A method for synthesizing bepidocalic acid

Abstract

This invention discloses a method for synthesizing bepidocrolic acid, belonging to the field of chemical pharmaceuticals. This invention selects caprolactone and ethyl 2-bromoisobutyrate, which are readily available and inexpensive in the market, as starting materials to obtain key intermediates C and I and important intermediate B (main chain) in high yield. This avoids the use of dangerous reagents (LDA, NaH), harsh conditions (-78°C), and expensive raw materials (TosMIC), which not only reduces the safety risks in the process but also reduces production costs.

Description

Technical Field

[0001] This invention belongs to the field of chemical pharmaceuticals, and specifically relates to bepidocalic acid. Background Technology

[0002] Bepadocyanine is an inhibitor of adenosine triphosphate citrate lyase (ACL) that lowers low-density lipoprotein cholesterol (LDL-C) by inhibiting cholesterol synthesis in the liver. Its chemical structure is as follows:

[0003]

[0004] The main synthetic routes for beptopylic acid reported in the literature are as follows:

[0005]

[0006] Starting with ethyl isobutyrate and 1,5-dibromopentane, 7-bromo-2,2-dimethylheptanoate was condensed with lithium diisopropylamino (LDA) at low temperature. Ethyl 7-bromo-2,2-dimethylheptanoate was then used as an alkylating agent and reacted with p-toluenesulfonylmethylisocyanate (TosMIC) under strongly alkaline conditions, catalyzed by tetrabutylammonium iodide (TBAI), to produce bis(2,2-dimethylheptanoate)-substituted p-toluenesulfonylmethylisocyanate. This was then hydrolyzed under acidic conditions to give diethyl 8-carbonyl-2,2,14,14-tetramethylpentadecanedioate. Diethyl 8-carbonyl-2,2,14,14-tetramethylpentadecanedioate was hydrolyzed in an ethanol system to give 8-carbonyl-2,2,14,14-tetramethylpentadecanedioic acid. Reduction with NaBH4 yielded the target product, bempedoic acid. However, the starting materials ethyl isobutyrate and 1,5-dibromopentane used in this method inevitably produce a disubstituted product, 2,2,8,8-tetramethyl-nonanediol diethyl ester (structure shown below), under the action of LDA.

[0007]

[0008] This method results in significant waste of raw materials, and the use of LDA, NaH, and ultra-low temperature conditions increases the potential safety risks and industrialization difficulties. Therefore, it is essential to find a safer, more economical, and practical preparation method. Summary of the Invention

[0009] In the literature, the preparation of the key intermediate (ethyl 7-bromo-2,2-dimethylheptanoate) requires the use of LDA (which is easily ignited) and ultra-low temperature conditions (-78°C), resulting in low reaction yields (reported yields are only 60%). The condensation process also requires the use of NaH (which decomposes into hydrogen gas upon contact with moisture), and the key raw material (TosMIC) is expensive. These factors increase the potential safety risks and operational difficulties in the industrialization of bepidocalic acid, keeping production costs high. To address these shortcomings, we have designed a novel synthetic route, as follows:

[0010]

[0011] This invention uses caprolactone as a starting material, which reacts with trimethyl orthoformate to obtain methyl 6-methoxyhexanoate (H, yield 78%). H undergoes self-condensation under titanium tetrachloride catalysis to give condensation product G. G is decarboxylated in the presence of sodium hydroxide to give product F (HF two-step yield 93%). F is treated with hydrobromic acid to give dibromide E (yield 92%). E is reduced with sodium borohydride to generate compound D (yield 93.9%). D is protected with trimethylchlorosilane to generate key intermediate C (96.0%). Additionally, this invention uses ethyl 2-bromoisobutyrate as a raw material, which reacts with zinc powder to quantitatively obtain key intermediate I (zinc reagent).

[0012] C and I are coupled in the presence of a catalyst / ligand to give an important intermediate B (yield 91%); B is hydrolyzed in an alcohol-water medium to give bepidocalic acid A (yield 88.0%), with an overall reaction yield of 48.2%.

[0013] This invention provides a method for synthesizing bepidocrolic acid. The method uses caprolactone as a starting material, reacting it with trimethyl orthoformate to obtain methyl 6-methoxyhexanoate. methyl 6-methoxyhexanoate undergoes self-condensation under titanium tetrachloride catalysis to obtain condensation product G. This condensation product is decarboxylated in the presence of sodium hydroxide to obtain product F. Product F is treated with hydrobromic acid to obtain dibromide E. Dibromide E is reduced with sodium borohydride to generate compound D. Compound D is protected with trimethylchlorosilane to generate the key intermediate C.

[0014] According to the above-mentioned method for synthesizing bepidocronic acid, the method also uses ethyl 2-bromoisobutyrate as a raw material, and quantitatively obtains key intermediate I by reacting it with zinc powder.

[0015] The present invention also provides a method for synthesizing bepidocrolic acid, the method comprising coupling C and I in the presence of a catalyst / ligand to obtain an important intermediate B; and hydrolyzing intermediate B in an alcohol-water medium to obtain bepidocrolic acid A.

[0016] This process uses readily available and inexpensive caprolactone and ethyl 2-bromoisobutyrate as starting materials to obtain key intermediates C and I, as well as important intermediate B (main chain), in high yield. It avoids the use of hazardous reagents (LDA, NaH), harsh conditions (-78℃), and expensive raw materials (TosMIC), which not only reduces the safety risks in the process but also lowers production costs. Detailed Implementation

[0017] The following embodiments are for further illustration of some preferred embodiments of the present invention and are not all embodiments. Other embodiments based on the present invention made by those skilled in the art without inventive effort are all within the scope of protection of the present invention.

[0018] In this invention, unless otherwise specified, all abbreviations have the conventional meanings understood by those skilled in the art.

[0019] Example 1) Preparation of methyl 6-methoxyhexanoate (H)

[0020]

[0021] In a 500 ml reaction flask, caprolactone (45.2 g, 0.396 mol), trimethyl orthoformate (84 g, 0.792 mol), sulfuric acid (2 ml), and methanol (250 ml) were added and the mixture was heated under reflux for 24 hours. After the reaction was completed, the solvent and unreacted trimethyl orthoformate were removed by concentration under reduced pressure. The mixture was cooled to room temperature, and ethyl acetate (150 ml) and saturated sodium bicarbonate aqueous solution (150 ml) were added. The mixture was stirred for 20 minutes and the layers were separated. The aqueous layer was extracted again with ethyl acetate (100 ml), and the organic layers were combined and washed with semi-saturated brine (80 ml). The organic layer was dried with anhydrous sodium sulfate, the drying agent was removed, and the solvent was removed under reduced pressure to obtain 49.5 g of methyl 6-methoxyhexanoate (colorless liquid), with a yield of 78%.

[0022] Example 2) Preparation of 1,11-dimethoxyundecane-6-one (F)

[0023]

[0024] ① Under nitrogen purging, add methyl 6-methoxyhexanoate H (48g, 0.3mol) and toluene (300ml) to a 1000ml reaction flask; while stirring, cool to approximately 0℃, add triethylamine (54.6g, 0.54mol), continue stirring, and cool to below -20℃; slowly add a solution of titanium tetrachloride (88.2g, 0.465mol) dissolved in dichloromethane (150ml). Maintain the internal temperature at -20℃±3℃ during the addition process; after the addition is complete, continue stirring and react for 1 hour. Slowly raise the temperature of the reaction solution to 25℃±3℃ and continue reacting for 3 hours. After the reaction is complete, slowly add cold water (300ml), ensuring the internal temperature does not exceed 30℃ during the water addition process; stir for 30 minutes to separate the layers. Extract the aqueous layer with toluene (100ml×2), combine the organic layers, and wash with a semi-saturated sodium chloride solution (100ml). Separate the aqueous layer;

[0025] ② The organic layer was placed in a 1000ml reaction flask, and dichloromethane was evaporated under reduced pressure until the reaction volume was approximately 300ml. While stirring, sodium hydroxide (48g, 1.2mol) and water (50ml) were added, and the reaction was carried out at 35°±3°C for 8 hours. After the reaction was complete, water (200ml) was added, and the mixture was stirred for 30 minutes. The layers separated, and the aqueous layer was extracted with toluene (80ml×2). The organic layers were combined and dried with anhydrous magnesium sulfate (20g). The drying agent was removed by filtration, and the solvent was removed by concentration to obtain 32.1g of oily 1,11-dimethoxyundecane-6-one, with a yield of 93%.

[0026] Example 3) Preparation of 1,11-dibromoundecane-6-one (E)

[0027]

[0028] In a 500 ml reaction flask equipped with a reflux condenser and a magnetic stirrer, 30.0 g (0.13 mol) of 1,11-dimethoxyundecane-6-one, 146 ml (1.3 mol) of 47% hydrobromic acid, and 6.5 g (0.013) of hexadecyltributylphosphine bromide were added. The mixture was stirred and heated under reflux (internal temperature approximately 115 °C) for 5 hours. After the reaction was completed, the mixture was cooled to room temperature and allowed to stand for 30 minutes. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (100 ml). The organic layers were combined and washed with a saturated sodium bicarbonate aqueous solution (60 ml). The aqueous layer was separated, and the organic layer was dried with anhydrous sodium sulfate. The drying agent was filtered off, and the solvent was removed by vacuum distillation under reduced pressure. Then, the mixture was vacuum distilled in an oil bath, and the fraction at 145-155 °C / 2 mmHg was collected to give 39.2 g of a pale yellow liquid of 1,11-dibromoundecane-6-one, with a yield of 92%.

[0029] Example 4) Preparation of 1,11-dibromoundecane-6-one (E)

[0030] The procedure was the same as in Example 3, except that the phase transfer catalyst was replaced with tetrabutylammonium bromide. The yield of 1,11-dibromoundecane-6-one was 32.2 g, with a yield of 75.5%.

[0031] Example 5) Preparation of 1,11-dibromoundecane-6-ol (D)

[0032]

[0033] In a 500 ml reaction flask, 33 g (0.1 mol) of 1,11-dibromoundecane-6-one, 100 ml of methanol, and 50 ml of water were added, stirred, and cooled to below -3 °C. Sodium borohydride (1.9 g, 0.05 mol) was added in portions while maintaining an internal temperature of -3 ± 3 °C. After the addition was complete, the reaction was carried out at the same temperature for 3 hours. After the reaction was complete, 100 ml of water was added, and the mixture was extracted with ethyl acetate (100 ml × 2). The extracts were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to give 31.0 g of 1,11-dibromoundecane-6-ol (colorless liquid). The yield was 93.9%.

[0034] Example 6) Preparation of 1,11-dibromoundecane-6-oxytrimethylsilyl ether (C)

[0035]

[0036] In a 500 mL reaction flask, 30.0 g (0.091 mol) of 1,11-dibromoundecane-6-ol, 200 mL of tetrahydrofuran, and 9.5 g (0.14 mol) of imidazole were added, and the mixture was stirred and cooled to below -3 °C. Trimethylchlorosilane (11.9 g, 0.11 mol) was slowly added dropwise while maintaining an internal temperature of -3 ± 3 °C. After the addition was complete, the reaction was carried out at the same temperature for 3 hours. After the reaction was complete, 200 mL of ethyl acetate was added, and the mixture was stirred for 30 minutes. The mixture was filtered to remove the imidazole salt. The filtrate was washed with 150 mL of saturated sodium bicarbonate solution, and the layers were separated. The aqueous layer was extracted with 100 mL of ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to remove the solvent, yielding 35.1 g of 1,11-dibromoundecane-6-oxytrimethylsilyl ether (colorless liquid). The yield was 96%.

[0037] Example 7: Preparation of (1-ethoxy-2-methyl-1-oxopropane-2-yl)zinc bromide (I)

[0038]

[0039] Under nitrogen purging, add anhydrous tetrahydrofuran (300ml) to a 500ml reaction flask; while stirring, add zinc powder (21.0g, 0.32mol) and iodine granules (0.5g), and slowly heat to 60±3℃. When the yellow color in the reaction solution fades, maintain the same temperature and add ethyl 2-bromoisobutyrate (43g, 0.22mol). After the addition is complete, maintain the internal temperature at 65±3℃ for 6 hours. After the reaction is completed, cool the reaction solution to room temperature and let it stand for 30 minutes. Transfer the supernatant into a dry 500ml dropping funnel filled with nitrogen for later use.

[0040] Example 8) Preparation of diethyl 2,2,14,14-tetramethyl-8-(trimethylsiloxy)pentadecanedicarboxylic acid (B)

[0041]

[0042] Under nitrogen purging, add 1,11-dibromoundecane-6-oxytrimethylsilyl ether (34 g, 0.085 mol), THF (250 ml), 2,6-bis(4-isopropyl-4,5-dihydrooxazol-2-yl)pyridine (ligand, 2.3 g, 0.008 mol), and nickel chloride dimethoxyethane (catalyst, 1.3 g, 0.006 mol) to a dried 1000 ml reaction flask and stir at room temperature for 20 minutes. While stirring, quickly add the prepared zinc reagent (in one batch) from a dropping funnel, maintaining the internal temperature below 30°C during addition. After addition, stir the reaction at (25±3°C) for 24 hours. Analyze the reaction using TLC (developing solvent). When the reaction of dibromosilyl ether (EA∶n-hexane=1∶6) was complete, ethanol (100 ml) was added and the mixture was stirred at room temperature for 30 minutes to decompose the excess zinc reagent. Ethyl acetate (400 ml) was added to dilute the reaction solution. The reaction solution was then transferred to a 2000 ml separatory funnel and washed with water (500 ml × 3). The organic layer was separated and dried with anhydrous magnesium sulfate (50 g). The mixture was filtered through a Buchner funnel (with a 1.5 cm thick layer of diatomaceous earth laid in advance). The filtrate was concentrated under reduced pressure to remove the solvent, yielding 36.6 g of light brown oily diethyl 2,2,14,14-tetramethyl-8-(trimethylsiloxy)pentadecanedicarboxylic acid, with a yield of 91.0%.

[0043] Example 9) Preparation of 2,2,14,14-Tetramethyl-8-hydroxypentadecanedicarboxylic acid (A, Bempedoic Acid).

[0044]

[0045] Add 35.0 g (0.074 mol) of 2,2,14,14-tetramethyl-8-(trimethylsiloxy)pentadecanedicarboxylic acid diethyl ester (B) and 350 ml of ethanol to a 1000 ml reaction flask. Slowly add 150 ml of 30% concentrated hydrochloric acid while stirring. Stir at room temperature for 1 hour to hydrolyze the silane ether. Then slowly raise the temperature to 80-85 °C and reflux for 8 hours to hydrolyze. After the reaction is complete, remove the solvent by vacuum distillation. After distillation, add 250 ml of water and use... Extracted with dichloromethane (250 ml × 3), the dichloromethane layers were combined; then back-extracted with 10% potassium hydroxide aqueous solution (500 ml × 3); the extract (aqueous layer) was transferred to a 2000 ml reaction flask, the pH was adjusted to 1 with concentrated hydrochloric acid, and then extracted with methyl tert-butyl ether (300 ml × 3). The extracts were combined, anhydrous magnesium sulfate (120 g) was added and dried, filtered, and the filtrate was concentrated under reduced pressure to obtain 22.4 g of bepidocalic acid (A) white solid, yield 88%.

[0046] It should be noted that the above preferred embodiments are merely illustrative of the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A method for synthesizing bepidocrolic acid, characterized in that, The method for synthesizing bepidocrolic acid uses caprolactone as a starting material, which reacts with trimethyl orthoformate to obtain methyl 6-methoxyhexanoate; methyl 6-methoxyhexanoate undergoes self-condensation under titanium tetrachloride catalysis to obtain condensation product G; the condensation product is decarboxylated in the presence of sodium hydroxide to obtain product F; product F is treated with hydrobromic acid to obtain dibromide E; dibromide E is reduced with sodium borohydride to generate compound D; compound D is protected with trimethylchlorosilane to generate key intermediate C; The method also uses ethyl 2-bromoisobutyrate as a raw material and tetrahydrofuran as a solvent to react with zinc powder to obtain key intermediate I; intermediate C is coupled to intermediate I in the presence of a catalyst / ligand, wherein the catalyst is nickel chloride dimethoxyethane and the ligand is 2,6-bis(4-isopropyl-4,5-dihydrooxazol-2-yl)pyridine. An important intermediate B was obtained; intermediate B was hydrolyzed in an alcohol-water medium to obtain bepidocalic acid A. The method route is as follows: 。

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