CN111423320B - Preparation method of nervonic acid and nervonic acid - Google Patents

Abstract

The invention discloses a preparation method of nervonic acid and nervonic acid, comprising: using 1-bromo-cis-13-dodecene to prepare a Grignard reagent, Grignard reagent, cuprous iodide and ethylene oxide Synthesis of 1-hydroxy-cis-15-tetradecene by the epoxy ring-opening reaction of Shi's reagent; 1-hydroxy-cis-15-tetradecene, iodobenzene acetate and TEMPO were oxidized to prepare nervonic acid. By means of chemical synthesis, using erucic acid as raw material, the synthesis of nervonic acid was completed through esterification, reduction, bromination, Grignard reaction and oxidation. The method for synthesizing nervonic acid of the invention has the advantages of cheap raw materials, easy operation, high yield, high product purity and the like.

Description

A kind of preparation method of nervonic acid and nervonic acid

technical field

The invention relates to a method for synthesizing natural products, belonging to the technical field of chemical synthesis, in particular to the efficient synthesis of nervonic acid with Grignard reaction as a key step, specifically a preparation method and nervonic acid.

Background technique

Neural acid, or cis-15-tetradecanoic acid, is an unsaturated fatty acid, which belongs to monounsaturated fatty acid in terms of its chemical structure, and the double bond at the 15th position is in a cis structure. Nervonic Acid, also known as Selacholeic Acid, was first isolated from human and bovine cerebrosides. Later, Japanese scientists separated and extracted Nervonic Acid from shark oil, so they called this acid Selacholeic Acid. It is rich in shark brains, but sharks are protected animals, so synthesis will become its means of acquisition.

Yuanbao maple and garlic fruit seed oil are the main materials for extracting, separating and purifying nervonic acid. However, due to the narrow distribution area of garlic fruit, large-scale planting cannot be carried out, so in fact, ingot maple is an important raw material for the separation of nervous acid in recent years. Patent CN200910074791.1 introduces the method of extracting nervonic acid from ingot maple oil by molecular distillation; patent CN200710053164.0 and CN20110119480.X respectively introduce the method of biosynthesizing low-content nervonic acid by using Mortierella chrysogenum and freshwater microalgae Method; patents CN200510048654.2 and CN201010117638.5 respectively introduce technical solutions for the synthesis and application of neuric acid salts such as zinc neuric acid and calcium neuric acid.

In recent years, foreign scientific research on nervonic acid (Nervonic Acid) has attracted widespread attention, driving the industrial chain of functional products with nervonic acid as the active ingredient. At present, domestic research is progressing slowly. Only about 80% of nervonic acid can be obtained through the separation and purification of garlic fruit oil, which cannot meet the high content requirements of the market for nervonic acid. The main reason is that natural nervonic acid is not easy to obtain and the source is very limited. In the past, the cost of the traditional separation and extraction process was relatively high. In order to solve the shortage of natural sources, it is hoped to obtain nervonic acid through synthetic means. But so far, there are few reports on the chemical synthesis of nervonic acid at home and abroad. Patent CN 103396304 A mainly introduces a chemical synthesis method of nervonic acid. This patent uses cis-13-docosenoic acid methyl ester as a raw material, and phosphorus trichloride is used as a chlorination reagent in the process of chlorination reaction, which will have an impact on the environment. In the carburization reaction, the traditional diethyl malonate is used as a raw material, which greatly reduces the atom utilization rate of the method.

Contents of the invention

The purpose of the present invention is to provide a preparation method of nervonic acid and nervonic acid, which have high intermediate yield, high atom utilization rate and are environmentally friendly.

In order to achieve the above object, the technical scheme that the present invention takes comprises:

A preparation method of nervonic acid, comprising: using 1-bromo-cis-13-dococene to prepare Grignard reagent, Grignard reagent, cuprous iodide and ethylene oxide through the epoxy ring opening of Grignard reagent Synthesis of 1-hydroxy-cis-15-tetradecene by reaction; 1-hydroxy-cis-15-tetradecene, iodobenzene acetate and TEMPO were oxidized to obtain nervonic acid.

Optionally, n (Grignard reagent): n (cuprous iodide): n (ethylene oxide)=1:1.5:1.5;

n(1-hydroxyl-cis-15-tetradecene):n(iodophenyl acetate):n(TEMPO)=1:2.2:0.2.

Optionally, the raw materials for the preparation of the Grignard reagent include magnesium chips, iodine and 1-bromo-cis-13-dodecene;

n(1-bromo-cis-13-dodecene):n(magnesium chips):n(iodine element)=1:3.0:0.1.

Optionally, the synthetic raw materials of the 1-bromo-cis-13-dococene include: n (erucitol): n (triethylamine): n (4-dimethylaminopyridine): n ( Methanesulfonyl chloride): n (lithium bromide)=1:1.2:0.1:1.2:5;

Synthetic raw materials are synthesized by alcohol sulfonylation and bromination.

Optionally, the synthesis of erucol includes: ethyl erucate, tetrahydrofuran and lithium aluminum hydride are synthesized by reduction reaction:

n (erucitol): n (lithium aluminum hydride) = 1:2.

A kind of nervous acid, which is prepared by the method of the present invention.

A kind of nervonic acid, its preparation method comprises: utilize 1-bromo-cis-13-dococene to prepare Grignard reagent, Grignard reagent, cuprous iodide and ethylene oxide undergo the epoxy ring-opening of Grignard reagent Synthesis of 1-hydroxy-cis-15-tetradecene by reaction; 1-hydroxy-cis-15-tetradecene, 1-hydroxy-cis-15-tetradecene, iodobenzene acetate and TEMPO were oxidized to obtain nervonic acid;

n (Grignard reagent): n (cuprous iodide): n (ethylene oxide)=1:1.5:1.5;

n(1-hydroxyl-cis-15-tetradecene):n(iodophenyl acetate):n(TEMPO)=1:2.2:0.2.

Optionally, the raw materials for the preparation of the Grignard reagent include magnesium chips, iodine and 1-bromo-cis-13-dodecene;

n(1-bromo-cis-13-dodecene):n(magnesium chips):n(iodine element)=1:3.0:0.1.

Optionally, the synthetic raw materials of the 1-bromo-cis-13-dococene include: n (erucitol): n (triethylamine): n (4-dimethylaminopyridine): n ( Methanesulfonyl chloride): n (lithium bromide)=1:1.2:0.1:1.2:5;

Synthetic raw materials are synthesized by alcohol sulfonylation and bromination.

Optionally, the synthesis of erucol includes: ethyl erucate, tetrahydrofuran and lithium aluminum hydride are synthesized by reduction reaction:

n (erucitol): n (lithium aluminum hydride) = 1:2.

Features and advantages of the present invention:

High reaction yield: The yield of each step of the preparation of intermediates is greatly improved compared with the previous patents, and the yield of some intermediates reaches more than 95%. High Atom Utilization: The cycloaddition protocol with ethylene oxide increases atom utilization.

Description of drawings

The accompanying drawings are used to provide a further understanding of the present disclosure, and constitute a part of the description, together with the following specific embodiments, are used to explain the present disclosure, but do not constitute a limitation to the present disclosure. In the attached picture:

Fig. 1 is the hydrogen spectrogram of the synthetic nervonic acid of the present invention;

Fig. 2 is the gas chromatogram of the synthetic nervonic acid of the present invention;

Fig. 3 is the mass spectrogram of the nervonic acid synthesized by the present invention.

Detailed ways

The purpose of the present invention is to use cheap and easy-to-obtain erucic acid (cis-13-docosenoic acid) as a starting material, and use Grignard reaction as a key reaction step to efficiently synthesize nervonic acid. The synthetic route is as follows:

The synthesis steps are as follows:

(1) Synthesis of ethyl erucate: take erucic acid as raw material, absolute ethanol as solvent, add catalytic amount of concentrated sulfuric acid, react under the condition of reflux, TLC detects the progress of the reaction, after the reaction, add saturated sodium bicarbonate solution Remove concentrated sulfuric acid, extract, and distill under reduced pressure.

(2) Synthesis of erucitol: use ethyl erucate as raw material, anhydrous tetrahydrofuran as solvent, lithium tetrahydrogen aluminum as reducing agent, stir overnight at room temperature under the condition of argon protection, TLC detection reaction progress, after the reaction is complete , Filtration, extraction, vacuum distillation. The ratio of the amount of substances of erucitol and lithium aluminum hydride in the reactant:

n (erucitol): n (lithium aluminum hydride) = 1:2;

(3) Synthesis of 1-bromo-cis-13-dococene: using erucitol as raw material, triethylamine as alkali, 4-dimethylaminopyridine as catalyst and reaction with methanesulfonyl chloride, and dichloromethane as Solvent, react overnight at room temperature, TLC to detect the progress of the reaction. After the reaction was complete, water was added to the system for extraction and distillation under reduced pressure. The crude product obtained from the reaction does not need to be purified, and anhydrous acetonitrile is added as a solvent to react with lithium bromide monohydrate, and the reaction is heated at 60°C. The progress of the reaction was detected by TLC. After the reaction was complete, water was added to the system for extraction and distillation under reduced pressure. The ratio of the amount of substances of erucitol, triethylamine, 4-dimethylaminopyridine, methanesulfonyl chloride and lithium bromide monohydrate in the reactant:

n (erucitol): n (triethylamine): n (4-dimethylaminopyridine): n (methanesulfonyl chloride): n (lithium bromide monohydrate) = 1:1.2:0.1:1.2:5;

(4) Synthesis of Grignard reagent: Add activated magnesium chips into the reaction system, add a catalytic amount of iodine, and first add a small amount of 1-bromo-cis-13-dodecene under slightly heated conditions Perform reaction initiation. After the initiation is completed, slowly drop 1-bromo-cis-13-dococene into the reaction system, and ensure that the system is in a state of slight reflux during the dropping process, and place the system in a heating device after the dropping is completed activated in. During the activation process, the consumption of magnesium chips was detected. After about 1 hour of activation, a large amount of magnesium chips were consumed, which proved that the Grignard reagent had been prepared. The ratio of the amount of 1-bromo-cis-13-dococene, magnesium chips and iodine simple substance in the reactant:

n(1-bromo-cis-13-dococene):n(magnesium chips):n(iodine element)=1:3.0:0.1;

(5) Synthesis of 1-hydroxy-cis-15-tetradecene: add cuprous iodide, ethylene oxide and anhydrous tetrahydrofuran to the reaction system, and stir evenly at -40°C. The Grignard reagent prepared in the previous step was slowly added dropwise to the reaction system, stirred at -40°C for 1 h, and then the reaction system was raised to room temperature and continued to stir for 3 h. The progress of the reaction was detected by TLC. After the reaction was complete, the system was quenched by adding saturated ammonium chloride solution, extracted, and distilled under reduced pressure. The ratio of the amount of Grignard reagent, cuprous iodide and oxirane in the reactant:

n (Grignard reagent): n (cuprous iodide): n (ethylene oxide)=1:1.5:1.5;

(6) Synthesis of nervonic acid: 1-hydroxy-cis-15-tetradecene and iodobenzene acetate were dissolved in the system of acetonitrile:water=1:1. The system was uniformly stirred for 3 minutes, and a catalytic amount of TEMPO was added to the reaction system. In the reaction at room temperature for 7h. The progress of the reaction was detected by TLC. After the reaction was complete, water was added to the system for extraction and distillation under reduced pressure. The ratio of the amount of substances of 1-hydroxyl-cis-15-tetradecene, iodobenzene acetate and TEMPO in the reactant:

n(1-hydroxyl-cis-15-tetradecene):n(iodophenyl acetate):n(TEMPO)=1:2.2:0.2;

The nervonic acid synthesized by the above method was reacted with methanol under the catalysis of concentrated sulfuric acid to prepare nervonic acid methyl ester. After GC-MS detection, the similarity with the data in the database was greater than 95%.

In the halogenation reaction of alcohol, the present invention uses lithium bromide monohydrate (LiBr·H ₂ O) as a halogen source, avoiding side reactions caused by using chlorine and bromine phosphides (eg PCl ₃ , PBr ₃ ). Because when phosphides of chlorine and bromine are used, the reaction is too violent, which may lead to changes in the cis-trans structure of the double bond. Secondly, the phosphides of chlorine and bromine contain a large amount of phosphorus, and the use of a large amount of phosphorus will inevitably cause phosphorus pollution and affect the environment; when carrying out the subsequent carburization reaction, the tradition is to use diethyl malonate for carburization, although The reaction is more efficient, but its atom utilization is very low. The present invention adopts Grignard reagent and ethylene oxide to carry out cycloaddition, and the utilization rate of atoms is greatly increased; 1-hydroxyl-cis-15-tetradecene is oxidized into nervonic acid reaction, usually using chromium trioxide or other Pyridine salt (CrO ₃ , PDC), using such a method will definitely generate a large amount of wastewater containing chromium ions, which will affect the environment. The present invention adopts the method of oxidizing TEMPO and iodobenzene acetate. Firstly, the conditions are mild so that a large amount of by-products will not be generated in the system. Secondly, the use of chromium-containing oxidizing agents is avoided to avoid environmental pollution.

Below by example the present invention will be further described, but the present invention is not limited to implemented example, as long as not departing from purpose of the present invention, all should be in the protection domain of the present invention.

Embodiment one:

Synthesis of mustard alcohol:

Taking erucic acid (0.3mol) as a raw material, absolute ethanol as a solvent, adding a catalytic amount of concentrated sulfuric acid, reacting under the condition of reflux, TLC detection of the reaction progress, adding saturated sodium bicarbonate solution after the reaction to remove the concentrated sulfuric acid, extraction, Vacuum distillation.

Using ethyl erucate (0.3mol) as the raw material, anhydrous tetrahydrofuran as the solvent, and lithium aluminum hydride (LiAlH ₄ 0.9mol) as the reducing agent, stir overnight at room temperature under the protection of argon, and check the progress of the reaction by TLC. After completion, the excess lithium aluminum tetrahydrogen was quenched with ethyl acetate, then an appropriate amount of water was added, extracted with ethyl acetate, and dried. Yield 93%.

In the prior art, the sodium borohydride reduction reaction catalyzed by aluminum trichloride is usually used. This scheme yield is not as high as this scheme, and the ethyl erucate of this scheme is commercially available, rather than self-made, causes the increase of cost.

Synthesis of 1-bromo-cis-13-dococene:

Erucol (0.3mol), 4-dimethylaminopyridine (DMAP 0.03mol) and triethylamine ( _Et3N 0.6mol) were dissolved in dichloromethane, methanesulfonyl chloride (0.36mol) was dissolved in dichloromethane , slowly added to the system at 0°C. Stir overnight at room temperature after the addition is complete. After the reaction is complete, add water, extract with dichloromethane, and dry without further purification. The yield is 93%. The crude product obtained from the reaction was added with anhydrous acetonitrile as a solvent, reacted with lithium bromide monohydrate (LiBr·H ₂ O 0.75 mol), and reacted by heating at 60°C. After the reaction was complete, water was added to the system, extracted with ethyl acetate, and dried. Yield 90%. The synthetic route is as follows:

Existing techniques are halogenation by phosphorus halides. The program will have a greater impact on the environment. This scheme adopts the inorganic salt of lithium bromide monohydrate as the halogenation reagent, which reduces the pollution to the environment due to the use of the halogenation reagent.

Synthesis of 1-hydroxy-cis-15-tetradecene:

Add activated magnesium scraps (Mg 1.5mol) to the reaction system, add a catalytic amount of iodine (I ₂ 0.05mol), first add a small amount of 1-bromo-cis-13-dodecene in a slightly heated conditions for reaction initiation. After the initiation is complete, slowly drop 1-bromo-cis-13-dodecene (0.5mol) into the reaction system, and ensure that the system is in a state of slight reflux during the dropwise addition, and remove the system after the dropwise addition is completed. Place in a heating device for activation. During the activation process, the consumption of magnesium chips was detected. After 1 hour of activation, a large amount of magnesium chips were consumed, which proved that the Grignard reagent had been prepared. Prepare another round-bottomed flask, add cuprous iodide (CuI 0.75mol), ethylene oxide (0.75mol) and anhydrous tetrahydrofuran, and stir evenly at -40°C under an argon-protected atmosphere. The newly prepared Grignard reagent was slowly added dropwise to the reaction system, stirred at -40°C for 1 h, and then the reaction system was raised to room temperature and continued to stir for 3 h. After the reaction was complete, the system was quenched by adding saturated ammonium chloride solution, extracted with ethyl acetate, distilled under reduced pressure, and dried. Yield 60%. The synthetic route is as follows:

Existing technology is to be the synthetic reaction of raw material with diethyl malonate. The biggest problem with this solution is that the utilization rate of atoms is too low. This scheme adopts the scheme of cycloaddition of oxirane, which greatly increases the utilization rate of atoms.

Synthesis of nervonic acid:

1-Hydroxy-cis-15-tetradecene (0.5 mol) and iodobenzene acetate [PhI(OAc) ₂ 1.1 mol] were dissolved in acetonitrile: water = 1:1 system. The system was uniformly stirred for 3 min, and a catalytic amount of TEMPO (0.1 mol) was added to the reaction system. In the reaction at room temperature for 7h. After the reaction was complete, water was added to the system, extracted with ethyl acetate, dried and distilled under reduced pressure. The obtained crude product was dissolved in acetone and recrystallized at -20°C. Yield 70%.

The existing technology is an oxidation reaction of a series of chromium-containing oxidants mainly based on PCC. PCC and some chromium-containing oxidants are clear carcinogens, which have a great impact on the environment and the body. This bill adopts the oxidation reaction of iodobenzene acetate and TEMPO to cleverly avoid the use of chromium-containing oxidants.

Nervous acid: melting point 40.5～42.1℃, molecular weight 366.62, molecular formula: C ₂₄ H ₄₆ O ₂ .

hydrogen spectrum. ¹ H NMR (CDCl ₃ , 500MHz) δ5.35(m, 2H, -CH=CH-), 2.34(t, J=7.6Hz, 2H, -CH ₂ -COOH), 2.01(m, 4H, -CH ₂ -CH=CH-CH ₂ -), 1.63(m, 2H), 1.27(m, 32H, -(CH ₂ ) _n -), 0.88(t, 3H, CH ₃ -C-).(Figure 1) .

GC-MS analysis of nervonic acid methyl ester: add the nervonic acid obtained above with a catalytic amount of concentrated sulfuric acid, make a solution in methanol, and stir overnight at 50°C. Extracted with ethyl acetate, dried, and distilled under reduced pressure to obtain methyl nervate. Methyl nervonic acid was detected by GC-MS (Fig. 2 is a gas chromatogram; Fig. 3 is a mass spectrogram), and the obtained data were compared with the standards in the library, and the similarity was greater than 95%. Content >95.0% (GC).

The preferred embodiments of the present disclosure have been described in detail above in conjunction with the accompanying drawings. However, the present disclosure is not limited to the specific details of the above embodiments. Within the scope of the technical concept of the present disclosure, various simple modifications can be made to the technical solutions of the present disclosure. These simple modifications all belong to the protection scope of the present disclosure.

In addition, it should be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner if there is no contradiction. The combination method will not be described separately.

In addition, various implementations of the present disclosure can be combined arbitrarily, as long as they do not violate the idea of the present disclosure, they should also be regarded as the content disclosed in the present disclosure.

Claims (5)

1. A method for preparing nervonic acid, which is characterized by comprising the following steps: preparing a Grignard reagent by using 1-bromo-cis-13-docosacene, and synthesizing 1-hydroxy-cis-15-tetracosacene by using the Grignard reagent, cuprous iodide and ethylene oxide through an epoxy ring-opening reaction of the Grignard reagent; the nervonic acid is prepared by oxidation reaction of 1-hydroxy-cis-15-tetracosene, iodobenzene acetate and TEMPO.

2. The method for producing a nervonic acid according to claim 1, wherein n (Grignard reagent) n (cuprous iodide) n (ethylene oxide) = 1.5;

n (1-hydroxy-cis-15-tetracosene): n (iodobenzene acetate) = n (TEMPO) = 1.

3. The method for preparing nervonic acid according to claim 1 or 2, wherein the raw materials for preparing the Grignard reagent comprise magnesium chips, elemental iodine, and 1-bromo-cis-13-docosene;

n (1-bromo-cis-13-docosene), n (magnesium turnings), n (elemental iodine) = 1.

4. The method of claim 1 or 2, wherein the starting material for synthesizing 1-bromo-cis-13-docosadecene comprises: n (erucic alcohol), n (triethylamine), n (4-dimethylaminopyridine), n (methanesulfonyl chloride), n (lithium bromide) = 1.2;

the synthetic raw materials are subjected to a synthetic reaction by utilizing a sulfonylation reaction and a bromination reaction of alcohol.

5. The method of claim 4, wherein the synthesis of the erucamol comprises: the erucic acid ethyl ester, tetrahydrofuran and lithium aluminum hydride are synthesized by reduction reaction:

n (erucic alcohol) =1:2.

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