阅读说明：本技术 一种贝派地酸的合成方法 (Synthesis method of piparidic acid ) 是由 黄欢 黄庆国 李凯 黄庆云 于 2020-07-11 设计创作，主要内容包括：本发明公开了一种贝派地酸的合成方法,包括以下步骤：以异丁腈(酯)为起始原料,与2,5-二溴戊烷在碱催化下反应,生成7-溴-2,2-二甲基庚腈(酯),然后与镁形成格氏试剂,再与甲酸酯发生反应生成8-羟基-2,2,14,14-四甲基十五烷二腈(酯),最后经碱水解并酸化得到贝派地酸。本发明合成线路短,所用的所有原料易得,成本低,每步反应收率高,纯度高,适合工业化生产。(The invention discloses a synthesis method of piparidic acid, which comprises the following steps: isobutyronitrile (ester) is used as a starting material and reacts with 2, 5-dibromopentane under the catalysis of alkali to generate 7-bromo-2, 2-dimethylheptanonitrile (ester), then the 7-bromo-2, 2-dimethylheptanonitrile (ester) and magnesium form a Grignard reagent, the Grignard reagent reacts with formate to generate 8-hydroxy-2, 2,14, 14-tetramethylpentadecanedinitrile (ester), and finally the bipedane acid is obtained by alkali hydrolysis and acidification. The invention has short synthesis route, easily obtained raw materials, low cost, high reaction yield and high purity in each step, and is suitable for industrial production.)

1. A synthesis method of pimelic acid comprises the following steps:

(1) reacting a compound shown in a formula (I) with 2, 5-dibromopentane under the catalysis of alkali to obtain a compound shown in a formula (II);

(2) forming a Grignard reagent by the compound of the formula (II) and magnesium, and reacting with HCOOR to obtain a compound of a formula (III);

(3) hydrolyzing and acidifying the compound of the formula (III) by alkali to obtain the triprotic acid;

wherein the structural formulas of the compound of the formula (I), the compound of the formula (II) and the compound of the formula (III) are as follows:

wherein X in the compounds of the formula (I), the formula (II) and the formula (III) is-CN or-COOR 1, and R1 is C1-C6 chain alkyl; wherein R in HCOOR is selected from alkyl, cycloalkyl, alkenyl and substituted phenyl.

2. Process for the synthesis of budesonide according to claim 1, wherein R in HCOOR is an alkyl group, preferably methyl.

3. The method for synthesizing pipadiric acid according to claim 1, wherein the base in the step (1) is at least one of sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide, n-butyllithium, Lithium Diisopropylamide (LDA), lithium bis (trimethylsilyl) amide (HMDSLi), sodium bis (trimethylsilyl) amide (HMDSNa), and potassium bis (trimethylsilyl) amide (HMDSK), and preferably is sodium hydride.

4. The synthesis method of biparidic acid according to claim 1, characterized in that the molar ratio of the base to the compound of formula (i) in step (1) is 1-5: 1, preferably 2-4: 1.

5. The synthesis method of pimelic acid according to claim 1, wherein the solvent used in the step (1) is one or a combination of tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran and 1, 4-dioxane, preferably the solvent used in the reaction is tetrahydrofuran.

6. The process for the synthesis of bipidelic acid according to claim 1, characterized in that the reaction temperature in step (1) is-78 ℃ to 10 ℃, more preferably-20 ℃ to 10 ℃.

7. The method for synthesizing bipidenoic acid according to claim 1, wherein the molar ratio of grignard reagent to formate in step (2) is 2.0-4.0: 1, preferably, the molar ratio of the Grignard reagent to the formate is 2-2.5: 1.

8. the synthesis method of budesonide acid according to claim 1, wherein the base in step (3) is any one or a combination of sodium hydroxide, potassium hydroxide and ammonia water, preferably sodium hydroxide.

9. The method for synthesizing pipidic acid according to claim 1, wherein the solvent in the step (3) is an alcohol solvent. Wherein the alcohol solvent is any one or combination of methanol, ethanol, isopropanol and tert-butanol, preferably ethanol.

10. The synthesis method of biparidic acid according to claim 1, characterized in that the temperature for preparing the middle Grignard reagent in step (2) is reflux reaction, and the temperature for dripping formic ester is-50 to 0 ℃, preferably-10 to 0 ℃; the reaction temperature in the step (3) is 50-100 ℃, and preferably 60-90 ℃.

Technical Field

The invention belongs to the field of chemical synthesis, and particularly relates to a synthesis method of piparidic acid.

Background

Dyslipidemia is one of the important risk factors of cardiovascular diseases, and the rise of low-density lipoprotein cholesterol (LDL-C) is closely related to cardiovascular events such as acute myocardial infarction, cerebral arterial thrombosis and the like. The statins can effectively reduce the level of LDL-C and reduce the occurrence of ischemic cardiovascular events, and are the main drugs for the current lipid-regulating treatment. However, statins still have limitations in terms of safety, with the risk of dose-related muscle side effects, mainly manifested as rhabdomyolysis. The beteparic acid (Bempedoic acid) is a long-chain carboxylic acid compound with a structural formula

The oral small-molecule adenosine triphosphate-citrate lyase (ACL) inhibitor is an oral small-molecule inhibitor of ATP (adenosine triphosphate) -citrate lyase), can reduce the biosynthesis of cholesterol by up-regulating an LDL receptor, reduces the level of LDL-C, and can be used for treating dyslipidemia and reducing the risk of other cardiovascular diseases. Compared with the existing statins widely used clinically, the bemidic acid has the advantages of better tolerance and can be used for treating the LDL-C which cannot be controlled by the existing method when being combined with the statins.

At present, the synthesis of the bipedac acid mainly comprises the following routes:

the synthetic route is that of original research company published in patent WO2004067489, as follows:

in the route, ethyl isobutyrate and 1, 5-dibromopentane are used as initial raw materials and are condensed by LDA at low temperature to obtain ethyl 7-bromo-2, 2-dimethylheptanoate; the compound and p-methyl benzenesulfonyl methyl isonitrile are reacted under the action of strong alkali to obtain an addition product intermediate; then hydrolyzing under acidic condition to obtain 8-oxo-2, 2,14, 14-tetramethyl pentadecanedioic acid diethyl ester; then carrying out alkalization hydrolysis in an ethanol system, and then carrying out acidification to obtain 8-oxo-2, 2,14, 14-tetramethylpentadecanedioic acid; finally, sodium borohydride is used for reduction and acidification to obtain the product of the pimelic acid. The use of p-toluenesulfonylmethyl isonitrile in the second step of the route is more toxic; a large amount of sodium borohydride is used in the last step, a large amount of hydrogen is generated in the post-treatment process, and the material flushing danger is easy to occur. In addition, the reaction steps in the route are multiple, the yield of each step of reaction is low, and the reaction conditions are harsh, so the route is not easy for industrial production.

The second synthetic route is a synthetic route disclosed in chinese patent CN111170855A, and is as follows:

in the route, isobutyrate is taken as a starting material and is subjected to alkylation reaction with 1, 4-dihalogenated alkane to obtain a compound 1; condensing the compound 1 with acetone dicarboxylic acid diester to obtain a compound 2; then, carrying out alkaline hydrolysis on the compound 2 in an ethanol system and then acidifying to obtain a compound 3; finally, sodium borohydride is used for reduction to obtain the bipartite acid. In the first step of the route, because the hydrogen activity in isobutyrate is low and the reaction conditions are harsh, ultralow temperature reaction is required, and the yield is low; the second condensation reaction results in a low yield in this step due to selectivity and polysubstitution problems. Therefore, the route has the problems of low total yield, harsh reaction conditions and the like.

The third synthetic route is a synthetic route disclosed in chinese patent CN111285760A, and is shown as follows:

the method comprises the steps of taking 2-bromo-2, 2-dimethyl methyl propionate as a starting material, reacting with pinacol borate to prepare aliphatic borate, carrying out Suzuki-like coupling reaction with 1, 9-dibromononanone under the catalysis of noble metal to obtain a coupling product, and finally hydrolyzing with sodium borohydride to obtain the besidiric acid. In the route, no commercial products exist in both 1, 9-dibromononanone and 2-bromo-2, 2-dimethyl methyl propionate, and the two raw materials are synthesized under harsh reaction conditions and low yield; in the route, noble metals are used in the first step and the second step, so that the reaction cost is high; since the 1, 9-dibromononanone in the second step is non-unsaturated bromide and the boric acid is aliphatic, the Suzuki coupling reaction hardly occurs, because the Suzuki coupling reaction is only performed between arylboronic acid or boronic ester and arylbromide (Tetrahedron Lett.1979,36,3437-3440.), obviously, the structure of the reaction substrate does not meet the conditions, so the coupling reaction is difficult to perform or the yield is low.

In conclusion, the prior art method of the beradix has the problems that reaction raw materials are difficult to obtain, the cost is high, or the toxicity of the used raw materials is high; the reaction conditions are harsh or the reaction selectivity is not good, so that the reaction yield is low; the designed reaction is difficult to perform due to the mechanism. Therefore, a new synthesis process route of the besmead acid is urgently needed to be found, the raw materials are easy to obtain, the reaction conditions are mild, the reaction yield is high, and the method is suitable for industrialized production.

Disclosure of Invention

Aiming at the problems in the prior art, the invention provides a novel method for synthesizing the piparidic acid, which has the advantages of short steps, easily obtained raw materials, mild reaction conditions, high yield and high purity, and is suitable for industrial production.

In order to solve the technical problems, the technical scheme adopted by the invention is as follows.

A synthesis method of pimelic acid comprises the following steps:

(1) reacting a compound shown in a formula (I) with 2, 5-dibromopentane under the catalysis of alkali to obtain a compound shown in a formula (II);

(2) forming a Grignard reagent by the compound of the formula (II) and magnesium, and reacting with HCOOR to obtain a compound of a formula (III);

(3) the compound of formula (III) is hydrolyzed with alkali and acidified to give the triprotic acid. The synthetic route is as follows:

wherein X in the compounds of formula (I), formula (II) and formula (III) is-CN or-COOR 1, R1 is C1-C6 chain alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, isopentyl, etc., preferably methyl, ethyl, n-propyl.

Wherein R in HCOOR is selected from alkyl, cycloalkyl, alkenyl and substituted phenyl, preferably alkyl, more preferably methyl.

The alkyl group as referred to herein means a straight or branched chain alkyl group having 1 to 6 carbon atoms, including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, and the like.

The alkenyl group in the present invention refers to a straight chain or branched group having a double bond at the end and 2 to 6 carbon atoms, and includes, but is not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like.

The cycloalkyl group as referred to herein means a saturated monocyclic cyclic hydrocarbon substituent having 3 to 6 carbon atoms, and includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The substituted phenyl refers to single substitution at any position or more than two substitutions at any position on a benzene ring. The substituent is selected from hydrogen, halogen, nitro, cyano and C1-4 alkyl.

The base in the step (1) is at least one of sodium hydride, sodium methoxide, sodium ethoxide, potassium tert-butoxide, n-butyllithium, Lithium Diisopropylamide (LDA), lithium bis (trimethylsilyl) amide (HMDSLi), sodium bis (trimethylsilyl) amide (HMDSNa) and potassium bis (trimethylsilyl) amide (HMDSK), and is preferably sodium hydride.

The molar ratio of the alkali to the compound of the formula (I) in the step (1) is 1-5: 1, preferably 2-4: 1.

The solvent used in the reaction in the step (1) is one or a combination of tetrahydrofuran, diethyl ether, 2-methyltetrahydrofuran and 1, 4-dioxane, and preferably the solvent used in the reaction is tetrahydrofuran.

The reaction temperature in the step (1) is-78 ℃ to 10 ℃. Preferably, the reaction temperature is from-20 ℃ to 10 ℃.

The molar ratio of the Grignard reagent to the formate in the step (2) is 2.0-4.0: 1, preferably, the molar ratio of the Grignard reagent to the formate is 2-2.5: 1.

the temperature for preparing the Grignard reagent in the step (2) is reflux reaction, and the temperature for dripping the formic ether is-50 to 0 ℃, preferably-10 to 0 ℃.

The compound of formula (III) can be hydrolyzed with or without purification to yield the triprotic acid. Preferably, the compound of formula (iii) is capable of undergoing hydrolysis without purification to yield the betadiric acid.

The alkali hydrolyzed in the step (3) can be any one or combination of sodium hydroxide, potassium hydroxide and ammonia water, and is preferably sodium hydroxide. The solvent is an alcohol solvent, and is any one or combination of methanol, ethanol, isopropanol and tert-butanol, preferably ethanol.

The reaction temperature in the step (3) is 50-100 ℃, and preferably 60-90 ℃.

The acid in the step (3) is a base capable of neutralizing the reaction, such as hydrochloric acid and sulfuric acid, and the pH value in the reaction is controlled to be 1-2.

Further, the method also comprises the steps of post-treatment such as filtration, concentration and the like.

Compared with the prior art, the invention has the beneficial effects that:

(1) the invention provides a new synthesis method of piparidic acid;

(2) the method has the advantages of short reaction steps, high yield and high purity of each step, and is suitable for industrial production;

(3) all the raw materials are easy to obtain, and the cost is low;

(4) the invention does not use toxic and dangerous raw materials, and the reaction is safer.

Detailed Description

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shifts () are given in units of 10-6 (ppm). NMR was measured using a Brucker AVANCE-400 NMR spectrometer using deuterated chloroform (CDCl3) as the solvent and Tetramethylsilane (TMS) as the internal standard.

MS was measured using a FINNIGAN LCQAD (ESI) mass spectrometer (manufacturer: Thermo, model: FINNIGAN LCQAdvantage MAX).