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

Preparation method of nervonic acid and nervonic acid Download PDF

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CN111423320B
CN111423320B CN202010241898.7A CN202010241898A CN111423320B CN 111423320 B CN111423320 B CN 111423320B CN 202010241898 A CN202010241898 A CN 202010241898A CN 111423320 B CN111423320 B CN 111423320B
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CN111423320A (en
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高锦明
赵鹏
王性炎
王佳运
张强
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Northwest A&F University
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    • C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
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    • C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
    • C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
    • C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
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    • C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
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Abstract

The invention discloses a preparation method of nervonic acid and nervonic acid, 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. The synthesis of nervonic acid is completed by using erucic acid as a raw material through esterification, reduction, bromination, grignard reaction and oxidation by means of chemical synthesis. The method for synthesizing the nervonic acid has the advantages of low price and easy obtainment of raw materials, easy operation, high yield, high product purity and the like.

Description

Preparation method of nervonic acid and nervonic acid
Technical Field
The invention relates to a synthetic method of a natural product, belongs to the technical field of chemical synthesis, and particularly relates to efficient synthesis of nervonic acid by taking a Grignard reaction as a key step, in particular to a preparation method of nervonic acid and nervonic acid.
Background
Nervonic acid, or cis-15-tetracosenoic acid, is an unsaturated fatty acid that is a monounsaturated fatty acid in terms of its chemical structure, and the double bond at position 15 is in the cis-structure. Nervonic Acid (Nervonic Acid), also known as shark Acid (selachoeicacid), was first isolated from human and bovine cerebrosides, and then subsequently isolated from shark oil by japanese scientists, so this Acid was called shark Acid. It is rich in shark brain, but shark is a protective animal, so synthesis will become its means of acquisition.
Acer truncatum and allium sativum seed oil are the main materials for extracting, separating and purifying nervonic acid. However, since the distribution area of the garlic bulbs is narrow and large-scale planting is impossible, acer truncatum is an important raw material for nervonic acid separation in recent years. Patent CN200910074791.1 describes a method for extracting nervonic acid from acer truncatum buge oil by molecular distillation; patents CN200710053164.0 and cn20110119480.X respectively describe methods for preparing low-content nervonic acid by biosynthesis using mortierella isabellina and fresh water microalgae; patents CN200510048654.2 and CN201010117638.5 respectively describe the synthesis and application of nervonic acid salts such as zinc nervonate and calcium nervonate.
In recent years, scientific research on Nervonic Acid (Nervonic Acid) has attracted much attention abroad, and a chain of functional product industries using Nervonic Acid as an active ingredient has been driven. At present, the research in China is slow in progress, only about 80% of nervonic acid can be obtained through separation and purification of the garlic fruit oil, the requirement of the market on high content of nervonic acid cannot be met, mainly because natural nervonic acid is not easy to obtain, the source is very limited, and the cost of the traditional separation and extraction process is high. To address the shortage of natural sources, it is desirable to obtain nervonic acid synthetically. However, few studies on the chemical synthesis of nervonic acid have been reported at home and abroad so far. Patent CN 103396304A mainly introduces a chemical synthesis method of nervonic acid. The patent takes cis-13-docosenoic acid methyl ester as a raw material, and phosphorus trichloride is taken as a chlorination reagent in the chlorination reaction process, so that the environment is influenced. The traditional diethyl malonate is used as a raw material in the recarburization reaction, so that the atom utilization rate of the method is greatly reduced.
Disclosure of Invention
The invention aims to provide a preparation method of nervonic acid and nervonic acid, which have the advantages of high yield of intermediates, high atom utilization rate and environmental friendliness.
In order to achieve the purpose, the technical scheme adopted by the invention comprises the following steps:
a method of preparing nervonic acid comprising: 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.
Alternatively, n (grignard reagent) n (cuprous iodide) n (ethylene oxide) = 1.5;
n (1-hydroxy-cis-15-tetracosene): n (iodobenzene acetate) = n (TEMPO) = 1.
Optionally, the raw materials for preparing the Grignard reagent comprise magnesium chips, iodine and 1-bromo-cis-13-docosacene;
n (1-bromo-cis-13-docosene), n (magnesium turnings), n (elemental iodine) = 1.
Optionally, the raw materials for synthesizing the 1-bromo-cis-13-docosacene comprise: 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.
Optionally, 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.
Nervonic acid, which is prepared by the method provided by the invention.
A nervonic acid, which is prepared by the method comprising: 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; carrying out oxidation reaction on 1-hydroxy-cis-15-tetracosene, iodobenzene acetate and TEMPO to prepare nervonic acid;
n (grignard reagent), n (cuprous iodide), n (ethylene oxide) = 1.5;
n (1-hydroxy-cis-15-tetracosene): n (iodobenzene acetate) = n (TEMPO) = 1.
Optionally, the raw materials for preparing the Grignard reagent comprise magnesium chips, iodine and 1-bromo-cis-13-docosacene;
n (1-bromo-cis-13-docosene), n (magnesium turnings), n (elemental iodine) = 1.
Optionally, the raw materials for synthesizing the 1-bromo-cis-13-docosacene comprise: 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.
Optionally, 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.
The characteristics and advantages of the invention are as follows:
the yield of the reaction is high: the yield of each step of the preparation of the intermediate is greatly improved compared with that of the prior patent, and the yield of partial intermediates reaches more than 95 percent. The atom utilization rate is high: the cycloaddition scheme using ethylene oxide increases the availability of atoms.
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The accompanying drawings, which are included to provide a further understanding of the disclosure and are incorporated in and constitute a part of this specification, illustrate embodiments of the disclosure and together with the description serve to explain the disclosure without limiting the disclosure. In the drawings:
FIG. 1 is a hydrogen spectrum of a nervonic acid synthesized according to the present invention;
FIG. 2 is a gas chromatogram of a nervonic acid synthesized according to the present invention;
FIG. 3 is a mass spectrum of the synthesized nervonic acid of the present invention.
Detailed Description
The invention aims to provide a method for efficiently synthesizing nervonic acid by taking cheap and easily-obtained erucic acid (cis-13-docosenoic acid) as an initial raw material and grignard reaction as a key reaction step. The synthetic route is as follows:
Figure GDA0003815867060000031
the synthesis steps are as follows:
(1) And (3) synthesizing ethyl erucate: erucic acid is used as a raw material, absolute ethyl alcohol is used as a solvent, a catalytic amount of concentrated sulfuric acid is added, the reaction is carried out under the condition of reflux, TLC detects the reaction progress, saturated sodium bicarbonate solution is added after the reaction is finished to remove the concentrated sulfuric acid, extraction is carried out, and reduced pressure distillation is carried out.
(2) Synthesis of erucic alcohol: the preparation method comprises the steps of taking ethyl erucate as a raw material, taking anhydrous tetrahydrofuran as a solvent, taking lithium aluminum hydride as a reducing agent, stirring overnight at room temperature under the protection of argon, detecting the reaction progress by TLC, and after the reaction is completed, filtering, extracting and distilling under reduced pressure. The ratio of the amounts of the materials of mustard alcohol and lithium aluminum hydride in the reactants:
n (erucic alcohol) =1:2;
(3) Synthesis of 1-bromo-cis-13-docosene: the method comprises the steps of taking erucic alcohol as a raw material, taking triethylamine as an alkali, taking 4-dimethylaminopyridine as a catalyst to react with methanesulfonyl chloride, taking dichloromethane as a solvent, reacting overnight at room temperature, and detecting the reaction progress by TLC. After the reaction is completed, adding water into the system, extracting, and distilling under reduced pressure. The crude product obtained by the reaction does not need to be purified, anhydrous acetonitrile is added as a solvent to react with lithium bromide monohydrate, and the reaction is carried out by heating at 60 ℃. The progress of the reaction was checked by TLC. After the reaction is completed, adding water into the system, extracting, and distilling under reduced pressure. The ratio of the amounts of the materials of erucyl alcohol, triethylamine, 4-dimethylaminopyridine, methanesulfonyl chloride and lithium bromide monohydrate in the reactants:
n (erucic alcohol), n (triethylamine), n (4-dimethylaminopyridine), n (methanesulfonyl chloride), n (lithium bromide monohydrate) = 1.2;
(4) Synthesis of grignard reagents: adding activated magnesium chips into a reaction system, adding a catalytic amount of iodine simple substance, adding a small amount of 1-bromo-cis-13-docosacene, and carrying out reaction initiation under a slightly-hot condition. After the initiation is finished, slowly dripping the 1-bromo-cis-13-docosacene into the reaction system, ensuring that the system is in a micro-reflux state in the dripping process, and after the dripping is finished, putting the system into a heating device for activation. And (3) detecting the consumption of the magnesium chips in the activation process, and after about 1 hour of activation, consuming a large amount of magnesium chips to prove that the preparation of the Grignard reagent is finished. The ratio of the amount of the substances of 1-bromo-cis-13-docosene, magnesium chips and iodine in the reactants:
n (1-bromo-cis-13-docosene), n (magnesium turnings), n (elemental iodine) = 1;
(5) Synthesizing 1-hydroxy-cis-15-tetracosene: cuprous iodide, ethylene oxide and anhydrous tetrahydrofuran are added into the reaction system and stirred evenly at the temperature of minus 40 ℃. Slowly dripping the Grignard reagent prepared in the previous step into the reaction system, stirring for 1h at-40 ℃, then heating the reaction system to room temperature, and continuing stirring for 3h. The progress of the reaction was checked by TLC. After the reaction is completed, adding saturated ammonium chloride solution into the system, quenching, extracting and distilling under reduced pressure. The mass ratio of grignard reagent, cuprous iodide and ethylene oxide in the reactants:
n (grignard reagent), n (cuprous iodide), n (ethylene oxide) = 1.5;
(6) Synthesis of nervonic acid: dissolving 1-hydroxy-cis-15-tetracosene and iodobenzene acetate in acetonitrile: water =1:1 in the system of (1). The system was stirred evenly for 3min and a catalytic amount of TEMPO was added to the reaction system. The reaction was carried out at room temperature for 7h. The progress of the reaction was checked by TLC. After the reaction is completed, adding water into the system, extracting, and distilling under reduced pressure. The mass ratio of 1-hydroxy-cis-15-tetracosene, iodobenzene acetate and TEMPO in the reactants is as follows:
n (1-hydroxy-cis-15-tetracosene): n (iodobenzene acetate) = n (TEMPO) = 1;
the nervonic acid synthesized by the method reacts with methanol under the catalysis of concentrated sulfuric acid to prepare the nervonic acid methyl ester, and the comparison similarity with data in a database is more than 95 percent through GC-MS detection.
In the invention, lithium bromide monohydrate (LiBr. H) is used in the halogenation reaction of alcohol 2 O) as halogen source, avoiding the use of chlorine and brominePhosphides (e.g. PCl) 3 ，PBr 3 ) Side reactions are brought about. Because the reaction is too vigorous when using phosphides of chlorine and bromine, it may lead to a change in the cis-trans structure of the double bond. Secondly, the phosphorus compounds of chlorine and bromine contain a large amount of phosphorus, and the use of a large amount of phosphorus inevitably causes phosphorus pollution and influences the environment; in the subsequent recarburization reaction, diethyl malonate is traditionally used for recarburization, and although the reaction is relatively efficient, the atom utilization rate is very low. The invention adopts Grignard reagent and ethylene oxide to carry out cycloaddition, so that the atom utilization rate is greatly increased; oxidation of 1-hydroxy-cis-15-tetracosene to nervonic acid, usually with chromium trioxide or its pyridine salt (CrO) 3 PDC), a large amount of waste water containing chromium ions is necessarily produced by such a method, which affects the environment. The method adopts a TEMPO and iodobenzene acetate oxidation mode, firstly, the condition is mild, a large amount of byproducts are not generated in the system, and secondly, the use of a chromium-containing oxidant is avoided, and the environmental pollution is avoided.
The present invention is further described below by way of examples, but the present invention is not limited to the examples, and the present invention should be construed as being within the scope of the present invention as long as the spirit of the present invention is not deviated.
The first embodiment is as follows:
synthesis of erucic alcohol:
erucic acid (0.3 mol) is used as a raw material, absolute ethyl alcohol is used as a solvent, a catalytic amount of concentrated sulfuric acid is added, the reaction is carried out under the condition of reflux, the TLC detects the reaction progress, saturated sodium bicarbonate solution is added after the reaction is finished to remove the concentrated sulfuric acid, the extraction is carried out, and the reduced pressure distillation is carried out.
Using ethyl erucate (0.3 mol) as raw material, anhydrous tetrahydrofuran as solvent, lithium aluminium hydride (LiAlH) 4 0.9 mol) as a reducing agent, stirring at room temperature overnight under the protection of argon, detecting the reaction progress by TLC, quenching excessive lithium aluminum hydride by ethyl acetate after the reaction is completed, adding a proper amount of water, extracting by ethyl acetate, and drying. The yield thereof was found to be 93%.
The prior art is generally directed to sodium borohydride reduction catalyzed by aluminum trichloride. The scheme yields were not as high as the scheme, and the ethyl erucate of the scheme was commercially available, rather than homemade, resulting in increased costs.
Synthesis of 1-bromo-cis-13-docosene:
erucamol (0.3 mol), 4-dimethylaminopyridine (DMAP 0.03 mol) and triethylamine (Et) 3 N0.6 mol) was dissolved in methylene chloride, and methanesulfonyl chloride (0.36 mol) was dissolved in methylene chloride and slowly added to the system at 0 ℃. After the addition was complete, the mixture was stirred at room temperature overnight. After the reaction was completed, water was added, extracted with dichloromethane, and dried, and further purification was not required, yielding 93%. Adding anhydrous acetonitrile into the crude product obtained by the reaction as a solvent, and reacting the crude product with lithium bromide monohydrate (LiBr. H) 2 O0.75 mol) and heating the mixture at 60 ℃. After the reaction is completed, adding water into the system, extracting by ethyl acetate and drying. The yield thereof was found to be 90%. The synthetic route is as follows:
Figure GDA0003815867060000061
the prior art is halogenation by phosphorus halides. This solution has a large impact on the environment. The proposal adopts the lithium bromide monohydrate, which is an inorganic salt, as the halogenating reagent, thereby reducing the pollution to the environment caused by the use of the halogenating reagent.
Synthesizing 1-hydroxy-cis-15-tetracosene:
adding activated magnesium chips (Mg 1.5 mol) into a reaction system, and adding a catalytic amount of iodine simple substance (I) 2 0.05 mol), a small amount of 1-bromo-cis-13-docosacene is added to carry out reaction initiation under mild heating conditions. After the initiation is finished, slowly dripping 1-bromo-cis-13-docosacene (0.5 mol) into a reaction system, ensuring that the system is in a micro-reflux state in the dripping process, and after the dripping is finished, putting the system into a heating device for activation. And (3) detecting the consumption condition of the magnesium chips in the activation process, and after 1h of activation, consuming a large amount of magnesium chips to prove that the preparation of the Grignard reagent is finished. A round-bottomed flask was prepared, and copper iodide (CuI 0.75 mol), ethylene oxide (0.75 mol) and anhydrous tetrahydrofuran were added thereto and stirred uniformly at-40 ℃ under an argon atmosphere. Mixing the newly prepared GrignardThe reagent was slowly added dropwise to the reaction system, stirred at-40 ℃ for 1h, then the reaction system was warmed to room temperature and stirred for 3h. After the reaction is completed, adding saturated ammonium chloride solution into the system, quenching, extracting by ethyl acetate, distilling under reduced pressure and drying. The yield thereof was found to be 60%. The synthetic route is as follows:
Figure GDA0003815867060000062
the prior art is a synthesis reaction using diethyl malonate as a raw material. The biggest problem with this approach is that the atom utilization is too low. The scheme adopts the scheme of cycloaddition of ethylene oxide, and the atom utilization rate is greatly increased.
Synthesis of nervonic acid:
1-hydroxy-cis-15-tetracosene (0.5 mol) and iodobenzene acetate [ PhI (OAc) 2 1.1mol]Dissolving in acetonitrile: water =1:1 in the system of (1). The system was stirred uniformly for 3min, and a catalytic amount of TEMPO (0.1 mol) was added to the reaction system. The reaction was carried out at room temperature for 7h. After the reaction is completed, adding water and ethyl acetate into the system, extracting, drying and distilling under reduced pressure. The crude product obtained is dissolved in acetone and recrystallized at-20 ℃. The yield thereof was found to be 70%.
The prior art is a series of oxidation reactions of chromium-containing oxidizers based on PCC. PCC and some chromium-containing oxidizers are well-defined carcinogens, and have a significant impact on the environment and on the body. The scheme adopts iodobenzene acetate and TEMPO oxidation reaction to skillfully avoid the use of a chromium-containing oxidant.
Nervonic acid: melting point of 40.5-42.1 deg.C, molecular weight of 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-) (FIG. 1).
GC-MS analysis of the methyl nervonate: the nervonic acid obtained above is added with a catalytic amount of concentrated sulfuric acid, and the mixture is stirred overnight at 50 ℃ in methanol as a solution. Extracting with ethyl acetate, drying, and distilling under reduced pressure to obtain methyl nervonate. And (3) detecting gas quality (GC-MS) of the methyl nervonate (figure 2 is a gas chromatogram, figure 3 is a mass spectrum), comparing the obtained data with standards in a database, and ensuring that the similarity is more than 95%. The content was >95.0% (GC).
The preferred embodiments of the present disclosure are described in detail with reference to the accompanying drawings, however, the present disclosure is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present disclosure within the technical idea of the present disclosure, and these simple modifications all belong to the protection scope of the present disclosure.
It should be noted that, in the foregoing embodiments, various features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, various combinations that are possible in the present disclosure are not described again.
In addition, any combination of various embodiments of the present disclosure may be made, and the same should be considered as the disclosure of the present disclosure, as long as it does not depart from the spirit of 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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