Intermediate as well as preparation method and application thereof

Abstract

The invention discloses an intermediate as well as a preparation method and application thereof. Disclosed, inter alia, are processes for the preparation of compounds of Formula IA wherein R1 and R2 are independently selected from C1-6 alkyl groups. The ethosuximide is synthesized by adopting the method disclosed by the invention, the use of highly toxic cyanide as a raw material can be avoided, and the method is mild in reaction condition, relatively high in yield, good in product quality, few in impurities and suitable for industrial production. # imgabs0 #

Description

Technical Field

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

[0002] As an anticonvulsant drug, ethosuximide is mainly used to treat minor epileptic seizures, that is, absence seizures and clonic seizures, but is ineffective for tonic-clonic and partial seizures. It can be used with other antiepileptic drugs for mixed epileptic seizures. The advantages of ethosuximide are safety, effectiveness, no sedative effect, long elimination half-life, and a single dose per day can control seizures. Ethosuximide contains a chiral carbon atom in its structure, but the marketed drug is a racemic mixture, not an optically pure enantiomer.

[0003] At present, the synthesis methods of ethosuximide reported in the literature mainly include the following three routes:

[0004] 1. Synthesis 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 is obtained by atmospheric distillation of the ammonium salt of 2-methyl-2-ethylsuccinic acid as a raw material (J Chem Soc, 1927, 600-605; J Chem Soc, 1927, 1252-1256). U.S. Patent No. 2,993,835, which uses ethosuximide as an active ingredient in a pharmaceutical composition for treating epileptic seizures, also cited the synthesis methods of these two documents to prepare ethosuximide. Hill RK et al. described in detail in the literature (J Org Chem, 1981, 46, 2757-2764) a method for preparing ethosuximide by reacting 2-methyl-2-ethylsuccinic acid with ammonia followed by vacuum distillation. Based on Hill RK's paper, Hine J et al. prepared ethosuximide by reacting 2-methyl-2-ethylsuccinic acid with ammonium hydroxide followed by vacuum distillation (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 (Organic Syntheses, 1964, 44, 59-61), using 2-butanone and ethyl 2-cyanoacetate as raw materials, passing through the intermediate 2,3-dicyano-3-methylvaleric acid ethyl ester, but the intermediate is not separated, and the cyano group and ester group are hydrolyzed under the acidic conditions provided by hydrochloric acid, and heated for decarboxylation to obtain 2-methyl-2-ethylsuccinic acid.

[0008]

[0009] 2. Synthesis route using N-substituted vinyl-α-chloro-α-methylthioacetamide as key intermediate (2)

[0010]

[0011] Ishibashi H et al. reported in the literature (Tetrahedron, 1995, 51(10), 2929-2938) that a Schiff base (1) was synthesized from 2-methylbutyraldehyde and p-methoxybenzylamine, which was reacted with 2-methylthioacetyl chloride to form an enamine, which was then chlorinated with N-chlorosuccinimide (NCS) to obtain a 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 sulfide group was removed by reduction with Raney nickel and ethanol to obtain intermediate (4). 4 was oxidized with chromium trioxide pyridine hydrochloride (PCC) to obtain succinimide (5). 5 was deprotected with ammonium cerium nitrate (CAN) to obtain ethosuximide.

[0012] 3. Synthesis route with copper-catalyzed O2 oxidation C=C cleavage to construct imide ring as the key step

[0013]

[0014] Junhua Li et al. reported in the literature (Chem Sci, 2019, 10, 9099-9103) that this route uses 2-methylbutyric acid and 3-bromopropylene as raw materials, reacts in the presence of lithium diisopropylamide to obtain intermediate 1, converts it into an acyl chloride with oxalyl chloride, and reacts with benzyloxyhydroxylamine hydrochloride in the presence of a base to obtain intermediate 2. The key step is that intermediate 2 is oxidized with oxygen in toluene using cuprous acetate as a catalyst and bathocuproine as a ligand to obtain intermediate 3, which is then hydrogenated at normal pressure under palladium-carbon catalysis and rearranged in the presence of 2-bromoacetophenone and triethylamine to obtain ethosuximide.

[0015] There are some problems with each of the above routes, which are briefly described as follows:

[0016] Route 1 inevitably uses highly toxic reagents such as potassium cyanide or sodium cyanide, which requires high qualifications for production companies, places great pressure on production safety, and has high regulatory requirements, making it difficult to achieve independent and controllable API production;

[0017] Route 2 uses intermediate 1 as a raw material and undergoes five steps of reaction, with a total yield of 5.76%, which is a relatively low yield. In addition, each step requires column chromatography for separation and purification. In the reaction process, heavy metal reagents such as chromium trioxide pyridine hydrochloride (PCC) and other environmentally-focused reagents are also used. The environmental pressure is high, and this route is not suitable for large-scale production of APIs.

[0018] Route 3 has certain merits. It is a novel method to construct an imide ring by oxidizing with oxygen under a catalyst. However, Route 3 has the following problems: 1) It uses 2-methylbutyric acid as a raw material, and requires at least 2 equivalents of LDA to remove the H at the α-position of the carboxyl group, resulting in a waste of raw materials. In addition, the carboxylate anion generated by the reaction of the carboxyl group with LDA will theoretically also participate in the reaction, resulting in an increase in by-products; 2) Column chromatography is used for post-treatment of each step of the reaction, which is not suitable for industrial production; 3) The last step of the reaction uses a hydrogenation process under palladium-carbon catalysis, which has special requirements for the qualifications of the manufacturer; 4) The last step is a rearrangement reaction, which theoretically will produce more impurities, and is not suitable as the last step in the production of raw materials; 5) The reaction of this route is on a scale of hundreds of milligrams, and the reaction conditions of many of the reactions are not suitable for industrial production. The reaction operation and / or post-treatment are complicated, and thus it is not suitable for scale-up as a production process.

[0019] In summary, the preparation methods of ethosuximide reported in the existing literature all have certain problems and are not suitable as a process for large-scale production of bulk drugs. It is necessary to develop an improved large-scale production process of ethosuximide bulk drugs or their analogs. The inventors have discovered an improved synthesis method of ethosuximide or its analogs through in-depth research. The method can avoid using highly toxic cyanide as a raw material, has mild reaction conditions, is simple and safe to operate during the reaction process, has a high yield, good product quality, and few impurities. The intermediates and final products are purified by recrystallization without using column chromatography for purification, and are 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] It includes the following steps:

[0024] The compound of formula I

[0025]

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

[0027] It is reacted with titanium trichloride, optionally in the presence of a titanium trichloride protective agent, optionally under an inert gas atmosphere, under heating conditions in a solvent to obtain a compound of formula IA.

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

[0029] In some embodiments, the titanium trichloride is 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% TiCl3 solution in 10%-36% hydrochloric acid, preferably a 15-20% TiCl3 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, for example, 0.8-2, 1-1.5, for example 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 found that the use of titanium trichloride protective agent significantly improves the yield of the reaction, reduces impurities, and does not require column chromatography separation of the product. The product can be purified by recrystallization to obtain ethosuximide that meets the pharmacopoeia standards.

[0034] In some embodiments, the titanium trichloride protective agent is selected from polyols, preferably selected from 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, such as 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 refers to 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 a 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 (e.g., 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 an insoluble solvent (i.e., a solvent in which the compound of Formula IA is insoluble), the readily soluble solvent is preferably selected from chloroform, ethyl acetate, acetone, ethanol (e.g., anhydrous ethanol), methanol, dichloromethane, acetonitrile, tetrahydrofuran or a combination thereof, the insoluble solvent is preferably 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 a compound of formula I:

[0043] The compound of formula (V)

[0044]

[0045] Wherein R1 and R2 are as defined for Formula I;

[0046] Treatment with an ether bond cleaving agent in an organic solvent at cooling temperature affords a 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 etherate, hydroiodic acid, hydrobromic acid and hydrochloric acid, and more preferably titanium tetrachloride, boron tribromide or boron trichloride.

[0048] In some embodiments, the ether bond cleavage reagent is used in an amount of 0.8-5.0 molar equivalents relative to the compound of formula V, for example, 0.8-2, 1-1.5, for example 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 0°C to -100°C, such as 0°C to -78°C, -30°C to -78°C, or -5°C to -40°C.

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

[0052] 1) In an organic solvent, under the action of a strong base, the compound of formula IIa is

[0053]

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

[0055] With the compound of formula IIb

[0056]

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

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

[0059]

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

[0061] 2) The compound of formula II is subjected to acid hydrolysis in a solvent, or is subjected to alkaline hydrolysis and then acidified to obtain a compound of formula III

[0062]

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

[0064] 3) the compound of formula III is reacted with a chlorinating agent to obtain the corresponding acid chloride, and then reacted with O-benzylhydroxylamine or a salt thereof 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 a salt thereof 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) Compound IV is oxidized with oxygen in an organic solvent under heating conditions under the action of a copper salt catalyst and a ligand to obtain compound V

[0068]

[0069] wherein R1 and R2 are as defined for 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, for example selected from C 1-6 Alkyl alkali metal compounds, such as n-butyl lithium, tert-butyl lithium, di-(C 1-6 Alkyl) amide 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 benzyl lithium, alkali metal hydrides such as sodium hydride, etc., more preferably selected from n-butyl lithium, lithium diisopropylamide and tert-butyl lithium; and / or

[0072] The cooling temperature is 0°C to -100°C, such as 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 1:2 to 2:1, such as 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 1:3 to 1.2:1, for example, 1:3 to 1:1, 1:2 to 1:1, 1:1.5 to 1:1, for example, 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 The alkanols are, for example, 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, and the like.

[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, and the like.

[0077] In some embodiments, the acid hydrolysis or alkaline 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, preferably heating under the boiling temperature conditions of the mixed solvent.

[0078] In some embodiments, the acid hydrolysis or acidification after alkaline hydrolysis is performed using an inorganic acid, such as sulfuric acid, hydrochloric acid and / or phosphoric acid (eg, dilute sulfuric acid, dilute hydrochloric acid, dilute phosphoric acid), and the like.

[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 chloroform, ethyl acetate, dichloromethane, 1,2-dichloroethane and other water-immiscible solvents, tetrahydrofuran, acetone or a combination thereof.

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

[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) and the like.

[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 benzotriazole-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, 0-40°C, or 5-20°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, cupric acetate, etc., 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 known as bathocuproine) or 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 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 the air (i.e., air is used for the oxidation reaction), more preferably high-purity oxygen.

[0089] It should be understood that those skilled in the art can easily detect the reaction process, thereby determine the reaction time. Each reaction of the present invention can be carried out for example 0.5 hour-5 days, for example 0.5-24 hours, 1-10 hours, for example 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 their research that when the prior art route 3 (Chem Sci, Junhua Li et al. 2019, 10, 9099-9103) is used to synthesize the compound 3a of the present invention on a large scale, the reaction yield is very low, there are many impurities, and it cannot be used for industrial production. The route adopted by the present invention obtains the compound 3a of the present invention with a very high yield, and can be used directly without purification, which is suitable for industrial production.

[0091] In addition, compared with the prior art methods, the synthetic route and method of the present invention have many advantages, such as 1) avoiding the use of highly toxic cyanide, precious metal catalytic hydrogenation, complicated routes, and / or many process impurities, and is more environmentally friendly and suitable for raw material drug production; 2) reducing or avoiding the use of chromatographic separation, and the separation and purification operation is simple, which is suitable for industrial production; and / or 3) the reaction conditions are mild, the reaction process is simple and safe to operate, the yield is 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, comprising the following steps:

[0093] The compound of formula (V)

[0094]

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

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

[0097]

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

[0099] 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 following step of preparing a compound of formula V:

[0101] 1) In an organic solvent, under the action of a strong base, the compound of formula IIa is

[0102]

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

[0104] With the compound of formula IIb

[0105]

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

[0107] Reaction at cooling temperature to obtain 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 is subjected to alkaline hydrolysis and then acidified 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 acid chloride, and then reacted with O-benzylhydroxylamine or a salt thereof 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 a salt thereof such as hydrochloride in the presence of an esterification condensation 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) Compound IV is oxidized with oxygen in an organic solvent under heating conditions under the action of a copper salt catalyst and a ligand to obtain compound V

[0117]

[0118] wherein R1 and R2 are as defined for formula I.

[0119] The reaction conditions (including reaction reagents, solvents, temperature, dosage, etc.) are 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 methyl at the same time.

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

[0124]

[0125] No literature reports were found after searching the Scifinder database. The present invention is the first to prepare, separate and purify the substance. The specific synthesis method and structural characterization of the compound are shown in the examples. The compound can be used as a key intermediate for 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] Use for preparing the 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] Used in the synthesis of ethosuximide.

[0135] According to the method of the present invention, ethosuximide is synthesized, and the molar yield of pure ethosuximide can reach 31.2% based on ethyl 2-methylbutyrate, the raw material of the first step reaction, and the product purity can reach more than 99%. The quality of the raw material meets the requirements of the United States Pharmacopoeia. The quality inspection methods such as HPLC can be carried out according to the method in the United States Pharmacopoeia (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 the problems of using highly toxic cyanide, noble metal catalytic hydrogenation, complicated routes, and / or many process impurities in the existing ethosuximide synthesis method, and is more environmentally friendly and suitable for raw material drug production;

[0138] 2) It can reduce or avoid the use of chromatographic separation, and the separation and purification operation is 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 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 the context indicates otherwise. Technical and scientific terms used herein that are not specifically defined have the meanings commonly understood by those skilled in the art to which the present invention belongs.

[0142] The term "alkyl" as used herein refers to a linear or branched saturated monovalent hydrocarbon group having 1 to 6 carbon atoms, for example, a linear or branched saturated monovalent hydrocarbon group having 1 to 4, 1 to 3 or 1 to 2 carbon atoms. Alkyl groups having 1 to 6 carbon atoms are simply represented as "C 1-6 Alkyl groups having 1 to 4 carbon atoms are simply represented by "C 1-4 Alkyl groups with other carbon number can also be represented in a similar manner. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl.

[0143] The term "titanium trichloride protective 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 (ie, inert) under the reaction conditions involved, including but not limited to nitrogen, argon, helium, and the like.

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

[0146] The term "cooling temperature" as used herein refers to a temperature lowered relative to room temperature (25°C), for example 0°C to -100°C, such as 0°C to -78°C, -30°C to -78°C or -5°C to -40°C.

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

[0148] The term “C 1-6 "Alkyl alkali metal compound" refers to a compound having C 1-6 A compound of the structure alkyl-M, wherein 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 (C 1-6 The compound of the structure of (i)-(2-N-M)-alkyl, wherein M is an alkali metal.

[0150] The term “C 1-6 The term "alkali metal salt of an alkanol" refers to an alkali metal salt of 1-6 A compound of the structure alkoxy-M, wherein M is an alkali metal.

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

[0152] The term “C 1-6 "Alkanol" refers to C 1-6 Alkyl-OH compounds, wherein alkyl is as defined above.

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

[0154] It should be understood that, unless otherwise specified or clearly contradicted by the context, when a subsequent embodiment or technical solution refers to a prior embodiment or technical solution and does not further define 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 of the prior embodiment or technical solution.

[0155] It should also be understood that the reaction of the present invention can be carried out under conventional reaction conditions known in the art. For example, a certain 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, elevated pressure or reduced pressure, as appropriate.

[0157] In this document, if both the name and structural formula of a compound are given, in the event of a discrepancy between the two, the structure of the compound shall prevail unless the context indicates that the structure of the compound is incorrect and the name is correct. BRIEF DESCRIPTION OF THE DRAWINGS

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

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

[0160] Figure 3 The MS spectrum of the key intermediate 3-methyl-3-ethyl-1-hydroxy-pyrrolidine-2,5-dione (1a) is shown. DETAILED DESCRIPTION

[0161] The present invention is further described in detail below with reference to specific embodiments.

[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 1000mL three-necked flask, add 203mL of 2.5mol / L n-butyllithium n-hexane solution, cool to -35~-40℃ in a low temperature bath, add ethyl 2-methylbutyrate (60.0g, 0.461mol) dissolved in 90mL of dry methyl tert-butyl ether dropwise with stirring, continue stirring for 1h, add 3-bromopropylene (61.3g, 0.507mol) dissolved in 90mL of dry methyl tert-butyl ether dropwise, continue stirring for 1h, cool and quench the reaction with saturated aqueous ammonium chloride solution, filter the generated white solid, wash the filter cake with ethyl acetate twice × 120mL, separate the filtrate in a separatory funnel, extract the aqueous phase with ethyl acetate twice × 150mL, and the combined organic phases are successively extracted with 120mL The product was washed with 1 mol / L hydrochloric acid, 120 mL saturated NaHCO3 aqueous solution, 120 mL saturated NaCl aqueous solution, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain 78.5 g of the title compound as a brown oil, which can be directly used in the next step without separation and purification.

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

[0168]

[0169] In a 2000mL eggplant-shaped bottle, add 78.5g of the crude compound 2a prepared in Example 1 and 942mL of methanol, add KOH (content 85%, 121.6g, 1.844mol) dissolved in 471mL of distilled water to form a solution, stir and reflux for 12h, remove most of the methanol by rotary evaporation under reduced pressure, cool to room temperature, transfer to a separatory funnel, and wash with n-heptane 2 times × 60mL. The aqueous phase is adjusted to pH 3-4 with 6.0mol / L hydrochloric acid, extracted with CH2Cl2 3 times × 100mL, the organic phases are combined, washed with 100mL of saturated NaCl aqueous solution, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain 56.4g of the title compound as a brown-red oil, which is directly used in the next step without separation and purification.

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

[0171]

[0172] In a 500 mL eggplant-shaped bottle, 56.4 g (397 mmol) of the crude compound 3a prepared in step 2 of Example 1 and 113 mL of CH2Cl2 were added. After sufficient cooling in an ice-water bath, 54.7 g (476 mmol) of thionyl chloride dissolved in 56 mL of CH2Cl2 was added. After the addition was complete, the reaction was stirred at room temperature for 2 h. The solvent and unreacted thionyl chloride were removed by distillation under reduced pressure, and 100 mL of THF was added to form a solution of the crude 2-methyl-2-ethyl-4-pentenoic acid chloride.

[0173] In a 1000mL three-necked flask, 564mL of chloroform and 282mL of distilled water were added, and 69.7g (437mmol) of O-benzylhydroxylamine hydrochloride and 58.9g (556mmol) of anhydrous sodium carbonate were added. After sufficient cooling in an ice-water bath, the solution of the crude 2-methyl-2-ethyl-4-pentenoic acid chloride prepared above was added dropwise. After the addition was completed, the reaction was stirred at room temperature for 2h, and the two phases were separated by a separatory funnel. The aqueous phase was extracted with chloroform twice × 120mL, and the organic phases were combined, washed with 1.0mol / L hydrochloric acid aqueous solution once × 120mL, washed with saturated NaHCO3 aqueous solution once × 120mL, and washed with saturated NaCl aqueous solution once × 120mL, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, 100.4g of a brown-red oil. Recrystallization was performed using 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 was 69.9% based on the raw material ethyl 2-methylbutyrate in Example 1, mp: 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 2000mL four-necked flask, add 79.8g (323mmol) of compound 4a prepared in step 3 of Example 1, 3.96g (32.3mmol) of cuprous acetate, 13.99g (38.8mmol) of bathocuproin and 1197mL of toluene, bubble high-purity oxygen into the reaction solution, heat to control the internal temperature at 75-80°C, stir the reaction for 33h, and cool naturally to room temperature. Use diatomaceous earth as a filter aid, filter with suction, wash with toluene, and concentrate under reduced pressure to obtain 81.6g of brown solid. Add 500mL of ethyl acetate to dissolve, transfer to a separatory funnel, wash with distilled water 3 times × 100mL, dry with anhydrous MgSO4, filter with suction, wash the filter cake with ethyl acetate twice, and concentrate the filtrate under reduced pressure to obtain 74.5g of brown solid. Recrystallize with a mixed solvent of n-heptane and ethyl acetate to obtain 48.2g of white solid with a yield of 60.3%. mp: 72-73°C.

[0178] 1 H NMR(600MHz, CDCl3)δ7.48(dd,J=6.2,3.3Hz,2H),7.40–7.32(m,3H),5.21–5.09(m,2H),2.50(d,J=18.0H z,1H),2.29(d,J=18.0Hz,1H),1.69–1.60(m,1H),1.55–1.44(m,1H),1.19(s,3H),0.79(t,J=7.5Hz,3H). 13 C NMR(151MHz, CDCl3)δ176.96,170.45,133.23,130.05(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 2000mL four-necked flask, add 48.2g (195mmol) of compound 5a prepared in step 4 of Example 1 and 482mL of chloroform, maintain the internal temperature at -73 to -78°C, and dropwise add 294g (1.17mol) of BBr3 dissolved in 96mL of chloroform. After the addition is complete, continue to stir and react within the temperature range for 1h. Add an appropriate amount of ice water to the reaction solution to quench the reaction, and continue to stir for 1h. Separate the two phases, extract the aqueous phase with chloroform twice × 100mL, combine the organic phases, wash with saturated NaCl aqueous solution once × 100mL, dry with anhydrous MgSO4, and concentrate under reduced pressure to obtain 61.3g of crude light brown oil. The obtained crude product was stirred and dispersed in 250mL saturated NaHCO3 aqueous solution, washed twice with 50mL n-hexane, the aqueous phase was cooled in an ice-water bath, the pH value was adjusted to 3-4 with 20% sulfuric acid, NaCl solid powder was added under stirring until saturated, filtered, the aqueous phase was extracted with chloroform twice × 100mL, the organic phases were combined, washed once with saturated NaCl aqueous solution × 100mL, dried over anhydrous MgSO4, and concentrated under reduced pressure to obtain 26.2g of light brown oil, which became white solid after vacuum drying at room temperature, with a yield of 85.5%. mp: 61-63℃.

[0182] 1 H NMR (600MHz, CDCl3) δ2.63(d,J=18.1Hz,1H),2.44(d,J=18.1Hz,1H),1.75(dq,J=1 4.9,7.5Hz,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[MH] - 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 1000mL three-necked flask, add 254mL of 2mol / L lithium diisopropylamide (LDA) in THF+n-hexane (v:v=12:25), cool to -73~-78℃ in a low temperature bath, add ethyl 2-methylbutyrate (60.0g, 0.461mol) dissolved in 90mL dry THF dropwise with stirring, continue stirring for 1h, add 3-propene bromide (90.0g, 0.692mol) dissolved in 90mL dry THF dropwise, continue stirring for 1h, cool and quench the reaction with saturated aqueous ammonium chloride solution, filter the generated white solid, wash the filter cake with ethyl acetate twice×120mL, separate the filtrate in a separatory funnel, extract the aqueous phase with ethyl acetate twice×150mL, and extract the combined organic phase with 120mL The product was washed with 1 mol / L hydrochloric acid, 120 mL saturated NaHCO3 aqueous solution, 120 mL saturated NaCl aqueous solution, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain 78.1 g of the title compound as a brown oil, which can be directly used in the next step without separation and purification.

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

[0189]

[0190] In a 2000mL eggplant-shaped bottle, add 78.1g of the crude compound 2a prepared in step 1 of Example 2 and 942mL of ethanol, add a solution of NaOH (36.9g, 0.922mol) dissolved in 471mL of distilled water, stir and reflux for 12h, remove most of the ethanol by vacuum rotary evaporation, cool to room temperature, transfer to a separatory funnel, and wash with n-heptane 2 times × 60mL. The aqueous phase is adjusted to pH 3-4 with 20% sulfuric acid, and the aqueous phase is extracted with CH2Cl2 3 times × 100mL, the organic phases are combined, washed with 100mL of saturated NaCl aqueous solution, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain 55.9g of the title compound as a brown-red oil, which is directly used in the next step 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 bottle, 55.9 g (393 mmol) of the crude compound 3a prepared in step 2 of Example 2 and 113 mL of CH2Cl2 were added. After sufficient cooling in an ice-water bath, 74.9 g (590 mmol) of oxalyl chloride dissolved in 56 mL of CH2Cl2 and a catalytic amount of N,N-dimethylformamide (DMF) were added. After the addition was complete, the reaction was stirred at room temperature for 2 h. The solvent and unreacted oxalyl chloride were removed by distillation under reduced pressure, and 100 mL of THF was added to form a solution of the crude 2-methyl-2-ethyl-4-pentenoic acid chloride.

[0194] In a 1000mL three-necked flask, 564mL of ethyl acetate (EA) and 282mL of distilled water were added, and 69.7g (437mmol) of O-benzylhydroxylamine hydrochloride and 76.8g (556mmol) of anhydrous potassium carbonate were added. After sufficient cooling in an ice-water bath, the solution of the crude 2-methyl-2-ethyl-4-pentenoic acid chloride prepared above was added dropwise. After the addition was completed, the mixture was stirred at room temperature for 2h. The two phases were separated by a separatory funnel, and the aqueous phase was extracted with EA twice × 120mL. The organic phases were combined, washed with 1.0mol / L hydrochloric acid aqueous solution once × 120mL, washed with saturated NaHCO3 aqueous solution once × 120mL, washed with saturated NaCl aqueous solution once × 120mL, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product, 98.6g of a brown-red oil. Recrystallization was performed using 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 was 68.9% based on the raw material ethyl 2-methylbutyrate in Example 2, mp: 45-46°C.

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

[0196]

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

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

[0199]

[0200] In a 2000mL four-necked flask, add 47.2g (191mmol) of compound 5a prepared in step 4 of Example 2 and 482mL of CH2Cl2, maintain the internal temperature at -35 to -40°C, and dropwise add 40.8g (215mmol) of TiCl4 dissolved in 96mL of CH2Cl2. After the addition is complete, continue to stir and react within the temperature range for 1h. Add an appropriate amount of ice water to the reaction solution to quench the reaction, and continue to stir for 1h. Separate the two phases, extract the aqueous phase with EA twice × 100mL, combine the organic phases, wash with saturated NaCl aqueous solution once × 100mL, dry with anhydrous MgSO4, and concentrate under reduced pressure to obtain 62.7g of crude light brown oil. The obtained crude product was dispersed in 250mL saturated NaHCO3 aqueous solution by stirring, washed twice with 50mL n-hexane, the aqueous phase was cooled in an ice-water bath, the pH value was adjusted to 3-4 with 20% sulfuric acid, NaCl solid powder was added under stirring until saturated, filtered, the aqueous phase was extracted with ethyl acetate twice × 100mL, the organic phases were combined, washed once with saturated NaCl aqueous solution × 100mL, dried over anhydrous MgSO4, and concentrated under reduced pressure to obtain 27.3g of light brown oil, which became white solid after vacuum drying at room temperature, with a yield of 90.9%. mp: 61-63℃.

[0201] Example 3

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

[0203]

[0204] Add 221mL (214.6mmol) of 15-20% TiCl3 solution in 30% hydrochloric acid to a 2000mL four-necked flask, add 150mL propylene glycol and 442mL distilled water under stirring. Dissolve 26.2g (166.7mmol) of compound 1a prepared in Example 1 in 56mL methanol and add it to a constant pressure dropping funnel for use. Under nitrogen protection, drop the solution in the constant pressure dropping funnel, heat to 80-90℃ and react for 5h. Pour the reaction solution into ice water under 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 20.2g of 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 221mL (214.6mmol) of 15-20% TiCl3 solution in 30% hydrochloric acid to a 2000mL four-necked flask, add 120mL glycerol and 442mL distilled water under stirring. Dissolve 27.3g (173.7mmol) of compound 1a prepared in Example 2 in 56mL methanol and add it to a constant pressure dropping funnel for use. Under nitrogen protection, drop the solution in the constant pressure dropping funnel, heat to an internal temperature of 70-80℃ and react for 4h. Pour the reaction solution into ice water under stirring, extract the aqueous phase with ethyl acetate, and wash with a saturated NaCl aqueous solution. Dry over anhydrous MgSO4, filter, and concentrate under reduced pressure to obtain 20.5g of 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 221mL (214.6mmol) of 15-20% TiCl3 solution in 30% hydrochloric acid to a 2000mL four-necked flask, and add 442mL of distilled water under stirring. Dissolve 26.2g (166.7mmol) of compound 1a obtained according to the preparation method of Example 1 in 56mL of methanol and add it to a constant pressure dropping funnel for use. Under nitrogen protection, drop the solution in the constant pressure dropping funnel, heat to an internal temperature of 70-80℃ and react for 5h. Pour the reaction solution into ice water under stirring, extract the aqueous phase with ethyl acetate, and wash with a saturated NaCl aqueous solution. Dry over anhydrous MgSO4, filter, and concentrate under reduced pressure to obtain 5.6g of crude product with a yield of 23.8%, which is an off-white waxy solid.

[0213] Example 6

[0214] Refining of Ethosuximide - Method 1

[0215] 2.000 g of the crude ethosuximide (white waxy solid) prepared in Example 3 was weighed and recrystallized 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 of up to 99.5%. mp: 46-48°C.

[0216] 1H NMR (600MHz, CDCl3) δ8.68(s,1H),2.66(d,J=18.4Hz,1H),2.47(d,J=18.4Hz,1H),1 .75(dq,J=14.9,7.5Hz,1H),1.65–1.56(m,1H),1.32(s,3H),0.93(t,J=7.5Hz,3H). 13 CNMR(151MHz,CDCl3)δ183.56,176.65,45.55,41.40,30.78,23.65,8.57.HRMS[MH] - calcd.for C7H 10 NO2,m / z:140.0712,found:140.0711.

[0217] Example 7

[0218] Refining of Ethosuximide - Method 2

[0219] 2.000 g of the crude ethosuximide (white waxy solid) prepared in Example 3 was weighed and recrystallized 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 of up to 99.5%. mp: 46-48°C.

[0220] The above contents are only basic descriptions of the concept of the present invention, and any equivalent changes 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; preferably, R1 is methyl and R2 is ethyl; It includes the following steps: The compound of formula I wherein R1 and R2 are as defined for Formula IA, It is reacted with titanium trichloride, optionally in the presence of a titanium trichloride protective agent, optionally under an inert gas atmosphere, under heating conditions in a solvent to obtain a compound of formula IA.

2. The method according to claim 1, wherein the reaction is carried out under an inert gas atmosphere; Preferably, the reaction is carried out in the presence of a titanium trichloride protective agent.

3. The method according to claim 1 or 2, wherein the titanium trichloride is in the form of a titanium trichloride solution, preferably, the titanium trichloride solution is an aqueous solution of titanium trichloride, and more preferably, the aqueous solution of titanium trichloride further contains hydrochloric acid; Preferably, the titanium trichloride solution is a 5-50% TiCl3 solution in 10%-36% hydrochloric acid, preferably a 15-20% TiCl3 solution in 30% hydrochloric acid; Preferably, titanium trichloride is used in an amount of 0.8-5.0 molar equivalents relative to the compound of formula I; Preferably, the titanium trichloride protective agent is selected from polyols, preferably propylene glycol, glycerol, pentaerythritol, inositol, etc. or a combination thereof; Preferably, the solvent is a mixed solvent of an organic solvent and water, more preferably, the organic solvent is selected from C 1-6 Alkyl alcohol (preferably ethanol, methanol), acetone and tetrahydrofuran; Preferably, the volume ratio (v / v) of the titanium trichloride protective agent to the solvent is 1:20 to 20:1; Preferably, the inert gas is selected from nitrogen, argon, helium, or a combination thereof; Preferably, the heating condition is 50-100°C.

4. The method according to any one of claims 1 to 3, further comprising the following purification step: after the reaction is completed, the compound of formula IA is recrystallized in an organic solvent to obtain a purified compound of formula IA; Preferably, the organic solvent used in the purification step is selected from chloroform, ethyl acetate, acetone, ethanol (e.g., anhydrous ethanol), methanol, dichloromethane, acetonitrile, tetrahydrofuran, cyclohexane, n-hexane, n-heptane, petroleum ether (60-90° C.), toluene or a combination thereof; Preferably, the organic solvent used in the purification step is preferably a combination of a readily soluble solvent and an insoluble solvent, the readily soluble solvent is preferably selected from chloroform, ethyl acetate, acetone, ethanol (e.g., anhydrous ethanol), methanol, dichloromethane, acetonitrile, tetrahydrofuran, or a combination thereof, and the insoluble 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.

5. The method according to any one of claims 1 to 4, further comprising the step of preparing the compound of formula I according to claim 1: The compound of formula V Wherein R1 and R2 are as defined in claim 1 for formula I; Treat with an ether bond cleavage agent in an organic solvent at cooling temperature to obtain a compound of formula I; Preferably, the ether bond cleavage reagent is preferably titanium tetrachloride, boron tribromide, boron trichloride, boron trifluoride etherate, hydroiodic acid, hydrobromic acid and hydrochloric acid, and more preferably titanium tetrachloride, boron tribromide or boron trichloride; Preferably, the ether bond cleavage agent is used in an amount of 0.8-5.0 molar equivalents relative to the compound of formula V; Preferably, the organic solvent is selected from halogenated hydrocarbon solvents, preferably selected from dichloromethane, chloroform, 1,2-dichloroethane or a combination thereof; Preferably, the cooling temperature is 0°C to -100°C.

6. The method according to claim 5, further comprising the step of preparing the compound of formula V: 1) In an organic solvent, under the action of a strong base, the compound of formula IIa is wherein R1 and R2 are as defined for formula I of claim 1, With the compound of formula IIb Wherein X is Cl, Br or I, preferably Br Reaction at cooling temperature to obtain compound II wherein R1 and R2 are as defined for formula I of claim 1, 2) The compound of formula II is subjected to acid hydrolysis in a solvent, or is subjected to alkaline hydrolysis and then acidified to obtain a compound of formula III wherein R1 and R2 are as defined for formula I of claim 1, 3) The compound of formula III is reacted with a chlorinating agent to obtain the corresponding acid chloride, and then reacted with O-benzylhydroxylamine or a salt thereof 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 a salt thereof such as hydrochloride in the presence of a condensing agent and a base to obtain a compound of formula IV, wherein R1 and R2 are as defined for formula I of claim 1, 4) Compound IV is oxidized with oxygen in an organic solvent under heating conditions under the action of a copper salt catalyst and a ligand to obtain compound V Wherein R1 and R2 are as defined in claim 5; Preferably, 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; Preferably, the strong base is preferably an organic strong base, for example selected from C 1-6 Alkyl alkali metal compounds, such as n-butyl lithium, tert-butyl lithium, di-(C 1-6 Alkyl) amide 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 benzyl lithium, alkali metal hydrides such as sodium hydride, etc., more preferably selected from n-butyl lithium, lithium diisopropylamide and tert-butyl lithium; and / or Preferably, the cooling temperature is 0°C to -100°C; Preferably, in step 1), the molar ratio of the compound of formula IIa to the compound of formula IIb is 1:2 to 2:1; Preferably, in step 1), the molar ratio of the compound of formula IIa to the strong base is 1:3 to 1.2:1; Preferably, 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 combinations thereof, preferably methanol and water, ethanol and water, tetrahydrofuran and water; Preferably, 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; Preferably, the acid hydrolysis or alkaline hydrolysis is carried out under heating conditions, preferably the heating conditions are 30-100°C. Preferably, the acid hydrolysis or acidification is carried out using an inorganic acid such as sulfuric acid, hydrochloric acid and / or phosphoric acid; Preferably, step 3) is carried out in a solvent, and the solvent is preferably an aprotic organic solvent, including but not limited to chloroform, ethyl acetate, dichloromethane, 1,2-dichloroethane and other water-immiscible solvents, tetrahydrofuran, acetone or a combination thereof; Preferably, in step 3), the chlorination agent is preferably thionyl chloride, oxalyl chloride, phosphorus trichloride and phosphorus pentachloride; Preferably, in step 3), the base is selected from alkali metal carbonates such as sodium carbonate, potassium carbonate, alkali metal bicarbonates 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; Preferably, in step 3), the condensing agent is selected from: dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, N,N'-carbonyldiimidazole and benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate; Preferably, in step 3), the reaction is at -30-90°C; Preferably, in step 4), the copper salt catalyst is preferably a monovalent copper salt and a divalent copper salt, such as cuprous acetate, cupric acetate, etc., more preferably cuprous acetate; Preferably, in step 4), the ligand is bathocuproine or 1,10-phenanthroline; Preferably, in step 4), the molar ratio of the compound of formula IV to the copper salt catalyst or ligand is 50:1 to 1:1; Preferably, 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; Preferably, in step 4), the heating condition is 50-100° C.; the oxygen is preferably selected from high-purity oxygen, industrial oxygen and oxygen in the air, more preferably high-purity oxygen.

7. A process for preparing a compound of formula I, Wherein R1 and R2 are independently selected from C 1-6 Alkyl; preferably, R1 is methyl and R2 is ethyl; It includes the following steps: The compound of formula V Wherein R1 and R2 are as defined for Formula I; Treat with an ether bond cleavage agent in an organic solvent at cooling temperature to obtain a compound of formula I The reaction conditions are as defined in claim 5.

8. The method according to claim 7, further comprising the step of preparing the compound of formula V according to claim 6.

9. Compounds of formula I or salts thereof Wherein R1 and R2 are independently selected from C 1-6 Alkyl, and R1 and R2 are not methyl at the same time; preferably, it is compound 1a or a salt thereof:

10. A compound of formula I or a salt thereof Wherein R1 and R2 are independently selected from C 1-6 Alkyl, for use in preparing a compound of formula IA, Wherein R1 and R2 are independently selected from C 1-6 Alkyl; preferably, R1 in Formula I and Formula IA is methyl and R2 is ethyl.

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