JPH0441457A - Production of eicosapentaenoic acid or its ester - Google Patents

Abstract

PURPOSE:To obtain the subject compound by using >=3 distillation columns including a separately installed fractionating column for the initial distillate of fatty acids having low carbon number, distilling main fraction from a mixture containing eicosapentaenoic acid or its derivative by a specific method, converting the compound into a urea adduct and extracting the adduct. CONSTITUTION:The objective fatty acid or its ester mixture is produced from natural oil and fat containing eicosapentaenoic acid or its ester by using >=3 distillation columns 1-4 including a separately installed fractionating column for the initial distillate of fatty acids having low carbon number, refluxing the column bottom liquid of the fractionating column to the former-stage distillation column, continuously distilling in a vacuum of <=10 Torr and a column bottom temperature of <=210 deg.C to recover the main fraction D composed mainly of eicosapentaenoic acid or its ester, contacting the main fraction with a urea solution, extracting with a non-polar solvent and distilling out the solvent to obtain the subject compound having a concentration of >=85%. Preferably, the fractionating column for the main distillate and the fractionating column for the latter distillate are separately installed to perform continuous distillation operation.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a method for producing highly concentrated eicosapentaenoic acid or its ester.

More specifically, the present invention discloses eicosapentaenoic acid (
The present invention relates to a novel manufacturing method that enables highly efficient production of highly concentrated products of EPA) or its esters.

(Prior art and its problems) It has been known that eicosapentaenoic acid (EPA) and its esters, amides, etc. are useful as prescription agents for preventing blood clot formation and treating thrombotic diseases. .

These eicosapentaenoic acids are present as such in natural oils and fats, especially marine oils and fats such as mackerel, sardines, and cod.
It is also known that eicosapentaenoic acids are contained in their derivatives such as glycerides, and studies are underway on methods for extracting eicosapentaenoic acids from these fish oils.

However, these natural oils and fats such as fish oil contain an overwhelmingly large amount of other contaminating fatty acids, such as those with 19 or less carbon atoms and 21 or more carbon atoms, in addition to eicosapentaenoic acid, which is an unsaturated fatty acid with 20 carbon atoms. Therefore, it is extremely difficult to selectively extract only eicosapentaenoic acids as a high-concentration (high-purity) product.

For example, as a method for producing eicosapentaenoic acids from natural oils and fats, there is a method in which a fatty acid mixture from natural oils and fats is esterified, this is precisely fractionated under reduced pressure, and then the obtained fraction is purified by a urea addition method. This has been proposed so far (Japanese Unexamined Patent Publication No. 57-149400).

10mm HQ, more preferably 0.1~0.01m+H
By this method, eicosapentaenoic acid ester with a concentration of about 80% has been obtained by precision fractionation in a rectification column packed with rings under a reduced pressure of Depending on the method, the eicosapentaenoic acid ester in the C2° fraction obtained by rectification is only about 30%, and even with urea treatment and subsequent vacuum distillation, its concentration can be reduced in high yield. It is extremely difficult to improve urea to 85% or more.Also, since it is actually necessary to treat a large amount of urea multiple times after distillation, it is difficult to improve production efficiency and reduce production costs. There were major limitations and there were major problems in putting the process into practical use.

At almost the same time as this method, two distillation columns are used to perform continuous distillation under reduced pressure conditions to obtain approximately 50% eicosapentaenoic acids as a CO fraction, followed by urea addition treatment and column chromatography purification. Although this method has been proposed by the applicant of the invention (Japanese Unexamined Patent Publication No. 58-8037), the efficiency of distillation purification and the overall process has been greatly improved, but it still has a high concentration of eicosapentaenoic acid or its equivalent of 85% or more. It has not been possible to successfully produce esters as a practical process; therefore,
There were limits to streamlining production processes and improving production efficiency.

In order to use eicosapentaenoic acid or its ester, which is useful as a medical prescription agent, clinically or for research aimed at applying it to a wider range of disease areas, it is necessary to have a concentration of 80% or more, for example. Even 85%
Although it is strongly desired to produce the above items in large quantities and with high efficiency, it has not been possible to meet such a request under the current circumstances as described above.

This invention was made in view of the above-mentioned circumstances, and it overcomes the drawbacks of conventional production and purification methods.
% or more of eicosapentaenoic acid or its ester,
The objective is to provide a new method that enables simple, highly efficient, and low cost acquisition.

(Means for Solving the Problems) The present invention solves the above problems by using a mixture of fatty acids or esters thereof obtained from natural fats and oils containing eicosapentaenoic acid or its derivatives as an initial distillate of low carbon number fatty acids. In a distillation column with three or more independent rectification columns, the bottom liquid of the rectification column is refluxed to the first distillation column, and
Continuous distillation is carried out at a reduced pressure of 0 Torr or less and a bottom temperature of 210° C. or less, and the obtained main fraction containing eicosapentaenoic acid or its ester as a main component is brought into contact with a urea methanol solution to produce a urea adduct. Provided is a method for producing eicosapentaenoic acid or its ester, which comprises performing an extraction treatment using a non-polar solvent and distilling off the non-polar solvent to obtain eicosapentaenoic acid or its ester with a concentration of 85% or more. .

The method of the present invention also includes sending the condensate of the top fraction of the first distillation column to the first distillation column, and rectifying the main fraction containing eicosapentaenoic acid or its ester as a main component. In a preferred embodiment, a column and a rectification column for the after-distillate (residual) fraction are provided independently to carry out continuous distillation.

Furthermore, one of the preferred embodiments of the present invention is that each distillation column has an independent vacuum system and condensation system.

Long-chain highly unsaturated fatty acids such as eicosapentaenoic acid have many double bonds in their molecules, so they are susceptible to thermal denaturation such as deterioration and polymerization due to heating during distillation, making distillation and concentration extremely difficult.

On the other hand, natural oils and fats containing eicosapentaenoic acids contain various fatty acids in addition to eicosapentaenoic acids, and since these have similar boiling points, they cannot be separated unless the height of the distillation column is made considerably high and the reflux amount is increased. can't do it,
However, this causes the problem of thermal denaturation due to an increase in bottom pressure and an accompanying rise in temperature.
Ultimately, it makes distillation purification extremely difficult.

For this reason, in conventional methods, concentration by distillation must be kept to a low level, and high-level purification must be carried out by subsequent urea addition treatment.

In addition, the load on subsequent processes inevitably becomes extremely heavy.

However, with the method of the present invention, such problems do not occur, and highly purified eicosapentaenoic acid or its eicosapentaenoic acid with a concentration of 80% or more, or even 85% or more, can be produced with simple operation and high efficiency by only distillation purification. Since the ester can be obtained, the subsequent urea addition treatment makes it possible to purify the product with extremely high efficiency and high concentration.

The fatty acid mixture targeted by the method of the present invention can be any one obtained from natural fats and oils containing a large amount of eicosapentaenoic acid or its derivatives such as glycerides, such as sardines, mackerel, herring, saury, etc. Fatty acid mixtures obtained from suitable sources such as fish, Antarctic krill, Antarctic krill, and zooplankton such as Kobeboda can be used.

These fatty acid mixtures are optionally esterified and continuously distilled.

In the continuous distillation method of the present invention, various methods such as a packed type, a spring type, and a tray type can be employed, and more preferably, a mesh plate-like body is used and the number of theoretical plates is 5 or more.

The continuous distillation in the method of the present invention, which consists of three or more distillation columns, is performed at a pressure of 10 Torr or less, more preferably,
0. It is carried out under reduced pressure conditions around ITorr and at a bottom temperature of 210°C or lower, more preferably 195°C or lower.

In any case, in this configuration of three or more distillation columns, one of the columns is made independent as a rectification column for recovering the initial fraction. For example, in the case of three columns, (I) first distillation column (II) second distillation column (first distillation column) (1) third distillation column (main distillation column and rear distillation column) ), and when it is composed of four towers, (I>
1st distillation column (It> 2nd distillation column (first distillation column) (I) 3rd distillation column (last distillation separation) (TV) 4th distillation column (main distillation column) .

Furthermore, in the case of three columns, (I) the first distillation column (first distillation column) (It) the second distillation column (second distillation column) (
■) It can also be divided into a third distillation column (main fraction rectification column). Of course, the configuration of the rectification column can also be further subdivided.

In any case, in the method of the present invention, it is essential that the bottom liquid of the initial fraction rectification column is returned as a reflux liquid to the previous stage, that is, the first distillation column in the above configuration example.

Further, it is also a preferred embodiment that the top fraction of the first distillation column is once condensed and then sent in the form of a condensate to the first fraction rectification column.

Furthermore, since it is necessary to strictly control the degree of vacuum and bottom temperature of each distillation column, it is preferable to provide an independent vacuum system for each column.

The C2° main fraction obtained by continuous distillation, ie, the main fraction containing eicosapentaenoic acid or its ester, is then treated with urea to produce a urea adduct. At this time, urea is used as a urea solution by dissolving it in a highly soluble solvent such as methanol or ethanol.8Usually, the urea concentration is about 5 to 20%.

The main fraction and this urea solution are mixed at a ratio of about 0.5 to 10 parts per 1 part by weight of the main fraction, and the mixture is forcibly cooled to below room temperature, preferably below 15°C. By such treatment, the degree of unsaturation in the main fraction is low, e.g.
C2o fatty acids having four unsaturated bonds can be precipitated and separated as a complex with urea.

Next, in the method of this invention, a nonpolar solvent such as hexane, isooctane, etc. is added to the reaction mixture, and the urea adduct and remaining urea are transferred to a methanol layer, etc., and fatty acids are transferred to a hexane layer, etc., for extraction and separation. .

Next, in order to remove impurities such as dyes and oxides, adsorption treatment is performed via an adsorption column as required.

The adsorption column used at this time is silica gel, activated clay,
Although alumina, activated carbon, etc. can be used, silica gel is particularly preferred.

Thereafter, the above solvent is distilled off.

Hereinafter, the method of the present invention will be explained in more detail with reference to the accompanying drawings.

FIG. 1 shows an example using four distillation columns.

For example, as shown in Figure 1, a fatty acid mixture (A
), four distillation columns (1) (2) (3) (4
) for continuous distillation.

Each distillation column (1) (2) (3) (4) is independently equipped with a vacuum system (5) (6) (7) (8) and a condensation system (9).
(10) (11) (12), and reboiler (13)
)<14)(15)(16) are also provided.

The distillation columns (1), (2), (3), and (4) are each 10T.
The vacuum is strictly controlled below orr and the bottom temperature is below 210°C. The degree of vacuum and temperature are closely related, and for this control it is preferable to make the vacuum systems (5), (6), (7), and (8) independent, but this is not necessarily necessary. This vacuum system may be configured as appropriate depending on the capacity of the pump, the control system, etc.

In the above configuration, first, the raw material (A) is transferred to the first distillation column (
1), for example near the top of the column, the top fraction is condensed in the condensation system (9), and the liquid is introduced into the first distillation column as the second distillation column (2), for example at the bottom of the column. will be introduced. Introduction in liquid form is one of the important factors in the method of this invention.

In the second distillation column (2), the first distillate (B) consisting of fatty acids with a lower carbon number (<01°) is used as the top fraction.
Collect. In addition, a part of the bottom liquid is transferred to the first distillation column (
1) is refluxed near the top of the column.

This is also a very important factor for the method of this invention. The bottom condensate of the first distillation column (1) is also reboiler (
13) and return it to the bottom of the column, and the third distillation column (
3) is introduced in liquid form near the top of the column.

The top fraction of the third distillation column (3) is supplied to the bottom of the fourth distillation column (4) as a condensate through a condensation system (11). In addition, the bottom condensate is heated by the reboiler (15) and returned to the bottom of the tower, and the after-distillate (residual) fraction (C), which is mainly composed of fatty acids longer than 021 and longer than eicosapentaenoic acid or its ester, is recovered. do.

In the fourth distillation column (4) into which the condensate from the top of the third distillation column (3) is introduced, the fraction from the top of the column is transferred to the condensate system (12
), a portion of which is refluxed near the top of the column, and a main fraction (D) containing eicosapentaenoic acid or its ester as a main fraction is recovered. On the other hand, the bottom condensate is heated in the boiler (16) and returned to the bottom of the column, and a portion is refluxed near the top of the third distillation column (3).

In addition, before introducing the raw material (A) into the first distillation column (1),
The process may be performed in a flash tank (17) maintained at reduced pressure to remove impurities such as air and moisture.

Furthermore, it is advantageous to employ a falling film evaporation type reboiler (13), (14), (15), and (16) that can shorten the heating time. Thereby, thermal deterioration can be more effectively prevented.

FIG. 2 illustrates the processing steps for producing a hull with urea. The main fraction with a concentration of eicosapentaenoic acid or its ester of 80% or more obtained by the above continuous distillation (
D).

As illustrated in FIG. 2, this main fraction (D) is sent to a contact column (21) with a urea solution, and is brought into contact with, for example, a urea methanol solution introduced from a tank (22). At this time,
The urea methanol solution is introduced at a temperature of about 35 to 45°C, and is forcedly cooled to below room temperature in the contact tower (21).

Next, the treatment liquid is passed through a tank (23) to a non-polar solvent,
The product is sent to a product extraction column (24), for example using n-hexane. The product solvent layer (E) from which the urea methanol solution and the urea adduct have been separated is sent to the next treatment step. The urea methanol solution and the urea adduct are sent to a tank (25),
After thermally decomposing the urea adduct, the residue extraction column (25')
The extraction process is carried out again in , and the residual solvent layer (G) is separated.

The non-polar solvent is passed through the cooling tube (26) or the heating tube (27).
) in the extraction tower (24) (2
5'). The solvent layers (E) and (G) are placed in a decanter (2
8) Take out from (29).

The product solvent layer (E) is then sent to a methanol rectification column (32) via a tank (31), as shown in FIG. Methanol condenser (33) and methanol evaporator (
By operating this rectification column (32) equipped with 34), a demethanol-treated product extraction solvent layer is obtained, and by handling this, residual urea is removed.

Next, this is passed through a tank (35) to an adsorption column (3).
6) (37) to remove impurities such as dyes and oxides, and then in an evaporator (38) to remove a solvent such as n-
Remove hexane.

This evaporator (38) is equipped with an n-hexane condenser (39).
Place.

Product (F) is thus obtained. The final concentration of product (F) increases to more than 85%.

Next, a specific manufacturing example of the manufacturing method of the present invention using the apparatus illustrated in FIGS. 1 to 3 will be shown.

Production Example 1> Fatty acid obtained from fish oil (60% below C19, C2o2
3%, 021 or more 17%) ethyl ester of the mixture,
Flash tank (17) maintained at a vacuum of I Torr
The first distillation column (1), which has a column diameter of 300 mr, a height of about 7 m, and is maintained at a vacuum of 0.1 Torr,
It was supplied at a rate of 5 to 20j/hr.

In this first distillation column (1), the column bottom temperature is 194 to 1
The temperature at the top of the column was set at 95°C and 124-125°C.

Moreover, a mesh plate with a four-ring mesh was installed inside, and the number of theoretical plates was set to four. In this first distillation column (1),
Since the fatty acid ester mixture with a temperature of 0.2° or more gathers at the bottom of the column, it becomes difficult to control the degree of vacuum and temperature at the bottom of the first distillation column. For this reason, the amount of packing material in the first distillation column was smaller than that in the second distillation column (2).

The top condensate of the first distillation column (1) was introduced into the bottom of the second distillation column (2). The bottom temperature of this second column is 184-1
85°C, the tower top temperature should be between io and 111°C,
0. It was operated at a vacuum of ITorr.

The number of theoretical plates was 6. In addition, the top fraction has a reflux ratio of 1:
2 and a portion was recovered as the first distillate (B).

As shown in Table 1, the composition of this initial distillate was 99% fatty acids of C1 and below, 1% of C2o modified icosapentaenoic acid ester and others, and 0% of fatty acids of 021 and above.

Regarding the second distillation column (2), the bottom liquid was controlled to have a constant liquid level and returned to the vicinity of the top of the first distillation column (1). In other words, this tower bottom condensate is used as the reflux liquid.
It was returned to the distillation column (1).

The bottom liquid of the first distillation column (1) was supplied to the vicinity of the top of the third distillation column (3). The pressure of this third distillation column (3) is 0. I
Torr reduced pressure conditions, and the bottom temperature was 194 to 19
5°C, and the tower top temperature was set at 124-125°C.

The number of theoretical plates was 4.

As the bottom liquid of the third distillation column (3), the after-distillation (residual) fraction (C
) were collected. The composition of this residue is as shown in Table 1.
0.1% of fatty acids of 019 or less, 20% of C2o-engineered icosapentaenoic acid ester, fatty acids of C21 or more 79.
It was 9%.

The top fraction of this third distillation column (3) is transferred to the fourth distillation column as a condensate.
It was supplied to the bottom of the distillation column (4). This fourth distillation column (4) having six theoretical plates was operated at a reduced pressure of 0.1 Torr so that the bottom temperature was 194 to 195°C and the top temperature was 110 to 111°C.

The bottom liquid was returned to the top of the third distillation column (3) as a reflux liquid. At this time, the liquid level at the bottom of the fourth distillation column was kept constant.

The top condensate was refluxed at a reflux ratio of 1:2, and the main fraction (D) was collected at the same time.

As shown in Table 1, the composition of this main fraction was 0.1% of C or lower fatty acids, 0% of 021 or higher fatty acids, and 99.9% of C2o eicosapentaenoic acid ester and others.

The concentration of eicosapentaenoic acid ethyl ester in the C2o fraction was 88%.

Comparative Example> For comparison, continuous vacuum distillation was attempted using the two-column distillation columns (41) and (42) (10 theoretical plates) shown in FIG.

At this time, each distillation column (41>(42) has an independent vacuum system (43) (44) and a condensing system (45) (46).
were installed, and Riborillar (47) and (48) were also placed.

The first distillate (B') is passed through the top of the first distillation column (41), the main distillate (D') is passed through the top of the second distillation column (42), and the rear distillate (residual) fraction (C) is passed through the bottom of the column (42).゛). Each distillation column (41) (42) was set to a reduced pressure condition of 0 and ITOrr. Although attempts were made to keep the bottom temperature of the first distillation column (41) below 195°C, temperature control was difficult and the temperature sometimes reached 210°C or above.

The compositions of the first distillate, main fraction, and rear distillate are shown in Table 2, and the separation and purification efficiency of the C2° fraction is far inferior to that of the method of this invention, and the control of the distillation operation is difficult. It became extremely difficult. In addition, eicosapentaenoic acid ethyl ester of the main fraction recovered as C2o fraction was 76%.
I stayed there. The bottom temperature of the first distillation column (41) is set to 195
Even if the temperature is controlled below °C, as is clear from Table 2,
However, the contamination of fatty acids with a lower carbon number, especially C18, was unavoidable, resulting in a completely unsatisfactory product.

Table 1 Table 2 Production Example 2> C2o-engineered methyl ester concentration obtained from Production Example 1: 99.
9%, eicosapentaenoic acid ethyl ester concentration 88%
The main fraction (D) was contacted with a 15% urea methanome solution in the contact column (21).

The temperature of this solution was 42°C, and the contact tower (21) was forcibly cooled to 10°C, and the solution was extracted using n-hexane cooled to 10°C in the extraction tower (24).

The obtained product solvent layer (E) is passed through a methanol rectification column (32
), methanol was removed, and urea was further separated.

The product solvent layer (E) contains fatty acid ester 12-1
3% methanol 5% hexane 82-83% Although a trace amount of urea was contained, methanol and urea were completely removed.

The treated solution is then passed through a silica gel adsorption column (36) (
37) to remove impurities such as dyes and oxides, and then distill off hexane in an evaporator (38) to obtain an eicosapentaenoic acid ethyl ester product (F). The concentration of this product was 93%.

(Effect of the invention) As explained in detail above, by the method of this invention, 8
It becomes possible to obtain eicosapentaenoic acid or its ester having a concentration (purity) of 5% or more, and even 90% or more. Moreover, highly efficient manufacturing is realized.

[Brief explanation of the drawing]

FIG. 1 is a schematic diagram of an apparatus configuration showing an embodiment of the method of the present invention. FIG. 2 is a schematic diagram showing an example of a conventional two-column system. 1.2, 3.4... Distillation column 5.6, 7.8... Vacuum system 9.10, 11.12... Condensation system 13.14, 15.16... Reboiler 21...・Contact tower 22...Tank 23...Tank 24...Product extraction tower 25...Tank 25'...Residue extraction tower 26...Cooling pipe 27...Heating pipe 28.29... Decanter 31... Tank 32... Methanol rectification column 33... Methanol evaporator 34... Methanol evaporator 35... Tank 36.37... Adsorption column 38...evaporator 39...hexane 11! Condenser A...Raw material B...First distillate C...Following distillate (residual) fraction D...Main distillate E...Product solvent layer F...Product G...Residual liquid solvent layer

Claims (7)

[Claims] (1) A mixture of fatty acids or esters thereof obtained from natural fats and oils containing eicosapentaenoic acid or its derivatives is purified in three or more distillation columns each having an independent rectification column for the initial fraction of low carbon number fatty acids. The bottom liquid of the distillation column is refluxed to the first stage distillation column and continuously distilled at a reduced pressure of 10 Torr or less and a bottom temperature of 210°C or less, and the main fraction containing eicosapentaenoic acid or its ester as a main component is converted into urea. Contacting with a solution to produce a urea adduct, extraction using a non-polar solvent, and then distilling off the solvent,
A method for producing eicosapentaenoic acid or an ester thereof, characterized by obtaining eicosapentaenoic acid or an ester thereof having a concentration of 85% or more. (2) A claim for sending the condensate of the overhead fraction to the first distillation column
1) The method for producing eicosapentaenoic acid or its ester. (3) The method for producing eicosapentaenoic acid or its ester according to claim (1) or (2), wherein the bottom liquid of the initial fraction rectification column is refluxed to the vicinity of the top of the first distillation column. (4) A claim in which a main fraction rectification column containing eicosapentaenoic acid or its ester as a main component and a rectification column for a high carbon number fatty acid post-fraction are separated and continuously distilled (
The method for producing eicosapentaenoic acid or its ester according to 1), (2) or (3). (5) The method for producing eicosapentaenoic acid or its ester according to claim (1), (2), (3) or (4), wherein each distillation column has an independent vacuum system and a condensation system. (6) Claims (1), (2), (3), (
4) or the method for producing eicosapentaenoic acid or its ester according to (5). (7) Claims (1) and (2) wherein the nonpolar solvent is hexane.
), (3), (4), (5) or (6), the method for producing eicosapentaenoic acid or its ester.