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Synthetic method of bempedoic acid

A synthesis method and compound technology, applied in chemical instruments and methods, carboxylic acid nitrile preparation, carboxylic acid ester preparation, etc., can solve problems such as difficult to obtain reaction raw materials, difficult to carry out designed reactions, difficult to carry out coupling reactions, etc.

Pending Publication Date: 2020-10-27
合肥市梓熤科技贸易有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In this route, neither 1,9-dibromononanone nor 2-bromo-2,2-dimethyl propionate methyl ester has any commercial products, and the synthesis of these two raw material reaction conditions is harsh and the yield is low; in this route Both the first step and the second step use noble metals, and the reaction cost is high; since the 1,9-dibromononanone in the second step is an unsaturated bromide, and the boric acid is aliphatic, the Suzuki coupling reaction hardly occurs, Because the Suzuki coupling reaction is the reaction between aryl boronic acid or boronic acid ester and aryl bromide (Tetrahedron Lett.1979,36,3437-3440.), obviously the reaction substrate structure does not meet the conditions, so the couple The joint reaction is difficult or the yield is low
[0016] In summary, the problems in the method of bempedelic acid in the prior art mainly include that the reaction raw materials are difficult to obtain, resulting in higher cost, or the raw materials used are highly toxic; the reaction conditions are harsh or the selectivity of the reaction is not good, resulting in the reaction Low yield; the designed reaction is difficult to carry out due to mechanistic reasons

Method used

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  • Synthetic method of bempedoic acid
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  • Synthetic method of bempedoic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] The first step: the preparation of 7-bromo-2,2-dimethylheptanitril

[0050]Under the protection of nitrogen, 50g (0.72mol, 1.0eq) of isobutyronitrile and 300mL of tetrahydrofuran were added to a 1000mL four-necked flask, and the temperature of the reaction system was slowly lowered to -20°C, and 86.8g (2.17mol, 3.0eq), control the temperature of the reaction system not to exceed -10°C, continue to stir the reaction at -20°C for 1 hour after the dropwise addition, slowly add 166g (0.72mol, 1.0eq) of 1,5-dibromopentane dropwise, During the dropwise addition, the reaction temperature was controlled not to exceed -10°C. After the dropwise addition, the temperature of the reaction was slowly raised to room temperature, and the reaction was stirred overnight, and the conversion of the raw materials was detected by GC. The reaction solution was quenched with saturated ammonium chloride, extracted with ethyl acetate (500 mL×3), the organic phases were combined, dried over anhyd...

Embodiment 2

[0059] The first step of preparation of 7-bromo-2,2-dimethylheptanoic acid methyl ester

[0060] Under nitrogen protection, add 74g (0.72mol, 1.0eq) of methyl isobutyrate and 300mL of tetrahydrofuran into a 1000mL four-neck flask, slowly lower the temperature of the reaction system to -20°C, and add 86.8g of sodium hydride (2.17 mol, 3.0eq), control the temperature of the reaction system not to exceed -10°C, continue to stir the reaction at -20°C for 1 hour after the dropwise addition, and slowly add 166g of 1,5-dibromopentane (0.72mol, 1.0eq ), the reaction temperature was controlled not to exceed -10°C during the dropwise addition. After the dropwise addition, the temperature of the reaction was slowly raised to room temperature, and the reaction was stirred overnight (12 hours), and the conversion of the raw materials was detected by GC. The reaction solution was extracted with saturated ammonium chloride, extracted with 500mL*3 ethyl acetate, the organic phases were combin...

Embodiment 3～5

[0069] Same condition as embodiment 1, just replace the alkali in the first step with following components, experimental result is as shown in table 1:

[0070] Table 1

[0071] Example alkali Yield of the first step reaction (%) Purity of the first step reaction (%) Example 3 Potassium tert-butoxide 85.1 98.4 Example 4 lithium diisopropylamide 94.6 99.1 Example 5 Lithium bis(trimethylsilyl)amide 90.8 98.5

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Abstract

The invention discloses a synthetic method of bempedoic acid. The method comprises the following steps of: taking isobutyronitrile (ester) as a starting raw material, carrying out reaction with 2, 5-dibromopentane under the catalysis of alkali to generate 7-bromo-2, 2-dimethylheptonitrile (ester), then forming a Grignard reagent with magnesium, carrying out reaction with formate to generate 8-hydroxy-2, 2, 14, 14-tetramethylpentadecane dinitrile (ester), and finally carrying out alkaline hydrolysis and acidification to obtain bempedoic acid. The synthetic route is short, all the used raw materials are easy to obtain, the cost is low, the yield of each step of reaction is high, and the purity is high, therefore the method is suitable for industrial production.

Description

[0001] field of invention [0002] The invention belongs to the field of chemical synthesis, and in particular relates to a synthesis method of bempedelic acid. Background technique [0003] Dyslipidemia is one of the important risk factors for cardiovascular disease, and elevated low-density lipoprotein cholesterol (LDL-C) is closely related to cardiovascular events such as acute myocardial infarction and ischemic stroke. Statins can effectively reduce LDL-C levels and reduce the occurrence of ischemic cardiovascular events, and are currently the main drugs for lipid-lowering treatment. However, there are still limitations in the safety of statins, and there is a risk of dose-related adverse muscle reactions, mainly manifested as rhabdomyolysis. Bempedoic acid is a long-chain carboxylic acid compound whose structural formula is [0004] [0005] It was developed by Esperion Company of the United States. On February 21, 2020, the US FDA approved the listing of bepedelic a...

Claims

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Application Information

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IPC IPC(8): C07C51/08C07C59/245C07C27/02
CPCC07C253/30C07C51/08C07C67/343C07C51/09C07C255/10C07C255/12C07C59/245C07C69/63C07C69/675
Inventor 黄欢黄庆国李凯黄庆云
Owner 合肥市梓熤科技贸易有限公司
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