JP2960918B2 - Method and apparatus for purifying lower alcohol esters of high purity highly unsaturated fatty acids - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method and an apparatus for purifying a lower-purity alcohol ester of a high-purity polyunsaturated fatty acid which is useful in the fields of pharmaceuticals, foods or feeds. The present invention relates to a method and a device for purifying a lower alcohol ester of a high-purity highly unsaturated fatty acid suitable for purifying a lower alcohol ester of an acid.

[0002]

2. Description of the Related Art Polyunsaturated fatty acids such as eicosapentaenoic acid and docosahexaenoic acid are contained in fish, algae, microorganisms, and the like. It is also noted for its physiological activity, and is used for pharmaceuticals, foods for specified health uses, general foods, livestock and marine feeds, and its market is expanding.

[0003] In the pharmaceutical field, ethyl ester of eicosapentaenoic acid (hereinafter abbreviated as EPA) is already commercially available as a blood-inhibiting agent, a hyperlipidemic solvent and an anti-inflammatory agent. Has a physiological activity such as an anticancer effect.

Further, docosahexaenoic acid (hereinafter referred to as DHA)
It is said that the triglyceride or phospholipid body has a drug effect such as a cerebral circulation improving agent, a blood coagulation inhibitor and the like. It has been suggested that there is a possibility of having a biological activity of an agent, an anti-obesity agent and the like, and therefore, an increase in demand for these highly pure polyunsaturated fatty acids is expected in the future.

A method for separating and purifying a high-purity EPA or DHA lower alcohol ester by distillation and purification using a mixture of a lower alcohol ester of a fatty acid containing EPA or DHA as a raw material is described below. A production method in which each fraction is treated with urea (Japanese Patent Application Laid-Open No. 57-149400) or a production method in which an intermediate concentrate obtained by subjecting the raw material of the mixture to urea addition is adsorbed and then subjected to distillation treatment (Japanese Patent Application Laid-Open No. Sho 57-149400). 57-1877397), a production method in which a fraction obtained by continuous distillation using a plurality of distillation columns is subjected to urea addition treatment and then adsorption treatment (JP-A-58-8037).
JP-A-59-118740), a mixture of fatty acid esters obtained by alcoholysis is subjected to urea addition treatment, vacuum distillation treatment, and separation with two kinds of solvents.
Japanese Patent Application Laid-Open No. 4-41457), a production method in which a urea addition treatment is performed, and then a vacuum distillation treatment is performed (JP-A-1-48898). Japanese Patent Application Laid-Open No. H8-100191) and a production method in which high vacuum distillation treatment is performed after urea addition treatment has been developed.

However, all of these methods are EPA
Alternatively, since there are problems with the DHA content purity, quality stability, yield, versatility of equipment used, etc., high-purity EP
It is not easy to produce A or DHA industrially on a commercial basis.

As for other separation and purification methods capable of purifying high-purity EPA or DHA, a production method in which silver nitrate treatment is performed (Japanese Patent Laid-Open No. 4-159398, etc.) or a production method in which supercritical processing is performed (Japanese Patent Laid-Open Publication No. And the like, but all of these methods are described in EP.
It is not easy to industrially produce high-purity EPA or DHA on a commercial basis due to problems such as the purity of A or DHA, the quality, the yield, and the versatility of equipment used.

[0008]

On the other hand, high-purity EPA
Alternatively, as a separation and purification method that can industrially purify DHA,
Production method in which three or more continuous distillation treatments in which the first fractionation rectification column is independent (Japanese Patent Laid-Open No. 4-128250, Japanese Patent Laid-Open No.
-247487, JP-A-5-222392) have been developed.

However, in each of the above methods, (1) since continuous distillation is carried out for a long time in a high-temperature distillation column, a high rate of heat-denaturation of EPA or DHA which is unstable to heat into foreign substances in the distillation process is high ( 2) Because of the special device specifications, the operation is complicated, the versatility is low, and the cost of the device is high.

[0010] Accordingly, the present invention provides a lower alcohol ester of a highly pure polyunsaturated fatty acid which can be produced industrially and at low cost without heat denaturing a lower alcohol ester of high purity EPA or DHA. It is an object of the present invention to provide a purification method and a purification apparatus.

[0011]

In order to achieve the above object, the invention of claim 1 is directed to a lower alcohol of unsaturated fatty acid.
Low purity eicosapentaenoic acid from ester mixtures
Purified Highly Unsaturated Fat for Purifying Higher Alcohol Esters
In a lower alcohol ester purification process of acid, the unsaturated
3 × 10 lower alcohol ester mixture of saturated fatty acids
^-3 Torr or lower column pressure and 80-85 ° C distillation temperature
Of eicosapentaenoic acid by molecular distillation
A step of pre-extraction the grade alcohol ester component, the
Lower alcohols of extracted eicosapentaenoic acid
The tellur component is supplied at a pressure in the column of 5 × 10 ⁻² Torr or less and
Vacuum distillation at a distillation temperature of 5 ° C or less
Extract the lower alcohol ester concentrate of sapentaenoic acid
And the step of discharging the extracted eicosapentaenoic acid.
Using lower-phase partitioning fillers for lower alcohol esters
High-performance liquid chromatography for high purity eicosape
For fractionating and purifying lower alcohol esters of antaenoic acid
Has a degree, and in the molecular distillation step, a residue
To lower alcohol esters of eicosapentaenoic acid
Extraction of condensed components and lower fraction of docosahexaenoic acid as fraction
Low eicosapentaenoic acid for alcohol esters
Extracting the component with higher grade alcohol ester component ratio, the upper
In the vacuum distillation step, the molecular distillation step
The extracted residual component and distillate component are respectively charged.
Characterized in that that.

Further, the invention of claim 2 is the invention of claim 1, wherein the vacuum distillation step is performed in the molecular distillation step.
And the extracted residual component or distillate component
Of eicosapentaenoic acid from the top of the first distillation column.
First vacuum from which condensed components of secondary alcohol ester are extracted
A distillation step and the rays extracted in the first vacuum distillation step.
Condensed component of lower alcohol ester of osapentaenoic acid
Eicosapentae from the bottom of the second distillation column
The lower alcohol ester concentrate of the acid is extracted
2 vacuum distillation steps .

[0013] The invention of claim 3 is the invention of claims 1 to
In the invention of Item 2, the fractionation and purification step is carried out by the reverse phase separation.
Stationary phase for high-performance liquid chromatography
Using octadecylated silica gel as the mobile phase
The use call, ketones, water or a mixture thereof
It is characterized by.

[0014] The invention of claim 4 is the invention of claims 1 to
In the invention of Item 2, the fractionation and purification step is carried out by the reverse phase separation.
Stationary phase for high-performance liquid chromatography
Characterized by using a filler loaded with silver nitrate
You.

[0015] Further, the invention according to claim 5 is characterized in that unsaturated fatty acids are reduced.
High purity eicosapen from grade alcohol ester mixture
High purity and high purity to purify lower alcohol ester of taenoic acid
Equipment for lower alcohol esters of highly unsaturated fatty acids
There are, lower alcohol ester mixture of the unsaturated fatty acids
Pressure in the tower of 3 × 10 ⁻³ Torr or less and 80 to 8
Lower alcohol of eicosapentaenoic acid at a distillation temperature of 5 ° C
A molecular distillation apparatus to pre-extract the glycol ester component, the extract
Eicosapentaenoic acid lower alcohol esthetics
Pressure in the column of 5 × 10 ^-2 Torr or less and 19
Lower eicosapentaenoic acid at a distillation temperature of 5 ° C or lower
Two-equipped vacuum distillation system for extracting concentrated components of coal ester
And the lower eicosapentaenoic acid extracted above.
Low grade of high purity eicosapentaenoic acid from coal ester
Packing material for reversed-phase distribution system for fractionating and purifying alcohol esters.
Purification by high performance liquid chromatography
A device and, a, the molecular distillation apparatus, e as residue
Concentrate of lower alcohol ester of icosapentaenoic acid
Extracting means for extracting docosahexa as a fraction
Eicosapen for lower alcohol esters of enic acid
An ingredient with a higher ratio of lower alcohol esters of taenoic acid
And a second extracting means for extracting, the vacuum distillation instrumentation
Is the residual content extracted by the first and second extraction means.
Component or distillate component is charged and from the top
Condensation of lower alcohol esters of eicosapentaenoic acid
A first distillation column min are extracted, extracted in the first distillation column
Eicosapentaenoic acid lower alcohol esthetics
Eriched fraction is charged and eicosapentae
The lower alcohol ester concentrate of the acid is extracted
And a second distillation column .

[0016]

[0017]

[0018]

[0019]

The EPA or DHA-containing natural fats and oils used in the present invention contain EPA or DHA in the constituent fatty acids.
There is no particular limitation as long as it contains, but generally it can be obtained from marine oils and fats, microbial lipids, etc.
Marine oils and fats are excellent in terms of quantity, more preferably sardine oil, tuna oil, bonito oil, squid liver oil and the like.

The lower alcohol ester of the fatty acid mixture obtained from the EPA or DHA-containing natural fats and oils used in the present invention is subjected to a transesterification treatment of the EPA or DHA-containing natural fats and oils with the lower alcohol by a conventional method. It can be obtained by

Here, the lower alcohol ester of a fatty acid mixture obtained from a natural oil or fat containing EPA or DHA refers to an ester derived from a lower alcohol having 4 or less carbon atoms, and the lower alcohol used for the esterification is methanol. , Ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, isobutanol and tert.-butanol.

Next, the configuration of the molecular distillation apparatus used in the present invention will be described with reference to FIG.

In the following description, the case where EPA is extracted is mainly described for convenience of explanation.

The molecular distillation apparatus 10 is a falling-film type molecular distillation apparatus, which is constituted mainly of a substantially cylindrical distillation tower 11. The distillation tower 11 has a cylindrical distillation tower main body 12 and a distillation tower main body 1.
2 has a wire brush 9 rotated by a motor (not shown) on the inner surface 12 a, and a columnar cooling tower 13 provided in the center of the interior of the distillation column main body 12.

Here, the EPA-containing raw material supplied from the raw material tank 14 in which the EPA-containing raw material (sardine oil ethyl ester) is stored is preheated by the preheater 15 and distilled from the top 16 of the cylindrical distillation column main body 12. Tower body 12
On the inner surface 12a. Inner surface 12 of distillation column main body 12
The EPA-containing raw material guided on the surface of the distillation column 12 forms a thin film on the inner surface 12a of the distillation column main body 12 by rotation of the wire brush 9, and is heated and evaporated. The mixture of the above esters containing fatty acid esters) falls on the way without reaching the cooling tower 13, flows out from the lower tower bottom 17 a, and is stored in the residual tank 18.

A substance having a relatively small molecular weight (a mixture of non-EPA substances mainly containing fatty acid esters having less than 20 carbon atoms) in the EPA-containing raw material evaporates from the inner surface 12a of the distillation column main body 12. , Reaches the cooling tower 13, is cooled and condensed on the surface of the cooling tower 13,
3 falls downward along the surface of the base 3, flows out of the bottom part 17 b, and is stored in the fraction tank 19.

Reference numeral 20 denotes a vacuum system for keeping the inside of the distillation column main body 12 at a vacuum.

The above is the molecular distillation apparatus 1 used in the present invention.
0 is a schematic configuration.

The molecular distillation apparatus used in the present invention is:
Not only a falling film type but also a stationary type or a rotary centrifugal type can be used.

The operating conditions for molecular distillation are EP
From the viewpoint of preventing denaturation and deterioration of A or DHA, 1 × 1
0 ⁻² Torr or less, more preferably 3 × 10 ⁻³ Torr
It is desirable to set the following column pressure and a distillation temperature of 70 to 90 ° C, more preferably 80 to 85 ° C.

The feature of the molecular distillation used in the present invention is that the molecules evaporated from the liquid phase in the distillation column do not collide with each other and reach the condensing surface of the cooling tower 13 which is unilaterally opposed. This is distillation (see, for example, Ogata et al., Chemical Experiment Procedures, Nankodo, p. 452).

The advantages of using the molecular distillation are that the present distillation method can be operated under a high vacuum column pressure of 10 ⁻² Torr or less, and the processing time in the distillation column is short. Therefore, it is excellent in separation and purification of heat unstable substances such as EPA or DHA, and the present apparatus is easy to operate, has high versatility, and is advantageous in terms of equipment costs. Is mentioned.

When performing a molecular distillation treatment in the concentration of the polyunsaturated fatty acid, it is general that only the obtained residue is subjected to a purification treatment in the next step. Not used for concentration.

However, the present inventors have conducted intensive studies and found that
By subjecting the fraction having an increased EPA ratio to DHA obtained by the molecular distillation treatment to a post-purification treatment, high-purity EPA having the same quality as that of the conventional residue can be obtained. It has been found that lower alcohol esters can be produced.

Next, as the two-column vacuum distillation apparatus used in the present invention, a continuous vacuum distillation column of any type such as a tray type, a packed type, and a spring type is used, but more preferably. Less degradation of EPA or DHA due to heat,
It is desirable to use a vacuum distillation column of a filling type such as Sulzer packing, which can be easily industrialized.

FIG. 2 is a schematic structural view of a packed vacuum distillation apparatus used in the present invention.
Are the first vacuum distillation tower (first distillation tower) 31 and the second vacuum distillation tower
A tower (second distillation tower) 32 is provided.

Here, E introduced to the first distillation column 31
PA crude ethyl ester has 2 carbon atoms including EPA fraction.
A mixture of esters mainly containing 0 fatty acids is extracted from the top and led to the second vacuum distillation column 32, where the double distillation of the esters mainly containing fatty acids having 20 carbon atoms is performed. It is configured so that a fraction mainly containing EPA having five bonds is extracted from the bottom.

That is, the EPA crude purified ester (EPA crude purified ethyl ester) stored in the residual fraction tank 18 or the fraction fraction tank 19 of the molecular distillation apparatus 10 is preheated by the preheater 33 and the first vacuum distillation column. 31
At the top 34 of the vehicle. EPA led to the top 34
In the first vacuum distillation column 31, a mixture of esters mainly containing a fatty acid having 20 carbon atoms is extracted from the top portion 34 side and guided to the condensation system 35, and the crude purified ester is introduced into the condensing system 35.
The ester fraction mainly containing the above fatty acids is contained in the bottom portion 36.
It is led to. The ester fraction mainly containing fatty acids having 21 or more carbon atoms led to the bottom 36 is further reboiler 3
7. It is led to the bottom 36 via the pump 38 and has 2 carbon atoms.
The ester fraction mainly containing 0 fatty acids is led to the top portion 34 in high yield and further to the condensing system 35.

Then, the carbon number 20 introduced into the condensation system 35
Is mainly introduced into the second distillation column 32 from the middle portion 40 of the second distillation column 32, and 2% of the ester fraction mainly containing the fatty acid having 20 carbon atoms. A fraction mainly containing EPA having five heavy bonds is extracted from the bottom portion 41, and an ester fraction mainly containing a fatty acid having 20 carbon atoms other than EPA is collected from the top portion 43 through the condensing system 4
4 to the outside.

The ester fraction mainly containing a fatty acid having 20 carbon atoms, including the EPA fraction, extracted from the bottom 41, is heated by the reboiler 42, and is again pumped by the pump 45 to the bottom of the second distillation column 32. 41, the fraction mainly composed of EPA is re-extracted from the bottom 41, and E is extracted with high yield.
It is configured so that PA can be collected. And EPA
The other fractions are discharged from the top 43 to the outside via the condensation system 44. 47 and 48 are vacuum systems.

The operating conditions of the two-column vacuum distillation apparatus 30 are as follows:
10 ^-1 Torr or less, more preferably 5 × 10 ^-2 Torr
It is desirable that the pressure in the column is not more than r and the distillation temperature is not more than 200 ° C, more preferably not more than 195 ° C.

Here, the vacuum distillation is an equilibrium distillation in which a gaseous phase evaporated from a liquid phase causes gas-liquid contact in a distillation column, and after the gaseous phase and the liquid phase reach an equilibrium state, the phases are separated. (For example, Japan Society for Chemical Engineering; Chemical Engineering Handbook (Maruzen), p. 597)
(See 1978), as a system, a tray type and a packed type vacuum distillation.

Next, with reference to FIG. 3, the structure of a high-performance liquid chromatography apparatus having a reversed-phase partitioning system filler used in the present invention will be described. The high-performance liquid chromatography apparatus 50 is mainly composed of a column 51 filled with a stationary phase, and the EPA concentrated fraction extracted from the vacuum distillation apparatus 30 shown in FIG. With the mobile phase for use in the column 51,
It is separated into a high-purity EPA fraction and other fractions via the UV detector 54.

Octadecylated silica gel (ODS) can be used as a filler used in the present invention for high-performance liquid chromatography of a reversed-phase distribution system, and a mixture of lower alcohol esters of each fatty acid can be used as a mobile phase. By using a mobile phase sufficient for separation, preferably an alcohol, ketone, water, or the like, alone or as a mixture, it becomes possible to obtain a high-purity lower alcohol ester of EPA.

Alternatively, as a column filler used in the high performance liquid chromatography used in the present invention, a filler in which silver nitrate is held on a carrier can be used, and as a mobile phase, a mixture of lower alcohol esters of each fatty acid is used. Mobile phase, preferably acetonitrile, sufficient to separate
By using ethanol alone or a mixture thereof, it becomes possible to obtain a high-purity lower alcohol ester of EPA.

In the above description, the case where EPA is extracted from a mixture of lower alcohol esters of fatty acids has been described. However, DHA can be extracted using a substantially similar apparatus.

That is, first, a DHA crude product is extracted using the molecular distillation apparatus 10 shown in FIG.

Next, as in the case of extracting EPA, DH
A The crude product is led to a vacuum distillation apparatus (residue tank 18
Only the DHA crude product extracted in step (1) is introduced into a vacuum distillation apparatus). Since DHA has 22 carbon atoms and has the highest molecular weight in the lower alcohol ester of the raw material fatty acid, a two-column vacuum distillation as shown in FIG. In the first vacuum distillation column 61 using the apparatus 60, the number of carbon atoms containing DHA was 2 from the bottom 66.
An ester fraction mainly containing 0 or more fatty acids is extracted.

That is, the DHA crude purified ester (DHA crude purified ethyl ester) stored in the residue tank 18 of the molecular distillation apparatus 10 is preheated by the pre-heater 63 to the top 64 of the first vacuum distillation column 61. Be guided. In the first vacuum distillation column 61, the roughly purified ester of DHA led to the top 64 is extracted from the top 64 with an ester mixture mainly containing a fatty acid having less than 20 carbon atoms and guided to the condensation system 65. The ester fraction mainly containing fatty acids having 20 or more carbon atoms is led to the bottom 66. The ester fraction mainly containing fatty acids having 20 or more carbon atoms led to the bottom portion 66 is further led to the bottom portion 66 via the reboiler 67 and the pump 68, and the ester fraction mainly containing fatty acids having 20 or more carbon atoms. The fraction is configured to be led to the tower bottom 66 with high yield.

A mixture of esters mainly containing a fatty acid having less than 20 carbon atoms is extracted from the top portion 64 and discharged to the outside as a residue fraction 1 via the condensation system 65. Further, among the fatty acid-containing ester fractions guided to the tower bottom 66, the ester fraction mainly containing a fatty acid having less than 20 carbon atoms is discharged to the outside as the residue fraction 2.

The ester fraction mainly containing fatty acids having 20 or more carbon atoms led to the bottom portion 66 is subjected to vacuum distillation second column 62.
Is introduced into the second vacuum distillation tower 62 from the middle part 70 of
Among the ester fractions mainly containing fatty acids having 20 to 22 carbon atoms, a fraction mainly containing DHA is extracted from the bottom part 71, and the ester fraction mainly containing fatty acids having 20 to 22 carbon atoms other than DHA Is discharged from the top 73 as a residual fraction 3 to the outside via the condensing system 74.

The ester fraction mainly containing fatty acids having 20 or more carbon atoms, including the DHA fraction extracted from the bottom 71, is heated by the reboiler 72, and is again pumped by the pump 75 to the second vacuum distillation column 62. Guided to the bottom 71, DH
The A-enriched fraction is re-extracted from the bottom 71, and DH
It is configured so that a fraction mainly composed of A can be collected. In addition, 77 and 78 are vacuum systems.

Also, a high-performance liquid chromatography apparatus similar to the high-performance liquid chromatography apparatus 50 shown in FIG. 3 can be used.

[0055]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Embodiments of the present invention will be described below based on specific examples.

<Example 1>"Production of high-purity EPA ethyl ester by the residue of molecular distillation" 100 kg of sardine oil was heated and stirred at 80 ° C for 1 hour to remove water, and then 50 kg of ethanol was obtained. And 2 kg of sodium hydroxide were added and dissolved, and the mixture was heated and stirred at 80 ° C. for 1 hour to produce 95 kg of sardine oil ethyl ester containing EPA ethyl ester 18.1% and DHA ethyl ester 10.9%. .

95 kg of sardine oil ethyl ester obtained
Using a falling film molecular distillation apparatus to 3 × 10 ⁻³ To
rr column pressure, 80 ° C. distillation temperature, feed rate 2
By distilling under the operating conditions of 0 Kg / h and a cooling tower temperature of 5 ° C., 61.2 Kg of a residual ethyl ester containing 23.8% of EPA ethyl ester was obtained in a yield of 64.
40.9%, and 30.9 Kg of a fraction ethyl ester containing 6.9% EPA ethyl ester in a yield of 32.5%
I got it.

Subsequently, 61.2 kg of the ethyl ester residue obtained from the molecular distillation was obtained using a two-column continuous vacuum distillation apparatus equipped with a filler inside the first and second distillation columns, for 5 minutes. × 10 ^-2 Torr tower pressure, 194-196 ° C
From the bottom of the second distillation column by distillation under the operating conditions of distillation temperature of 3 kg / h and feed rate of the raw material of 3 kg / h.
15.9 kg of ethyl ester of the main fraction containing 75.6% of ethyl ester were obtained in a yield of 26.0%.

The heat-denatured substance of EPA ethyl ester contained in the ethyl ester of the main fraction obtained by the vacuum distillation treatment was reduced to 0.8% by molecular distillation as a pre-concentration step. Content.

Using ethyl ester of the main fraction obtained by vacuum distillation as a raw material, high-performance liquid chromatography packed with reversed-phase ODS was used to elute the EPA-concentrated fraction with aqueous methanol or aqueous ethanol as the mobile phase. After that, by distilling off the solvent in a vacuum distillation apparatus,
A high-purity EPA ethyl ester containing 98.5% of EPA ethyl ester having a colorless and transparent liquid appearance was obtained at a yield of 60.1%.

<Example 2>"Production of high-purity EPA ethyl ester by molecular distillation fraction" EPA ethyl ester obtained in Example 1 described above.
30.9 Kg of a molecular distillation cut ethyl ester containing 9% and 2.1% DHA ethyl ester were added to the first and second fractions.
Using a two-column continuous vacuum distillation apparatus equipped with a filler inside the distillation column, a column pressure of 5 × 10 ⁻² Torr, 194
1. Main distillation ethyl ester containing 72.1% of EPA ethyl ester from the bottom of the second distillation column by distillation under operating conditions of a distillation temperature of ~ 196 ° C and a feed rate of raw material of 3 kg / h. 6 kg was obtained with a yield of 8.4%.

The heat-denatured substance of EPA ethyl ester contained in the ethyl ester of the main fraction obtained by the vacuum distillation treatment had a content of 0.5% due to the molecular distillation treatment as a pre-concentration step. Met.

Using the ethyl ester of the main fraction obtained by vacuum distillation as a raw material, high-performance liquid chromatography packed with reversed-phase ODS was used to elute the EPA-concentrated fraction with aqueous methanol or aqueous ethanol as the mobile phase. After that, by distilling off the solvent in a vacuum distillation apparatus,
A high-purity EPA ethyl ester containing 97.9% of EPA ethyl ester having a colorless and transparent liquid appearance was obtained at a yield of 58.2%.

<Comparative Example>"Purification of sardine oil ethyl ester by four-column vacuum distillation" The sardine oil ethyl ester described in Example 1 was mixed with a two-column continuous vacuum distillation apparatus at 5 × 10 5 ^-2 Torr, a distillation process was performed under operating conditions of a pressure inside the column and a distillation temperature of 194 ° C. to 196 ° C., and a fraction recovered from the bottom of the first distillation column was
Using a new two-column continuous vacuum distillation apparatus, 5 × 1
Distillation was carried out under operating conditions of 0 ^-2 Torr in the tower and a distillation temperature of 194 to 196 ° C, and EPA ethyl ester 8 was obtained.
A main cut ethyl ester containing 5.3% was obtained.

However, by performing the distillation treatment under high temperature conditions for a long time, the E content contained in the ethyl ester of the main fraction obtained by the four-column vacuum distillation treatment was obtained.
The content of the thermally denatured substance of PA ethyl ester was 1.8%, which was inferior in quality as compared with the present invention.

<Example 3>"Production of high-purity DHA ethyl ester by the residue of molecular distillation" 100 kg of bonito oil was heated and stirred at 80 ° C for 1 hour to remove water, and then 50 kg of ethanol was obtained. And 2 kg of sodium hydroxide were added and dissolved, and the mixture was heated and stirred at 80 ° C. for 1 hour to produce 95 kg of bonito oil ethyl ester.

95 kg of sardine oil ethyl ester obtained
Using a falling film molecular distillation apparatus to 3 × 10 ⁻³ To
rr tower pressure, 85 ° C. distillation temperature, feed rate 2
By distilling under operating conditions of 0 Kg / h and a cooling tower temperature of 5 ° C, 67.4 Kg of a residual ethyl ester containing 34.6% of DHA ethyl ester was obtained in a yield of 70.
Obtained at 9%.

Subsequently, 67.4 kg of the ethyl ester residue obtained from the molecular distillation was obtained using a two-column continuous vacuum distillation apparatus equipped with a filler inside the first and second distillation columns, for 5 minutes. × 10 ^-2 Torr tower pressure, 194-196 ° C
Of the second distillation column from the bottom of the second distillation column by distillation under the operating conditions of a distillation temperature of 3 kg / h and a feed rate of the raw material of 3 kg / h.
12.5 Kg of the main cut ethyl ester containing 80.8% of the ethyl ester were obtained in a yield of 18.5%.

The heat-denatured substance of DHA ethyl ester contained in the main fraction ethyl ester obtained by the vacuum distillation treatment was reduced to 0.4% by the molecular distillation treatment as a pre-concentration step. Content.

Using the ethyl ester of the main fraction obtained by vacuum distillation as a raw material, high-performance liquid chromatography packed with reversed-phase ODS was used to elute the EPA-concentrated fraction with aqueous methanol or aqueous ethanol as the mobile phase. After that, the solvent is distilled off with a vacuum distillation apparatus to give a DHA ethyl ester 9 having a colorless and transparent liquid appearance.
High purity DHA ethyl ester containing 7.8% was obtained in 45.5% yield.

<Example 4>"Production of high-purity EPA ethyl ester by high-performance liquid chromatography using a silver nitrate column" [0086] Contains 75.6% of EPA ethyl ester obtained by vacuum distillation treatment in Example 1. The main fraction ethyl ester to be used is subjected to high-performance liquid chromatography equipped with a filler supporting silver nitrate, and the EPA-enriched fraction is eluted using an acetonitrile-methanol mixture as a mobile phase, and then subjected to vacuum distillation. By removing the solvent, EPA ethyl ester 9 having a colorless and transparent liquid appearance is obtained.
High purity EPA ethyl ester containing 6.3% was obtained in a yield of 54.5%.

[0072]

The high purity EPA produced by the present invention
Alternatively, since the lower alcohol ester of DHA can be produced at a relatively low cost by introducing a molecular distillation process, it is possible to produce a high-quality high-purity lower alcohol ester with less oxidative deterioration during the production process at a relatively low cost. In the fields of feed and feed, it is possible to supply products of excellent quality and price on an industrial scale.

[Brief description of the drawings]

FIG. 1 is a schematic configuration diagram in a case where a EPA or DHA-containing raw material is preconcentrated by a molecular distillation apparatus by applying the present invention.

FIG. 2 shows preconcentrated E in the molecular distillation apparatus shown in FIG.
The PA-containing raw material is vacuum-distilled with a two-column vacuum distillation apparatus,
The schematic block diagram at the time of acquiring a PA concentration fraction.

FIG. 3 shows EPA obtained by the vacuum distillation apparatus shown in FIG.
FIG. 4 is a schematic configuration diagram in the case where a concentrated fraction is further supplied to a high-performance liquid chromatography apparatus to obtain a high-purity EPA fraction.

FIG. 4 shows D pre-concentrated by the molecular distillation apparatus shown in FIG.
The HA-containing raw material is vacuum-distilled with a two-column vacuum distillation apparatus,
The schematic block diagram at the time of acquiring an HA concentration fraction.

[Explanation of symbols]

 Reference Signs List 9 wire brush 10 molecular distillation apparatus 11 distillation tower 12 distillation tower main body 12a inner surface of distillation tower main body 13 cooling tower 14 raw material tank 15 preheater 16 tower top 17a bottom 17b bottom 18 residual tank 19 distillation tank 20 vacuum system 30 vacuum Distillation apparatus 31 Vacuum distillation first tower (first distillation tower) 32 Vacuum distillation second tower (second distillation tower) 33 Preheater 34 Top part 35 Condensing system 36 Bottom part 37 Reboiler 38 Pump 40 Middle part 41 Bottom part 42 Reboiler 43 Top 44 Condensation system 45 Pump 47 Vacuum system 48 Vacuum system 50 High-performance liquid chromatography apparatus 51 Column 52 Pump 53 Liquid feed pump 54 UV detector 60 Vacuum distillation apparatus 61 First vacuum distillation column (first distillation column) 62 Vacuum distillation second tower (second distillation tower) 63 Preheater 64 Top 65 Condensed 66 搭底 portion 67 reboiler 68 pump 70 median portion 71 搭底 portion 72 reboiler 73 搭頂 74 Condensed 75 pump 77 a vacuum system 78 vacuum system

────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-5-222392 (JP, A) JP-A-9-302380 (JP, A) JP-A 10-310551 (JP, A) (58) Field (Int.Cl. ⁶ , DB name) C11C 1/10 C07C 67/54

Claims (5)

(57) [Claims] 1. A method for purifying a high-purity highly unsaturated fatty acid lower alcohol ester, which comprises purifying a high-purity eicosapentaenoic acid lower alcohol ester from an unsaturated fatty acid lower alcohol ester mixture, comprising: 3
A step of pre-extracting the lower alcohol ester component of eicosapentaenoic acid by molecular distillation at a pressure in the column of ^10-3 Torr or less and a distillation temperature of 80 to 85 ° C .; Extracting the lower alcohol ester enriched component of eicosapentaenoic acid by vacuum distillation of the component at a column pressure of 5 × 10 ⁻² Torr or less and a distillation temperature of 195 ° C. or less; and lowering the extracted eicosapentaenoic acid. Subjecting the alcohol ester to high-performance liquid chromatography using a reversed-phase partitioning filler to fractionate and purify the lower alcohol ester of high-purity eicosapentaenoic acid. Concentrate of lower alcohol ester of eicosapentaenoic acid as a component Extracting, as a fraction, a component having an increased ratio of a lower alcohol ester component of eicosapentaenoic acid to a lower alcohol ester of docosahexaenoic acid, and in the vacuum distillation step, the residual component extracted in the molecular distillation step and the fraction And a lower alcohol ester of high-purity highly unsaturated fatty acid, wherein each component is added to the mixture. 2. The vacuum distillation step, wherein a residual component or a distillate component extracted in the molecular distillation step is introduced, and a condensed component of a lower alcohol ester of eicosapentaenoic acid is extracted from the top of the first distillation column. A first vacuum distillation step, and a lower alcohol ester of eicosapentaenoic acid, which is condensed with the condensed component of eicosapentaenoic acid extracted in the first vacuum distillation step, from the bottom of the second distillation column. second high purity altitude lower alcohol esters method for purifying unsaturated fatty acids according to claim 1, characterized in that it comprises a vacuum distillation step, a the concentration component is extracted. 3. The fractionation and purification step is characterized in that octadecylated silica gel is used as a stationary phase to be subjected to the reverse phase partitioning high performance liquid chromatography, and alcohol, ketone, water or a mixture thereof is used as a mobile phase. 3. The method for purifying a lower alcohol ester of a high-purity highly unsaturated fatty acid according to claim 1 or 2. 4. The method according to claim 1, wherein, in the fractionation and purification step, a filler carrying silver nitrate is used as a stationary phase to be subjected to the reversed-phase partitioning high performance liquid chromatography. For purifying lower alcohol esters of high-purity highly unsaturated fatty acids. 5. An apparatus for purifying a lower-purity alcohol ester of eicosapentaenoic acid of high purity from a lower-alcohol ester mixture of unsaturated fatty acids, wherein the lower-alcohol ester mixture of unsaturated fatty acids is provided. A molecular distillation apparatus for pre-extracting a lower alcohol ester component of eicosapentaenoic acid at a column pressure of not more than 3 × 10 ⁻³ Torr and a distillation temperature of 80 to 85 ° C., and a lower alcohol ester component of the extracted eicosapentaenoic acid A two-equipped vacuum distillation apparatus for extracting a lower alcohol ester concentrated component of eicosapentaenoic acid at a column pressure of 5 × 10 ^-2 Torr or less and a distillation temperature of 195 ° C. or less; High purity eicosapen from alcohol esters A fractionation purification device comprising a high-performance liquid chromatography having a reversed-phase partitioning material for fractionating and purifying a lower alcohol ester of taenoic acid, wherein the molecular distillation device has a lower eicosapentaenoic acid content as a residue. First extraction means for extracting an alcohol ester concentrated component, and second extraction means for extracting, as a fraction, a component having a higher ratio of a lower alcohol ester component of eicosapentaenoic acid to a lower alcohol ester of docosahexaenoic acid. In the vacuum distillation apparatus, either the residual component or the distillate component extracted by the first and second extraction means is charged, and a lower alcohol ester condensed component of eicosapentaenoic acid is extracted from the top of the column. A first distillation column, and a lower alcohol extract of eicosapentaenoic acid extracted in the first distillation column. A second distillation column into which a ter concentrated fraction is charged and a lower alcohol ester concentrated component of eicosapentaenoic acid is extracted from the bottom of the column, and apparatus.