Synthesis method for bempedoic acid and bempedoic acid intermediate, and bempedoic acid intermediate

Abstract

The present invention provides a preparation method for bempedoic acid and a bempedoic acid intermediate, and a bempedoic acid intermediate. The preparation method comprises: taking a novel intermediate compound 6 as a raw material, and carrying out hydrolysis, removal of protecting groups on hydroxyl groups, and reduction to obtain bempedoic acid; and taking caprolactone as a starting material, carrying out self-condensation of caprolactone, and then carrying out ring opening, bromination, carbonyl protection, and α-alkylation to obtain the intermediate compound 6. The preparation method for bempedoic acid in the present invention is simple, convenient and safe to operate, high in yield, low in production cost, and easy for industrial production.

Description

Bepedolic acid and its intermediate synthesis method and intermediates thereof Technical Field

[0001] The present 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 adenosine triphosphate citrate lyase (ACL) inhibitor that lowers 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) for marketing in the United States in February 2020. 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 further reduction in LDL-C. Its molecular structure is shown below:

[0003] Currently, there are many reported synthetic routes for the synthesis of bempedoic acid at home and abroad, all of which have problems such as 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:

[0004] This route uses ethyl isobutyrate and 1,5-dibromopentane as starting materials. At low temperature, lithium diisopropylamide (LDA) condenses to produce ethyl 7-bromo-2,2-dimethylheptanoate (Compound 1). Compound 1 then reacts with p-toluenesulfonic acid methyl isocyanide (TosMIC) under strong alkaline conditions, catalyzed by tetrabutylammonium iodide (TBAI), to produce Compound 2. Compound 3 is then hydrolyzed under acidic conditions to produce Compound 3. Compound 3 is hydrolyzed in an ethanol system to produce Compound 4, which is then reduced with NaBH4 to yield the target product, bempedoic acid. This process involves alkylation at the α-position in the first step, resulting in poor selectivity and the inability to avoid disubstituted impurities. The p-toluenesulfonic acid methyl isocyanide used in the second step is highly toxic and difficult to obtain, resulting in poor atom economy. Furthermore, the use of hazardous sodium hydride (NaH) is unfavorable for industrial production. Furthermore, the use of excess 1,5-dibromopentane to enhance selectivity results in high residual impurities such as 1,5-dibromopentane, requiring distillation and purification. 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 high losses and potential risks and is not suitable for industrial production.

[0005] The synthesis route of Bempedoic Acid reported in prior art CN116396158 is shown in Route 2 below:

[0006] This route uses caprolactone as the starting material and proceeds through ring-opening methylation, titanium tetrachloride-catalyzed Dieckmann condensation, alkaline decarboxylation, bromination, sodium borohydride reduction, and trimethylsilane protection (6 steps) to obtain the key intermediate 1,11-dibromodoundec-6-oxytrimethylsilyl ether. This is then coupled with (1-ethoxy-2-methyl-1-oxopropan-2-yl)zinc bromide to obtain diethyl 2,2,14,14-tetramethyl-8-(trimethylsilyloxy)pentadecanedicarboxylate. Finally, it is hydrolyzed under acidic conditions and deprotected to obtain bempedoic acid. Although this route uses inexpensive caprolactone as the starting material, it is relatively long and the high price of ethyl 2-bromoisobutyrate used significantly increases production costs.

[0007] The synthesis route of Bempedoic Acid reported in prior art CN114907204 is shown in Route 3 below:

[0008] This route uses valerolactone as the starting material and proceeds through Dieckmann condensation, bromination, ethylene glycol protection, copper-catalyzed Grignard coupling, and sodium borohydride reduction to obtain the target compound, bempedoic acid. While this route is ingenious and simple, the expensive and difficult-to-obtain 3,3-dimethyloxetan-2-one used in the Grignard coupling reaction is difficult to control, resulting in low yields, limiting its industrial application.

[0009] 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.

[0010] Summary of the Invention

[0011] One aspect of the present invention is to provide a method for preparing bepedrucic acid.

[0012] In a preferred embodiment, the preparation method of bepedruic acid comprises the following steps:

[0013] (e) hydrolyzing compound 6 and removing the carbonyl protecting group to obtain compound 7, and

[0014] (f) Reducing compound 7 to obtain bepedrulic acid, the reaction formula is as follows:

[0015] 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 atoms to which they are connected together form The C1-C6 straight or branched alkyl, C1-C6 alkenyl or C1-C6 cycloalkyl group is optionally further substituted by an alkyl, alkoxy, cycloalkyl or aryl substituent.

[0016] 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

[0017] 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 25-120°C.

[0018] 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.

[0019] In another preferred embodiment, in step (e), compound 6 is first decarbonylated and then hydrolyzed to obtain compound 7.

[0020] 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.

[0021] In another preferred embodiment, the method for preparing bepedrucic acid further comprises step (d) reacting compound 5 with isobutyrate to obtain compound 6, as shown in the following reaction formula:

[0022] wherein X is selected from Cl, Br or I.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] In another preferred embodiment, the method for preparing bepedruic acid further comprises step (c) reacting compound 4 with an alcohol to produce compound 5, as shown in the following reaction formula:

[0027] 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.

[0028] In another preferred embodiment, the method for preparing bepedruic acid further comprises step (b) reacting compound 2 with a halogenating agent to obtain compound 4, as shown in the following reaction formula:

[0029] In another preferred embodiment, in step (b), the halogenating agent is selected from thionyl chloride, hydrogen bromide, phosphine 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, and toluene.

[0030] In another preferred embodiment, the method for preparing bepedruic acid further comprises the following steps:

[0031] (b') hydrolyzing compound 2 to form compound 3, and

[0032] (b") Compound 3 is reacted with a halogenating agent to obtain compound 4, as shown in the following reaction formula:

[0033] 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 in step (b') is 50-90°C, more preferably 60-80°C. In another preferred embodiment, the solvent used in the hydrolysis reaction in step (b') is selected from methanol, ethanol, propanol, water, or a combination thereof.

[0034] In another preferred embodiment, in step (b"), the halogenating agent is selected from thionyl chloride, hydrogen bromide, phosphine tribromide or iodine. In another preferred embodiment, the halogenation reaction temperature in 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.

[0035] In another preferred embodiment, the method for preparing bepedruic acid further comprises step (a) allowing compound 1 to undergo self-condensation to obtain compound 2, as shown in the following reaction formula:

[0036] 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, wherein the base is selected from triethylamine, tributylamine, diisopropylethylamine or a combination thereof, more 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.

[0037] In another preferred embodiment, the preparation method of bepedruic acid comprises the following steps:

[0038] (d) reacting compound 5 with isobutyrate to obtain compound 6, and

[0039] (e) hydrolyzing compound 6 and removing the carbonyl protecting group to obtain compound 7,

[0040] The reaction formula is as follows:

[0041] 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 group is optionally further substituted by an alkyl, alkoxy, cycloalkyl or aryl substituent.

[0042] 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

[0043] In another preferred embodiment, the preparation method of bepedruic acid comprises the following steps:

[0044] (c) reacting compound 4 with an alcohol to generate compound 5,

[0045] (d) reacting compound 5 with isobutyrate to obtain compound 6, and

[0046] (e) compound 6 and decarbonylating the protecting group to obtain compound 7,

[0047] The reaction formula is as follows:

[0048] 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 group is optionally further substituted by an alkyl, alkoxy, cycloalkyl or aryl substituent.

[0049] 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

[0050] In another preferred embodiment, the preparation method of bepedruic acid comprises the following steps:

[0051] (b) reacting compound 2 with a halogenating agent to obtain compound 4,

[0052] (c) reacting compound 4 with an alcohol to generate compound 5,

[0053] (d) reacting compound 5 with isobutyrate to obtain compound 6, and

[0054] (e) hydrolyzing compound 6 and removing the carbonyl protecting group to obtain compound 7,

[0055] (f) reducing compound 7 to obtain bepedruic acid,

[0056] The reaction formula is as follows:

[0057] 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 group is optionally further substituted by an alkyl, alkoxy, cycloalkyl or aryl substituent.

[0058] 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

[0059] In another preferred embodiment, the preparation method of bepedruic acid comprises the following steps:

[0060] (b') hydrolyzing compound 2 to form compound 3, and

[0061] (b") reacting compound 3 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 bepedruic acid,

[0066] The reaction formula is as follows:

[0067] 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 group is optionally further substituted by an alkyl, alkoxy, cycloalkyl or aryl substituent.

[0068] 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

[0069] In another preferred embodiment, in the preparation method of bepedrucic acid, the preparation method of compound 2 comprises the steps of: (a) allowing compound 1 to undergo self-condensation to obtain compound 2,

[0070] Another aspect of the present invention provides a compound, the structure of which is shown in Formula 5 or Formula 6 below:

[0071] Wherein, X is selected from Cl, Br or I; 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 group is optionally further substituted by an alkyl, alkoxy, cycloalkyl or aryl substituent.

[0072] 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 atoms to which they are connected together form The C1-C6 straight or branched alkyl, C1-C6 alkenyl or C1-C6 cycloalkyl group is optionally further substituted by an alkyl, alkoxy, cycloalkyl or aryl substituent.

[0073] 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

[0074] 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

[0075] Another aspect of the present invention provides a method for preparing compound 5, comprising the following steps:

[0076] (b) reacting compound 2 with a halogenating agent to obtain compound 4,

[0077] (c) reacting compound 4 with an alcohol to generate compound 5,

[0078] The reaction formula is as follows:

[0079] Another aspect of the present invention provides a method for preparing compound 5, comprising the following steps:

[0080] (b') hydrolyzing compound 2 to form compound 3, and

[0081] (b") reacting compound 3 with a halogenating agent to obtain compound 4,

[0082] (c) reacting compound 4 with an alcohol to generate compound 5,

[0083] The reaction formula is as follows:

[0084] Another aspect of the present invention provides a method for preparing compound 6, comprising the following steps:

[0085] (b) reacting compound 2 with a halogenating agent to obtain compound 4,

[0086] (c) reacting compound 4 with an alcohol to generate compound 5,

[0087] (d) reacting compound 5 with isobutyrate to obtain compound 6,

[0088] The reaction formula is as follows:

[0089] Another aspect of the present invention provides a method for preparing compound 6, comprising the following steps:

[0090] (b') hydrolyzing compound 2 to form compound 3, and (b") reacting compound 3 with a halogenating agent to obtain compound 4,

[0091] (c) reacting compound 4 with an alcohol to generate compound 5,

[0092] (d) reacting compound 5 with isobutyrate to obtain compound 6,

[0093] The reaction formula is as follows:

[0094] Another aspect of the present invention provides the use of Compound 5 and Compound 6 in the preparation of bepedrucic acid.

[0095] Another aspect of the present invention provides a method for preparing compound 4, which comprises the following steps:

[0096] (a) allowing compound 1 to undergo self-condensation to obtain compound 2,

[0097] (b) reacting compound 2 with a halogenating agent to obtain compound 4,

[0098] The reaction formula is as follows:

[0099] wherein X is selected from Cl, Br or I, more preferably Br.

[0100] In another preferred embodiment, the preparation method of compound 4 provided by the present invention comprises the following steps:

[0101] (a) allowing compound 1 to undergo self-condensation to obtain compound 2,

[0102] (b') hydrolyzing compound 2 to form compound 3, and

[0103] (b") reacting compound 3 with a halogenating agent to obtain compound 4,

[0104] The reaction formula is as follows:

[0105] wherein X is selected from Cl, Br or I, more preferably Br.

[0106] 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 described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0107] 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.

[0108] Figure 1 is the H NMR spectrum of compound 3 (1,11-dihydroxyundecan-6-one);

[0109] Figure 2 is the H NMR spectrum of compound 4 (1,11-dibromodendec-6-one);

[0110] Figure 3 is the H NMR spectrum of compound 5 (2,2-bis(5-bromopentyl)-1,3-dioxolane);

[0111] FIG4 is a hydrogen NMR spectrum of compound 6 (7,7′-(1,3-dioxolane-2,2-diyl)bis(2,2-dimethylheptanoate) diethyl ester). DETAILED DESCRIPTION

[0112] After extensive and in-depth research, the inventors have developed a novel method for preparing bepedoic acid. This method uses ε-caprolactone as the starting material. After self-condensation, hydrolysis, bromination, carbonyl protection, and esterification, a novel intermediate 6 is obtained. This intermediate is then hydrolyzed and deprotected of the hydroxyl protecting group, followed by reduction to yield bepedoic acid. This method addresses the problems of high cost, low yield, and poor product quality associated with existing chemical synthesis methods for bepedoic acid.

[0113] Preparation of compound 2

[0114] In the present invention, the method described in Example 7 of the prior art WO2023 / 147657A1 can be used as the starting material to carry out the reaction.

[0115] Preparation of compound 4

[0116] In the present invention, compound 4 can be prepared using compound 2 as a raw material by the following steps:

[0117] (b) reacting compound 2 with a halogenating agent to obtain compound 4,

[0118] The reaction formula is as follows:

[0119] wherein X is selected from Cl, Br or I.

[0120] In the present invention, compound 4 can be prepared by using compound 2 as a raw material through the following steps:

[0121] (b') hydrolyzing compound 2 to form compound 3, and

[0122] (b") reacting compound 3 with a halogenating agent to obtain compound 4,

[0123] The reaction formula is as follows:

[0124] 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 this field 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 in 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.

[0125] In step (b'), the hydrolysis of compound 2 is carried out under alkaline conditions. During the hydrolysis process to form compound 3, compound 2 is first hydrolyzed in the presence of a base to form an intermediate compound 2'. Compound 2' is then heated (e.g., 50-90°C, more preferably 60-80°C) to remove the carboxyl group adjacent to the carbonyl group to produce 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, and the like.

[0126] Preparation of compound 5

[0127] In the present invention, compound 5 can be prepared by using compound 4 as a raw material through the following steps:

[0128] Step (c) Compound 4 reacts with an alcohol to produce Compound 5, as shown in the following reaction formula:

[0129] wherein X is selected from Cl, Br or I, 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 group is optionally further substituted by an alkyl, alkoxy, cycloalkyl or aryl substituent.

[0130] The reaction in this step is carried out in the presence of an acid, which acts as a catalyst. The acid and its amount used in this step are commonly used in the art for this type of reaction. Such acids include, but are not limited to, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid, sulfosalicylic acid, naphthalenesulfonic acid, and trifluoroacetic acid. The acid is used in a catalytic amount. Preferably, the molar ratio of the acid to compound 4 is 0.01 to 0.1:1. The alcohol used to form the ketal with the carbonyl group of compound 4 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, more preferably 3 to 7:1. The reaction solvent used in this step is commonly used in the art for this type of reaction, including, but not limited to, cyclohexane, toluene, and ethylene glycol dimethyl ether. The reaction temperature in this step is conventional for this type of reaction, for example, 70 to 120°C.

[0131] Preparation of compound 6

[0132] In step (d), compound 6 can be prepared from compound 5 by the following steps:

[0133] Compound 5 is reacted with isobutyrate to obtain compound 6, as shown in the following reaction formula:

[0134] 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 group is optionally further substituted by an alkyl, alkoxy, cycloalkyl or aryl substituent.

[0135] This step can be carried out in an aprotic solvent, including but 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 the use of any solvent). In the absence of any solvent, the isobutyrate acts as a solvent. The reaction in this step is carried out in the presence of a base, which is a strong organic non-nucleophilic base, including but not limited to lithium diisopropylamide or sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, etc. The function of the base is to remove the hydrogen at the α-position of the isobutyrate, forming a carbon anion. This carbon anion 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 this type of reaction, 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 addition process of this step is carried out at -20 to -5°C. First, add the base to the solvent, then add the isobutyrate dropwise, stir for 20 to 40 minutes, and then add compound 5. After the reaction of this step is completed, a termination reagent is added to the above reaction solution. The termination reagent is preferably water, saturated ammonium chloride or dilute hydrochloric acid, more preferably water.

[0136] Preparation of Bepedolic Acid

[0137] Bepedolic acid can be prepared using compound 6 as a raw material by the following steps:

[0138] (e) hydrolyzing compound 6 and removing the hydroxy protecting group to obtain compound 7, and

[0139] (f) Compound 7 is reduced to obtain bepedonic acid, as shown in the following reaction formula:

[0140] 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 this type of reaction in this area. 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 alkali is the conventional amount used for this type of reaction, and preferably the molar ratio thereof to compound 6 is 3 to 10: 1. The amount of solvent is the conventional amount used for this type of reaction, and the volume weight ratio of compound 6 is preferably 5 to 50 mL / g.

[0141] In step (e), the removal of the hydroxy protecting group under acidic conditions can be carried out according to conventional operations for 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 hydroxy protecting group is carried out 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.

[0142] In step (f), the reduction of compound 7 to obtain bepedruic acid can be carried out according to methods disclosed in the prior art, for example, WO2004067489 and CN114907204.

[0143] Reducing agents that can be used in the present invention include, but are 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, and propanol. In some specific embodiments, compound 7 is reduced in an alkaline system using sodium borohydride as a reducing agent. The amount of sodium borohydride used is conventional 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.

[0144] During the reaction process of the present invention, each step can be detected by commonly used means in the art (e.g., thin layer chromatography or liquid chromatography) to determine that the reaction of the step is complete when the starting material disappears or the starting material does not decrease within a period of time, and the reaction is terminated.

[0145] As used herein, the term "room temperature" or "normal temperature" refers to a temperature of 4-40°C, preferably, 25±5°C.

[0146] The term "C1-C6 straight or branched chain alkyl" refers to a straight or branched chain hydrocarbon group having the specified number of carbon atoms (i.e., C1-C6 represents 1 to 6 carbon atoms). 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, and the like.

[0147] 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.

[0148] middle, Indicates the connection position of the formed ketal to the main chain.

[0149] The main advantages of the present invention are:

[0150] The present invention provides a method for preparing bepedolactic acid. Caprolactone is used as a starting material. After self-condensation, it is hydrolyzed, halogenated, carbonyl-protected, and α-alkylated to obtain a novel intermediate compound 6. Compound 6 is then hydrolyzed, deprotected, and reduced to obtain the target product. This method has a simple preparation process, a short route, and a high yield. The reagents used are readily available and inexpensive, and the method is reproducible. The product is of high quality and purity, with reduced production costs and ease of industrial production.

[0151] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight. The reagents and raw materials used in the following examples are generally commercially available unless otherwise stated.

[0152] The "purity" mentioned in the following examples refers to HPLC purity.

[0153] Example 1: Preparation of 3-(6-hydroxyhexanoyl)oxirane-2-one (Compound 2)

[0154] 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 also added and the reaction was maintained at this temperature for 3 h. After completion, dilute hydrochloric acid (150 ml of concentrated hydrochloric acid in 450 ml of water) was added. The layers were separated, and the aqueous phase was extracted twice with 450 ml of dichloromethane each time. The combined organic phases were washed once with water (450 ml) and once with saturated brine (450 ml), dried over magnesium sulfate, and concentrated under reduced pressure to yield 3-(6-hydroxyhexanoyl)oxirane-2-one as a pale yellow oil (139 g, 92.7% yield, 91% purity). ESI-MS (m / z): [M+H] + =227.1

[0155] Other reaction conditions for the preparation steps of Compound 2 were studied, and specific examples are shown in Table 1 below.

[0156] Table 1.

[0157] Example 12: Preparation of 1,11-dibromodendec-6-one (Compound 4)

[0158] 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 heated to 75°C for 6 hours. After completion, the reaction was cooled to room temperature, methanol (690 ml) was added, and the mixture was stirred overnight. The mixture was then concentrated under reduced pressure. Dichloromethane (450 ml) was added to the concentrate, and the mixture was stirred to dissolve. The mixture was then extracted with water twice, each time using 450 ml of water. The mixture was then washed once with saturated brine (450 ml). The organic phases were combined, dried over magnesium sulfate, and concentrated under reduced pressure to yield 1,11-dibromodundecan-6-one as a pale yellow oil (174 g, 87.6% yield, 90% purity). 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).

[0159] Other reaction conditions for the preparation steps of compound 3 were studied, and specific examples are shown in Table 2 below.

[0160] Table 2.

[0161] Example 19: Preparation of 2,2-bis(5-bromopentyl)-1,3-dioxolane (Compound 5)

[0162] 1,11-Dibromodoundec-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. The mixture was heated to reflux and allowed to react for 6 hours. Upon completion, the mixture was cooled to room temperature and extracted with saturated sodium bicarbonate solution (870 ml). The organic phase was further washed with saturated brine (870 ml), dried over magnesium sulfate, and concentrated under reduced pressure to yield 187.6 g of 2,2-bis(5-bromopentyl)-1,3-dioxolane as a pale yellow oil, 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).

[0163] Other reaction conditions for the preparation steps of compound 5 were studied, and specific examples are shown in Table 3 below.

[0164] Table 3.

[0165] Example 33: Preparation of dimethyl 7,7'-(1,3-dioxolane-2,2-diyl)bis(2,2-dimethylheptanoate) (Compound 6)

[0166] Diisopropylamine (141.7 g, 1.4 mol) was added to anhydrous tetrahydrofuran (1.87 L). After nitrogen replacement, the temperature was lowered to -10 ° C. n-Butyl lithium (559 ml, 1.4 mol) was slowly added. After stirring for 30 min, 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. The temperature was raised to 20-30 ° C and the reaction was carried out for 6 hours. After the reaction was complete, water (950 ml) was added, followed by ethyl acetate (1.87 L), and 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 pale yellow oil, 190.7 g, with a yield of 92% and a purity of 97%.

[0167] 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).

[0168] Example 34: Preparation of diethyl 7,7'-(1,3-dioxolane-2,2-diyl)bis(2,2-dimethylheptanoate) (Compound 6)

[0169] Diisopropylamine (141.7 g, 1.4 mol) was added to anhydrous tetrahydrofuran (1.87 L). After nitrogen replacement, the temperature was lowered to -10 ° C. n-Butyl lithium (559 ml, 1.4 mol) was slowly added. After stirring for 30 min, ethyl isobutyrate (151 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. 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, and 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, with a yield of 90% and a purity of 97%.

[0170] 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).

[0171] Other reaction conditions for the preparation step of compound 6 were studied, and specific examples are shown in Table 4 below.

[0172] Table 4.

[0173] Example 54: Preparation of 1,11-dihydroxyundecan-6-one (Compound 3)

[0174] 3-(6-Hydroxyhexanoyl)oxirane-2-one (138 g, 0.605 mol) and sodium hydroxide (72.6 g, 1.815 mol) were added to a solution of methanol (500 ml) and water (250 ml) at room temperature. The mixture was stirred at room temperature overnight and then heated to 65°C for 3 hours. After completion, the reaction was cooled to room temperature, diluted with water (1.25 L), and concentrated under reduced pressure to remove the methanol. The concentrate was adjusted to pH 1-2 with concentrated hydrochloric acid (250 ml) and extracted with dichloromethane (500 ml x 2). The organic phase was washed once with saturated brine (450 ml). The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure to yield 1,11-dihydroxyundecan-6-one as a pale yellow oil (102 g, 83.4% yield, 93% purity). MS: [M+H] + =203.1.

[0175] ESI-MS (m / z): [M+H] + =203.1. 1 HNMR (300MHz, CDCl3): δ3.63(t,J=6.0Hz,4H), 2.41(t,J=6.0Hz,4H,), 1.64-1.52(m,8H), 1.40-1.29(m,4H).

[0176] Other reaction conditions for the preparation step of compound 3 were studied, and specific examples are shown in Table 5 below.

[0177] Table 5.

[0178] Example 62: Preparation of 1,11-dibromodendec-6-one (Compound 4)

[0179] 1,11-Dihydroxyundecan-6-one (102 g, 0.505 mol) was added to a 40% aqueous hydrobromic acid solution (306.4 g, 1.515 mol) at room temperature and refluxed for 6 hours. After completion of the reaction, the mixture was cooled to room temperature and extracted with dichloromethane (500 ml x 2). The organic phase was washed once with saturated brine (450 ml). The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure to yield 1,11-dibromodendecan-6-one as a pale yellow oil (154 g, 93.6% yield, 93% purity). 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).

[0180] Other reaction conditions for the preparation of compound 4 were studied, and specific examples are listed in Table 6 below.

[0181] Table 6.

[0182] Example 69: Preparation of 2,2,14,14-tetramethyl-8-oxopentadecane dioic acid (Compound 7)

[0183] Diethyl 7,7'-(1,3-dioxolane-2,2-diyl)bis(2,2-dimethylheptanoate) (200g, 0.45mol) and 20% sodium hydroxide solution (450ml) were added to ethanol (1L) at room temperature and heated under reflux for 3h. After completion of the reaction, water (1L) was added and the mixture was cooled to room temperature. Extraction was then performed twice with 500ml of ethyl acetate. The aqueous phase was collected and the pH was adjusted to 1-2 with 2mol / L hydrochloric acid at 20-30°C. The mixture was stirred at this temperature for 3h and filtered to obtain the crude product. The crude product was added to methanol (1L) at room temperature and stirred until dissolved. Purified water (200ml) was added and stirred for 30min. Purified water (400ml) was added and stirred for 1h. After stirring for 1h, the mixture was filtered and dried to obtain 133.1g of 2,2,14,14-tetramethyl-8-oxopentadecane dioic acid as a pale yellow solid with a yield of 86% and a purity of 99%.

[0184] ESI-MS (m / z): [M+H] + =343.2. 1 HNMR (300MHz, CDCl3): δ13.00-10.40 (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).

[0185] Example 70: Preparation of 2,2,14,14-tetramethyl-8-oxopentadecane dioic acid (Compound 7)

[0186] At room temperature, add 60g of diethyl 7,7'-(1,3-dioxolane-2,2-diyl)bis(2,2-dimethylheptanoate) to methanol (300ml) and a dilute aqueous sulfuric acid solution (6.6g of concentrated sulfuric acid dissolved in 114g of water). Stir thoroughly, heat to 55-65°C, and allow to react for 3 hours. Then, add 109g of 30% sodium hydroxide solution to the reaction system, heat to 75-85°C, and continue reacting for 4-6 hours. After completion of the reaction, concentrate under reduced pressure to remove the methanol, cool to 0-10°C, and add tertiary methyl ether (300ml). At this temperature, adjust the pH to 1-2 with concentrated hydrochloric acid. After separation, extract the aqueous phase once with tertiary methyl ether (150ml). Combine the tertiary methyl ether phases and wash three times with water (300ml x 3). After concentrating tert-methyl ether under reduced pressure until about 100 ml remained, n-heptane (600 ml) was added dropwise at 50-60°C and the temperature was lowered for crystallization. Filtering and drying afforded 42.2 g of an off-white solid, 2,2,14,14-tetramethyl-8-oxopentadecane dioic acid, with a yield of 91% and a purity of 98.6%.

[0187] Example 71: 2,2,14,14-Tetramethyl-8-hydroxypentadecanedioic acid (Bempedoic acid)

[0188] Under nitrogen, add sodium hydroxide (33.2 g) to purified water (660 g). Stir to dissolve, then add 2,2,14,14-tetramethyl-8-oxopentadecane dioic acid (133 g). Add sodium borohydride (8.2 g) in a sodium hydroxide solution (0.31 g sodium hydroxide, 57.6 g purified water) dropwise at 20-30°C. Incubate for 2 h. After completion, add methyl tert-butyl ether (1 kg), cool to 0-10°C, and add concentrated hydrochloric acid (130 g) dropwise to adjust the pH to 1-2. Allow to stand and separate. Wash the organic phase twice with 500 ml of water each time. Concentrate the organic phase under reduced pressure until 150 ml remains in the kettle, then stop concentrating. Heat the remaining contents to 55°C, add n-heptane (450 g), and stir for 30 min. 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%).

[0189] ESI-MS (m / z): [M+H] + =345.2. 1 HNMR (300MHz, DMSO-d6): δ11.99 (brs, 2H), 4.20 (d, J = 5.3Hz, 1H), 3.35 (brs, 1H), 1.53-1.12 (m, 20H), 1.06 (s, 12H).

[0190] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

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 bepedrucic 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 or 2, 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 (e), compound 6 is first decarbonylated and then hydrolyzed to obtain compound 7, 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 atoms connected thereto are selected from Formation 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) reacting compound 2 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, 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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