JP3005638B2 - Method for producing high concentration eicosapentaenoic acid or ester thereof - Google Patents

Description

The present invention relates to a method for producing high-concentration eicosapentaenoic acid or an ester thereof. More specifically, the present invention relates to a novel production method which enables highly efficient production of eicosapentaenoic acid (EPA) or an ester thereof at a high concentration, which is useful as a prescription agent for treating and preventing thrombotic diseases. is there.

(Prior art and its problems) Eicosapentaenoic acid (EPA) and its esters and amides have been known to be useful as prescription agents for preventing thrombus formation and treating thrombotic diseases. .

These eicosapentaenoic acids are known to be contained in natural fats and oils, especially marine oils and fats such as mackerel, sardine and cod, as such or as derivatives thereof such as glyceride. Investigations on a method for extracting the icosapentaenoic acids have been made.

However, the natural fats and oils composed of these fish oils and the like contain overwhelmingly large amounts of other contaminating fatty acids having 19 or less carbon atoms, such as eicosapentaenoic acid, which is an unsaturated fatty acid having 20 carbon atoms, such as 19 or more carbon atoms. Therefore, it is extremely difficult to efficiently extract only eicosapentaenoic acids selectively as a high-concentration (high-purity) product.

For example, as a method for producing eicosapentaenoic acids from natural fats and oils, a method in which a fatty acid mixture from natural fats and oils is esterified, precision-fractionated under reduced pressure, and then the obtained fraction is purified by a urea adduct method Has been proposed (JP-A-57-149400).

Eicosapentaenoic acid ester of about 80% purity can be obtained by this method of precision fractionation in a ring packed rectification column under reduced pressure of 10 mmHg, more preferably 0.1 to 0.01 mmHg, and further purification by urea adduct method. I have. However, even by this method, only the C ₂₀ fraction in eicosapentaenoic acid esters obtained by rectification 30
%, And it is necessary to employ a complicated and troublesome treatment process such as a urea adduct treatment and a subsequent vacuum distillation. For this reason, there are great restrictions on reducing production costs as well as improving production efficiency.
There were problems with the practical application of the process.

At substantially the same time as this process, using a distillation column 2 columns, a method of continuous distillation under reduced pressure to obtain 50% or so of eicosapentaenoic acid as C ₂₀ fraction, followed by urea addition treatment and column chromatography purification It has also been proposed by the applicant of the present invention (JP-A-58-8037). Although the efficiency of distillation purification is greatly improved by this method, eicosapentaenoic acid or an ester thereof having a high concentration (high purity) of 80% or more cannot be obtained without further urea addition treatment.

In addition, even in this method, the urea addition treatment process is indispensable, so that there is a limit in rationalizing the production process and improving the 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 application to a wider range of disease areas, for example, its concentration (purity) must be as follows. It is strongly desired to produce large quantities of 80% or more, and even 85% or more, with high efficiency. However, under the circumstances described above, it was not possible to respond to such a request.

The present invention has been made in view of the above circumstances, and overcomes the drawbacks of the conventional production and purification methods to achieve a concentration of 80%.
It is an object of the present invention to provide a new method capable of easily and efficiently obtaining an eicosapentaenoic acid or an ester thereof having a high concentration of at least 10%.

(Means for Solving the Problems) The present invention solves the above-mentioned problems by providing a fatty acid or an ester mixture thereof obtained from natural fats and oils containing eicosapentaenoic acid or a derivative thereof with a low-carbon fatty acid first fraction. In the three or more distillation towers in which the rectification towers are independent, the bottom liquid of the rectification tower of the first fraction is refluxed to the distillation tower and continuously distilled at a reduced pressure of 10 Torr or less and a bottom temperature of 210 ° C. or less. And a process for producing high-concentration eicosapentaenoic acid or an ester thereof having a concentration of 80% or more.

In addition, the method of the present invention includes the step of sending the condensate of the top fraction of the first-stage distillation column to the second-stage first-fractionation rectification column or the main fraction containing eicosapentaenoic acid or an ester thereof as a main component. In a preferred embodiment, the rectification column and the rectification column for the post-distillation (residual) are independently provided to perform continuous distillation.

Alternatively, the present invention also has a preferred embodiment in which each distillation column has an independent vacuum system and a condensing system.

Since long-chain highly unsaturated fatty acids such as eicosapentaenoic acid have many double bonds in the molecule, they are liable to undergo thermal denaturation such as polymerization by heating during distillation, and are extremely difficult to concentrate by distillation.

On the other hand, natural fats and oils containing eicosapentaenoic acids contain various fatty acids in addition to eicosapentaenoic acids, and since these have close boiling points, the height of the distillation column is considerably increased, and the distillation column is separated unless the amount of reflux is increased. Can not do. However, this causes a problem of thermal denaturation due to an increase in the bottom pressure of the column and a concomitant increase in the temperature, and ultimately makes the distillation and purification of eicosapentaenoic acids extremely difficult.

However, according to the method of the present invention, it is possible to obtain high-purity eicosapentaenoic acid or an ester thereof having a concentration of 85% or more with high efficiency and a simple operation only by distillation purification without occurrence of such a problem. I do.

As the mixture of fatty acids or esters thereof targeted by the method of the present invention, any one obtained from natural fats and oils rich in derivatives such as eicosapentaenoic acid or glyceride thereof can be used. For example, sardines, mackerel, herring And a mixture of fatty acids or esters obtained from suitable fish such as fish such as Pacific saury, animal marine plankton such as Antarctic krill, horsetail krill and copepoda.

These fatty acid mixtures are optionally esterified and continuously distilled.

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

The continuous distillation in the method of the present invention comprising three or more distillation columns is 10 Torr or less, more preferably 0.1 Torr or less.
r reduced pressure conditions around, and 210 ° C. or less, more preferably
It is carried out at a bottom temperature of 195 ° C. or lower.

Regarding the configuration of the three or more distillation columns, in any case, one of them 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 fraction rectification column) (III) third distillation column (main fraction and rear fraction rectification column) ) And four columns, (I) first distillation column (II) second distillation column (first fraction rectification column) (III) third distillation column (second fraction rectification) (IV) Divided into 4th distillation column (main fraction rectification column). Of course, without being limited to these,
The configuration of the rectification column can be further subdivided.

In any case, in the method of the present invention, it is essential that the bottom liquid of the first fraction rectification column is returned to the former stage, that is, in the above configuration example, as the reflux liquid to the first distillation column. In a preferred embodiment, the top distillate of the first distillation column is once condensed and then sent to the first fraction rectification column in the form of a condensate.

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

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

FIG. 1 shows an example in which four distillation columns are used.

For example, as shown in FIG. 1, four distillation columns (1), (2) and (3) are used for the fatty acid mixture (A).
Distill continuously using (4).

Each distillation column (1) (2) (3) (4) is independently provided 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 1 Tor.
Strictly control to a reduced pressure of r or less and a bottom temperature of 200 ° C or less. Since the degree of vacuum and the temperature are closely related, it is preferable to provide an independent vacuum system in each distillation column, but for this control, the vacuum systems (5), (6), (7), (8) Are not necessarily required to be completely independent of each other. This vacuum system may be appropriately configured according to the capacity of the vacuum pump, the control system, and the like.

In the above configuration, first, the raw material (A) is introduced into the first distillation column (1), for example, near the top thereof, and the overhead fraction is condensed in the condensation system (9), and the second distillation column (2) Into the first fraction rectification column, for example, at the bottom of the column. This introduction in liquid form is an important factor in the process of the invention.

In the second distillation column (2), the first fraction (B) comprising fatty acids having a lower carbon number (<C ₁₉ ) as a top fraction thereof
Collect. A part of the bottom liquid is refluxed near the top of the first distillation column (1). This is also one of the characteristics of the method of the present invention. The condensate at the bottom of the first distillation column (1) is also heated by the reboiler (13) and returned to the bottom, and is introduced in a liquid state near the top of the third distillation column (3).

The top component of the third distillation column (3) is supplied as a condensate to the bottom of the fourth distillation column (4) via the condensation system (11). The bottom condensate is heated by a reboiler (15) and returned to the bottom of the column, and a residual (remaining) fraction (C) mainly composed of fatty acids having a chain length of ₂₁ or more longer than eicosapentaenoic acid or its ester is removed. to recover.

The fourth condensate is introduced from the top of the third distillation column (3).
In the distillation column (4), the distillation components from the top are condensed in the condensing system (12), a part of which is refluxed near the top, and a main fraction mainly composed of eicosapentaenoic acid or an ester thereof. Collect (D). On the other hand, the condensate at the bottom of the column is heated by the reoiler (16) and returned to the bottom, and a part of the condensate is returned to the vicinity of the top of the third distillation column (3).

Before introducing the raw material (A) into the first distillation column (1), the raw material (A) may be treated in a flash tank (17) kept at a reduced pressure to remove impurities such as air and moisture. In addition, reboilers (13) (14) (15) (16)
It is also advantageous to employ a falling film evaporation type that can shorten the heating time. Thereby, thermal denaturation can be more effectively prevented.

Next, a specific example of the manufacturing method of the present invention using the apparatus illustrated in FIG. 1 will be described.

<Production Example 1> Fatty acids obtained from fish oil (C ₁₉ or less 60%, C ₂₀ 23%, C ₂₀
The ethyl ester of ₂₁ or more 17%) mixture was treated with flash tank (17) maintained at 1Torr vacuum, then
The column was supplied at a rate of 15 to 20 / hr to the first distillation column (1) having a column diameter of 300 mm, a height of about 7 m and a vacuum of 0.1 Torr.

In the first distillation column (1), the bottom temperature was adjusted to 195 ° C or lower, more specifically, 193 to 195 ° C. The number of theoretical plates was four. This first distillation column (1)
The, since the C ₂₀ or more fatty acid ester mixture collects in the bottom, to control the vacuum and temperature in the bottom of the first distillation column becomes difficult. Therefore, the amount of packing in the first distillation column was smaller than that in the second distillation column (2).

The condensate at the top of the first distillation column (1) was introduced into the bottom of the second distillation column (2). The bottom temperature of this second tower is 184-185 ° C
And operated at a reduced pressure of 0.1 Torr. The number of theoretical plates was six. The overhead fraction was refluxed at a reflux ratio of 1: 2, and a part was recovered as an initial fraction (B).

The composition of the initial fraction, as shown in Table 1, C ₁₉ following fatty acids 99%, was C ₂₀ eicosapentaenoic acid ester other 1% 0% C ₂₁ or more fatty acids.

In the second distillation column (2), the bottom liquid is controlled to be constant as the liquid level, and the bottom liquid is transferred to the first distillation column (1).
To the vicinity of the top. That is, the bottom condensate was returned to the first distillation column (1) as a reflux liquid. The bottom liquid of the first distillation column (1) was supplied near the top of the third distillation column (3). At this time, the pressure was reduced to 0.1 Torr, and the bottom temperature was similarly set to 195 ° C. or lower. The number of theoretical plates was four.

As the bottom liquid of the third distillation column (3), a fraction (C) was recovered. The composition of distillate after this, as shown in Table 1, C ₁₉ following fatty acids 0.1%, was C ₂₀ eicosapentaenoic acid ester other 20% 79.9% C ₂₁ or more fatty acids.

The top fraction of the third distillation column (3) was supplied as a condensate to the bottom of the fourth distillation column (4). The fourth distillation column (4) having six theoretical plates has a reduced pressure of 0.1 Torr and a bottom temperature of 195.
The operation was performed so as to be not more than ° C.

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

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

The composition of the main fraction, as shown in Table 1, C ₁₉ following fatty acids 0.1% C ₂₁ following fatty acids 0% was C ₂₀ eicosapentaenoic acid ester other 99.9%.

Concentration of eicosapentaenoic acid ethyl ester of to C ₂₀ fraction was 88%.

<Comparative Example> For comparison, continuous vacuum distillation was attempted using a distillation column (21) (22) (10 theoretical plates) having the two-column configuration shown in FIG.

At this time, each distillation column (21) (22) was provided with an independent vacuum system (23) (24) and a condensing system (25) (26), and reboilers (27) (28) were also arranged.

The first fraction (B ') from the top of the first distillation column (21), the main fraction (D') from the top of the second distillation column (22), and the late fraction (residue) from the bottom (C) ') Was collected. Each of the distillation columns (21) and (22) was set under a reduced pressure of 0.1 Torr. First
An attempt was made to lower the bottom temperature of the distillation column (21) to 195 ° C. or lower, but it was difficult to control the temperature, and the temperature could be 210 ° C. or higher.

The compositions of the first fraction, the main fraction and the second fraction were as shown in Table 2. Separation and purification efficiency to C ₂₀ fraction is inferior far in comparison with the method of the present invention, also, control of the distillation was extremely difficult. Moreover, eicosapentaenoic acid ethyl ester concentration of the main fraction recovered as C ₂₀ fraction 76
% Stayed. The bottom temperature of the first distillation column (21) is 195 ° C
As apparent from Table 2, even if the control was performed as described below, mixing of a lower carbon number, particularly a _C18 fatty acid, could not be avoided, and the product was completely unsatisfactory.

<Production Example 2> A raw material (A) containing 18% of eicosapentaenoic acid ethyl ester in the same manner as in Production Example 1 using five distillation columns.
Was fed to the first distillation column at a rate of 16 / hr at a temperature of 40 ° C. At this time, the top distillates of the first distillation column (1) and the third distillation column (3) were directly supplied to the second distillation column (2) and the fourth distillation column (4). The condensate at the top of the fourth distillation column (4) was placed at the bottom of a fifth distillation column (not shown). The product was obtained from the top of the fifth distillation column. Also, each distillation column has a 4mm
A mesh plate having the size of the mesh was inserted.

Thus, a 93% concentration of eicosapentaenoic acid ester containing no C ₂₁ <was obtained.

(Effect of the Invention) As described in detail above, the method of the present invention
Eicosapentaenoic acid or its ester having a concentration (purity) of 85% or more can be obtained by only the distillation method. Highly efficient production can be realized by simple operations.

Moreover, the product obtained by the present invention is characterized as a high-purity product which can be converted into a medical formulation as such.

[Brief description of the drawings]

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-tower system. 1,2,3,4 …… Distillation tower 5,6,7,8 …… Vacuum system 9,10,11,12 …… Condensation system 13,14,15,16 …… Reboiler A …… Raw material B …… First fraction C: Late fraction (residual) fraction D: Main fraction

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI C11B 3/12 C11B 3/12 C11C 1/10 C11C 1/10 // B01D 3/10 B01D 3/10 (56) References Features JP-A-58-8037 (JP, A) JP-A-57-149400 (JP, A) JP-A-64-48898 (JP, A) JP-A-57-187397 (JP, A) JP, B2) JP 55-11660 (JP, B2) (58) Fields investigated (Int. Cl. ⁷ , DB name) C11B 7/00 C11B 3/12 C11C 1/10 C07C 57/03 C07C 51 / 44 C07C 69/587 C07C 67/54

Claims (5)

(57) [Claims] (1) A mixture of fatty acids or esters thereof obtained from natural fats and oils containing eicosapentaenoic acid or a derivative thereof, in a distillation column of three or more columns independent of a rectification column for a low-carbon fatty acid first fraction, The bottom liquid of the first fraction is refluxed to the distillation column, and the pressure is reduced to 10 Torr or less and
A process for producing high-concentration eicosapentaenoic acid or an ester thereof having a concentration of 80% or more, which comprises continuously distilling at the following bottom temperature. 2. The process for producing eicosapentaenoic acid or an ester thereof according to claim 1, wherein the condensate from the top fraction of the first distillation column is sent to the second fractionation column. 3. The process for producing eicosapentaenoic acid or an ester thereof according to claim 1, wherein the bottom liquid of the first fraction rectification column is refluxed near the top of the first distillation column. 4. The continuous distillation of a main fraction rectification column containing eicosapentaenoic acid or an ester thereof as a main component and a rectification column of a high carbon number fatty acid rear distillate independently of each other. ), The method for producing eicosapentaenoic acid or an ester thereof according to (2) or (3). 5. The method according to claim 1, wherein each distillation column has an independent vacuum system and a condensing system.
The method for producing eicosapentaenoic acid or an ester thereof described above.