2938) that Schiff base (1) was synthesized from 2-methylbutyraldehyde and p-methoxybenzylamine, reacted with 2-methylthioacetyl chloride to form enamine, and then chlorinated with N-chlorosuccinimide (NCS) to obtain the key intermediate N-substituted vinyl-α-chloro-α-methylthioacetamide (2). Intermediate 2 was heated at 35 °C and then treated with silica to obtain 3-methylthio-5-hydroxypyrrolidone (3). The thioether group was removed by reduction with Raney nickel and ethanol to obtain intermediate (4). 4 was oxidized with pyridinium chlorochromate (PCC) to obtain succinimide (5). The p-methoxybenzyl protecting group of 5 was removed with ammonium cerium(IV) nitrate (CAN) to obtain ethosuximide.

[0012] 3. Synthetic route with the key step of constructing an imide ring by copper-catalyzed O2 oxidation of C=C cleavage

[0013]

[0014] Junhua Li et al. reported in the literature (Chem Sci, 2019, 10, 9099-9103) that this route used 2-methylbutyric acid and 3-bromopropene as raw materials, reacted in the presence of lithium diisopropylamide to obtain intermediate 1. After converting it to an acyl chloride with oxalyl chloride, it was reacted with O-benzylhydroxylamine hydrochloride in the presence of a base to obtain intermediate 2. The key step was that intermediate 2 was oxidized with oxygen in toluene using cuprous acetate as the catalyst and bathocuproine as the ligand to obtain intermediate 3. Then, it was hydrogenated under normal pressure with palladium on carbon, and rearranged in the presence of 2-bromoacetophenone and triethylamine to obtain ethosuximide.

[0015] The above routes all have some problems, which are briefly described as follows:

[0016] Route 1 inevitably requires the use of highly toxic reagents potassium cyanide or sodium cyanide, which has high requirements for the qualifications of production enterprises, high production safety pressure, high regulatory requirements, and it is difficult to achieve autonomous and controllable production of bulk drugs;

[0017] Route 2 uses intermediate 1 as the raw material and undergoes five-step reactions with a total yield of 5.76%, which is relatively low. Moreover, column chromatography is required for separation and purification in each step, and environmentally key-concern reagents such as the heavy metal reagent pyridinium chlorochromate (PCC) are also used during the reaction process, resulting in great environmental pressure. This route is not suitable for large-scale production of the API;

[0018] Route 3 has certain advantages. Using oxygen oxidation under a catalyst to construct an imide ring is a novel method. However, Route 3 has the following problems: 1) Using 2-methylbutyric acid as the raw material, at least 2 equivalents of LDA are required to remove the H at the α-position of the carboxyl group, causing waste of raw materials, and theoretically the carboxylate anion formed by the reaction of the carboxyl group with LDA will also participate in the reaction, resulting in an increase in by-products; 2) Column chromatography is used for the work-up after each step of this route, which is not suitable for industrial production; 3) The hydrogenation process under palladium-carbon catalysis is used in the last step of this reaction, which has special requirements for the qualifications of the manufacturer; 4) The last step of the reaction is a rearrangement reaction, which will theoretically produce more impurities and is not suitable as the last step in the production of the API; 5) This route is a milligram-scale reaction, and the reaction conditions of many of the reactions are not suitable for industrial production, and the reaction operation and / or work-up are complex, so it is not suitable for scaling up as a production process.

[0019] In summary, the methods for preparing ethosuximide reported in the existing literature all have certain problems and are not suitable as processes for large-scale production of the API. It is necessary to develop an improved process for large-scale production of ethosuximide API or its analogs. Through in-depth research, the inventors have discovered an improved synthesis method for ethosuximide or its analogs. This method can avoid using highly toxic cyanides as raw materials, has mild reaction conditions, simple and safe reaction process operation, high yield, good product quality, few impurities, purifies the intermediate and the final product by recrystallization, and does not use column chromatography for purification, making it suitable for industrial production. Summary of the Invention

[0020] In a first aspect, the present invention provides a method for preparing a compound of formula IA,

[0021]

[0022] wherein R1 and R2 are independently selected from C 1-6 alkyl; preferably, R1 is methyl and R2 is ethyl;

[0023] which comprises the following steps:

[0024] Reacting a compound of formula I

[0025]

[0026] wherein R1 and R2 are as defined for formula IA,

[0027] The reaction is carried out with titanium trichloride in the presence of a titanium trichloride protective agent, in an inert gas atmosphere, and under heating in a solvent to obtain a compound of formula IA.

[0028] In some embodiments, the reaction is carried out under an inert gas atmosphere.

[0029] In some embodiments, the titanium trichloride exists in the form of a titanium trichloride solution. Preferably, the titanium trichloride solution is an aqueous titanium trichloride solution. More preferably, the aqueous titanium trichloride solution further contains hydrochloric acid.

[0030] In some embodiments, the titanium trichloride solution is a 5-50% TiCl 3 solution in 10%-36% hydrochloric acid, preferably a 15-20% TiCl 3 solution in 30% hydrochloric acid.

[0031] In some embodiments, titanium trichloride is used in an amount of 0.8-5.0 molar equivalents relative to the compound of formula I, e.g., 0.8-2, 1-1.5, e.g., 0.9, 1.0, 1.1, 1.2, 1.5, 1.8, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 molar equivalents.

[0032] In some embodiments, the reaction is carried out in the presence of a titanium trichloride protecting agent.

[0033] The inventors unexpectedly discovered that the use of titanium trichloride as a protective agent significantly improves the yield of the reaction, reduces impurities, and eliminates the need for column chromatography separation of the product. The product can be purified by recrystallization to obtain ethosuximide that meets pharmacopoeial standards.

[0034] In some embodiments, the titanium trichloride protective agent is selected from polyols, preferably propylene glycol, glycerol, pentaerythritol, inositol or a combination thereof.

[0035] In some embodiments, the solvent is a mixed solvent of an organic solvent and water. Preferably, the organic solvent is selected from C 1-6 Alkyl alcohol (preferably ethanol, methanol), acetone, tetrahydrofuran or a combination thereof.

[0036] In some embodiments, the volume ratio (v / v) of the titanium trichloride protective agent to the solvent is 1:20 to 20:1, for example, 1:10 to 10:1, 1:5 to 5:1, or 1:3 to 3:1.

[0037] In some embodiments, the inert gas is selected from nitrogen, argon, helium, or a combination thereof, more preferably nitrogen.

[0038] In some embodiments, the heating condition is 50-100°C, such as 60-95°C, 70-90°C or 70-85°C.

[0039] In some embodiments, the method further comprises the following purification step: after the reaction is completed, the compound of formula IA is recrystallized in an organic solvent to obtain the purified compound of formula IA.

[0040] In some embodiments, the organic solvent used in the purification step is selected from chloroform, ethyl acetate, acetone, ethanol (such as anhydrous ethanol), methanol, dichloromethane, acetonitrile, tetrahydrofuran, cyclohexane, n-hexane, n-heptane, petroleum ether (60 - 90 °C), toluene, or a combination thereof.

[0041] In some embodiments, the organic solvent used in the purification step is preferably a combination of a readily soluble solvent (i.e., a solvent in which the compound of formula IA is readily soluble) and a sparingly soluble solvent (i.e., a solvent in which the compound of formula IA is sparingly soluble). The readily soluble solvent is preferably selected from chloroform, ethyl acetate, acetone, ethanol (such as anhydrous ethanol), methanol, dichloromethane, acetonitrile, tetrahydrofuran, or a combination thereof. The sparingly soluble solvent is preferably selected from cyclohexane, n-hexane, n-heptane, petroleum ether (60 - 90 °C), toluene, or a combination thereof. More preferably, the solvent is a combination of n-hexane and ethyl acetate, a combination of n-heptane and ethyl acetate, or a combination of n-hexane and chloroform.

[0042] In some embodiments, the method further comprises the following step of preparing the compound of formula I:

[0043] Treating the compound of formula (V)

[0044]

[0045] wherein R1 and R2 are as defined for formula I;

[0046] with an ether bond cleavage reagent in an organic solvent at a cooling temperature to obtain the compound of formula I as described above.

[0047] In some embodiments, the ether bond cleavage reagent is preferably titanium tetrachloride, boron tribromide, boron trichloride, boron trifluoride diethyl etherate, hydroiodic acid, hydrobromic acid, hydrochloric acid, etc., and more preferably titanium tetrachloride, boron tribromide, or boron trichloride.

[0048] In some embodiments, relative to the compound of formula V, the ether bond cleavage reagent is used in an amount of 0.8 - 5.0 molar equivalents, for example, in an amount of 0.8 - 2, 1 - 1.5, such as 0.9, 1.0, 1.1, 1.2, 1.5, 1.8, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 molar equivalents.

[0049] In some embodiments, the organic solvent is selected from halogenated hydrocarbon solvents, preferably selected from dichloromethane, chloroform, 1,2 - dichloroethane, or a combination thereof.

[0050] In some embodiments, the cooling temperature is from 0 °C to -100 °C, such as from 0 °C to -78 °C, from -30 °C to -78 °C, or from -5 °C to -40 °C.

[0051] In some embodiments, the method further comprises the step of preparing a compound of formula V as follows:

[0052] 1) Reacting a compound of formula IIa

[0053]

[0054] wherein R1 and R2 are as defined for formula I,

[0055] with a compound of formula IIb

[0056]

[0057] wherein X is Cl, Br or I, preferably Br

[0058] at the cooling temperature to obtain a compound of formula II

[0059]

[0060] wherein R1 and R2 are as defined for formula I,

[0061] 2) Subjecting the compound of formula II to acid hydrolysis in a solvent, or to base hydrolysis followed by acidification, to obtain a compound of formula III

[0062]

[0063] wherein R1 and R2 are as defined for formula I,

[0064] 3) Reacting the compound of formula III with a chlorinating reagent to obtain the corresponding acyl chloride, and then reacting with O-benzylhydroxylamine or its salt such as hydrochloride in the presence of a base to obtain a compound of formula IV, or reacting the compound of formula III with O-benzylhydroxylamine or its salt such as hydrochloride in the presence of a condensing agent and a base to obtain a compound of formula IV,

[0065]

[0066] wherein R1 and R2 are as defined for formula I,

[0067] 4) Oxidizing the compound of formula IV with oxygen in an organic solvent under heating conditions in the presence of a copper salt catalyst and a ligand to obtain a compound of formula V

[0068]

[0069] Wherein R1 and R2 are as defined in formula I.

[0070] In some embodiments, in step 1), the organic solvent is preferably an aprotic solvent, such as methyl tert-butyl ether, tetrahydrofuran, toluene, diethyl ether, dioxane, n-hexane, or a combination thereof, more preferably diethyl ether, toluene, tetrahydrofuran, methyl tert-butyl ether, or a combination thereof;

[0071] The strong base is preferably an organic strong base, such as selected from C 1-6 alkyl alkali metal compounds, such as n-butyllithium, tert-butyllithium, di-(C 1-6 alkyl)amino alkali metal compounds such as lithium diisopropylamide, C 1-6 alkali metal salts of alkanols such as sodium ethoxide, potassium ethoxide, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, potassium methoxide, benzyl alkali metal compounds such as benzyllithium, alkali metal hydrides such as sodium hydride, etc., more preferably selected from n-butyllithium, lithium diisopropylamide, and tert-butyllithium; and / or

[0072] The cooling temperature is from 0 °C to -100 °C, such as from 0 °C to -78 °C, -30 °C to -78 °C, or -5 °C to -40 °C.

[0073] In some embodiments, in step 1), the molar ratio of the compound of formula IIa to the compound of formula IIb is from 1:2 to 2:1, such as from 1:1.5 to 1.5:1, 1:1.2 to 1.2:1, or 1.1:1 to 1:1.1, such as 1:1.

[0074] In some embodiments, in step 1), the molar ratio of the compound of formula IIa to the strong base is from 1:3 to 1.2:1, such as from 1:3 to 1:1, 1:2 to 1:1, 1:1.5 to 1:1, such as 1:1.

[0075] In some embodiments, in step 2), the solvent is a mixed solvent of an organic solvent and water, wherein the organic solvent is preferably a solvent miscible with water, preferably selected from C 1-6 alkanols such as methanol, ethanol, propanol, tetrahydrofuran, acetone, dioxane, or a combination thereof, and the mixed solvent system is preferably methanol and water, ethanol and water, tetrahydrofuran and water, etc.

[0076] In some embodiments, the base is selected from alkali metal hydroxides such as potassium hydroxide, sodium hydroxide, lithium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate, etc.

[0077] In some embodiments, the acid hydrolysis or base hydrolysis is carried out under heating conditions. Preferably, the heating conditions refer to 30 - 100 °C, such as 30 - 70 °C, 60 - 95 °C, 70 - 90 °C, or 70 - 85 °C, and preferably heated under the boiling temperature conditions of the mixed solvent.

[0078] In some embodiments, the acidification after acid hydrolysis or base hydrolysis uses an inorganic acid, such as sulfuric acid, hydrochloric acid, and / or phosphoric acid (such as dilute sulfuric acid, dilute hydrochloric acid, dilute phosphoric acid), etc.

[0079] In some embodiments, step 3) is carried out in a solvent, and the solvent is preferably an aprotic organic solvent, including but not limited to solvents immiscible with water such as chloroform, ethyl acetate, dichloromethane, 1,2-dichloroethane, etc., tetrahydrofuran, acetone, or a combination thereof.

[0080] In some embodiments, in step 3), the chlorinating reagent is preferably thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, etc.

[0081] In some embodiments, in step 3), the base is selected from alkali metal carbonates such as sodium carbonate, potassium carbonate, alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, alkali metal hydroxides such as potassium hydroxide, sodium hydroxide, triethylamine, pyridine, 4-dimethylaminopyridine, or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), etc.

[0082] In some embodiments, in step 3), the condensing agent is selected from: dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), N,N'-carbonyldiimidazole (CDI), and benzotriazol-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU).

[0083] In some embodiments, in step 3), the reaction is carried out at -30 - 90 °C, such as -20 to 60 °C, 0 to 40 °C, or 5 to 20 °C.

[0084] In some embodiments, in step 4), the copper salt catalyst is preferably a monovalent copper salt and a divalent copper salt, such as cuprous acetate, copper acetate, etc., and more preferably cuprous acetate.

[0085] In some embodiments, in step 4), the ligand is preferably 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline (also called bathocuproine), 1,10-phenanthroline.

[0086] In some embodiments, in step 4), the molar ratio of the compound of formula IV to the copper salt catalyst or the ligand is 50:1 to 1:1, such as 20:1 to 2:1, 10:1 to 5:1.

[0087] In some embodiments, in step 4), the organic solvent is an aprotic organic solvent, preferably xylene, toluene, benzene, nitrobenzene, n-heptane, n-hexane, cyclohexane or a combination thereof.

[0088] In some embodiments, in step 4), the heating condition refers to 50 - 100 °C, such as 60 - 95 °C, 70 - 90 °C, 70 - 85 °C, 60 - 90 °C or 75 - 85 °C; the oxygen is preferably selected from high-purity oxygen, industrial oxygen and oxygen in air (i.e., using air for the oxidation reaction), and more preferably high-purity oxygen.

[0089] It should be understood that those skilled in the art can easily detect the reaction progress to determine the reaction time. Each reaction of the present invention can be carried out for, for example, 0.5 hours - 5 days, such as 0.5 - 24 hours, 1 - 10 hours, such as 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 1 day, 2 days or 3 days.

[0090] The inventors found in the research that when using the existing technical route 3 (Chem Sci, Junhua Li et al. 2019, 10, 9099 - 9103) to synthesize the compound 3a of the present invention on a relatively large scale, the reaction yield was very low, there were many impurities, and it could not be used for industrial production. However, the route adopted in the present invention can obtain the compound 3a of the present invention with extremely high yield and can be directly used without purification, which is suitable for industrial production.

[0091] In addition, compared with the existing technical methods, the synthesis route and method of the present invention have many advantages. For example, 1) it can avoid problems such as the use of highly toxic cyanides, noble metal-catalyzed hydrogenation, cumbersome routes, and / or many process impurities, and is more environmentally friendly and suitable for the production of active pharmaceutical ingredients; 2) it can reduce or eliminate the use of chromatographic separation, the separation and purification operation is simple, and it is suitable for industrial production; and / or 3) the reaction conditions are mild, the reaction process operation is simple and safe, the yield is relatively high, the product quality is good, and there are few impurities, which is suitable for industrial production.

[0092] In a second aspect, the present invention provides a method for preparing a compound of formula I, which comprises the following steps:

[0093] Treating a compound of formula (V)

[0094]

[0095] wherein R1 and R2 are as defined above;

[0096] with an ether bond cleavage reagent in an organic solvent at a cooling temperature to obtain a compound of formula I

[0097]

[0098] wherein R1 and R2 are as defined above.

[0099] wherein the reaction conditions (including reaction reagents, solvents, temperature, dosage, etc.) are as defined in the first aspect.

[0100] In some embodiments, the method further comprises the step of preparing a compound of formula V as follows:

[0101] 1) Reacting a compound of formula IIa

[0102]

[0103] wherein R1 and R2 are as defined for formula I,

[0104] with a compound of formula IIb

[0105]

[0106] wherein X is Cl, Br or I, preferably Br

[0107] at a cooling temperature to obtain a compound of formula II

[0108]

[0109] wherein R1 and R2 are as defined for formula I,

[0110] 2) The compound of formula II is subjected to acid hydrolysis in a solvent, or subjected to base hydrolysis and then acidification to obtain a compound of formula III

[0111]

[0112] wherein R1 and R2 are as defined for formula I,

[0113] 3) The compound of formula III is reacted with a chlorinating agent to obtain the corresponding acyl chloride, and then reacted with O-benzylhydroxylamine or its salt such as hydrochloride in the presence of a base to obtain a compound of formula IV, or the compound of formula III is reacted with O-benzylhydroxylamine or its salt such as hydrochloride in the presence of an esterification condensing agent and a base to obtain a compound of formula IV,

[0114]

[0115] wherein R1 and R2 are as defined for formula I,

[0116] 4) The compound of formula IV is oxidized with oxygen in an organic solvent under heating conditions in the presence of a copper salt catalyst and a ligand to obtain a compound of formula V

[0117]

[0118] Wherein R1 and R2 are as defined in formula I.

[0119] Wherein each reaction condition (including reaction reagents, solvents, temperature, dosage, etc.) is as defined in the first aspect.

[0120] In a third aspect, the present invention provides a compound of formula I or a salt thereof

[0121]

[0122] Wherein R1 and R2 are as defined above, and R1 and R2 are not simultaneously methyl.

[0123] In some embodiments, the present invention provides compound 1a or a salt thereof:

[0124]

[0125] After searching the Scifinder database, no literature report was found. The present invention prepared, isolated and purified this substance for the first time. The specific synthesis method and structural characterization of this compound are shown in the examples. This compound can be used as a key intermediate in the synthesis of ethosuximide.

[0126] In a fourth aspect, the present invention provides a compound of formula I or a salt thereof

[0127]

[0128] Wherein R1 and R2 are as defined above,

[0129] for use in the preparation of a compound of formula IA

[0130]

[0131] Wherein R1 and R2 are as defined above.

[0132] In some embodiments, the present invention provides compound 1a or a salt thereof:

[0133]

[0134] for use in the synthesis of ethosuximide.

[0135] When synthesizing ethosuximide according to the method of the present invention, based on ethyl 2-methylbutyrate as the raw material for the first-step reaction, the molar yield of the pure ethosuximide product can reach 31.2%, and the product purity can reach over 99%. The quality of the active pharmaceutical ingredient fully meets the requirements of the United States Pharmacopeia. Quality inspection methods such as HPLC can be carried out according to the methods in the United States Pharmacopeia (https: / / online.uspnf.com / uspnf / document / 1_GUID-D16B79C0-A06D-447A-86E6-78A0A05076B9_3_en-US).

[0136] The synthesis method of the present invention has the following advantages:

[0137] 1) It can avoid problems existing in the prior art of ethosuximide synthesis methods, such as the use of highly toxic cyanides, noble metal-catalyzed hydrogenation, cumbersome routes, and / or many process impurities, etc., and is more environmentally friendly and suitable for the production of bulk drugs;

[0138] 2) It can reduce or avoid the use of chromatographic separation, and the separation and purification operations are simple, which is suitable for industrial production; and / or

[0139] 3) The reaction conditions are mild, the reaction process is simple and safe to operate, the yield is relatively high, the product quality is good, and there are few impurities, which is suitable for industrial production.

[0140] Definition:

[0141] The terms or symbols used in this application have the meanings described below, unless otherwise specified in the context. The technical and scientific terms not specifically defined herein have the meanings commonly understood by those skilled in the art to which the present invention pertains.

[0142] The term "alkyl" as used herein refers to a straight-chain or branched-chain saturated monovalent hydrocarbon group having 1 to 6 carbon atoms, such as having 1, 2, 3, 4, 5, or 6 carbon atoms, for example, a straight-chain or branched-chain saturated monovalent hydrocarbon group having 1 to 4, 1 to 3, or 1 to 2 carbon atoms. An alkyl having 1 to 6 carbon atoms is simply represented as "C 1-6 alkyl", an alkyl having 1 to 4 carbon atoms is simply represented as "C 1-4 alkyl", and alkyls with other numbers of carbon atoms can also be represented in a similar manner. Examples of alkyls include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl, etc.

[0143] The term "titanium trichloride protecting agent" as used herein refers to a polyol, such as a polyol containing 2-6 (e.g., 2, 3, 4, 5, or 6) hydroxyl groups and having 2-6 (e.g., 2, 3, 4, 5, or 6) carbon atoms, preferably propylene glycol, glycerol, pentaerythritol, inositol, etc.

[0144] The term "inert gas" as used herein refers to a gas that is inactive (i.e., inert) under the reaction conditions involved, including but not limited to nitrogen, argon, helium, etc.

[0145] It should be understood that for a reaction, the "solvent" refers to a solvent that can dissolve or partially dissolve the reactants and / or reagents and does not affect the normal progress of the reaction. The common "solvents" used in the reaction are known to those skilled in the art and include, but are not limited to, organic solvents such as protic organic solvents such as methanol and ethanol, and aprotic organic solvents such as chloroform, ethyl acetate, acetone, dichloromethane, tetrahydrofuran, toluene; non-organic solvents such as water, etc.

[0146] As used herein, the term "cooling temperature" refers to a temperature that is lower than room temperature (25 °C), such as 0 °C to -100 °C, such as 0 °C to -78 °C, -30 °C to -78 °C, or -5 °C to -40 °C.

[0147] As used herein, the term "condensing agent" refers to a common condensing agent that can help a carboxylic acid or its activated form form an amide bond with a compound containing an amino group, including but not limited to HBTU, DCC, EDCI, DIC, or CDI.

[0148] As used herein, the term "C 1-6 alkyl alkali metal compound" refers to a compound having a C 1-6 alkyl-M structure, where M is an alkali metal.

[0149] As used herein, the term "di-(C 1-6 alkyl)amino alkali metal compound" refers to a compound having a (C 1-6 alkyl)2-N-M structure, where M is an alkali metal.

[0150] As used herein, the term "C 1-6 alkanol alkali metal salt" refers to a compound having a C 1-6 alkoxy-M structure, where M is an alkali metal.

[0151] As used herein, the term "alkali metal" refers to the metallic elements in Group IA of the periodic table excluding hydrogen (H), including lithium (Li), sodium (Na), potassium (K), cesium (Cs), etc., especially lithium, sodium, or potassium.

[0152] As used herein, the term "C 1-6 alkanol" refers to a C 1-6 alkyl-OH compound, where the alkyl is as defined above.

[0153] In this article, the term "titanium trichloride" is used interchangeably with TiCl3.

[0154] It should be understood that, unless otherwise specified or there is an obvious contradiction in the context, when a subsequent embodiment or technical solution refers to a prior embodiment or technical solution and does not further limit the variables or features therein, the variables or features in the subsequent embodiment or technical solution have the same meaning or definition as the corresponding variables or features in the prior embodiment or technical solution.

[0155] It should be further understood that the reactions of the present invention can be carried out under conventional reaction conditions known in the art. For example, the reaction temperature and pressure can be controlled according to the characteristics of the reactants until the reaction is complete.

[0156] The reaction can be carried out under normal pressure, increased pressure or reduced pressure, depending on the circumstances.

[0157] In this text, if the name and structural formula of a compound are given simultaneously for a compound, in the case of inconsistency between the two, the structure of the compound shall prevail, unless the context indicates that the structure of the compound is incorrect while the name is correct. Description of the Drawings

[0158] Figure 1 Showing the 1 1H-NMR spectrum of the key intermediate 3-methyl-3-ethyl-1-hydroxy-pyrrolidine-2,5-dione (1a).

[0159] Figure 2 Showing the 13 13C-NMR spectrum of the key intermediate 3-methyl-3-ethyl-1-hydroxy-pyrrolidine-2,5-dione (1a).

[0160] Figure 3 Showing the MS spectrum of the key intermediate 3-methyl-3-ethyl-1-hydroxy-pyrrolidine-2,5-dione (1a). Detailed Description of the Invention

[0161] The present invention will be further described in detail below with reference to specific examples.

[0162] Example 1

[0163] Synthesis of the key intermediate 3-methyl-3-ethyl-1-hydroxy-pyrrolidine-2,5-dione (1a) - Method 1

[0164] Step 1: Preparation of ethyl 2-methyl-2-ethyl-4-pentenoate (Compound 2a)

[0165]

[0166] In a 1000 mL three-necked flask, 203 mL of a 2.5 mol / L n-butyllithium solution in n-hexane was added. The temperature was lowered to an internal temperature of -35 to -40 °C in a low-temperature bath. While stirring, ethyl 2-methylbutyrate (60.0 g, 0.461 mol) dissolved in 90 mL of dry methyl tert-butyl ether was added dropwise. After addition, stirring was continued for 1 h. Then, 3-bromopropene (61.3 g, 0.507 mol) dissolved in 90 mL of dry methyl tert-butyl ether was added dropwise. After addition, stirring was continued for 1 h. The reaction was quenched with a saturated aqueous ammonium chloride solution under cooling. The resulting white solid was filtered by suction. The filter cake was washed twice with 120 mL of ethyl acetate each time. The filtrate was separated into layers in a separatory funnel. The aqueous phase was extracted twice with 150 mL of ethyl acetate each time. The combined organic phases were washed successively with 120 mL of 1 mol / L hydrochloric acid, 120 mL of saturated aqueous NaHCO3, and 120 mL of saturated aqueous NaCl, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain 78.5 g of the title compound, a brown oil. It can be directly used for the next reaction without separation and purification.

[0167] Step 2: Preparation of 2-methyl-2-ethyl-4-pentenoic acid (Compound 3a)

[0168]

[0169] In a 2000 mL eggplant-shaped flask, 78.5 g of the crude product of Compound 2a prepared in Example 1 and 942 mL of methanol were added. A solution of KOH (85% content, 121.6 g, 1.844 mol) dissolved in 471 mL of distilled water was added. The mixture was stirred and refluxed for 12 h. Most of the methanol was removed by rotary evaporation under reduced pressure. After cooling to room temperature, it was transferred to a separatory funnel and washed twice with 60 mL of n-heptane each time. The pH of the aqueous phase was adjusted to 3 - 4 with 6.0 mol / L hydrochloric acid and extracted three times with 100 mL of CH2Cl2 each time. The combined organic phases were washed with 100 mL of saturated aqueous NaCl, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain 56.4 g of the title compound, a reddish-brown oil, which was directly used for the next reaction without separation and purification.

[0170] Step 3: Preparation of N-benzyloxy-2-methyl-2-ethyl-4-pentenamide (Compound 4a)

[0171]

[0172] Add 56.4 g (397 mmol) of the crude product of compound 3a prepared in Step 2 of Example 1 and 113 mL of CH2Cl2 to a 500 mL eggplant-shaped flask. After cooling thoroughly in an ice-water bath, add 54.7 g (476 mmol) of thionyl chloride dissolved in 56 mL of CH2Cl2. After addition, stir the reaction at room temperature for 2 h. Distill off the solvent and unreacted thionyl chloride under reduced pressure, and add 100 mL of THF to form a solution of the crude product of 2-methyl-2-ethyl-4-pentenoic acid chloride.

[0173] Add 564 mL of chloroform and 282 mL of distilled water to a 1000 mL three-necked flask. Add 69.7 g (437 mmol) of O-benzylhydroxylamine hydrochloride and 58.9 g (556 mmol) of anhydrous sodium carbonate. After cooling thoroughly in an ice-water bath, dropwise add the solution of the crude product of 2-methyl-2-ethyl-4-pentenoic acid chloride prepared above. After addition, stir the reaction at room temperature for 2 h. Separate the two phases with a separatory funnel. Extract the aqueous phase with chloroform 2 times × 120 mL. Combine the organic phases, wash with 1.0 mol / L hydrochloric acid aqueous solution 1 time × 120 mL, saturated NaHCO3 aqueous solution 1 time × 120 mL, saturated NaCl aqueous solution 1 time × 120 mL, dry over anhydrous Na2SO4, filter, and concentrate under reduced pressure to obtain a crude product, 100.4 g of a brownish-red oily substance. Recrystallize with a mixed solvent of n-hexane and chloroform to obtain 79.8 g of a light brown solid. The total yield of the three-step reaction based on ethyl 2-methylbutyrate, the raw material of Example 1, is 69.9%, m.p.: 45 - 46 °C.

[0174] 1 H NMR(600MHz,CDCl3)δ8.29(s,1H),7.44–7.30(m,5H),5.77–5.62(m,1H),5.05(s,1H),5.03(d,J=4.6Hz,1H),4.90(s,2H),2.38(dd,J=13.8,7.0Hz,1H),2.09(dd,J=13.8,7.8Hz,1H),1.67(dq,J=14.9,7.5Hz,1H),1.45–1.36(m,1H),1.05(s,3H),0.84(t,J=7.5Hz,3H). 13 C NMR(151MHz,CDCl3)δ174.30,135.49,133.91,129.32(2C),128.72,128.58(2C),118.37,78.13,45.26,43.34,32.08,20.13,8.76.HRMS[M+H] + calcd.forC 15 H 22NO2, m / z: 248.1651, found: 248.1651.

[0175] Step 4: Preparation of 1-(benzyloxy)-3-methyl-3-ethylpyrrolidine-2,5-dione (Compound 5a)

[0176]

[0177] In a 2000 mL four-necked flask, add 79.8 g (323 mmol) of Compound 4a prepared in Step 3 of Example 1, 3.96 g (32.3 mmol) of cuprous acetate, 13.99 g (38.8 mmol) of bathocuproine, and 1197 mL of toluene. Bubble high-purity oxygen into the reaction solution, heat to control the internal temperature at 75 - 80 °C, stir and react for 33 h, and naturally cool to room temperature. Using diatomaceous earth as a filter aid, filter by suction, wash with toluene, and concentrate under reduced pressure to obtain 81.6 g of a brown solid. Add 500 mL of ethyl acetate to dissolve it, transfer it to a separatory funnel, wash it 3 times with 100 mL of distilled water each time, dry it over anhydrous MgSO4, filter by suction, wash the filter cake 2 times with ethyl acetate, and concentrate the filtrate under reduced pressure to obtain 74.5 g of a brown solid. Recrystallize with a mixed solvent of n-heptane and ethyl acetate to obtain 48.2 g of a white solid, with a yield of 60.3%. m.p.: 72 - 73 °C.

[0178] 1 H NMR (600 MHz, CDCl3) δ 7.48 (dd, J = 6.2, 3.3 Hz, 2H), 7.40–7.32 (m, 3H), 5.21–5.09 (m, 2H), 2.50 (d, J = 18.0 Hz, 1H), 2.29 (d, J = 18.0 Hz, 1H), 1.69–1.60 (m, 1H), 1.55–1.44 (m, 1H), 1.19 (s, 3H), 0.79 (t, J = 7.5 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 176.96, 170.45, 133.23, 130.05 (2C), 129.41, 128.45 (2C), 78.33, 41.47, 37.94, 30.88, 23.88, 8.33. HRMS [M + H] + calcd. for C 14 H 18 NO3, m / z: 248.1287, found: 248.1639.

[0179] Step 5: Preparation of 3-methyl-3-ethyl-1-hydroxypyrrolidine-2,5-dione (Compound 1a)

[0180]

[0181] In a 2000 mL four-necked flask, 48.2 g (195 mmol) of the compound 5a prepared in Step 4 of Example 1 and 482 mL of chloroform were added. The internal temperature was maintained at -73 to -78 °C, and 294 g (1.17 mol) of BBr3 dissolved in 96 mL of chloroform was added dropwise. After the addition was complete, the reaction was stirred at this temperature range for 1 h. An appropriate amount of ice water was added to the reaction solution to quench the reaction, and stirring was continued for 1 h. The two phases were separated, the aqueous phase was extracted with chloroform 2 times × 100 mL, the organic phases were combined, washed with saturated NaCl aqueous solution 1 time × 100 mL, dried over anhydrous MgSO4, and concentrated under reduced pressure to obtain 61.3 g of a crude light brown oily substance. The obtained crude product was stirred and dispersed in 250 mL of saturated NaHCO3 aqueous solution, washed with 50 mL of n-hexane 2 times. The aqueous phase was cooled sufficiently in an ice bath, the pH value was adjusted to 3 - 4 with 20% sulfuric acid, solid NaCl powder was added with stirring until saturation, filtered, the aqueous phase was extracted with chloroform 2 times × 100 mL, the organic phases were combined, washed with saturated NaCl aqueous solution 1 time × 100 mL, dried over anhydrous MgSO4, and concentrated under reduced pressure to obtain 26.2 g of a light brown oily substance, which was dried in vacuo at room temperature to become a white solid, with a yield of 85.5%. m.p.: 61 - 63 °C.

[0182] 1 H NMR(600MHz,CDCl3)δ2.63(d,J=18.1Hz,1H),2.44(d,J=18.1Hz,1H),1.75(dq,J=14.9,7.5Hz,1H),1.61(dq,J=14.9,7.5Hz,1H),1.32(s,3H),0.88(t,J=7.5Hz,3H)(H in N-OH not appear). 13 C NMR(151MHz,CDCl3)δ178.49,171.91,41.84,38.01,31.16,23.83,8.54.HRMS[M-H] - calcd.for C7H 10 NO3,m / z:156.0661,found:156.0659.

[0183] Example 2

[0184] Synthesis of the key intermediate 3-methyl-3-ethyl-1-hydroxy-pyrrolidine-2,5-dione (1a) - Method 2

[0185] Step 1: Preparation of ethyl 2-methyl-2-ethyl-4-pentenoate (Compound 2a)

[0186]

[0187] In a 1000 mL three-necked flask, add 254 mL of a THF + n-hexane (v:v = 12:25) solution of 2 mol / L lithium diisopropylamide (LDA). Cool the mixture to an internal temperature of -73 to -78 °C in a low-temperature bath. While stirring, add ethyl 2-methylbutyrate (60.0 g, 0.461 mol) dissolved in 90 mL of dry THF dropwise. After addition, continue stirring for 1 h. Then add allyl bromide (90.0 g, 0.692 mol) dissolved in 90 mL of dry THF dropwise. After addition, continue stirring for 1 h. Quench the reaction with saturated aqueous ammonium chloride solution under cooling. Filter the resulting white solid by suction. Wash the filter cake with ethyl acetate twice (2 × 120 mL). Separate the layers of the filtrate in a separatory funnel. Extract the aqueous phase with ethyl acetate twice (2 × 150 mL). Wash the combined organic phases successively with 120 mL of 1 mol / L hydrochloric acid, 120 mL of saturated aqueous NaHCO3 solution, and 120 mL of saturated aqueous NaCl solution. Dry over anhydrous MgSO4, filter, and concentrate under reduced pressure to obtain 78.1 g of the title compound, a brown oil. It can be directly used for the next reaction without separation and purification.

[0188] Step 2: Preparation of 2-methyl-2-ethyl-4-pentenoic acid (Compound 3a)

[0189]

[0190] In a 2000 mL eggplant-shaped flask, add 78.1 g of the crude product of Compound 2a prepared in Step 1 of Example 2 and 942 mL of ethanol. Add a solution of NaOH (36.9 g, 0.922 mol) dissolved in 471 mL of distilled water. Stir and reflux for 12 h. Rotate and evaporate most of the ethanol under reduced pressure. Cool to room temperature and transfer to a separatory funnel. Wash with n-heptane twice (2 × 60 mL). Adjust the pH of the aqueous phase to 3 - 4 with 20% sulfuric acid. Extract the aqueous phase with CH2Cl2 three times (3 × 100 mL). Combine the organic phases, wash with 100 mL of saturated aqueous NaCl solution, dry over anhydrous MgSO4, filter, and concentrate under reduced pressure to obtain 55.9 g of the title compound, a brownish-red oil. It can be directly used for the next reaction without separation and purification.

[0191] Step 3: Preparation of N-benzyloxy-2-methyl-2-ethyl-4-pentenamide (Compound 4a)

[0192]

[0193] In a 500 mL eggplant-shaped flask, add 55.9 g (393 mmol) of the crude product of compound 3a prepared in Step 2 of Example 2 and 113 mL of CH2Cl2. After cooling thoroughly in an ice-water bath, add 74.9 g (590 mmol) of oxalyl chloride dissolved in 56 mL of CH2Cl2 and a catalytic amount of N,N-dimethylformamide (DMF). After addition, stir the reaction at room temperature for 2 h. Distill off the solvent and unreacted oxalyl chloride under reduced pressure. Add 100 mL of THF to form a solution of the crude product of 2-methyl-2-ethyl-4-pentenoic acid chloride.

[0194] In a 1000 mL three-necked flask, add 564 mL of ethyl acetate (EA) and 282 mL of distilled water. Add 69.7 g (437 mmol) of O-benzylhydroxylamine hydrochloride and 76.8 g (556 mmol) of anhydrous potassium carbonate. After cooling thoroughly in an ice-water bath, dropwise add the solution of the crude product of 2-methyl-2-ethyl-4-pentenoic acid chloride prepared above. After addition, stir at room temperature for 2 h. Separate the two phases with a separatory funnel. Extract the aqueous phase with EA 2 times × 120 mL. Combine the organic phases. Wash with 1.0 mol / L hydrochloric acid aqueous solution 1 time × 120 mL, saturated NaHCO3 aqueous solution 1 time × 120 mL, and saturated NaCl aqueous solution 1 time × 120 mL. Dry over anhydrous Na2SO4, filter, and concentrate under reduced pressure to obtain a crude product, 98.6 g of a brownish-red oily substance. Recrystallize with a mixed solvent of n-heptane and ethyl acetate to obtain 78.6 g of a light brown solid. The total yield of the three-step reaction based on ethyl 2-methylbutyrate, the starting material of Example 2, is 68.9%. m.p.: 45 - 46 °C.

[0195] Step 4: Preparation of 1-(benzyloxy)-3-methyl-3-ethylpyrrolidine-2,5-dione (Compound 5a)

[0196]

[0197] In a 2000 mL four-necked flask, add 78.6 g (318 mmol) of compound 4a prepared in Step 3 of Example 2, 3.90 g (31.8 mmol) of cuprous acetate, 13.77 g (38.2 mmol) of bathocuproine, and 1197 mL of xylene. Bubble high-purity oxygen into the reaction solution, heat to control the internal temperature at 85 - 90 °C, and stir the reaction for 35 h. Naturally cool to room temperature. Filter with diatomaceous earth as a filter aid, wash with xylene, and concentrate under reduced pressure to obtain 80.2 g of a brown solid. Add 500 mL of ethyl acetate to dissolve, transfer to a separatory funnel, wash with distilled water 3 times × 100 mL, dry over anhydrous MgSO4, filter, wash the filter cake with ethyl acetate 2 times, and concentrate the filtrate under reduced pressure to obtain 73.6 g of a brown solid. Recrystallize with a mixed solvent of n-heptane and ethyl acetate to obtain 47.2 g of a white solid, with a yield of 60.0%. m.p.: 72 - 73 °C.

[0198] Step 5: Preparation of 3-methyl-3-ethyl-1-hydroxypyrrolidine-2,5-dione (Compound 1a)

[0199]

[0200] Add 47.2 g (191 mmol) of Compound 5a prepared in Step 4 of Example 2 and 482 mL of CH2Cl2 to a 2000 mL four-necked flask. Maintain the internal temperature at -35 to -40 °C, and add dropwise 40.8 g (215 mmol) of TiCl4 dissolved in 96 mL of CH2Cl2. After the addition is complete, continue to stir and react within this temperature range for 1 h. Add an appropriate amount of ice water to the reaction solution to quench the reaction, and continue to stir for 1 h. Separate the two phases. Extract the aqueous phase with EA 2 times × 100 mL. Combine the organic phases, wash with saturated NaCl aqueous solution 1 time × 100 mL, dry over anhydrous MgSO4, and concentrate under reduced pressure to obtain 62.7 g of a crude light brown oily substance. Stir and disperse the obtained crude product into 250 mL of saturated NaHCO3 aqueous solution, wash with 50 mL of n-hexane 2 times. While cooling the aqueous phase sufficiently in an ice bath, adjust the pH value to 3-4 with 20% sulfuric acid. Add solid NaCl powder to saturation with stirring, filter. Extract the aqueous phase with ethyl acetate 2 times × 100 mL. Combine the organic phases, wash with saturated NaCl aqueous solution 1 time × 100 mL, dry over anhydrous MgSO4, and concentrate under reduced pressure to obtain 27.3 g of a light brown oily substance, which becomes a white solid after vacuum drying at room temperature, with a yield of 90.9%. m.p.: 61-63 °C.

[0201] Example 3

[0202] Preparation of 3-methyl-3-ethylpyrrolidine-2,5-dione (ethosuximide) - Method 1

[0203]

[0204] Add 221 mL (214.6 mmol) of a 15-20% TiCl3 solution in 30% hydrochloric acid to a 2000 mL four-necked flask. With stirring, add 150 mL of propylene glycol and 442 mL of distilled water. Dissolve 26.2 g (166.7 mmol) of Compound 1a prepared in Example 1 in 56 mL of methanol, and add it to a constant pressure dropping funnel for standby. Under nitrogen protection, add dropwise the solution in the constant pressure dropping funnel, and raise the temperature to 80-90 °C and react for 5 h. Pour the reaction solution into ice water with stirring. Extract the aqueous phase with chloroform and wash with saturated NaCl aqueous solution. Dry over anhydrous MgSO4, filter, and concentrate under reduced pressure to obtain 20.2 g of a crude product, with a yield of 86.0%, which is a white waxy solid.

[0205] Example 4

[0206] Preparation of 3-Methyl-3-ethylpyrrolidine-2,5-dione (Ethosuximide) - Method 2

[0207]

[0208] Add 221 mL (214.6 mmol) of a 15 - 20% TiCl₃ solution in 30% hydrochloric acid to a 2000 mL four-necked flask. With stirring, add 120 mL of glycerol and 442 mL of distilled water. Dissolve 27.3 g (173.7 mmol) of Compound 1a prepared in Example 2 in 56 mL of methanol, and add it to a constant-pressure dropping funnel for standby. Under nitrogen protection, dropwise add the solution in the constant-pressure dropping funnel, and raise the temperature to an internal temperature of 70 - 80 °C and react for 4 h. With stirring, pour the reaction solution into ice water, extract the aqueous phase with ethyl acetate, and wash it with saturated NaCl aqueous solution. Dry over anhydrous MgSO₄, filter, and concentrate under reduced pressure to obtain 20.5 g of a crude product with a yield of 83.6%, which is a white waxy solid.

[0209] Example 5

[0210] Preparation of 3-Methyl-3-ethylpyrrolidine-2,5-dione (Ethosuximide) - Method 3 (Without Using TiCl₃ Protective Agent)

[0211]

[0212] Add 221 mL (214.6 mmol) of a 15 - 20% TiCl₃ solution in 30% hydrochloric acid to a 2000 mL four-necked flask. With stirring, add 442 mL of distilled water. Dissolve 26.2 g (166.7 mmol) of Compound 1a prepared according to the preparation method of Example 1 in 56 mL of methanol, and add it to a constant-pressure dropping funnel for standby. Under nitrogen protection, dropwise add the solution in the constant-pressure dropping funnel, and raise the temperature to an internal temperature of 70 - 80 °C and react for 5 h. With stirring, pour the reaction solution into ice water, extract the aqueous phase with ethyl acetate, and wash it with saturated NaCl aqueous solution. Dry over anhydrous MgSO₄, filter, and concentrate under reduced pressure to obtain 5.6 g of a crude product with a yield of 23.8%, which is an off-white waxy solid.

[0213] Example 6

[0214] Purification of Ethosuximide - Method 1

[0215] Weigh 2.000 g of the crude ethosuximide (white waxy solid) prepared in Example 3, and recrystallize it with a mixed solvent of n-hexane and chloroform to obtain 1.744 g of a white powdery solid with a yield of 87.2% and a purity as high as 99.5%. m.p.: 46 - 48 °C.

[0216] 11H NMR (600 MHz, CDCl3) δ 8.68 (s, 1H), 2.66 (d, J = 18.4 Hz, 1H), 2.47 (d, J = 18.4 Hz, 1H), 1.75 (dq, J = 14.9, 7.5 Hz, 1H), 1.65–1.56 (m, 1H), 1.32 (s, 3H), 0.93 (t, J = 7.5 Hz, 3H). 13 13C NMR (151 MHz, CDCl3) δ 183.56, 176.65, 45.55, 41.40, 30.78, 23.65, 8.57. HRMS [M-H] - calcd. for C7H 10 NO2, m / z: 140.0712, found: 140.0711.

[0217] Example 7

[0218] Refinement of ethosuximide - Method 2

[0219] Weighed 2.000 g of the crude ethosuximide (white waxy solid) prepared in Example 3, and recrystallized it with a mixed solvent of n - heptane and ethyl acetate to obtain 1.685 g of a white powdery solid, with a yield of 84.5% and a purity as high as 99.5%. m.p.: 46 - 48 °C.

[0220] The above - mentioned content is only the basic description under the concept of the present invention, and any equivalent transformation made according to the technical solution of the present invention shall fall within the protection scope of the present invention.

Claims

1. A method for preparing a compound of formula IA, wherein R1 and R2 are independently selected from C 1-6 alkyl; and it comprises the following steps: reacting a compound of formula I wherein R1 and R2 are as defined for formula IA, with titanium trichloride in the presence of a titanium trichloride protecting agent, in an inert gas atmosphere, under heating conditions in a solvent to obtain a compound of formula IA; the titanium trichloride protecting agent is selected from polyhydric alcohols.

2. The method according to claim 1, characterized in that R1 is methyl and R2 is ethyl.

3. The method according to claim 1, wherein the titanium trichloride is present in the form of a titanium trichloride solution.

4. The method according to claim 3, wherein The titanium trichloride solution is an aqueous solution of titanium trichloride.

5. The method according to claim 4, wherein The aqueous solution of titanium trichloride further contains hydrochloric acid.

6. The method according to claim 4, wherein The titanium trichloride solution is a 5 - 50% TiCl3 solution in 10% - 36% hydrochloric acid.

7. The method according to claim 6, wherein The titanium trichloride solution is a 15 - 20% TiCl3 solution in 30% hydrochloric acid.

8. The method according to claim 1, wherein Relative to the compound of formula I, titanium trichloride is used in an amount of 0.8 - 5.0 molar equivalents.

9. The method according to claim 1, characterized in that, The polyhydric alcohol is selected from propylene glycol, glycerol, pentaerythritol, inositol or a combination thereof.

10. The method according to claim 1, wherein The solvent is a mixed solvent of an organic solvent and water, and the organic solvent is selected from C 1-6 alkyl alcohols, acetone, and tetrahydrofuran.

11. The method according to claim 10, characterized in that, C 1-6 The alkyl alcohol is selected from ethanol and methanol.

12. The method according to claim 1, characterized in that, The volume ratio of the titanium trichloride protecting agent to the solvent is 1:20 to 20:

1.

13. The method according to claim 1, characterized in that, The inert gas is selected from nitrogen, argon, helium, or a combination thereof.

14. The method according to claim 1, wherein The heating conditions refer to 50 - 100 °C.

15. The method according to any one of claims 1 - 14, the method further comprising the following purification step: after the reaction is completed, recrystallizing the compound of formula IA in an organic solvent to obtain a purified compound of formula IA.

16. The method according to claim 15, wherein The organic solvent used in the purification step is selected from chloroform, ethyl acetate, acetone, ethanol, methanol, dichloromethane, acetonitrile, tetrahydrofuran, cyclohexane, n - hexane, n - heptane, petroleum ether, toluene or a combination thereof.

17. The method according to claim 15, characterized in that, The organic solvent used in the purification step is selected from a combination of a readily soluble solvent and a sparingly soluble solvent, the readily soluble solvent is selected from chloroform, ethyl acetate, acetone, ethanol, methanol, dichloromethane, acetonitrile, tetrahydrofuran, or a combination thereof, and the sparingly soluble solvent is selected from cyclohexane, n - hexane, n - heptane, petroleum ether, toluene, or a combination thereof.

18. The method according to claim 16 or 17, characterized in that, The ethanol is anhydrous ethanol, and the boiling point of the petroleum ether is 60 - 90 °C.

19. The method according to claim 17, wherein The solvent is a combination of n - hexane and ethyl acetate, a combination of n - heptane and ethyl acetate, or a combination of n - hexane and chloroform.

20. The method according to claim 1, the method further comprising the following step of preparing the compound of formula I as claimed in claim 1: reacting a compound of formula V wherein R1 and R2 are as defined for formula I in claim 1; with an ether bond cleavage reagent in an organic solvent at a cooling temperature to obtain a compound of formula I.

21. The method according to claim 20, wherein The ether bond cleavage reagent is titanium tetrachloride, boron tribromide, boron trichloride, boron trifluoride diethyl etherate, hydroiodic acid, hydrobromic acid and hydrochloric acid.

22. The method according to claim 20, wherein The ether bond cleavage reagent is titanium tetrachloride, boron tribromide or boron trichloride.

23. The method according to claim 20, wherein Relative to the compound of formula V, the ether bond cleavage reagent is used in an amount of 0.8 - 5.0 molar equivalents.

24. The method according to claim 20, wherein The organic solvent is selected from halogenated hydrocarbon solvents.

25. The method according to claim 20, wherein The organic solvent is selected from dichloromethane, chloroform, 1,2 - dichloroethane or a combination thereof.

26. The method according to claim 20, wherein The cooling temperature is 0 °C to - 100 °C.

27. The method according to claim 20, the method further comprising the following step of preparing the compound of formula V: 1) In an organic solvent and under the action of a strong base, a compound of formula IIa wherein R1 and R2 are as defined in formula I of claim 1, is reacted with a compound of formula IIb wherein X is Cl, Br or I; at a cooling temperature to obtain a compound of formula II wherein R1 and R2 are as defined in formula I of claim 1, 2) The compound of formula II is subjected to acid hydrolysis in a solvent, or subjected to base hydrolysis and then acidification to obtain a compound of formula III wherein R1 and R2 are as defined in formula I of claim 1, 3) The compound of formula III is reacted with a chlorinating reagent to obtain the corresponding acyl chloride, and then in the presence of a base, reacted with O-benzylhydroxylamine or its salt to obtain a compound of formula IV, or the compound of formula III is reacted with O-benzylhydroxylamine or its salt in the presence of a condensing agent and a base to obtain a compound of formula IV, wherein R1 and R2 are as defined in formula I of claim 1, 4) The compound of formula IV is oxidized with oxygen in an organic solvent and under heating conditions in the presence of a copper salt catalyst and a ligand to obtain a compound of formula V wherein R1 and R2 are as defined in claim 20.

28. The method according to claim 27, wherein The salt is a hydrochloride.

29. The method according to claim 27, wherein X is Br.

30. The method according to claim 27, wherein In step 1), the organic solvent is selected from aprotic solvents.

31. The method according to claim 27, wherein In step 1), the organic solvent is selected from methyl tert-butyl ether, tetrahydrofuran, toluene, diethyl ether, dioxane, n-hexane or a combination thereof.

32. The method according to claim 27, wherein In step 1), the organic solvent is diethyl ether, toluene, tetrahydrofuran, methyl tert-butyl ether or a combination thereof.

33. The method according to claim 27, wherein The strong base is selected from organic strong bases, and the organic strong bases are selected from C 1-6 alkyl alkali metal compounds, di-(C 1-6 alkyl) amino alkali metal compounds, C 1-6 alkali metal salts of alkanols, benzyl alkali metal compounds, alkali metal hydrides.

34. The method according to claim 33, wherein The said C 1-6 The alkyl alkali metal compound is selected from n-butyllithium and tert-butyllithium. The di-(C 1-6 alkyl)amine-based alkali metal compound is selected from lithium diisopropylamide. The C 1-6 alkali metal salt of alkanol is selected from sodium ethoxide, potassium ethoxide, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, and potassium methoxide. The benzyl alkali metal compound is selected from benzyllithium. The alkali metal hydride is selected from sodium hydride.

35. The method according to claim 27, wherein The strong base is selected from n-butyllithium, lithium diisopropylamide and tert-butyllithium.

36. The method according to claim 27, wherein In step 1), the cooling temperature is 0 °C to -100 °C.

37. The method according to claim 27, wherein In step 1), the molar ratio of the compound of formula IIa to the compound of formula IIb is 1:2 to 2:

1.

38. The method according to claim 27, wherein In step 1), the molar ratio of the compound of formula IIa to the strong base is 1:3 to 1.2:

1.

39. The method according to claim 27, wherein In step 2), the solvent is a mixed solvent of an organic solvent and water, and the organic solvent is a solvent miscible with water.

40. The method according to claim 39, wherein The organic solvent is selected from C 1-6 alkanols, tetrahydrofuran, acetone, dioxane, or a combination thereof.

41. The method according to claim 40, wherein The said C 1-6 alkanols are selected from methanol, ethanol, and propanol.

42. The method according to claim 39, wherein The mixed solvent is selected from methanol and water, ethanol and water, tetrahydrofuran and water.

43. The method according to claim 27, wherein In step 2), the base is selected from alkali metal hydroxides and alkali metal carbonates.

44. The method according to claim 43, wherein The alkali metal hydroxides are selected from potassium hydroxide, sodium hydroxide, lithium hydroxide; the alkali metal carbonates are selected from sodium carbonate, potassium carbonate.

45. The method according to claim 27, characterized in that, In step 2), the acid hydrolysis or base hydrolysis is carried out under heating conditions.

46. The method according to claim 45, characterized in that, The heating conditions refer to 30 - 100 °C.

47. The method according to claim 27, wherein In step 2), the acid hydrolysis or acidification uses inorganic acids such as sulfuric acid, hydrochloric acid and / or phosphoric acid.

48. The method according to claim 27, wherein Step 3) is carried out in a solvent selected from aprotic organic solvents.

49. The method according to claim 48, wherein The solvent is chloroform, ethyl acetate, dichloromethane, 1,2-dichloroethane, tetrahydrofuran, acetone or a combination thereof.

50. The method according to claim 27, wherein In step 3), the chlorinating reagent is thionyl chloride, oxalyl chloride, phosphorus trichloride and phosphorus pentachloride.

51. The method according to claim 27, wherein In step 3), the base is selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, triethylamine, pyridine, 4-dimethylaminopyridine or 1,8-diazabicyclo[5.4.0]undec-7-ene.

52. The method according to claim 51, wherein The alkali metal carbonate is selected from sodium carbonate and potassium carbonate, the alkali metal bicarbonate is selected from sodium bicarbonate and potassium bicarbonate, and the alkali metal hydroxide is selected from potassium hydroxide and sodium hydroxide.

53. The method according to claim 27, wherein In step 3), the condensing agent is selected from: dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, N,N'-carbonyldiimidazole, and benzotriazol-N,N,N',N'-tetramethyluronium hexafluorophosphate.

54. The method according to claim 27, wherein In step 3), the reaction is carried out at a temperature of -30 to 90 °C.

55. The method according to claim 27, wherein In step 4), the copper salt catalyst is selected from cuprous salts and cupric salts.

56. The method according to claim 55, wherein The copper salt catalyst is selected from cuprous acetate and copper acetate.

57. The method according to claim 55, characterized in that, The copper salt catalyst is cuprous acetate.

58. The method according to claim 27, wherein In step 4), the ligand is 1,10-phenanthroline.

59. The method according to claim 27, characterized in that, In step 4), the ligand is bathocuproine.

60. The method according to claim 27, wherein In step 4), the molar ratio of the compound of formula IV to the copper salt catalyst is from 50:1 to 1:

1.

61. The method according to claim 27, wherein In step 4), the molar ratio of the compound of formula IV to the ligand is from 50:1 to 1:

1.

62. The method according to claim 27, wherein In step 4), the organic solvent is an aprotic organic solvent.

63. The method according to claim 62, characterized in that, The organic solvent is selected from xylene, toluene, benzene, nitrobenzene, n-heptane, n-hexane, cyclohexane or a combination thereof.

64. The method according to claim 27, wherein In step 4), the heating condition refers to 50 - 100 °C.

65. The method according to claim 27, wherein In step 4), the oxygen is selected from high-purity oxygen, industrial oxygen, and oxygen in air.

66. The method according to claim 27, wherein In step 4), the oxygen is selected from high-purity oxygen.

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