CN113582840A

CN113582840A - Preparation method of inositol fatty acid ester

Info

Publication number: CN113582840A
Application number: CN202110969566.5A
Authority: CN
Inventors: 梁少华; 康宝; 孙聪; 王树堃; 孟鹏程; 杨瑞楠; 明朝利; 郭志华; 杨硕; 陈阳
Original assignee: Henan Qiyi Grain And Oil Engineering Technology Co ltd; Henan University of Technology
Current assignee: Henan Qiyi Grain And Oil Engineering Technology Co ltd; Henan University of Technology
Priority date: 2021-08-23
Filing date: 2021-08-23
Publication date: 2021-11-02

Abstract

The embodiment of the invention provides a preparation method of inositol fatty acid ester, which relates to the technical field of chemical synthesis and is characterized in that inositol and fatty acyl chloride are mixed and heated to 150-180 ℃ for reaction under the condition of stirring in the environment of more than 0.09MPa of vacuum degree. The method is simple and convenient to operate, does not need a catalyst, can improve the reaction efficiency, can effectively avoid side reaction, and is particularly suitable for industrial large-scale production.

Description

Preparation method of inositol fatty acid ester

Technical Field

The invention relates to the technical field of chemical synthesis, and particularly relates to a preparation method of inositol fatty acid ester.

Background

Inositol is also known as inositol, hexahydroxycyclohexane, cyclitol, carninosite, and inositol, and belongs to B vitamins. Inositol has 9 isomers in total due to the different orientation of the hydroxyl groups relative to the plane of the ring. Inositol is an essential nutrient for the growth and survival of human cells, can form inositol phosphate, plays a role similar to choline, promotes the metabolism of fat in the liver, has the function of reducing blood fat, and participates in life activities such as signal transmission, nutrient storage and the like in the growth and development process of plants. Inositol exists mainly in the form of phosphatidylinositol in animal bodies and is intensively distributed in tissues such as brain pith, cardiac muscle, skeletal muscle and the like; the plant exists mainly in the form of inositol phosphate (phytic acid), and can be complexed with calcium, zinc, iron and the like to form insoluble compounds, so that the digestion and absorption of organisms on the insoluble compounds are interfered. In the absence of inositol in the animal diet, hair loss occurs, affecting development. Despite the huge inositol reserve in China, the related deeply processed products are deficient and the resource utilization rate is limited. Although inositol has good use value, the application of inositol is limited to a certain extent because the inositol has good water solubility and poor fat solubility. Therefore, the inositol is modified to improve the stability and fat solubility, and has important significance for expanding the application of the inositol in the fields of medicines, cosmetics, foods and the like.

At present, the synthesis method of inositol derivatives comprises a chemical method and an enzymatic method, although the enzymatic catalytic synthesis is a current green method, in the synthesis research of the inositol derivatives, most of products synthesized by the enzymatic method are products with better water solubility, and most of acyl donors are simple acids, the research of enzymatic synthesis of inositol fatty acid ester is reported rarely, and the price of the enzyme is high, so that the industrial production is difficult to realize. The conventional method also has the problems of difficult purification, separation and purification, difficult solvent recovery, residue and the like. In view of this, there is a lack in the art of a simple and efficient method for the synthesis of inositol fatty acid esters.

Disclosure of Invention

The invention aims to provide a preparation method of inositol fatty acid ester, which is simple and convenient to operate, has few side reactions and can synthesize the inositol fatty acid ester rapidly and efficiently without the participation of a catalyst.

The embodiment of the invention is realized by the following steps:

a method for preparing an inositol fatty acid ester, comprising:

inositol and fatty acyl chloride are mixed and heated to 150-180 ℃ for reaction under the vacuum degree of more than 0.09 MPa.

The embodiment of the invention has the beneficial effects that:

the embodiment of the invention provides a preparation method of inositol fatty acid ester, which comprises the steps of mixing inositol and fatty acyl chloride, and heating to 150-180 ℃ for reaction in an environment with a vacuum degree of more than 0.09 MPa. The method is simple and convenient to operate, does not need a catalyst, can improve the reaction efficiency, can effectively avoid side reaction, and is particularly suitable for industrial large-scale production.

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.

The following is a detailed description of a method for producing an inositol fatty acid ester according to an embodiment of the present invention.

A method for preparing an inositol fatty acid ester, comprising:

Inositol is solid at normal temperature, has a melting point as high as 224-227 ℃, is easily soluble in water, and has poor solubility in an organic solvent. In contrast, fatty acid chlorides are mostly liquids at room temperature, and are poorly soluble in water, but readily soluble in a variety of organic solvents due to their long fatty chains, which lead to poor hydrophilicity. Due to the great property difference between the two, the existing conventional solvent combination is difficult to dissolve the two simultaneously, and the few solvent systems (DMF, DMSO) capable of achieving simultaneous dissolution have the problem of difficult separation, so the reaction processes of the two in the prior art can only be heterogeneous reaction usually.

In heterogeneous reactions, the contact between the two starting molecules is limited, and if a phase transfer catalyst is not used, the reaction proceeds very slowly and little to no product is obtained. If a phase transfer catalyst is used, the problems of high production cost and difficult separation and purification of the product are faced. Therefore, the prior art lacks a simple and efficient method for preparing inositol fatty acid ester.

In view of the above, after a great number of attempts, the inventors found that inositol and fatty acid chloride are directly mixed in a solvent-free environment, and the inositol and fatty acid chloride are reacted at a high temperature of 150 to 180 ℃ under stirring conditions to increase molecular motion, so that the contact opportunity between inositol molecules and fatty acid chloride molecules can be significantly increased, and the conversion rate of the reaction can be increased. However, the reaction carried out by this method has a new problem that under such high-temperature and high-concentration reaction conditions, a small amount of hydroxyl groups in the inositol molecule are oxidized to form carbonyl groups or even broken bonds to form open-chain carboxylic acids, and the oxidized inositol may react with unoxidized inositol, although this side oxidation reaction is not serious, and is almost negligible for small-scale laboratory preparations. However, once scaled up to commercial scale gram scale reactions, the effect of the by-products becomes quite significant. On the one hand, side reactions cause loss of starting materials, resulting in a reduction in yield. In another invention, the by-products are mixed with the product, which causes difficulty in separation and purification and affects the purity of the product. In order to solve such a problem, the inventors have made extensive attempts and found that a desired effect can be achieved by lowering the reaction pressure. When the vacuum degree of the reaction reaches more than 0.09MPa, the side reaction can be better inhibited, and the inhibiting effect is correspondingly improved along with the improvement of the vacuum degree. Therefore, a degree of vacuum of 0.09MPa or more is a preferable reaction condition.

Further, the fatty acyl chloride is obtained by fatty acid acylation with a carbon chain length of 8-18. For example, fatty acids are acylated by reaction with phosphorus trichloride. Alternatively, the fatty acid includes any one of lauric acid, oleic acid and linoleic acid. Fatty acids with long fatty chains all exhibit strong hydrophobicity, so that heterogeneous reactions occur when reacting with inositol.

Alternatively, the molar ratio of inositol to fatty acid chloride is 1: 3 to 15. Preferably, the molar ratio of inositol to fatty acid chloride is 1: 6-9. The inventors have found, after extensive attempts, that the reaction between inositol and fatty acid chloride does not occur in which the polyhydroxy group is acylated because of the increase in fatty acid chloride. Whatever the amount of fatty acid chloride used, it is possible to obtain, for reasons of steric hindrance, a monoester product. In such a case, the inventors have made it possible to enhance the reaction efficiency and ensure complete reaction of inositol by increasing the amount of fatty acid chloride used to promote the reaction. On the other hand, the raw material variety in the crude product after reaction is reduced, and the post-treatment difficulty is reduced.

Optionally, the reaction time of the inositol and the fatty acyl chloride is 10-60 min, and preferably 40-60 min. Within the above time frame, complete conversion of inositol can be substantially ensured. In practice, the reaction is terminated when the inositol reaction is complete, as monitored by TLC.

Further, the preparation method of inositol fatty acid ester provided by the embodiment of the present invention further comprises:

after the reaction is finished, adding an organic solvent and water into the reaction solution for bidirectional extraction; separating an organic phase after extraction, and desolventizing the organic phase to obtain a crude product; and carrying out column chromatography on the crude product to obtain the inositol fatty acid ester. Wherein the organic solvent comprises at least one of chloroform, dichloromethane, ethyl acetate, and diethyl ether. The volume ratio of water to organic solvent is 1:1 to 3. Under the extraction conditions, impurities can be effectively removed, and inositol fatty acid ester can fully enter an organic phase, so that the yield of the product is improved. Optionally, the column chromatography adopts a 100-200 mesh silica gel column, and the elution machine adopts a mixed system of normal hexane and diethyl ether, wherein the volume fraction of the diethyl ether is 2-10%.

the reaction solution is distilled under reduced pressure, redundant fatty acid is recovered, and then organic solvent and water are added into the reaction solution for bidirectional extraction.

In the case of adopting excessive fatty acid chloride for reaction, the excessive fatty acid chloride can be recovered by reduced pressure distillation, so that the waste of raw materials can be reduced on the one hand, and the separation difficulty of the subsequent column chromatography link can be reduced on the other hand.

Further, in the extraction process, the pH of the mixed solution is adjusted to 8-10, and then the organic phase is separated. The mixed liquid is adjusted to be alkaline, so that excessive fatty acid chloride can be converted into fatty acid salt, and the fatty acid salt enters a water phase to be primarily separated from inositol fatty acid ester, thereby reducing the separation difficulty of subsequent column chromatography. It is worth mentioning that in case of a large excess of fatty acid chloride, if the pH is directly adjusted, severe emulsification will occur, and the efficiency and effect of liquid separation will be reduced. Only after the most fatty acid chlorides were distilled off under reduced pressure, the remaining fatty acid chlorides were removed by pH adjustment.

The features and properties of the present invention are described in further detail below with reference to examples. Since the difference in polarity between the product and its oxidized product is small and the product is difficult to separate by column chromatography after mixing with the oxidized product, the yield in examples and comparative examples is actually the yield of the product and the oxidized product mixed, and the actual content of the product can be obtained by multiplying the yield by the purity. In addition, the purity of the products in the examples and the comparative examples is determined by randomly selecting a part of the products, performing secondary separation by HPLC (which is not suitable for HPLC as a whole due to large amount of the products), and determining the purity according to the ratio of the mass of the products after separation to the mass of the products before separation.

Example 1

This example provides a method for preparing an inositol fatty acid ester, comprising the steps of:

s1, inositol (0.36 g, 2 mmol) and oleoyl chloride (1.81 g, 6 mmol) are mixed and heated to 150 ℃ for 20 min under a vacuum degree of 0.09 MPa.

S2, after the reaction is finished, adding 5ml of water and 10ml of chloroform into the reaction solution for bidirectional extraction; and separating an organic phase after extraction, and desolventizing the organic phase to obtain a crude product.

S3, performing column chromatography on the crude product by using a 100-200-mesh silica gel column, and selecting 95:5 n-hexane-ether as an eluent to obtain the inositol oleate (0.765 g, yield 86.0% and purity 94.1%).

The product of inositol oleate is characterized as follows:

HPLC-MS characterization: m/z 444.4 ([ M-H)]^-Inositol laurate, theoretical calculated mass 444.6).

Example 2

s1, inositol (3.6 g, 20 mmol) and oleoyl chloride (18.1 g, 60 mmol) are mixed and heated to 150 ℃ for reaction for 60 min under the vacuum degree of 0.095 MPa.

S2, after the reaction is finished, adding 50ml of water and 100ml of chloroform into the reaction solution for bidirectional extraction; and separating an organic phase after extraction, and desolventizing the organic phase to obtain a crude product.

S3, performing column chromatography on the crude product by adopting a 100-200-mesh silica gel column, wherein the column chromatography is performed by adopting a method comprising the following steps of: 5 n-hexane-ether as an eluent, inositol oleate (7.21 g, yield 81.1%, purity 93.8%) was obtained.

Example 3

s1, inositol (1.8 g, 10 mmol) and linoleoyl chloride (29.9 g, 100 mmol) are mixed and heated to 180 ℃ under a vacuum of 0.095 MPa for 30 min.

S2, after the reaction is finished, adding 100ml of water and 300ml of dichloromethane into the reaction solution for bidirectional extraction; and separating an organic phase after extraction, and desolventizing the organic phase to obtain a crude product.

S3, performing column chromatography on the crude product by adopting a 100-200-mesh silica gel column, wherein the column chromatography is performed by adopting a method comprising the following steps of: 10 n-hexane-ether as an eluent, inositol linoleate (3.94 g, yield 89.0%, purity 92.6%) was obtained.

The product of inositol linoleate was characterized as follows:

HPLC-MS characterization: m/z 442.4 ([ M-H ]]^-Inositol laurate, 442.6 on theoretical calculated mass).

Example 4

s1, inositol (1.8 g, 10 mmol) and lauroyl chloride (10.9 g, 50 mmol) are mixed, and the mixture is heated to 150 ℃ for reaction for 20 min under the vacuum degree of 0.098 MPa.

S2, after the reaction is finished, adding 100ml of water and 100ml of ethyl acetate into the reaction solution for bidirectional extraction; and separating an organic phase after extraction, and desolventizing the organic phase to obtain a crude product.

S3, performing column chromatography on the crude product by adopting a 100-200-mesh silica gel column, wherein the column chromatography is performed by adopting a method comprising the following steps of: 5 n-hexane-ether as eluent, inositol laurate (3.04 g, yield 83.9%, purity 93.3%) was obtained.

The inositol laurate product is characterized as follows:

and (3) infrared spectrum characterization: IR (KBr) v_max（cm^-1): 2917, 2859, 1758, 1234 and 1030, 1158 and 1119, 720-660;

HPLC-MS characterization: m/z 363.2 ([ M-H)]^-Inositol laurate, 363.4 on a theoretical calculated mass basis).

Comparative example 1

This comparative example provides a process for the preparation of an inositol fatty acid ester, which is essentially the same as the procedure of example 1, except that it is carried out under normal pressure. This reaction yielded inositol oleate (0.772 g, 86.8% yield, 89.3% purity).

Comparative example 2

This comparative example provides a process for the preparation of an inositol fatty acid ester, which is essentially the same as the procedure of example 2, except that it is carried out under normal pressure. This reaction yielded inositol oleate (7.03 g, 79.1% yield, 84.6% purity).

Comparative example 3

This comparative example provides a process for the preparation of an inositol fatty acid ester, which is essentially the same as the procedure of example 3, except that it is carried out under normal pressure. This reaction yielded inositol linoleate (3.78 g, 85.4% yield, 82.5% purity).

Comparative example 4

This comparative example provides a process for the preparation of an inositol fatty acid ester, which is essentially the same as the procedure of example 4, except that it is carried out under normal pressure. This reaction yielded inositol laurate (2.84 g, 78.3% yield, 79.4% purity).

It can be seen from the comparison of examples 1 to 4 with comparative examples 1 to 4 that inositol undergoes oxidation to different degrees during the preparation of inositol fatty acid esters when an atmospheric reaction is used, and that such oxidation is not significant in the case of a small amount of reaction (example 1 vs comparative example 1), but is significant in the case of a large amount of reaction. The oxidation product may exist in various forms, resulting in a reduction in the purity of the product and also causing difficulties in isolation and purification. This multi-product mix is fashionable in small production and can be separated by HPLC, but this separation is obviously not suitable for large-scale industrial production. On the contrary, the embodiment of the invention can effectively inhibit the oxidation of fatty acyl chloride by a reaction mode under a reduced pressure condition, so that the inositol fatty acid ester product with high purity can be obtained, and the method is more suitable for large-scale industrial application.

Comparative examples 5 to 9.

Comparative examples 5 to 9 each provide a method for producing an inositol fatty acid ester, which is substantially the same as the operation method of example 4, and the reaction conditions and results are shown in the following table, and the reaction results were obtained by sampling and HNMR detection.

As can be seen from the above table, in comparative example 1, when the reaction is carried out according to the raw material ratio of 1:1, the reaction efficiency is very low, and the conversion rate reaches only 37% after 1 hour of reaction. In comparative example 2, the reaction was carried out at room temperature, and after 1 hour of reaction, no product could be seen by HNMR examination. In comparative examples 7-9, solvents are respectively screened, and a small amount of products can be obtained in chloroform, but the conversion rate is not more than 3%, products cannot be seen in acetone or ethyl acetate, on one hand, the boiling point of the solvent limits the reaction temperature, and on the other hand, the dilution of the solvent is equal to the reduction of the concentration of the raw materials, which is not beneficial to the reaction.

In summary, the embodiments of the present invention provide a method for preparing inositol fatty acid ester, which includes mixing inositol and fatty acyl chloride, and heating to 150-180 ℃ for reaction in an environment with a vacuum degree of 0.09MPa or more. The method is simple and convenient to operate, does not need a catalyst, can improve the reaction efficiency, can effectively avoid side reaction, and is particularly suitable for industrial large-scale production.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for producing an inositol fatty acid ester, comprising:

2. The method according to claim 1, wherein the fatty acid chloride is obtained by acylation of a fatty acid having a carbon chain length of 8 to 18.

3. The production method according to claim 2, wherein the fatty acid includes any one of lauric acid, oleic acid, and linoleic acid.

4. The method according to claim 3, wherein the molar ratio of the inositol and the fatty acid chloride is 1: 3 to 15.

5. The method according to claim 3, wherein the reaction time of the inositol and the fatty acid chloride is 10 to 60 min.

6. The method of claim 1, further comprising:

after the reaction is finished, adding an organic solvent and water into the reaction solution for bidirectional extraction; separating an organic phase after extraction, and desolventizing the organic phase to obtain a crude product;

and carrying out column chromatography on the crude product to obtain the inositol fatty acid ester.

7. The method according to claim 6, wherein the organic solvent comprises at least one of chloroform, dichloromethane, ethyl acetate, and diethyl ether.

8. The method according to claim 6, wherein the volume ratio of the water to the organic solvent is 1:1 to 3.

9. The method of claim 6, further comprising:

and (3) distilling the reaction solution under reduced pressure, recovering redundant fatty acid, and then adding an organic solvent and water into the reaction solution for bidirectional extraction.

10. The method according to claim 7, wherein the pH of the mixed solution is adjusted to 8 to 10 during the extraction, and the organic phase is separated.