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Synthetic method of bepidic acid

A synthesis method and compound technology, which is applied in the field of synthesis of the compound bempedelic acid, can solve problems such as unfavorable raw material drug quality control, difficulty in industrial production, poor atom economy, etc., and achieve green production process, simplified operation, and reduced dosage Effect

Active Publication Date: 2021-03-12
NANJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The p-toluenesulfonylmethyl isocyanate used in the second step of the process is highly toxic and has poor atom economy, and will produce potential genotoxic impurities (p-toluenesulfonyl derivatives) after the third step of hydrolysis ), which is not conducive to the quality control of raw materials
Alternatively use NaBH 4 When used as a reducing agent, its dosage is more than ten times that of the substrate, which is highly dangerous
In short, the synthesis method has low efficiency, large loss, high potential risk, and is not easy for industrial production

Method used

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  • Synthetic method of bepidic acid

Examples

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Embodiment 1

[0035] (1) Preparation of compound 1: In a 250mL two-necked flask, the nitrogen was replaced three times, then ethyl isobutyrate (4.2g, 36mmol) and 40mL tetrahydrofuran were added, stirred at -40°C for 10 minutes, and then diisopropyl was added dropwise Lithium amide (18mL, 36mmol), reacted for 1 hour, added 1,5-dibromopentane (11.8g, 51.6mmol) dropwise, reacted for 0.5 hour, moved to room temperature for 8 hours, and then used 15mL ice Quenched with water, extracted three times with ethyl acetate, combined the organic phases, dried over anhydrous sodium sulfate, concentrated to dryness, and passed through the column to obtain compound 1 (7.2 g, 76%).

[0036] (2) Preparation of compound 2: Add dibenzyl malonate (1.42g, 5mmol), 15mL toluene and 15mL dimethylformamide into a 100mL single-necked bottle, stir for 5 minutes in an ice bath, and then add sodium hydride in batches (360mg, 12mmol, 60%), after reacting for 1 hour, compound 1 (2.78g, 10.5mmol) was added, and the tempera...

Embodiment 2

[0042] (1) Preparation of compound 1: In a 250mL two-necked flask, the nitrogen was replaced three times, then ethyl isobutyrate (4.2g, 36mmol) and 40mL tetrahydrofuran were added, stirred at -40°C for 10 minutes, and then diisopropyl was added dropwise Lithium amide (18mL, 36mmol), reacted for 1 hour, added 1,5-dibromopentane (9.2g, 40.0mmol) dropwise, reacted for 0.5 hour, moved to room temperature for 8 hours, and then used 15mL ice Quenched with water, extracted three times with ethyl acetate, combined the organic phases, dried over anhydrous sodium sulfate, concentrated to dryness, and passed through the column to obtain compound 1 (6.5 g, 69%).

[0043] (2) Preparation of compound 2: Add dibenzyl malonate (1.42g, 5mmol), 15mL toluene and 15mL dimethylformamide into a 100mL single-necked bottle, stir for 5 minutes in an ice bath, and then add sodium hydride in batches (180mg, 6mmol, 60%), after reacting for 1 hour, compound 1 (1.32g, 5mmol) was added, and the temperature ...

Embodiment 3

[0049] (1) Preparation of compound 1: In a 250mL two-necked flask, the nitrogen was replaced three times, then ethyl isobutyrate (4.2g, 36mmol) and 40mL tetrahydrofuran were added, stirred at -40°C for 10 minutes, and then diisopropyl was added dropwise Lithium amide (18mL, 36mmol), reacted for 1 hour, added 1,5-dibromopentane (12.5g, 54.5mmol) dropwise, reacted for 0.5 hour, moved to room temperature and reacted for 8 hours, and then used 15mL ice Quenched with water, extracted three times with ethyl acetate, combined the organic phases, dried over anhydrous sodium sulfate, concentrated to dryness, and passed through the column to obtain compound 1 (6.9 g, 73%).

[0050] (2) Preparation of compound 2: Add dibenzyl malonate (1.42g, 5mmol), 15mL toluene and 15mL dimethylformamide into a 100mL single-necked bottle, stir for 5 minutes in an ice bath, and then add sodium hydride in batches (375mg, 12.5mmol, 60%), after reacting for 1 hour, compound 1 (3.31g, 12.5mmol) was added, h...

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Abstract

The invention belongs to the field of medicine synthesis, and relates to a novel synthesis method of a compound bepidic acid. The preparation method comprises the following steps: (1) carrying out primary alkylation on ethyl isobutyrate and 1, 5-dibromopentane under the action of lithium diisopropylamide to generate a compound 1; (2) carrying out alkylation twice on dibenzyl malonate and the compound 1 under the action of sodium hydride to generate a compound 2; (3) removing benzyl from the compound 2 under the action of Pd / C and hydrogen to obtain a compound 3; (4) carrying out electrochemical reaction on the compound 3 in a methanol solution of methanol and ammonia to obtain a compound 4; (5) finally carrying out sodium borohydride hydrolysis and potassium hydroxide hydrolysis on the compound 4, and acidifying to obtain the final bepidic acid. The method is carried out under electrochemical conditions, is mild in conditions and high in efficiency, and is suitable for industrial production.

Description

[0001] Technical field [0002] The invention belongs to the field of pharmaceutical synthesis, and relates to a new method for synthesizing the compound bepedelic acid. Background technique [0003] The chemical structure of bempedelic acid is shown in the following formula: [0004] [0005] Bepedelic acid is a small molecule inhibitor of adenosine triphosphate citrate lyase (ACL), which is used to reduce endogenous cholesterol, reduce the increase of LDL-C level by up-regulating LDL receptors, and alleviate muscle-related side effects. Bepedelic acid coenzyme A inhibits ACL in the same way as statins inhibit HMG-CoA reductase. An important distinguishing feature of bempedelic acid is that, unlike statins, it does not inhibit cholesterol synthesis in skeletal muscle. The enzyme required to convert bempedelate to bempedelate-CoA is absent in skeletal muscle. Therefore, bempedelic acid is not expected to mediate adverse effects associated with inhibition of biological in...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C51/09C07C59/285C25B3/07C25B3/20
CPCC07C51/09C25B3/00C07C67/31C07C67/317C07C67/343C07C59/285C07C69/675C07C69/34C07C69/63
Inventor 王亚辉田丽芳许志敏
Owner NANJING UNIV OF TECH
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