Preparation method of bepedioic acid and intermediate thereof, and intermediate of bepedioic acid

Abstract

According to the preparation method, a novel intermediate compound 6 is taken as a raw material and subjected to hydrolysis, hydroxyl protecting group removal and reduction to obtain the bepedioic acid, caprolactone can be taken as a starting material of the intermediate compound 6, and after caprolactone is subjected to self-condensation, the intermediate compound 6 can be subjected to hydrolysis, hydroxyl protecting group removal and reduction to obtain the bepedioic acid. And carrying out ring opening, bromination, carbonyl protection and alpha alkylation to obtain a compound 6. The preparation method of the bepedioic acid is simple, convenient and safe to operate, high in yield, low in production cost and easy for industrial production. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of organic compound preparation, and more specifically, relates to a synthesis method of bepedrucic acid and its intermediates and the intermediates thereof. Background Art

[0002] Bempedoic acid is an inhibitor of adenosine triphosphate citrate lyase (ACL), which can reduce low-density lipoprotein cholesterol (LDL-C) by inhibiting cholesterol synthesis in the liver. The drug was approved by the U.S. Food and Drug Administration (FDA) in February 2020 and is available in the United States. It is the first non-statin oral cholesterol-lowering drug approved by the FDA in nearly 20 years. It is used to treat adult patients with heterozygous familial hypercholesterolemia or adult patients with atherosclerotic cardiovascular disease who need to further reduce LDL-C. Its molecular structure is shown below:

[0003]

[0004] At present, there are many reported synthetic routes for the synthesis of bempedoic acid at home and abroad, all of which have the problems of complicated process routes and high production costs. The synthetic route of bempedoic acid reported in prior art WO2004067489 is shown in the following route 1:

[0005]

[0006] This route uses ethyl isobutyrate and 1,5-dibromopentane as starting materials. At low temperature, 7-bromo-2,2-dimethylheptanoic acid ethyl ester (Compound 1) is obtained by condensation with lithium diisopropylamide (LDA). Compound 1 is used as an alkylating agent and is reacted with p-toluenesulfonic acid methyl isocyanate (TosMIC) under strong alkaline conditions, and is catalyzed by tetrabutylammonium iodide (TBAI) to obtain Compound 2; then it is hydrolyzed under acidic conditions to obtain Compound 3, and Compound 3 is hydrolyzed in an ethanol system to obtain Compound 4, which is then reduced by NaBH4 to finally obtain the target product Bempedoic Acid. The first step of this process is alkylation at the α position, which has poor selectivity and cannot avoid disubstituted impurities. The p-toluenesulfonylmethyl isocyanate used in the second step is highly toxic and difficult to obtain, and has poor atom economy. In addition, sodium hydride, a hazardous material, is used, which is not conducive to industrial production operations. In addition, excessive 1,5-dibromopentane is used to improve selectivity, resulting in large residual impurities such as 1,5-dibromopentane, and distillation purification is required. After the third step of hydrolysis, potential genotoxic impurities (p-methylbenzenesulfonyl derivatives) will be produced, which is not conducive to the quality control of the raw material drug. In summary, this route has large losses and high potential risks and is not suitable for industrial production.

[0007] The synthesis route of Bempedoic Acid reported in prior art CN116396158 is shown in the following route 2:

[0008]

[0009] This route uses caprolactone as the starting material, and obtains the key intermediate 1,11-dibromodenc-6-oxytrimethylsilyl ether through ring-opening methylation, titanium tetrachloride-catalyzed dieckmann condensation, alkaline decarboxylation, bromination, sodium borohydride reduction and trimethylsilane protection (6 steps), and then couples with (1-ethoxy-2-methyl-1-oxopropane-2-yl) zinc bromide to obtain 2,2,14,14-tetramethyl-8-(trimethylsilyloxy)pentadecanedicarboxylic acid diethyl ester, and finally hydrolyzes under acidic conditions and deprotects to obtain Bempedoic Acid. Although this route uses cheap caprolactone as the starting material, the route is long, and the price of the ethyl 2-bromoisobutyrate used is relatively high, which greatly increases the production cost.

[0010] The synthesis route of Bempedoic Acid reported in prior art CN114907204 is shown in the following route 3:

[0011]

[0012] This route uses valerolactone as the starting material, and obtains the target compound Bempedoic Acid through Dieckmann condensation, bromination, ethylene glycol protection, copper-catalyzed Grignard coupling and sodium borohydride reduction. The above route is cleverly designed and simple, but the 3,3-dimethyloxacyclobutane-2-one used is expensive and difficult to obtain. At the same time, the Grignard coupling reaction is difficult to control and the yield is low, which limits the industrial application of this route.

[0013] In summary, it is of great significance to develop a synthetic route that is simple and safe to operate, has low production cost, high yield and quality, and has practical industrial application value. Summary of the invention

[0014] One aspect of the present invention is to provide a method for preparing bepedrucic acid.

[0015] In a preferred embodiment, the preparation method of bepedrucic acid comprises the following steps:

[0016] (e) hydrolyzing compound 6 and removing the carbonyl protecting group to obtain compound 7, and

[0017] (f) reducing compound 7 to obtain bepedrulic acid, the reaction formula is as follows:

[0018]

[0019] wherein R1 is selected from a C1-C6 straight or branched alkyl group, a C1-C6 alkenyl group or a C1-C6 cycloalkyl group, R2 and R3 are each independently selected from a C1-C6 straight or branched alkyl group, or R2 and R3 and the oxygen and carbon to which they are connected together form The C1-C6 straight or branched alkyl, C1-C6 alkenyl or C1-C6 cycloalkyl is optionally further substituted by an alkyl, alkoxy, cycloalkyl or aryl substituent.

[0020] In another preferred embodiment, R1 is selected from methyl or ethyl, R2 and R3 and the oxygen and carbon to which they are connected together form

[0021] In another preferred embodiment, in step (e), the hydrolysis is carried out under alkaline conditions, and the base used is selected from NaOH, KOH, LiOH, Ba(OH)2, Me3SnOH, or a combination thereof, more preferably, NaOH. In another preferred embodiment, in step (e), the solvent used is selected from water, water / methanol or water / ethanol. In another preferred embodiment, in step (e), the hydrolysis reaction temperature is 25 to 120°C.

[0022] In another preferred embodiment, in step (e), the decarbonylation protecting group is carried out under acidic conditions, and the acid used is selected from hydrochloric acid, sulfuric acid, sulfuric acid, hydrobromic acid, or a combination thereof, more preferably, hydrochloric acid. In another preferred embodiment, in step (e), the decarbonylation protecting group is carried out at room temperature.

[0023] In another preferred embodiment, in step (f), the reducing agent used in the reduction reaction is selected from sodium borohydride, potassium borohydride, lithium borohydride, sodium tricyanoborohydride or sodium triacetoxyborohydride, more preferably, sodium borohydride. In another preferred embodiment, in step (f), the solvent used in the reduction reaction is selected from water, methanol, ethanol, or a combination thereof. In another preferred embodiment, the reduction system further contains an inorganic base, and the inorganic base is selected from NaOH, KOH, LiOH, or a combination thereof, more preferably, NaOH.

[0024] In another preferred embodiment, the method for preparing bepedrucic acid further comprises step (d) reacting compound 5 with isobutyrate to obtain compound 6, and the reaction formula is as follows:

[0025]

[0026] wherein X is selected from Cl, Br or I.

[0027] In another preferred embodiment, the reaction of step (d) is carried out in the presence of a base, and the base is selected from lithium diisopropylamide or sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, or a combination thereof, more preferably lithium diisopropylamide. In another preferred embodiment, the isobutyrate is selected from methyl isobutyrate, ethyl isobutyrate, n-propyl isobutyrate, isopropyl isobutyrate, n-butyl isobutyrate, tert-butyl isobutyrate or isobutyl isobutyrate, more preferably methyl isobutyrate or ethyl isobutyrate.

[0028] In another preferred embodiment, the reaction of step (d) is carried out in a solvent-free system. In another preferred embodiment, the reaction of step (d) is carried out in an aprotic solvent, and the aprotic solvent is selected from tetrahydrofuran, 2,-methyltetrahydrofuran, methyl tert-butyl ether, toluene, or a combination thereof, more preferably, tetrahydrofuran. In another preferred embodiment, in step (d), the reaction temperature is -30 to 50°C, more preferably 0 to 30°C.

[0029] In another preferred embodiment, the reaction of step (d) is carried out in the presence of a lithium reagent stabilizer, and the lithium reagent stabilizer is selected from DMPU, HMPA, N,N-dimethylethylenediamine, or a combination thereof, more preferably DMPU.

[0030] In another preferred embodiment, the method for preparing bepedrucic acid further comprises step (c) reacting compound 4 with alcohol to generate compound 5, and the reaction formula is as follows:

[0031]

[0032] In another preferred embodiment, in step (c), the reaction of compound 4 with alcohol is carried out in the presence of an acid, and the acid is selected from p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, sulfosalicylic acid, naphthalenesulfonic acid, trifluoroacetic acid, or a combination thereof, more preferably, p-toluenesulfonic acid. In another preferred embodiment, the alcohol is selected from methanol, ethanol, propanol, ethylene glycol, 1,3-propylene glycol or 1,2-propylene glycol, more preferably, ethylene glycol. In another preferred embodiment, in step (c), the reaction solvent is selected from cyclohexane, toluene, ethylene glycol dimethyl ether, or a combination thereof. In another preferred embodiment, the reaction temperature of step (c) is 60 to 150°C, more preferably 80 to 120°C.

[0033] In another preferred embodiment, the method for preparing bepedrucic acid further comprises step (b) reacting compound 2 with a halogenating agent to obtain compound 4, and the reaction formula is as follows:

[0034]

[0035] In another preferred embodiment, in step (b), the halogenating agent is selected from thionyl chloride, hydrogen bromide, phosphorus tribromide or iodine, more preferably, hydrogen bromide. In another preferred embodiment, the reaction temperature of step (b) is 45-100° C., more preferably, 60-100° C. In another preferred embodiment, in step (b), the solvent used in the reaction is selected from acetic acid, water, toluene.

[0036] In another preferred embodiment, the method for preparing bepedrucic acid further comprises the following steps:

[0037] (b') hydrolyzing compound 2 to form compound 3, and

[0038] (b") reacting compound 3 with a halogenating agent to obtain compound 4, as shown in the following reaction formula:

[0039]

[0040] In another preferred embodiment, in step (b'), the hydrolysis reaction is carried out under alkaline conditions, and the base used in the hydrolysis reaction is selected from KOH, NaOH, LiOH, or a combination thereof, more preferably NaOH. In another preferred embodiment, the reaction temperature of step (b') is 50-90°C, more preferably, 60-80°C. In another preferred embodiment, the solvent used in the hydrolysis reaction of step (b') is selected from methanol, ethanol, propanol, water, or a combination thereof.

[0041] In another preferred embodiment, in step (b"), the halogenating agent is selected from thionyl chloride, hydrogen bromide, phosphorus tribromide or iodine. In another preferred embodiment, the halogenation reaction temperature of step (b") is 45-100°C, more preferably, 60-100°C. In another preferred embodiment, the solvent used in the reaction of step (b") is selected from acetic acid, water and toluene.

[0042] In another preferred embodiment, the method for preparing bepedrucic acid further comprises the step (a) of allowing compound 1 to undergo self-condensation to obtain compound 2, and the reaction formula is as follows:

[0043]

[0044] In another preferred embodiment, in step (a), the self-condensation reaction of compound 1 is carried out in the presence of titanium tetrachloride and a base, and the base is selected from triethylamine, tributylamine, diisopropylethylamine or a combination thereof, preferably triethylamine. In another preferred embodiment, in step (a), the reaction solvent is selected from dichloromethane, toluene, chloroform, preferably dichloromethane. In another preferred embodiment, in step (a), the reaction temperature is -80 to 50°C, more preferably, -20 to 30°C.

[0045] In another preferred embodiment, the preparation method of bepedrucic acid comprises the following steps:

[0046] (d) reacting compound 5 with isobutyrate to obtain compound 6, and

[0047] (e) hydrolyzing compound 6 and removing the carbonyl protecting group to obtain compound 7,

[0048] The reaction formula is as follows:

[0049]

[0050] wherein X is selected from Cl, Br or I; R1 is selected from C1-C6 straight chain or branched alkyl, C1-C6 alkenyl or C1-C6 cycloalkyl; R2 and R3 are each independently selected from C1-C6 straight chain or branched alkyl, or R2 and R3 and the oxygen and carbon to which they are connected together form The C1-C6 straight or branched alkyl, C1-C6 alkenyl or C1-C6 cycloalkyl is optionally further substituted by an alkyl, alkoxy, cycloalkyl or aryl substituent.

[0051] In another preferred embodiment, X is selected from Br, R1 is selected from methyl or ethyl, R2 and R3 and the oxygen and carbon to which they are connected together form

[0052] In another preferred embodiment, the preparation method of bepedrucic acid comprises the following steps:

[0053] (c) reacting compound 4 with an alcohol to generate compound 5,

[0054] (d) reacting compound 5 with isobutyrate to obtain compound 6, and

[0055] (e) removing the carbonyl protecting group from compound 6 to obtain compound 7,

[0056] The reaction formula is as follows:

[0057]

[0058] wherein X is selected from Cl, Br or I; R1 is selected from C1-C6 straight chain or branched alkyl, C1-C6 alkenyl or C1-C6 cycloalkyl; R2 and R3 are each independently selected from C1-C6 straight chain or branched alkyl, or R2 and R3 and the oxygen and carbon to which they are connected together form The C1-C6 straight or branched alkyl, C1-C6 alkenyl or C1-C6 cycloalkyl is optionally further substituted by an alkyl, alkoxy, cycloalkyl or aryl substituent.

[0059] In another preferred embodiment, X is selected from Br, R1 is selected from methyl or ethyl, R2 and R3 and the oxygen and carbon to which they are connected together form

[0060] In another preferred embodiment, the preparation method of bepedrucic acid comprises the following steps:

[0061] (b) reacting compound 2 with a halogenating agent to obtain compound 4,

[0062] (c) reacting compound 4 with an alcohol to generate compound 5,

[0063] (d) reacting compound 5 with isobutyrate to obtain compound 6, and

[0064] (e) hydrolyzing compound 6 and removing the carbonyl protecting group to obtain compound 7,

[0065] (f) reducing compound 7 to obtain bepedrucic acid,

[0066] The reaction formula is as follows:

[0067]

[0068] wherein X is selected from Cl, Br or I; R1 is selected from C1-C6 straight chain or branched alkyl, C1-C6 alkenyl or C1-C6 cycloalkyl; R2 and R3 are each independently selected from C1-C6 straight chain or branched alkyl, or R2 and R3 and the oxygen and carbon to which they are connected together form The C1-C6 straight or branched alkyl, C1-C6 alkenyl or C1-C6 cycloalkyl is optionally further substituted by an alkyl, alkoxy, cycloalkyl or aryl substituent.

[0069] In another preferred embodiment, X is selected from Br, R1 is selected from methyl or ethyl, R2 and R3 and the oxygen and carbon to which they are connected together form

[0070] In another preferred embodiment, the preparation method of bepedrucic acid comprises the following steps:

[0071] (b') hydrolyzing compound 2 to form compound 3, and

[0072] (b") reacting compound 3 with a halogenating agent to obtain compound 4,

[0073] (c) reacting compound 4 with an alcohol to generate compound 5,

[0074] (d) reacting compound 5 with isobutyrate to obtain compound 6, and

[0075] (e) hydrolyzing compound 6 and removing the carbonyl protecting group to obtain compound 7,

[0076] (f) reducing compound 7 to obtain bepedrucic acid,

[0077] The reaction formula is as follows:

[0078]

[0079] wherein X is selected from Cl, Br or I; R1 is selected from C1-C6 straight chain or branched alkyl, C1-C6 alkenyl or C1-C6 cycloalkyl; R2 and R3 are each independently selected from C1-C6 straight chain or branched alkyl, or R2 and R3 and the oxygen and carbon to which they are connected together form The C1-C6 straight or branched alkyl, C1-C6 alkenyl or C1-C6 cycloalkyl is optionally further substituted by an alkyl, alkoxy, cycloalkyl or aryl substituent.

[0080] In another preferred embodiment, X is selected from Br, R1 is selected from methyl or ethyl, R2 and R3 and the oxygen and carbon to which they are connected together form

[0081] In another preferred example, in the method for preparing bepedrucic acid, the method for preparing compound 2 comprises the steps of: (a) allowing compound 1 to undergo self-condensation to obtain compound 2,

[0082]

[0083] Another aspect of the present invention provides a compound, whose structure is shown in Formula 5 or Formula 6 below:

[0084] wherein X is selected from Cl, Br or I; R2 and R3 are each independently selected from a C1-C6 straight chain or branched alkyl group, or R2 and R3 and the oxygen and carbon connected thereto together form The C1-C6 straight or branched alkyl, C1-C6 alkenyl or C1-C6 cycloalkyl is optionally further substituted by an alkyl, alkoxy, cycloalkyl or aryl substituent.

[0085] wherein R1 is selected from a C1-C6 straight or branched alkyl group, a C1-C6 alkenyl group or a C1-C6 cycloalkyl group, R2 and R3 are each independently selected from a C1-C6 straight or branched alkyl group, or R2 and R3 and the oxygen and carbon to which they are connected together form The C1-C6 straight or branched alkyl, C1-C6 alkenyl or C1-C6 cycloalkyl is optionally further substituted by an alkyl, alkoxy, cycloalkyl or aryl substituent.

[0086] In another preferred embodiment, in the compound shown in Formula 5, X is selected from Br, R2 and R3 and the oxygen and carbon connected thereto together form

[0087] In another preferred embodiment, in the compound shown in Formula 6, R1 is selected from methyl or ethyl, R2 and R3 and the oxygen and carbon to which they are connected together form

[0088] In another aspect, the present invention provides a method for preparing compound 5, comprising the following steps:

[0089] (b) reacting compound 2 with a halogenating agent to obtain compound 4,

[0090] (c) reacting compound 4 with an alcohol to generate compound 5,

[0091] The reaction formula is as follows:

[0092]

[0093] In another aspect, the present invention provides a method for preparing compound 5, comprising the following steps: (b') hydrolyzing compound 2 to form compound 3, and (b") reacting compound 3 with a halogenating agent to obtain compound 4.

[0094] (c) reacting compound 4 with an alcohol to generate compound 5,

[0095] The reaction formula is as follows:

[0096]

[0097] In another aspect, the present invention provides a method for preparing compound 6, comprising the following steps: (b) reacting compound 2 with a halogenating agent to obtain compound 4,

[0098] (c) reacting compound 4 with an alcohol to generate compound 5,

[0099] (d) Compound 5 is reacted with isobutyrate to obtain compound 6, and the reaction formula is as follows:

[0100]

[0101] In another aspect, the present invention provides a method for preparing compound 6, comprising the following steps: (b') hydrolyzing compound 2 to form compound 3, and (b") reacting compound 3 with a halogenating agent to obtain compound 4.

[0102] (c) reacting compound 4 with an alcohol to generate compound 5,

[0103] (d) Compound 5 is reacted with isobutyrate to obtain compound 6, and the reaction formula is as follows:

[0104]

[0105] In another aspect, the present invention provides the use of compound 5 and compound 6 in the preparation of bepedrucic acid.

[0106] In another aspect, the present invention provides a method for preparing compound 4, which comprises the following steps:

[0107] (a) allowing compound 1 to undergo self-condensation to obtain compound 2,

[0108] (b) reacting compound 2 with a halogenating agent to obtain compound 4,

[0109] The reaction formula is as follows:

[0110]

[0111] Wherein X is selected from Cl, Br or I, more preferably Br.

[0112] In another preferred embodiment, the preparation method of compound 4 provided by the present invention comprises the following steps:

[0113] (a) allowing compound 1 to undergo self-condensation to obtain compound 2,

[0114] (b') hydrolyzing compound 2 to form compound 3, and

[0115] (b") reacting compound 3 with a halogenating agent to obtain compound 4,

[0116] The reaction formula is as follows:

[0117]

[0118] Wherein X is selected from Cl, Br or I, more preferably Br.

[0119] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0120] The following drawings are used to illustrate specific embodiments of the present invention and are not used to limit the scope of the present invention defined by the claims.

[0121] Figure 1 This is the H NMR spectrum of compound 3 (1,11-dihydroxyundecan-6-one);

[0122] Figure 2 This is the H NMR spectrum of compound 4 (1,11-dibromodendecan-6-one);

[0123] Figure 3 This is the H NMR spectrum of compound 5 (2,2-bis(5-bromopentyl)-1,3-dioxolane);

[0124] Figure 4 This is the H NMR spectrum of compound 6 (7,7'-(1,3-dioxolane-2,2-diyl)bis(2,2-dimethylheptanoate) diethyl ester). DETAILED DESCRIPTION

[0125] After extensive and in-depth research, the inventors have developed a new method for preparing bepedoic acid. The method uses ε-caprolactone as a raw material, and after self-condensation, hydrolysis, bromination, carbonyl protection and esterification obtain a novel intermediate 6, which is hydrolyzed and dehydroxylated, and then reduced to obtain bepedoic acid. The method solves the problems of high cost, low yield and poor product quality of the existing chemical synthesis method of bepedoic acid.

[0126] Preparation of compound 2

[0127] In the present invention, the method described in Example 7 of the prior art WO2023 / 147657A1 can be used with caprolactone as the starting material.

[0128] Preparation of compound 4

[0129] In the present invention, compound 4 can be prepared by using compound 2 as a raw material through the following steps:

[0130] (b) reacting compound 2 with a halogenating agent to obtain compound 4,

[0131] The reaction formula is as follows:

[0132]

[0133] wherein X is selected from Cl, Br or I.

[0134] In the present invention, compound 4 can be prepared by using compound 2 as a raw material through the following steps:

[0135] (b') hydrolyzing compound 2 to form compound 3, and

[0136] (b") reacting compound 3 with a halogenating agent to obtain compound 4,

[0137] The reaction formula is as follows:

[0138]

[0139] In the above steps (b) and (b"), the halogenating agent includes but is not limited to hydrogen chloride, thionyl chloride, hydrogen bromide, phosphine tribromide, hydrogen iodide, iodine, etc. The halogenating agent is a conventional amount used in the art for such reactions. Preferably, the molar ratio of the halogenating agent to compound 2 is 1 to 10:1, more preferably 4 to 6:1. The solvent used for the halogenation reaction includes but is not limited to acetic acid, water, and toluene. In a specific embodiment of the present invention, the halogenation reaction is carried out in a hydrogen bromide acetic acid solution, and the reaction temperature is preferably 45 to 100°C, more preferably, 50 to 80°C.

[0140] In the above step (b'), the hydrolysis of compound 2 is carried out under alkaline conditions. In the process of hydrolysis to form compound 3, compound 2 is first hydrolyzed in the presence of a base to form an intermediate compound 2', and then compound 2' removes the carboxyl group adjacent to the carbonyl group under heating conditions (for example, 50 to 90° C., preferably 60 to 80° C.) to generate compound 3. The base used in this step is preferably an inorganic nucleophilic strong base, including but not limited to KOH, NaOH, and LiOH. The solvent used in the reaction of step (b') is a commonly used solvent for such reactions in the art, including but not limited to methanol, ethanol, propanol, water, etc.

[0141] Preparation of compound 5

[0142] In the present invention, compound 5 can be prepared by using compound 4 as a raw material through the following steps:

[0143] Step (c) Compound 4 is reacted with an alcohol to generate Compound 5, and the reaction formula is as follows:

[0144]

[0145] wherein X is selected from Cl, Br or I, R2 and R3 are each independently selected from a C1-C6 straight chain or branched alkyl group, or R2 and R3 and the oxygen and carbon to which they are connected together form The C1-C6 straight or branched alkyl, C1-C6 alkenyl or C1-C6 cycloalkyl is optionally further substituted by an alkyl, alkoxy, cycloalkyl or aryl substituent.

[0146] The reaction of this step is carried out in the presence of an acid, and the acid acts as a catalyst in this step. The acid and its dosage that can be used in this step are commonly used acid catalysts and dosages for such reactions in the art. The acid includes but is not limited to p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, sulfosalicylic acid, naphthalenesulfonic acid, and trifluoroacetic acid. The amount of the acid used is a catalytic amount. Preferably, the molar ratio of the acid to compound 4 is preferably 0.01 to 0.1:1. The alcohol is used to form a ketal with the carbonyl group of compound 4, and the alcohol includes but is not limited to methanol, ethanol, propanol, ethylene glycol, 1,3-propylene glycol, or 1,2-propylene glycol. The molar ratio of the alcohol to compound 4 is preferably 2 to 10:1, and more preferably 3 to 7:1. The reaction solvent that can be used in this step is a commonly used solvent for such reactions in the art, including but not limited to cyclohexane, toluene, and ethylene glycol dimethyl ether. The reaction temperature of this step is a conventional temperature for such reactions in the art, for example, 70 to 120°C.

[0147] Preparation of compound 6

[0148] Step (d) Compound 6 can be prepared from compound 5 by the following steps:

[0149] Compound 5 is reacted with isobutyrate to obtain compound 6, and the reaction formula is as follows:

[0150]

[0151] wherein X is selected from Cl, Br or I; R1 is selected from C1-C6 straight chain or branched alkyl, C1-C6 alkenyl or C1-C6 cycloalkyl, R2 and R3 are each independently selected from C1-C6 straight chain or branched alkyl, or R2 and R3 and the oxygen and carbon to which they are connected together form The C1-C6 straight or branched alkyl, C1-C6 alkenyl or C1-C6 cycloalkyl is optionally further substituted by an alkyl, alkoxy, cycloalkyl or aryl substituent.

[0152] This step can be carried out in an aprotic solvent, and the aprotic solvent includes but is not limited to tetrahydrofuran, 2-methyltetrahydrofuran, and methyl tert-butyl ether. This step can also be carried out in a solvent-free system (i.e., without using any solvent). In the absence of any solvent, the isobutyrate acts as a solvent. The reaction of this step is carried out in the presence of a base, and the base is an organic non-nucleophilic strong base, including but not limited to lithium diisopropylamide or sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, etc. The role of the base is to remove the H at the α position of the isobutyrate to form a carbon anion, which is nucleophilic and can undergo nucleophilic substitution with compound 5 to obtain compound 6. The amount of base used is the conventional amount used in the art for such reactions, for example, the molar ratio of base to isobutyrate is 1 to 1.5:1. The molar ratio of isobutyrate to compound 4 is preferably 2 to 5:1. The reaction temperature of this step is preferably room temperature. The adding process of this step is carried out at -20 to -5°C, first adding a base to the solvent, then dropping isobutyrate, stirring for 20 to 40 minutes, and then adding compound 5. After the reaction of this step is completed, a termination reagent is added to the above reaction solution, and the termination reagent is preferably water, saturated ammonium chloride or dilute hydrochloric acid, more preferably water.

[0153] Preparation of Bepedolactic Acid

[0154] Bepedol acid can be prepared using compound 6 as a raw material by the following steps:

[0155] (e) hydrolyzing compound 6 and removing the hydroxy protecting group to obtain compound 7, and

[0156] (f) reducing compound 7 to obtain bepedrulic acid, the reaction formula is as follows:

[0157]

[0158] In step (e), the hydrolysis of compound 6 can be carried out under alkaline conditions or under other conditions. Hydrolysis under alkaline conditions can be carried out according to the conventional operation of such reactions in the art. The base used for hydrolysis includes but is not limited to NaOH, KOH, LiOH, Ba(OH)2, Me3SnOH, and the solvent used for hydrolysis includes but is not limited to water, methanol, ethanol, propanol, and the hydrolysis temperature is 20 to 120°C. The amount of the base is the conventional amount used for such reactions, and preferably the molar ratio thereof to compound 6 is 3 to 10:1. The amount of the solvent is the conventional amount used for such reactions, and the volume weight ratio of compound 6 is preferably 5 to 50 mL / g.

[0159] In step (e), the removal of the hydroxy protecting group under acidic conditions can be carried out according to the conventional operation of such reactions in the art. The removal of the carbonyl protecting group can be carried out under acidic conditions, and the acid used includes but is not limited to inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, and the solvent includes but is not limited to water, methanol, ethanol, and propanol. The removal of the hydroxy protecting group can be carried out at room temperature. In some specific embodiments, the reaction of the removal of the hydroxy protecting group is reacted in a hydrochloric acid aqueous solution with a pH of 1 to 2 for 2 to 4 hours. In some specific embodiments, compound 6 is first hydrolyzed under alkaline conditions, and the crude product obtained by treating the hydrolysis reaction solution is directly dehydroxylated under acidic conditions to obtain compound 7.

[0160] In step (f), the reduction of compound 7 to obtain bepedrulic acid can be carried out according to the methods disclosed in the prior art, for example, WO2004067489 and CN114907204.

[0161] The reducing agent that can be used in the present invention includes but is not limited to sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride. The solvent used in the reduction reaction includes but is not limited to water, methanol, ethanol, propanol. In some specific embodiments, compound 7 uses sodium borohydride as a reducing agent and is reduced in an alkaline system. The amount of sodium borohydride used is the conventional amount in the art, and preferably the molar ratio of sodium borohydride to compound 7 is 0.9 to 1.1:1. The molar ratio of the base to compound 7 is 2 to 3:1.

[0162] In the reaction process of the present invention, each step can be detected by commonly used means in the art (eg, thin layer chromatography or liquid chromatography) to detect the disappearance of the raw material or the non-reduction of the raw material within a period of time to determine that the reaction of the step is complete and terminate the reaction.

[0163] As used herein, the term "room temperature" or "normal temperature" refers to a temperature of 4-40°C, preferably, 25±5°C.

[0164] The term "C1-C6 straight or branched chain alkyl" refers to a straight or branched chain hydrocarbon group having a specified number of carbon atoms (i.e., C1-C6 means 1-6 carbons). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, etc.

[0165] The term "alkenyl" refers to an unsaturated alkyl group having one or more double bonds. Similarly, the term "alkynyl" refers to an unsaturated alkyl group having one or more triple bonds.

[0166] middle, Indicates the connection position of the formed ketal to the main chain.

[0167] The main advantages of the present invention are:

[0168] The preparation method of bepedol acid of the present invention uses caprolactone as a starting material, and after self-condensation, hydrolysis, halogenation, carbonyl protection and α-alkylation are performed to obtain a novel intermediate compound 6, and compound 6 is hydrolyzed, deprotected and reduced to obtain the target product. The preparation process of the method is simple, the route is short, the yield is high, the reagents used are easily available and cheap, the repeatability is good, the product quality is good, the purity is high, the production cost is reduced, and it is easy to industrially produce.

[0169] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples that do not specify specific conditions are usually based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are weight percentages and weight parts. The reagents and raw materials used in the following examples are generally commercially available unless otherwise specified.

[0170] Example 1: Preparation of 3-(6-hydroxyhexanoyl)oxirane-2-one (Compound 2)

[0171] ε-caprolactone (150 g, 1.31 mol) and triethylamine (199.6 g, 1.97 mol) were added to dichloromethane (1.5 L) at -20 °C, titanium tetrachloride (124.2 g, 0.655 mol) was added, and the reaction was kept warm for 3 h. After the reaction was completed, a dilute hydrochloric acid aqueous solution (150 ml of concentrated hydrochloric acid was added to 450 ml of water) was added, and the liquid was separated. The aqueous phase was extracted twice with dichloromethane, each time with 450 ml, and the organic phases were combined, washed once with water (450 ml) and saturated brine (450 ml), and dried over magnesium sulfate and concentrated under reduced pressure to produce 3-(6-hydroxyhexanoyl)oxirane-2-one as a light yellow oil, 139 g, yield 92.7%; purity 91%. ESI-MS (m / z): [M+H] + =227.1

[0172] Other reaction conditions for the preparation step of compound 2 were studied, and specific examples are shown in Table 1 below.

[0173] Table 1.

[0174]

[0175] Example 12: Preparation of 1,11-dibromodecane-6-one (Compound 4)

[0176] 3-(6-Hydroxyhexanoyl)oxirane-2-one (138 g, 0.605 mol) was added to a hydrobromic acid / acetic acid solution (109 g, 2.42 mol) at room temperature, and the temperature was raised to 75°C for reaction for 6 hours. After the reaction was completed, the temperature was lowered to room temperature, methanol (690 ml) was added, stirred overnight, and concentrated under reduced pressure. Dichloromethane (450 ml) was added to the concentrate, stirred and dissolved, and then water was added and extracted twice, each time with 450 ml, and then washed once with saturated brine (450 ml), and the organic phases were combined, dried over magnesium sulfate, and concentrated under reduced pressure to produce 1,11-dibromonodecan-6-one as a light yellow oil, 174 g, with a yield of 87.6% and a purity of 90%. ESI-MS (m / z): [M+H] + =329.0. 1 HNMR (300MHz, CDCl3): δ3.39 (t, J = 9Hz, 4H), 2.41 (t, J = 6Hz, 4H) 1.90-1.80 (m, 4H), 1.64-1.54 (m, 4H), 1.46-1.36 (m, 4H).

[0177] Other reaction conditions for the preparation step of compound 3 were studied, and specific examples are shown in Table 2 below.

[0178] Table 2.

[0179] Example Acid type Acid dosage Reaction temperature Conversion rate Example 13 40% hydrobromic acid aqueous solution 4eq 75℃ 72.1％ Embodiment 14 Phosphorus tribromide 2eq 25℃ 64.8％ Embodiment 15 33% hydrobromic acid acetic acid solution 3eq 75℃ 87.0％ Example 16 33% hydrobromic acid acetic acid solution 5eq 75℃ 86.9％ Embodiment 17 33% hydrobromic acid acetic acid solution 4eq 50℃ 68.7％ Embodiment 18 33% hydrobromic acid acetic acid solution 4eq 80℃ 85.8％

[0180] Example 19: Preparation of 2,2-bis(5-bromopentyl)-1,3-dioxolane (Compound 5)

[0181] 1,11-dibromodecane-6-one (174 g, 0.53 mol), ethylene glycol (174 ml) and p-toluenesulfonic acid (9.1 g, 0.05 mol) were added to cyclohexane (1.75 L) at room temperature, and the temperature was raised to reflux for 6 hours. After the reaction was completed, the temperature was lowered to room temperature, and a saturated sodium bicarbonate solution (870 ml) was added for extraction and washing. The organic phase was further washed with saturated brine (870 ml), dried over magnesium sulfate, and concentrated under reduced pressure to produce 2,2-bis(5-bromopentyl)-1,3-dioxolane as a light yellow oil, 187.6 g, with a yield of 95.0% and a purity of 95%. ESI-MS (m / z): [M+H] + =371.0. 1 HNMR (300MHz, CDCl3): δ3.92 (s, 4H), 3.40 (t, J = 6Hz, 4H) 1.90-1.81 (m, 4H), 1.62-1.57 (m, 4H), 1.46-1.33 (m, 4H).

[0182] Other reaction conditions for the preparation step of compound 5 were studied, and specific examples are shown in Table 3 below.

[0183] Table 3.

[0184]

[0185]

[0186] Example 32: Preparation of 7,7'-(1,3-dioxolane-2,2-diyl)bis(2,2-dimethylheptanoate) dimethyl ester (Compound 6)

[0187] Diisopropylamine (141.7 g, 1.4 mol) was added to anhydrous tetrahydrofuran (1.87 L), the temperature was lowered to -10 ° C after nitrogen replacement, n-butyl lithium (559 ml, 1.4 mol) was slowly added, methyl isobutyrate (132.8 g, 1.3 mol) was added dropwise after stirring for 30 min, 2,2-bis(5-bromopentyl)-1,3-dioxolane (187 g, 0.50 mol) was added after stirring for 30 min, the temperature was raised to 20-30 ° C and the reaction was carried out for 6 hours. After the reaction was completed, water (950 ml) was added, ethyl acetate (1.87 L) was added, the mixture was stirred and separated, the aqueous phase was washed with ethyl acetate (2 L), dried over magnesium sulfate and concentrated under reduced pressure to produce 7,7'-(1,3-dioxolane-2,2-diyl)bis(2,2-dimethylheptanoate) dimethyl ester as a light yellow oil, 190.7 g, yield 92%, purity 97%.

[0188] ESI-MS (m / z): [M+H] + =415.2. 1 HNMR (300MHz, CDCl3): δ3.92 (d, J=1.80Hz, 4H), 1.59-1.32 (m, 20H), 1.23 (t, J=4.65Hz, 6H), 1.16 (s, 12H).

[0189] Example 33: Preparation of 7,7'-(1,3-dioxolane-2,2-diyl)bis(2,2-dimethylheptanoate) diethyl ester (Compound 6)

[0190] Diisopropylamine (141.7 g, 1.4 mol) was added to anhydrous tetrahydrofuran (1.87 L), the temperature was lowered to -10 ° C after nitrogen replacement, n-butyl lithium (559 ml, 1.4 mol) was slowly added, and ethyl isobutyrate (151 g, 1.3 mol) was added dropwise after stirring for 30 min. After stirring for 30 min, 2,2-bis(5-bromopentyl)-1,3-dioxolane (187 g, 0.50 mol) was added, and the temperature was raised to 20-30 ° C for reaction for 6 hours. After the reaction was completed, water (950 ml) was added, ethyl acetate (1.87 L) was added, the mixture was stirred and separated, the aqueous phase was washed with ethyl acetate (1.87 L), dried over magnesium sulfate and concentrated under reduced pressure to produce 7,7'-(1,3-dioxolane-2,2-diyl)bis(2,2-dimethylheptanoate) diethyl ester as a light yellow oil, 201.2 g, yield 90%, purity 97%.

[0191] ESI-MS (m / z): [M+H] + =443.1. 1 HNMR (300MHz, CDCl3): δ4.11 (t, J = 7.14Hz, 4H), 3.92 (d, J = 1.80Hz, 4H), 1.59-1.32 (m, 20H), 1.23 (t, J = 4.65Hz, 6H), 1.16 (s, 12H).

[0192] Other reaction conditions for the preparation step of compound 6 were studied, and specific examples are shown in Table 4 below.

[0193] Table 4.

[0194]

[0195]

[0196] Example 53: Preparation of 1,11-dihydroxyundecan-6-one (Compound 3)

[0197] 3-(6-Hydroxyhexanoyl)oxirane-2-one (138g, 0.605mol) and sodium hydroxide (72.6g, 1.815mol) were added to a solution of methanol (500ml) and water (250ml) at room temperature, stirred at room temperature overnight, and then heated to 65°C for reaction for 3 hours. After the reaction was completed, the temperature was lowered to room temperature, water (1.25L) was added for dilution, and the methanol was removed by concentration under reduced pressure. The concentrate was adjusted to pH 1-2 with concentrated hydrochloric acid (250ml), and dichloromethane (500ml×2) was added for extraction. The organic phase was washed once with saturated brine (450ml), and the organic phases were combined, dried over magnesium sulfate, and concentrated under reduced pressure to produce 1,11-dihydroxyundecane-6-one as a light yellow oil, 102g, with a yield of 83.4%; purity 93%. MS: [M+H] + =203.1.

[0198] ESI-MS (m / z): [M+H] + =203.1. 1 HNMR (300MHz, CDCl3): δ3.63 (t, J=6.0Hz,

[0199] 4H), 2.41 (t, J = 6.0Hz, 4H,), 1.64-1.52 (m, 8H), 1.40-1.29 (m, 4H).

[0200] Other reaction conditions for the preparation step of compound 3 were studied, and specific examples are shown in Table 5 below.

[0201] Table 5.

[0202]

[0203]

[0204] Example 61: Preparation of 1,11-dibromodecane-6-one (Compound 4)

[0205] 1,11-dihydroxyundecane-6-one (102g, 0.505mol) was added to 40% hydrobromic acid aqueous solution (306.4g, 1.515mol) at room temperature, and the temperature was raised to reflux for 6 hours. After the reaction was completed, the temperature was lowered to room temperature, and dichloromethane (500ml×2) was added for extraction. The organic phase was washed once with saturated brine (450ml), and the organic phases were combined, dried over magnesium sulfate, and concentrated under reduced pressure to produce 1,11-dibromoundecane-6-one as a light yellow oil, 154g, with a yield of 93.6% and a purity of 93%. ESI-MS (m / z): [M+H] + =329.0. 1HNMR (300MHz, CDCl3): δ3.39 (t, J = 9Hz, 4H,), 2.41 (t, J = 6Hz, 4H), 1.90-1.80 (m, 4H), 1.64-1.54 (m, 4H), 1.46-1.36 (m, 4H).

[0206] Other reaction conditions for the preparation step of compound 4 were studied, and specific examples are shown in Table 6 below.

[0207] Table 6.

[0208] Example Acid type Acid dosage Reaction temperature Conversion rate Embodiment 62 33% hydrobromic acid acetic acid solution 3eq 75℃ 92.1％ Embodiment 63 Phosphorus tribromide 3eq 25℃ 84.8％ Embodiment 64 40% hydrobromic acid aqueous solution 5eq 75℃ 97.0％ Embodiment 65 40% hydrobromic acid aqueous solution 10eq 75℃ 96.9％ Embodiment 66 40% hydrobromic acid aqueous solution 3eq 50℃ 88.7％ Embodiment 67 40% hydrobromic acid aqueous solution 3eq 80℃ 95.8％

[0209] Example 68: Preparation of 2,2,14,14-tetramethyl-8-oxopentadecane dioic acid (Compound 7)

[0210] Add 7,7'-(1,3-dioxolane-2,2-diyl)bis(2,2-dimethylheptanoate) diethyl ester (200g, 0.45mol) and 20% sodium hydroxide solution (450ml) to ethanol (1L) at room temperature, and heat to reflux for reaction for 3h. After the reaction is completed, add water (1L) and cool to room temperature, extract twice with ethyl acetate, each time with 500ml, collect the aqueous phase, adjust the pH of the aqueous phase to 1-2 with 2mol / L hydrochloric acid solution at 20-30℃, keep warm and stir for 3h, filter and dry to obtain the crude product. Add the crude product to methanol (1L) at room temperature, stir to dissolve, add purified water (200ml), stir for 30min, continue to add purified water (400ml), stir for 1h, filter and dry to obtain a light yellow solid 2,2,14,14-tetramethyl-8-oxopentadecane dioic acid, 133.1g, yield 86%; purity 99%.

[0211] ESI-MS (m / z): [M+H] + =343.2. 1 HNMR (300MHz, CDCl3): δ13.00-10.40

[0212] (br, 2H), 2.38 (t, J = 7.4Hz, 4H), 1.71-1.44 (m, 8H), 1.37-1.22 (m, 8H), 1.18 (s, 12H).

[0213] Example 69: 2,2,14,14-Tetramethyl-8-hydroxypentadecanedioic acid (Bempedoic acid)

[0214] Under nitrogen protection, add sodium hydroxide (33.2g) to purified water (660g), stir and dissolve, then add 2,2,14,14-tetramethyl-8-oxopentadecane dioic acid (133g), keep warm at 20-30℃, add sodium borohydride (8.2g)-sodium hydroxide aqueous solution (sodium hydroxide: 0.31g, purified water: 57.6g), keep warm and react for 2h. After the reaction is completed, add methyl tert-butyl ether (1kg), cool to 0-10℃, add concentrated hydrochloric acid (130g), adjust the pH of the liquid to 1-2, stand and separate, wash the organic phase with water twice, each time with 500ml. When the organic phase is concentrated under reduced pressure to 150ml remaining in the kettle, stop concentrating. Heat the remaining materials in the kettle to 55℃, add n-heptane (450g), keep warm and stir for 30min. The temperature was lowered to 20°C, stirred for 3 h, and then filtered and dried to obtain BEM (131 g, 98%; purity 99.5%).

[0215] ESI-MS (m / z): [M+H] + =345.2. 1 HNMR (300MHz, DMSO-d6): δ11.99 (brs,

[0216] 2H), 4.20 (d, J = 5.3Hz, 1H), 3.35 (brs, 1H), 1.53-1.12 (m, 20H), 1.06 (s, 12H).

[0217] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. A method for preparing bepedrucic acid, characterized in that: The method comprises the following steps: (e) hydrolyzing compound 6 and removing the carbonyl protecting group to obtain compound 7, and (f) reducing compound 7 to obtain bepedruic acid, The reaction formula is as follows: wherein R1 is selected from a C1-C6 straight or branched alkyl group, a C1-C6 alkenyl group or a C1-C6 cycloalkyl group, R2 and R3 are each independently selected from a C1-C6 straight or branched alkyl group, or R2 and R3 and the oxygen and carbon to which they are connected together form The C1-C6 straight or branched alkyl, C1-C6 alkenyl or C1-C6 cycloalkyl is optionally further substituted by an alkyl, alkoxy, cycloalkyl or aryl substituent.

2. The method for preparing bepedrucic acid according to claim 1, characterized in that: R1 is selected from methyl or ethyl, R2 and R3 and their attached oxygen and carbon together form 3. The method for preparing bepedrucic acid according to claim 1, characterized in that: In step (e), the hydrolysis is carried out under alkaline conditions, and the base used is selected from NaOH, KOH, LiOH, Ba(OH)2, Me3SnOH or a combination thereof, more preferably, NaOH, and / or In step (e), the decarbonylation protecting group is carried out under acidic conditions, and the acid used is selected from hydrochloric acid, sulfuric acid, hydrobromic acid, or a combination thereof, more preferably, hydrochloric acid, and / or In step (f), the reducing agent used for reduction is selected from sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride, more preferably, sodium borohydride.

4. The method for preparing bepedrucic acid according to claim 1, characterized in that: The preparation method further comprises step (d) of reacting compound 5 with isobutyrate to obtain compound 6 by α-alkylation reaction, and the reaction formula is as follows: wherein X is selected from Cl, Br or I, more preferably, Br.

5. The method for preparing bepedrucic acid according to claim 4, characterized in that: The reaction of step (d) is carried out in the presence of a base, wherein the base is selected from lithium diisopropylamide or sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, or a combination thereof, more preferably lithium diisopropylamide, more preferably diisopropylamine, and / or The isobutyrate is selected from methyl isobutyrate, ethyl isobutyrate, n-propyl isobutyrate, isopropyl isobutyrate, n-butyl isobutyrate, tert-butyl isobutyrate or isobutyl isobutyrate, more preferably, methyl isobutyrate or ethyl isobutyrate, and / or The reaction is carried out in a solvent-free system or in an aprotic solvent, wherein the aprotic solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, toluene, or a combination thereof, more preferably tetrahydrofuran.

6. The method for preparing bepedrucic acid according to claim 4, characterized in that: The preparation method further comprises step (c) reacting compound 4 with alcohol to generate compound 5, and the reaction formula is as follows:

7. The method for preparing bepedrucic acid according to claim 6, characterized in that: In step (c), the reaction of compound 4 with alcohol is carried out in the presence of an acid selected from p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, sulfosalicylic acid, naphthalenesulfonic acid, trifluoroacetic acid, or a combination thereof, more preferably, p-toluenesulfonic acid, and / or The alcohol is selected from methanol, ethanol, propanol, ethylene glycol, 1,3-propylene glycol or 1,2-propylene glycol.

8. The method for preparing bepedrucic acid according to claim 6, characterized in that: The preparation method further comprises step (b) of reacting compound 2 with a halogenating agent to obtain compound 4, and the reaction formula is as follows:

9. The method for preparing bepedrucic acid according to claim 6, characterized in that: The preparation method further comprises the following steps: (b') hydrolyzing compound 2 to form compound 3, and (b") Compound 3 is reacted with a halogenating agent to obtain compound 4, and the reaction formula is as follows:

10. The method for preparing bepedrucic acid according to claim 8 or 9, characterized in that: The halogenating agent is selected from thionyl chloride, hydrogen bromide, phosphine tribromide or iodine, preferably hydrogen bromide, and / or The hydrolysis reaction of compound 2 is carried out under alkaline conditions, and the base is selected from NaOH, KOH and LiOH, or a combination thereof.

11. The method for preparing bepedrucic acid according to claim 8 or 9, characterized in that: The preparation method further comprises the step (a) of allowing compound 1 to undergo self-condensation to obtain compound 2, and the reaction formula is as follows:

12. The method for preparing bepedrucic acid according to claim 11, characterized in that: In step (a), the condensation reaction is carried out in the presence of titanium tetrachloride and a base, wherein the base is selected from triethylamine, tributylamine, diisopropylethylamine, or a combination thereof, more preferably triethylamine.

13. A method for preparing bepedolactic acid, characterized in that: The method comprises the following steps: (d) reacting compound 5 with isobutyrate to obtain compound 6 by α-alkylation, and (e) hydrolyzing compound 6 and removing the carbonyl protecting group to obtain compound 7, The reaction formula is as follows: wherein X is selected from Cl, Br or I; R1 is selected from C1-C6 straight chain or branched alkyl, C1-C6 alkenyl or C1-C6 cycloalkyl; R2 and R3 are each independently selected from C1-C6 straight chain or branched alkyl, or R2 and R3 and the oxygen and carbon to which they are connected together form wherein the C1-C6 straight or branched alkyl, C1-C6 alkenyl or C1-C6 cycloalkyl is optionally further substituted by an alkyl, alkoxy, cycloalkyl or aryl substituent; more preferably, X is selected from Br, R1 is selected from methyl or ethyl, R2 and R3 and the oxygen and carbon to which they are connected together form 14. A method for preparing bepedolactic acid, characterized in that: The method comprises the following steps: (c) dehydrating compound 4 with alcohol to generate compound 5, (d) reacting compound 5 with isobutyrate α-alkyl to obtain compound 6, and (e) Compound 6 is hydrolyzed and decarbonylated to obtain compound 7, and the reaction formula is as follows: wherein X is selected from Cl, Br or I; R1 is selected from C1-C6 straight chain or branched alkyl, C1-C6 alkenyl or C1-C6 cycloalkyl; R2 and R3 are each independently selected from C1-C6 straight chain or branched alkyl, or R2 and R3 and the oxygen and carbon to which they are connected together form wherein the C1-C6 straight or branched alkyl, C1-C6 alkenyl or C1-C6 cycloalkyl is optionally further substituted by an alkyl, alkoxy, cycloalkyl or aryl substituent; more preferably, X is selected from Br, R1 is selected from methyl or ethyl, R2 and R3 and the oxygen and carbon to which they are connected together form 15. A method for preparing bepedolactic acid, characterized in that: The method comprises the following steps: (b) reacting compound 2 with a halogenating agent to obtain compound 4, (c) reacting compound 4 with an alcohol to generate compound 5, (d) reacting compound 5 with isobutyrate to obtain compound 6, and (e) hydrolyzing compound 6 and removing the carbonyl protecting group to obtain compound 7, (f) reducing compound 7 to obtain bepedrulic acid, the reaction formula is as follows: wherein X is selected from Cl, Br or I; R1 is selected from C1-C6 straight chain or branched alkyl, C1-C6 alkenyl or C1-C6 cycloalkyl; R2 and R3 are each independently selected from C1-C6 straight chain or branched alkyl, or R2 and R3 and the oxygen and carbon to which they are connected together form wherein the C1-C6 straight or branched alkyl, C1-C6 alkenyl or C1-C6 cycloalkyl is optionally further substituted by an alkyl, alkoxy, cycloalkyl or aryl substituent; more preferably, X is selected from Br, R1 is selected from methyl or ethyl, R2 and R3 and the oxygen and carbon to which they are connected together form 16. A method for preparing bepedolactic acid, characterized in that: The method comprises the following steps: (b') hydrolyzing compound 2 to form compound 3, and (b") reacting compound 3 with a halogenating agent to obtain compound 4, (c) reacting compound 4 with an alcohol to generate compound 5, (d) reacting compound 5 with isobutyrate to obtain compound 6, and (e) hydrolyzing compound 6 and removing the carbonyl protecting group to obtain compound 7, (f) reducing compound 7 to obtain bepedrulic acid, the reaction formula is as follows: wherein X is selected from Cl, Br or I; R1 is selected from C1-C6 straight chain or branched alkyl, C1-C6 alkenyl or C1-C6 cycloalkyl; R2 and R3 are each independently selected from C1-C6 straight chain or branched alkyl, or R2 and R3 and the oxygen and carbon to which they are connected together form wherein the C1-C6 straight or branched alkyl, C1-C6 alkenyl or C1-C6 cycloalkyl is optionally further substituted by an alkyl, alkoxy, cycloalkyl or aryl substituent; more preferably, X is selected from Br, R1 is selected from methyl or ethyl, R2 and R3 and the oxygen and carbon to which they are connected together form 17. The method for preparing bepedrucic acid according to claims 15 and 16, characterized in that: The preparation method of compound 2 comprises the steps of: (a) allowing compound 1 to undergo self-condensation to obtain compound 2, 18. A compound, the structure of which is shown in Formula 5 or Formula 6: wherein X is selected from Cl, Br or I; R2 and R3 are each independently selected from H, C1-C6 straight chain or branched alkyl, wherein the C1-C6 straight chain or branched alkyl is optionally further substituted by an alkyl, alkoxy, cycloalkyl, aryl substituent, or R2 and R3 and the oxygen and carbon to which they are connected together form More preferably, X is selected from Br, R2 and R3 and the oxygen and carbon to which they are attached together form in, R1 is selected from C1-C6 straight chain or branched alkyl, C1-C6 alkenyl or C1-C6 cycloalkyl, R2 and R3 are each independently selected from C1-C6 straight chain or branched alkyl, or R2 and R3 and the oxygen and carbon to which they are connected together form wherein the C1-C6 straight or branched alkyl, C1-C6 alkenyl or C1-C6 cycloalkyl is optionally further substituted by an alkyl, alkoxy, cycloalkyl or aryl substituent; more preferably, R1 is selected from methyl or ethyl, R2 and R3 and the oxygen and carbon to which they are connected together form 19. A method for preparing compound 5, characterized in that: The preparation method comprises the following steps: (b) reacting compound 2 with a halogenating agent to obtain compound 4, (c) reacting compound 4 with an alcohol to generate compound 5, The reaction formula is as follows: Or the preparation method comprises the following steps: (b') hydrolyzing compound 2 to form compound 3, and (b") reacting compound 3 with a halogenating agent to obtain compound 4, (c) reacting compound 4 with an alcohol to generate compound 5, The reaction formula is as follows:

20. A method for preparing compound 6, characterized in that: The preparation method comprises the following steps: (b) reacting compound 2 with a halogenating agent to obtain compound 4, (c) reacting compound 4 with an alcohol to generate compound 5, (d) reacting compound 5 with isobutyrate to obtain compound 6, The reaction formula is as follows: Or the preparation method comprises the following steps: (b') hydrolyzing compound 2 to form compound 3, and (b") reacting compound 3 with a halogenating agent to obtain compound 4, (c) reacting compound 4 with an alcohol to generate compound 5, (d) reacting compound 5 with isobutyrate to obtain compound 6, The reaction formula is as follows:

21. A method for preparing compound 4, characterized in that: The preparation method comprises the following steps: (a) allowing compound 1 to undergo self-condensation to obtain compound 2, (b) Compound 2 is reacted with a halogenating agent to obtain compound 4, and the reaction formula is as follows: wherein X is selected from Cl, Br or I, more preferably Br, Or the preparation method comprises the following steps: (a) allowing compound 1 to undergo self-condensation to obtain compound 2, (b') hydrolyzing compound 2 to form compound 3, and (b") reacting compound 3 with a halogenating agent to obtain compound 4, the reaction formula is as follows: Wherein X is selected from Cl, Br or I, more preferably Br.

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