Synthesis method of bepidolic acid and intermediate thereof

Abstract

The invention provides a preparation method of bepedioic acid and an intermediate thereof, the preparation method of the bepedioic acid comprises the following steps: reacting a compound 4 with a compound 5 in the presence of alkali to obtain a compound 6, and hydrolyzing the compound 6 and removing a hydroxyl protecting group to obtain the bepedioic acid, and the reaction formula is shown in the specification. The preparation method of the bepedioic acid is short in route, low in cost, high in yield of each step of reaction, few in by-products and suitable for industrial large-scale production.

Description

Technical Field

[0001] This invention belongs to the field of organic compound preparation, and more specifically, relates to a method for synthesizing bepidocal acid and its intermediates. Background Technology

[0002] Bempedoic acid is an inhibitor of adenosine triphosphate citrate lyase (ACL), which lowers low-density lipoprotein cholesterol (LDL-C) by inhibiting cholesterol synthesis in the liver. Approved by the U.S. Food and Drug Administration (FDA) in February 2020, it is the first non-statin oral cholesterol-lowering drug approved by the FDA in nearly 20 years for the treatment of adult patients with heterozygous familial hypercholesterolemia or adult patients with atherosclerotic cardiovascular disease requiring further LDL-C reduction. Its molecular structure is shown below:

[0003]

[0004] Currently, several synthetic routes for bepidocalic acid have been reported both domestically and internationally, but all suffer from problems such as cumbersome processes and high production costs. The synthetic route for bepidocalic acid reported in existing technology WO2004067489 is shown in Route 1 below:

[0005]

[0006] This route uses ethyl isobutyrate and 1,5-dibromopentane as starting materials. At low temperature, they are condensed with lithium diisopropylamino (LDA) to obtain ethyl 7-bromo-2,2-dimethylheptanoate (compound 1). Compound 1 is used as an alkylating agent and reacts with p-toluenesulfonylmethylisocyanate (TosMIC) under strongly alkaline conditions, catalyzed by tetrabutylammonium iodide (TBAI), to obtain compound 2. Then, it is hydrolyzed under acidic conditions to obtain compound 3. Compound 3 is hydrolyzed in an ethanol system to obtain compound 4, which is then reduced with NaBH4 to finally obtain the target product, bepidocrolic acid. The first step, α-position alkylation, has poor selectivity and cannot avoid disubstituted impurities. The second step uses p-toluenesulfonylmethylisocyanate, which is highly toxic and difficult to obtain, resulting in poor atom economy. It also uses the hazardous material sodium hydride, which is unfavorable for industrial production. Furthermore, the use of excessive 1,5-dibromopentane to improve selectivity leads to high residual levels of 1,5-dibromopentane and related impurities, requiring further distillation purification. The third step of hydrolysis can produce potentially genotoxic impurities (p-methylbenzenesulfonyl derivatives), which is detrimental to the quality control of the active pharmaceutical ingredient. In summary, this route involves high losses and potential risks, making it unsuitable for industrial production.

[0007] The synthetic route for bepidocalic acid reported in existing technology CN116396158 is shown in route 2 below:

[0008]

[0009] This route uses caprolactone as the starting material, and proceeds through a 6-step process: ring-opening methylation, Claisen condensation catalyzed by titanium tetrachloride, alkaline decarboxylation, bromination, sodium borohydride reduction, and trimethylsilane protection, to obtain the key intermediate 1,11-dibromoundecane-6-oxytrimethylsilyl ether. This intermediate is then coupled with zinc bromide (1-ethoxy-2-methyl-1-oxopropane-2-yl) to give diethyl 2,2,14,14-tetramethyl-8-(trimethylsiloxy)pentadecanedicarboxylic acid. Finally, it is hydrolyzed under acidic conditions and deprotected to give bepidocrolic acid. Although this route uses inexpensive caprolactone as the starting material, it is lengthy, and the expensive ethyl 2-bromoisobutyrate used significantly increases production costs.

[0010] The synthetic route for bepidocalic acid reported in prior art CN114907204 is shown in route 3 below:

[0011]

[0012] This route uses valproic acid as the starting material, and proceeds via Claisen condensation, bromination, ethylene glycol protection, copper-catalyzed Grignard coupling, and sodium borohydride reduction to obtain the target compound, Bepidocrolic acid. While the route is ingeniously designed and concise, the expensive and difficult-to-obtain 3,3-dimethyloxetane-2-one used, coupled with the challenging control of the Grignard coupling reaction and its low yield, limits its industrial application.

[0013] The synthetic route for bepidocalic acid reported in existing technology CN114907204 is shown in route 4 below:

[0014]

[0015] This route uses caprolactone as the starting material, and proceeds through a 6-step process: ring-opening methylation, Dieckmann condensation catalyzed by titanium tetrachloride, alkaline decarboxylation, bromination, sodium borohydride reduction, and trimethylsilane protection, to obtain the key intermediate 1,11-dibromoundecane-6-oxytrimethylsilyl ether. This intermediate is then coupled with zinc bromide (1-ethoxy-2-methyl-1-oxopropane-2-yl) to give diethyl 2,2,14,14-tetramethyl-8-(trimethylsiloxy)pentadecanedicarboxylic acid. Finally, hydrolysis and deprotection under acidic conditions yield bepidocrolic acid. Although this route uses inexpensive caprolactone as the starting material, it is relatively long. Furthermore, the high price of ethyl 2-bromoisobutyrate significantly increases production costs.

[0016] The synthetic route for bepidocalic acid reported in prior art CN114907204 is shown in route 5 below:

[0017]

[0018] This route uses ethyl isobutyrate and 1,11-dibromoundecane-6-ol as starting materials, which undergo a condensation reaction to obtain compound III, and finally hydrolyze under alkaline conditions to obtain bepidocrolic acid. While the route is ingeniously designed and short, it involves numerous side reactions, makes product purification difficult, and results in low yields.

[0019] In conclusion, it is of great significance to develop a synthetic route that is simple and safe to operate, has low production costs, high yield and quality, and has practical industrial application value. Summary of the Invention

[0020] To address the shortcomings of existing methods for preparing bepidocalic acid, one objective of this invention is to provide a method for preparing bepidocalic acid. This method has a short route, uses low-cost raw materials, and achieves high yields in each reaction step with few byproducts. Post-processing is simple, facilitating large-scale industrial production. To achieve this objective, the invention employs the following technical solution:

[0021] A method for preparing bepidocalic acid includes the following steps:

[0022] Compound 4 reacts with compound 5 in the presence of a base to give compound 6, and

[0023] Compound 6 is hydrolyzed and dehydroxylated to give beptopic acid.

[0024] The reaction formula is as follows:

[0025]

[0026] Wherein, R1 is selected from silyl, benzyl, alkyl, or allyl, wherein the silyl, benzyl, alkyl, or allyl is optionally further substituted with alkyl, alkoxy, cycloalkyl, or aryl, and R2 is selected from C1-C6 alkyl.

[0027] In another preferred embodiment, R1 is selected from trimethylsilyl, tert-butylmethylsilyl, tert-butyldiphenylsilyl, methoxymethyl, and R2 is selected from methyl or ethyl.

[0028] In another preferred embodiment, the base is selected from organic nonnucleophilic strong bases.

[0029] In another preferred embodiment, the organic non-nucleophilic strong base is selected from lithium diisopropylamino or sodium di(trimethylsilyl)amino, potassium di(trimethylsilyl)amino or lithium di(trimethylsilyl)amino.

[0030] In another preferred embodiment, the organic non-nucleophilic strong base is selected from lithium diisopropylamino.

[0031] In another preferred embodiment, compound 6 is first hydrolyzed under alkaline conditions to generate an acid, and then dehydroxylated under acidic conditions to generate bepidocal acid.

[0032] In another preferred embodiment, the method for preparing compound 4 includes the steps of:

[0033] Compound 3 reacts with a hydroxyl protecting agent to give compound 4, as shown in the following reaction formula:

[0034]

[0035] In another preferred embodiment, the hydroxyl protecting agent is selected from trimethylchlorosilane, tert-butyldimethylchlorosilane, tert-butyldiphenylchlorosilane, benzyl chloride, 2-tetrahydropyran, methoxymethyl chloride, allyl chloride, or combinations thereof, more preferably trimethylchlorosilane.

[0036] In another preferred embodiment, compound 3 reacts with a hydroxyl protecting agent in the presence of an acid-binding agent. In yet another preferred embodiment, the acid-binding agent is selected from pyridine, imidazole, triethylamine, or combinations thereof, more preferably triethylamine.

[0037] In another preferred embodiment, the molar ratio of compound 3 to the hydroxyl protecting group is 1:1.05 to 3.0, preferably 1:1.05 to 1.5.

[0038] In another preferred embodiment, the molar ratio of compound 3 to the acid-binding agent is 1:1.2 to 3.6, preferably 1.5 to 2.0.

[0039] In another preferred embodiment, the method for preparing compound 3 includes the steps of:

[0040] Compound 1 reacts with a brominating agent to give compound 2, and

[0041] Compound 2 is reduced to give compound 3.

[0042] The reaction formula is as follows:

[0043]

[0044] In another preferred embodiment, the brominating agent is selected from hydrogen bromide, hydrobromic acid, phosphine tribromide, or combinations thereof, more preferably hydrogen bromide.

[0045] In another preferred embodiment, the molar ratio of the brominating agent to the compound 1 is 2 to 30:1, more preferably 8 to 15:1.

[0046] In another preferred embodiment, the reducing agent used for reduction is selected from sodium borohydride, lithium aluminum hydride, potassium borohydride, aluminum isopropoxide, or combinations thereof, more preferably sodium borohydride.

[0047] In another preferred embodiment of the present invention, the method for preparing bepidocalic acid provided by the present invention includes the following steps:

[0048] Compound 3 reacts with a hydroxyl protecting agent to give compound 4;

[0049] Compound 4 reacts with compound 5 in the presence of a base to give compound 6; and

[0050] Compound 6 is hydrolyzed and dehydroxylated to give beptopic acid.

[0051] The reaction formula is as follows:

[0052]

[0053] Wherein, R1 is selected from silyl, benzyl, C1-C6 alkyl or allyl, wherein the silyl, benzyl, C1-C6 alkyl or allyl is optionally further replaced by C1-C6 alkyl, C1-C6 alkoxy, C5-C6 cycloalkyl or aryl, and R2 is selected from C1-C6 alkyl.

[0054] In another preferred embodiment, R1 is selected from trimethylsilyl, tert-butylmethylsilyl, tert-butyldiphenylsilyl, methoxymethyl, and R2 is selected from methyl or ethyl.

[0055] In another preferred embodiment of the present invention, the method for preparing bepidocalic acid provided by the present invention includes the following steps:

[0056] Compound 2 is reduced to give compound 3;

[0057] Compound 3 reacts with a hydroxyl protecting agent to give compound 4;

[0058] Compound 4 reacts with compound 5 in the presence of a base to give compound 6; and

[0059] Compound 6 was hydrolyzed to give bepidocrolic acid.

[0060] The reaction formula is as follows:

[0061]

[0062] Wherein, R1 is selected from silyl, benzyl, C1-C6 alkyl or allyl, wherein the silyl, benzyl, C1-C6 alkyl or allyl is optionally further replaced by C1-C6 alkyl, C1-C6 alkoxy, C5-C6 cycloalkyl or aryl, and R2 is selected from C1-C6 alkyl.

[0063] In another preferred embodiment, R1 is selected from trimethylsilyl, tert-butylmethylsilyl, tert-butyldiphenylsilyl, methoxymethyl, and R2 is selected from methyl or ethyl.

[0064] In another preferred embodiment of the present invention, the method for preparing bepidocalic acid provided by the present invention includes the following steps:

[0065] (1) Compound 1 reacts with a brominating agent to give compound 2.

[0066] (2) Compound 2 was reduced to give compound 3;

[0067] (3) Compound 3 reacts with a hydroxyl protectant to give compound 4;

[0068] (4) Compound 4 reacts with compound 5 in the presence of a base to give compound 6; and

[0069] (5) Compound 6 was hydrolyzed and dehydroxylated to give beptopic acid.

[0070] The reaction formula is as follows:

[0071]

[0072] Wherein, R1 is selected from silyl, benzyl, C1-C6 alkyl or allyl, wherein the silyl, benzyl, C1-C6 alkyl or allyl is optionally further replaced by C1-C6 alkyl, C1-C6 alkoxy, C5-C6 cycloalkyl or aryl, and R2 is selected from C1-C6 alkyl.

[0073] In another preferred embodiment, R1 is selected from trimethylsilyl, tert-butylmethylsilyl, tert-butyldiphenylsilyl, methoxymethyl, and R2 is selected from methyl or ethyl.

[0074] In another preferred embodiment of the present invention, the method for preparing bepidocalic acid provided by the present invention includes the following steps:

[0075] (1) Compound 1 reacts with a brominating agent to give compound 2;

[0076] (2) Compound 2 was reduced to give compound 3;

[0077] (3) Compound 3 reacts with trimethylchlorosilane to give compound 4-1;

[0078] (4) Compound 4-1 reacts with compound 5-1 in the presence of a base to give compound 6, and

[0079] (5) Compound 6 was hydrolyzed to give bepidocrolic acid.

[0080] The reaction formula is as follows:

[0081]

[0082] Another aspect of the present invention provides a method for preparing compound 6, comprising the following steps:

[0083] Compound 4 reacts with compound 5 in the presence of a base to give compound 6, as shown in the following reaction equation:

[0084]

[0085] Wherein, R1 is selected from silyl, benzyl, C1-C6 alkyl or allyl, wherein the silyl, benzyl, C1-C6 alkyl or allyl is optionally further replaced by C1-C6 alkyl, C1-C6 alkoxy, C5-C6 cycloalkyl or aryl, and R2 is selected from C1-C6 alkyl.

[0086] In another preferred embodiment, R1 is selected from trimethylsilyl, tert-butylmethylsilyl, tert-butyldiphenylsilyl, methoxymethyl, and R2 is selected from methyl or ethyl. Attached Figure Description

[0087] The following figures are used to illustrate specific embodiments of the invention and are not intended to limit the scope of the invention as defined by the claims.

[0088] Figure 1 The HPLC chromatogram of compound 6 obtained in Example 22;

[0089] Figure 2a and Figure 2b The mass spectrum of compound 6 obtained in Example 22;

[0090] Figure 3 The H-NMR spectrum of compound 6 obtained in Example 22;

[0091] Figure 4 The mass spectrum of bepidocalic acid obtained in Example 26;

[0092] Figure 5 The image shows the ¹H-NMR spectrum of bepidocalic acid obtained in Example 26. Detailed Implementation

[0093] To address the shortcomings of existing methods for preparing bepidocrolic acid, the inventors, through extensive and in-depth research, have developed a novel method for its preparation. This method uses hydroxyl-protected 1,11-dibromoundecane-6-ol and isobutyrate as starting materials to obtain compound 6, which is then subjected to ester hydrolysis and dehydroxyl protecting group removal to yield bepidocrolic acid. This method not only has a short route but also uses readily available raw materials, and each reaction step exhibits high yield and purity. The purification method is simple and facilitates large-scale industrial production. Based on these findings, this invention was completed.

[0094] Preparation of bepidocalic acid

[0095] In one specific embodiment of the present invention, the method for preparing bepidocalic acid of the present invention includes the following steps:

[0096] (1) Compound 1 reacts with a brominating agent to give compound 2.

[0097] (2) Compound 2 was reduced to give compound 3;

[0098] (3) Compound 3 reacts with a hydroxyl protectant to give compound 4;

[0099] (4) Compound 4 reacts with compound 5 in the presence of a base to give compound 6; and

[0100] (5) Compound 6 was hydrolyzed and dehydroxylated to give beptopic acid.

[0101] The reaction formula is as follows:

[0102]

[0103] Wherein, R1 is selected from silyl, benzyl, C1-C6 alkyl or allyl, wherein the silyl, benzyl, C1-C6 alkyl or allyl is optionally further substituted by substituents of C1-C6 alkyl, C1-C6 alkoxy, C5-C6 cycloalkyl or aryl, and R2 is selected from C1-C6 alkyl.

[0104] In step (1), the reaction of compound 1 with a brominating agent to obtain compound 2 can be carried out according to conventional methods for such reactions in the art. The brominating agent used includes, but is not limited to, hydrogen bromide, hydrobromic acid, and phosphine tribromide. The amount of brominating agent used is the conventional amount used for such reactions in the art. For example, the molar ratio of the brominating agent to compound 1 is 1–30:1, more preferably 8–15:1. The reaction temperature is preferably 60–100°C, more preferably 80–90°C. The reaction time is preferably 8–24 hours, more preferably 10–16 hours. In some preferred embodiments of the present invention, an aqueous solution of hydrogen bromide is used as the reaction medium.

[0105] In some preferred embodiments of the present invention, after the reaction is completed, an organic solvent is added to the reaction solution for extraction, the organic phase is washed with an alkaline aqueous solution, and the concentrated product is directly used in the next reaction.

[0106] In step (2), the reduction of compound 2 to compound 3 can be carried out according to conventional methods for such reactions in the art. The reducing agent used includes, but is not limited to, sodium borohydride, lithium aluminum hydride, potassium borohydride, aluminum isopropoxide, or combinations thereof. The amount of reducing agent used is conventional in such reactions in the art. For example, the molar ratio of reducing agent to compound 2 is 0.5 to 1.2:1. The solvent used in the reduction reaction includes, but is not limited to, water, methanol, and ethanol. The amount of reaction solvent used is conventional in such reactions in the art. For example, the volume ratio of reaction solvent to the weight of compound 2 is preferably 5 to 10 mL / g, more preferably 5 to 7 mL / g. The temperature of the reduction reaction is preferably 0-40°C, more preferably 20-30°C. The reaction time is preferably 1 to 10 hours, more preferably 2 to 4 hours.

[0107] In some preferred embodiments of the present invention, after the reaction is completed, an acidic aqueous solution is added to the reaction solution and the solution is concentrated to dryness. The resulting residue is added to a mixture of water and methyl tert-butyl ether, and the organic phase is concentrated. The product obtained is directly used in the next reaction.

[0108] In step (3), in some preferred embodiments of the present invention, compound 3 reacts with a hydroxyl protecting agent in the presence of an acid-binding agent to obtain compound 4. The hydroxyl protecting agent includes, but is not limited to, silyl protecting agents, benzyl protecting agents, C1-C6 alkyl protecting agents, and allyl protecting agents. Examples include trimethylchlorosilane, tert-butyldimethylchlorosilane, tert-butyldiphenylchlorosilane, benzyl chloride, 2-tetrahydropyran, methoxymethyl chloride, and allyl chloride. The molar ratio of compound 3 to the hydroxyl protecting agent is preferably 1:1.05 to 3.0, more preferably 1:1.05 to 1.5. The acid-binding agent includes, but is not limited to, pyridine, imidazole, and triethylamine. The molar ratio of compound 3 to the acid-binding agent is preferably 1:1.2 to 3.6, more preferably 1.5 to 2.0. The reaction solvent is a commonly used solvent in the art for carrying out such reactions, including, but not limited to, dichloromethane, DMF, and ethanol. The amount of solvent used is 10-30 mL / g, more preferably 10-20 mL / g, in a volume-to-weight ratio to compound 3. The reaction temperature in this step is preferably 0-120°C, more preferably 0-40°C. The reaction time in this step is preferably 1-24 hours, more preferably 5-8 hours.

[0109] In some preferred embodiments of the present invention, after the reaction is completed in this step, water is added to the reaction solution, the liquid is separated, the organic phase is concentrated, and the product obtained is directly used for the next reaction.

[0110] In step (4), the reaction between compound 4 and compound 5 is carried out in an aprotic solvent, which includes, but is not limited to, tetrahydrofuran, 2,-methyltetrahydrofuran, methyl tert-butyl ether, toluene, dichloromethane, 1,2-dichloroethane, and DMF, preferably tetrahydrofuran. The amount of solvent used is 1 to 50 mL / g, more preferably 5 to 10 mL / g, in a volume ratio to compound 4. The reaction between compound 4 and compound 5 can also be carried out under solvent-free conditions, i.e., without the use of any solvent. In some preferred embodiments of the present invention, the molar ratio of compound 4 to compound 5 is preferably 1:2.0 to 5.0, more preferably 1:2.1 to 3.0. The base used in this step is an organic non-nucleophilic strong base, which includes, but is not limited to, lithium diisopropylamino or sodium di(trimethylsilyl)amino, potassium di(trimethylsilyl)amino, and lithium di(trimethylsilyl)amino. In some preferred embodiments of the present invention, the reaction temperature of this step is preferably -70 to 30°C, more preferably -20 to 0°C. The reaction time is preferably 0.5 to 10 hours, more preferably 1 to 4 hours. In some preferred embodiments of the present invention, the molar ratio of compound 5 to the base is preferably 1:1.02 to 1.5, more preferably 1:1 to 1.05.

[0111] In some preferred embodiments of the present invention, after the reaction is completed in this step, water (termination agent) is added to the reaction solution, the liquid is separated, the organic phase is concentrated, and the product obtained is directly used for the next reaction.

[0112] In step (5), the hydrolysis of compound 6 to prepare bepidocrolic acid can be carried out according to methods disclosed in the prior art. In some preferred embodiments of the present invention, in this step, compound 6 is first hydrolyzed under alkaline conditions, and then dehydroxylated under acidic conditions to obtain bepidocrolic acid. The alkaline conditions are solutions prepared by dissolving an inorganic base in water and an organic solvent. The base used in this step includes, but is not limited to, sodium hydroxide and potassium hydroxide. The acid used includes, but is not limited to, sulfuric acid and hydrochloric acid. The solvent used includes, but is not limited to, alcohols, such as methanol and ethanol.

[0113] In some preferred embodiments of the present invention, after the reaction is completed, the organic solvent is removed by vacuum concentration, and then extracted with methyl tert-butyl ether. After washing the organic phase, it is concentrated to 1 / 3 to 1 / 2 of the original volume, and then n-heptane is added. The target compound solid is precipitated by cooling.

[0114] In the description of this invention, "silicone-based" refers to silicon-based groups that protect hydroxyl groups commonly used in the art, such as trimethylsilyl, tert-butylmethylsilyl, tert-butyldiphenylsilyl, etc.

[0115] In the description of this invention, "C1-C6 alkyl" refers to a straight-chain or linear alkyl group containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, etc. These alkyl groups may be further substituted with other groups; in this invention, alkoxy groups are preferred.

[0116] In the description of this invention, "C1-C6 alkoxy" refers to a straight-chain or linear alkoxy group containing 1 to 6 carbon atoms.

[0117] In the description of this invention, the molecular formula of "benzyl" is C6H5CH2-, wherein the benzene ring may be further replaced by common substituents (e.g., alkyl, alkoxy, cycloalkyl, aryl, etc.).

[0118] In the description of this invention, the molecular formula of "allyl" is H2C=CH-CH2-, wherein the carbon on the double bond can be further replaced by common substituents (e.g., alkyl, alkoxy, cycloalkyl, aryl, etc.).

[0119] Compared with the prior art, the main advantages of the preparation method of bepidocalic acid of the present invention include: short route, low cost of raw materials, high yield of each reaction step, easy product purification, simple operation, and suitability for large-scale industrial production.

[0120] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise stated, percentages and parts are weight percentages and parts by weight. The reagents and raw materials used in the following embodiments are generally commercially available unless otherwise specified.

[0121] In the following examples, the high-performance liquid chromatographs used were Thermo Fisher Scientific, models Vanquish and Ultimate 3000; the nuclear magnetic resonance spectrometers used were Bruker, model AVANCE III.

[0122] 300, the mass spectrometer used is manufactured by Agilent, model 1200+6120.

[0123] Example 1 Preparation of 1,11-dibromo-6-undecanone (compound 2)

[0124] 1,11-Dihydroxyundecane-6-one (8.00 g, 39.55 mmol, compound 1) was added to 47% hydrobromic acid solution (102.12 g, 593.2 mmol) at room temperature, and the mixture was heated to 90 °C for 12 hours. After the reaction was complete, the mixture was cooled to room temperature and extracted with 50 mL of cyclohexane. The organic phase was washed once with 100 mL of 5% sodium bicarbonate solution and once with 25 mL of water. 0.4 g (5% w / w) of activated carbon was added to the cyclohexane phase, and the mixture was stirred at 45 °C for 1 h. The mixture was then cooled to 30 °C and filtered. The filtrate was concentrated under reduced pressure to produce 12.31 g of 1,11-dibromoundecane-6-one, a yellow oil, with a molar yield of 93.0% and an HPLC purity of 98.0%. ESI-MS m / z: calculated value: 325.99, determined value: 327.0 (M+l). + .

[0125] Examples 2-3 described below are basically similar to the reactions in Example 1, except that the amount of compound 1 used is 10.0 mmol. Other differences are shown in Table 1 below.

[0126] Table 1

[0127] Types of acids Acid dosage reaction temperature molar yield Example 2 33% hydrobromic acid acetic acid solution 4eq 75℃ 72.1％ Example 3 Phosphorus tribromide 4eq 75℃ 64.8％ Example 4 47% hydrobromic acid solution 10eq 90℃ 87.0％ Example 5 47% hydrobromic acid solution 10eq 75℃ 83.3％

[0128] Example 6 Preparation of 1,11-dibromoundecane-6-ol (compound 3)

[0129] 1,11-Dibromo-6-undecanone (10.00 g, 29.87 mmol, HPLC purity 98.0%, compound 2) and methanol (50 mL) were added to a 250 mL jacketed flask at room temperature. Sodium borohydride (0.69 g, 18.29 mmol) was added in portions at a controlled temperature of 20–30 °C, and the reaction was allowed to proceed for 3 h. After the reaction was complete, the temperature was lowered to 0–15 °C, 100 mL of 2N hydrochloric acid was added, and the mixture was stirred for 15 min. The reaction mixture was then concentrated to dryness, followed by the addition of 100 mL of water and 100 mL of methyl tert-butyl ether. The mixture was extracted and separated. The methyl tert-butyl ether phase was washed twice with 100 mL of water, and then concentrated under reduced pressure to obtain 1,11-dibromoundecan-6-ol (9.37 g, molar yield 93.6%, HPLC purity 98.5%; ESI-MS m / z: calculated value: 328.00, determined value: 329.0 (M+l)). + ).

[0130] Examples 7-12 described below are basically similar to the reactions in Example 6, except that the amount of compound 2 used is 10.0 mmol. Other differences are shown in Table 2 below.

[0131] Table 2

[0132] Types of reducing agents Dosage of reducing agent reaction temperature molar yield Example 7 Lithium aluminum hydride 0.5eq 25℃ 75.3％ Example 8 Potassium borohydride 0.5eq 5℃ 89.8％ Example 9 Aluminum isopropoxide 1.5eq 25℃ 80.4％ Example 10 Sodium borohydride 0.7eq 5℃ 94.3％ Example 11 Sodium borohydride 1.0eq 25℃ 93.4％ Example 12 Sodium borohydride 1.0eq 30℃ 90.8％

[0133] Example 13 Preparation of ((1,11-dibromoundecane-6-yl)oxy)trimethylsilane (compound 4)

[0134] 1,11-Dibromoundecane-6-ol (7.50 g, 22.38 mmol, HPLC purity 98.5%, compound 3) and 115 mL of dichloromethane were added to a 500 mL four-necked flask at room temperature. The mixture was cooled to 5 °C, and imidazole (2.78 g, 40.90 mmol) was added, followed by trimethylchlorosilane (3.70 g, 34.08 mmol). The reaction was allowed to proceed for 6 h. After the reaction was complete, 30 mL of water was added to the system, and the mixture was stirred for 15 min. The mixture was separated, and the DCM phase was washed once more with 30 mL of water. The organic phase was concentrated under reduced pressure to obtain 8.89 g of a deep yellow oil ((1,11-dibromoundecane-6-yl)oxy)trimethylsilane, with a molar yield of 95.1% and an HPLC purity of 96.3%. ESI-MS m / z: calculated value: 400.04, determined value: 401.0 (M+l). + .

[0135] Examples 14-21 described below are basically similar to the reactions in Example 13, except that the amount of compound 3 used is 10.0 mmol. Other differences are shown in Table 3 below.

[0136] Table 3

[0137]

[0138] Example 22 Preparation of diethyl 2,2,14,14-tetramethyl-8-trimethylsiloxypentadecanedioate (compound 6)

[0139] At room temperature, 80 mL of tetrahydrofuran and 25 mL of 2M diisopropylaminolithium tetrahydrofuran solution were added to a 250 mL jacketed flask. The mixture was cooled to -10 °C, and then at -10 ± 5 °C, ethyl isobutyrate (5.31 g, 45.74 mol) and ((1,11-dibromoundecane-6-yl)oxy)trimethylsilane (8.00 g, 19.15 mmol, HPLC purity 96.3%, compound 5) were added dropwise to the reaction system. The reaction was maintained at this temperature for 2 h. After the reaction was complete, 80 mL of water was added to the system, and the mixture was stirred for 30 min. The mixture was allowed to stand and separated. The organic phase was concentrated under reduced pressure to dryness to obtain a dark red oily substance, 2,2,14,14-tetramethyl-8-trimethylsiloxypentadecanedioic acid diethyl ester (8.84 g, molar yield 93.1%, HPLC purity 95.4%) (HPLC chromatogram shown in [reference needed]). Figure 1 ESI-MS m / z: Calculated value: 472.36, Measured value: 473.2 (M+l) + Mass spectrometry Figure 2a and Figure 2b ; 1H-NMR (DMSO, 300MHz) (H NMR spectrum can be found in...) Figure 3 ): δ4.08~4.16m 4H, δ1.38~1.52t 4H, δ1.30~1.45m 16H, δ1.15~1.24m 12H, δ0.86~0.94t 7H, δ0.07~0.16s9H).

[0140] Other examples are described below, which are basically similar to the reactions in Example 22, with the differences shown in Table 4 below.

[0141] Table 4

[0142]

[0143] Example 26 Preparation of 2,2,14,14-Tetramethyl-8-hydroxypentadecanedioic acid (Beppedic acid)

[0144] Diethyl 2,2,14,14-tetramethyl-8-trimethylsiloxypentadecanedioate (25.4 g, 51.58 mmol, HPLC purity 96.0%) and sodium hydroxide (12.9 g, 322.35 mmol) were added to a solution of methanol (127 mL) and water (64 mL) at room temperature. The reaction was refluxed for 4–8 hours. After the reaction was complete, the mixture was cooled to room temperature, and the pH of the reaction system was adjusted to 1–2 with hydrochloric acid. Stirring was continued for 4 hours. After dilution with water (127 mL), the methanol was removed by concentration under reduced pressure. 1000 mL of methyl tert-butyl ether was added to the concentrate, and the mixture was extracted and separated. The organic phase was washed twice with water (100 mL), and then concentrated under reduced pressure until 75 mL remained in the reactor. Concentration was stopped. The remaining material in the reactor was heated to 55 °C, and n-heptane (150 mL) was added. The mixture was kept at this temperature and stirred for 30 min. Crystallization was precipitated by slow cooling to 10℃, followed by stirring at this temperature for 3 hours. The mixture was then filtered and dried to obtain bepidocrolic acid (16.8 g, molar yield 94.1%; HPLC purity 99.5%; ESI-MS m / z: calculated value: 344.26, determined value: 343.3 (M⁻¹)). - (See mass spectrum) Figure 4 ); 1 H-NMR (DMSO, 300MHz) (H NMR spectrum can be found in...) Figure 5 ): δ12.00brs 1H, δ4.21br 2H, δ3.33brs 1H, δ1.53~1.12m 20H, δ1.00~1.07s12H).

[0145] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A method for preparing bepidocalic acid, characterized in that, The method includes the following steps: Compound 4 reacts with compound 5 in the presence of a base to give compound 6, and Compound 6 is hydrolyzed and dehydroxylated to give beptopic acid. The reaction formula is as follows: Wherein, R1 is selected from silyl, benzyl, C1-C6 alkyl or allyl, wherein the silyl, benzyl, C1-C6 alkyl or allyl is optionally further replaced by C1-C6 alkyl, C1-C6 alkoxy, C5-C6 cycloalkyl or aryl, and R2 is selected from C1-C6 alkyl.

2. The method for preparing bepidocalic acid according to claim 1, characterized in that, R1 is selected from trimethylsilyl, tert-butylmethylsilyl, tert-butyldiphenylsilyl, methoxymethyl, and R2 is selected from methyl or ethyl.

3. The method for preparing bepidocalic acid according to claim 1 or 2, characterized in that, The base is selected from organic non-nucleophilic strong bases. Preferably, the organic non-nucleophilic strong base is selected from lithium diisopropylamino or sodium di(trimethylsilyl)amino, potassium di(trimethylsilyl)amino, lithium di(trimethylsilyl)amino, or combinations thereof, and more preferably, lithium diisopropylamino.

4. The method for preparing bepidocalic acid according to claim 1 or 2, characterized in that, The preparation method of compound 4 includes the following steps: Compound 3 reacts with a hydroxyl protecting agent to give compound 4, as shown in the following reaction formula: Preferably, the hydroxyl protecting agent is selected from trimethylchlorosilane, tert-butyldimethylchlorosilane, tert-butyldiphenylchlorosilane, benzyl chloride, 2-tetrahydropyran, methoxymethyl chloride, allyl chloride, or combinations thereof; more preferably, trimethylchlorosilane, and / or Preferably, the reaction of compound 3 with the hydroxyl protectant is carried out in the presence of an acid-binding agent, preferably selected from pyridine, imidazole, triethylamine, or combinations thereof, and more preferably, triethylamine.

5. The method for preparing bepidocalic acid according to claim 4, characterized in that, The preparation method of compound 3 includes the following steps: Compound 1 reacts with a brominating agent to give compound 2, and Compound 2 is reduced to give compound 3. The reaction formula is as follows:

6. The method for preparing bepidocalic acid according to claim 5, characterized in that, The brominating agent is selected from hydrogen bromide, hydrobromic acid, phosphine tribromide, or combinations thereof, more preferably hydrogen bromide, and / or The reducing agent used is selected from sodium borohydride, lithium aluminum hydride, potassium borohydride, aluminum isopropoxide, and preferably sodium borohydride.

7. A method for preparing bepidocalic acid, characterized in that, The method includes the following steps: Compound 3 reacts with a hydroxyl protecting agent to give compound 4. Compound 4 reacts with compound 5 in the presence of a base to give compound 6, and Compound 6 is hydrolyzed and dehydroxylated to give beptopic acid. The reaction formula is as follows: Wherein, R1 is selected from silyl, benzyl, C1-C6 alkyl, or allyl, wherein the silyl, benzyl, C1-C6 alkyl, or allyl is optionally further substituted by C1-C6 alkyl, C1-C6 alkoxy, C5-C6 cycloalkyl, or aryl, and R2 is selected from C1-C6 alkyl groups.

8. A method for preparing bepidocalic acid, characterized in that, The method includes the following steps: (1) Compound 1 reacts with a brominating agent to give compound 2. (2) Compound 2 was reduced to give compound 3; (3) Compound 3 reacts with a hydroxyl protectant to give compound 4; (4) Compound 4 reacts with compound 5 in the presence of a base to give compound 6; and (5) Compound 6 was hydrolyzed and dehydroxylated to give beptopic acid. The reaction formula is as follows: Wherein, R1 is selected from silyl, benzyl, C1-C6 alkyl, or allyl, wherein the silyl, benzyl, C1-C6 alkyl, or allyl is optionally further substituted by C1-C6 alkyl, C1-C6 alkoxy, C5-C6 cycloalkyl, or aryl, and R2 is selected from C1-C6 alkyl groups.

9. A method for preparing bepidocalic acid, characterized in that, The method includes the following steps: (1) Compound 1 reacts with a brominating agent to give compound 2. (2) Compound 2 is reduced to give compound 3. (3) Compound 3 reacts with trimethylchlorosilane to give compound 4-1. (4) Compound 4-1 reacts with compound 5-1 in the presence of a base to give compound 6, and (5) Compound 6 was hydrolyzed to give bepidocalic acid. The reaction formula is as follows: 。 10. A method for preparing compound 6, characterized in that, The method includes the following steps: Compound 4 reacts with compound 5 in the presence of a base to give compound 6, as shown in the following reaction equation: Wherein, R1 is selected from silyl, benzyl, C1-C6 alkyl, or allyl, wherein the silyl, benzyl, C1-C6 alkyl, or allyl is optionally further substituted by C1-C6 alkyl, C1-C6 alkoxy, C5-C6 cycloalkyl, or aryl, and R2 is selected from C1-C6 alkyl. More preferably, R1 is selected from trimethylsilyl, tert-butylmethylsilyl, tert-butyldiphenylsilyl, methoxymethyl, and R2 is selected from methyl or ethyl.

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