JP3040136B2 - Method for producing 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, there is a method of esterifying a fatty acid mixture from natural fats and oils, precision fractionating this under reduced pressure, and then purifying the obtained fraction by a urea addition method. It has been proposed so far (JP-A-57-149400).

This method of precision fractionation in a ring-packed rectification column under reduced pressure of 10 mm Hg, more preferably 0.1-0.01 mm Hg, and further purification by urea addition method, results in 80%
Eicosapentaenoic acid ester having a concentration of about 10% is obtained. However, even by this method, C ₂₀ distillate eicosapentaenoic acid esters obtained by rectification is only only only about 30%, yet urea adduct process and,
Furthermore, it is extremely difficult to improve the concentration to 85% or more in high yield even by subsequent vacuum distillation.
In addition, since a large amount of urea treatment is actually required after distillation, the production efficiency is improved,
There are great restrictions on reducing the production cost, and there is a big problem in putting the process into practical use.

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 this method has greatly improved the efficiency of distillation purification and the entire process, it has not succeeded in producing a high concentration of eicosapentaenoic acid or its ester of 85% or more as a practical process. For this reason, there were limits to the rationalization of the production process and the improvement of the production efficiency.

In order to use eicosapentaenoic acid or its ester useful as a medical prescription agent clinically or for research aiming at application to a wider range of disease areas, for example, its concentration is 80% or more, Further, it is strongly desired to produce a large quantity of 85% or more with high efficiency. However, such a situation has not been able to meet such demands in the above-mentioned situation.

The present invention has been made in view of the circumstances described above, and overcomes the drawbacks of the conventional production and purification methods to achieve a concentration of 85%.
% Or more of eicosapentaenoic acid or an ester thereof,
It is an object of the present invention to provide a new method that enables easy, high-efficiency, and low-cost acquisition.

(Means for Solving the Problems) In order to solve the above-mentioned problems, the present invention provides a mixture of fatty acids or esters thereof obtained from natural fats and oils containing eicosapentaenoic acid or a derivative thereof, for the first time in low-carbon fatty acid fatty acids. 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 pre-stage distillation tower, and continuously at a reduced pressure of 10 Torr or less and a bottom temperature of 210 ° C. or less. The main fraction containing eicosaventaenoic acid or its ester as a main component is contacted with a urea solution to form a urea adduct, subjected to an extraction treatment using a non-polar solvent, and then distilled the solvent. In addition, the present invention provides a process for producing eicosapentaenoic acid or an ester thereof, characterized in that eicosapentaenoic acid or an ester thereof having a concentration of 85% or more is obtained.

Further, the method of the present invention may include a step of sending the concentrated liquid of the top fraction of the first-stage distillation column to the second-stage first-fractionation rectification column or a 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.

Furthermore, the present invention also has one of the preferred embodiments in that each distillation column has an independent vacuum system and condensation 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 pressure at the bottom of the column and a concomitant increase in the temperature, which ultimately makes distillation purification extremely difficult.

For this reason, in the conventional method, concentration by distillation was suppressed to a low level, and it was necessary to perform high-level purification by a subsequent urea addition treatment or the like. In addition, the load of the subsequent process had to be extremely large.

However, according to the method of the present invention, such a problem does not occur, and only by distillation purification, a simple operation can be performed with high efficiency at a high efficiency of 80% or more, and even more preferably 85% or more. In order to enable the ester to be obtained, the subsequent urea addition treatment
Purification to a highly concentrated product with extremely high efficiency becomes possible.

As the fatty acid mixture targeted by the method of the present invention, any one obtained from natural fats and oils containing a large amount of derivatives such as eicosapentaenoic acid or glyceride thereof can be used, for example, sardines, mackerel, herring, saury and the like. Fatty acid mixtures obtained from suitable fish and animal marine plankton such as Antarctic krill, horse chestnut krill, copepoda and the like can be used.

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, when it is constituted by three columns, (I) first distillation column (II) second distillation column (first fraction rectification column) (III) third rectification column (main fraction and rear fraction rectification) (I) First distillation column (II) Second distillation column (first fraction rectification column) (III) Third distillation column (separate fraction separation) (IV) Divide 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.

Main fraction to C ₂₀ obtained by continuous distillation, ie, main fraction containing eicosapentaenoic acid or an ester thereof is then urea treated to produce a urea adduct. At this time, urea is dissolved in a highly soluble solvent such as methanol or ethanol and used as a urea solution. Usually, the urea concentration is about 5 to 20%.

The main fraction and the urea solution are mixed at a ratio of about 0.5 to 10 parts with respect to 1 part by weight of the main fraction, and the mixture is forcibly cooled to room temperature or lower, more preferably 15 ° C. or lower. Such processing may be separated by precipitation low degree of unsaturation in the main fraction, for example C ₂₀ fatty acids having 1-4 unsaturated bonds in a complex with urea.

Next, in the method of the present invention, a non-polar solvent, for example, hexane, isooctane or the like is added to the reaction mixture,
The urea adduct and the remaining urea are transferred to a methanol layer or the like, and the fatty acids are transferred to a hexane layer or the like, and extracted and separated.

Next, if necessary, an adsorption treatment is performed through an adsorption column to remove impurities such as dyes and oxides.

As the adsorption column at this time, silica gel, activated clay, alumina, activated carbon, or the like can be used, and silica gel is particularly preferred. Thereafter, the solvent is distilled off.

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.

These distillation columns (1), (2), (3) and (4)
Strictly control to a reduced pressure of rr or less and a bottom temperature of 210 ° C or less. The degree of vacuum and the temperature are closely related, and it is preferable to make the vacuum systems (5), (6), (7), and (8) independent for this control, but this is not always essential. 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) is condensed. ) Is introduced in liquid form, for example, into the bottom of the first fraction rectification column. This introduction in liquid form is one of the important factors in the method of the present 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 a very important factor for 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 fraction of the third distillation column (3) is supplied as a concentrated liquid to the bottom of the fourth distillation column (4) via the condensing 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 distillate from the top is condensed (1
In 2), it is condensed, a part is refluxed near the top of the column, and a main fraction (D) mainly composed of eicosapentaenoic acid or its ester is recovered. On the other hand, the bottom condensate is heated by the reboiler (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)
Although the heating time can be shortened, it is advantageous to employ a falling film evaporation type. Thereby, heat denaturation can be prevented more effectively.

FIG. 2 exemplifies a processing step of producing a urea adduct. The main fraction (D) in which the concentration of eicosapentaenoic acid or its ester obtained by the above continuous distillation is 80% or more is treated.

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

The processing liquid is then passed through the tank (23) to the non-polar solvent,
The product is sent to a product extraction column (24) using, for example, 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 processing step. The urea methanol solution and the urea adduct are sent to a tank (25) to thermally decompose the urea adduct, and then subjected to an extraction treatment again in a residue extraction tower (25 ') to separate a residue solvent layer (G). The non-polar solvent is cooled or heated in a cooling pipe (26) or a heating pipe (27) and sent to an extraction tower (24) (25 '). The solvent layers (E) and (G) are taken out from the decanters (28) and (29).

Next, the product solvent layer (E) was, as shown in FIG.
It is sent to the methanol rectification column (32) via the tank (31).
Methanol condenser (33) and methanol evaporator (34)
In the rectification column (32) in which is disposed, a product extraction solvent layer subjected to demethanol treatment is obtained, and the remaining urea is removed by passing through this layer.

Then, this is passed through the adsorption column (3) through the tank (35).
6) Lead to (37) to remove impurities such as dyes and oxides,
Subsequently, the solvent such as n-hexane is removed in the evaporator (38).

An n-hexane condenser (39) is arranged in the evaporator (38).

Thus, a product (F) is obtained. The final concentration of product (F) rises to over 85%. Next, a specific example of the manufacturing method of the present invention using the apparatus illustrated in FIGS. 1 to 3 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 is 194 to 195.
° C, and the top temperature was adjusted to 124 to 125 ° C. Further, a stitched plate having a 4 mm stitch was provided therein, and the number of theoretical plates was four. In this first distillation column (1),
Since the C ₂₀ or more fatty acid ester mixture is collected, the control of vacuum and temperature in the bottom of the first distillation column becomes difficult. For this reason, the amount of packing in the first distillation column is the second amount.
It was less than the distillation column (2).

The top condensate of the first distillation column (1) is supplied to the second distillation column (2).
At the bottom of the column. The bottom temperature of the second tower is 184 to 185
℃, the tower top temperature was 110-111 ℃, was operated at a reduced pressure of 0.1 Torr. The number of theoretical plates was six. Also,
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.

The second distillation column (2) was controlled so that the bottom liquid was constant as the liquid level, and returned to the vicinity of the top of the first distillation column (1). 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). The pressure of this third distillation tower (3) is 0.1T
The pressure was reduced to orr, the bottom temperature was 194 to 195 ° C, and the top temperature was 124 to 125 ° C. 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 pressure of 0.1 Torr and a bottom temperature of 194.
It operated so that it might be ~ 195 degreeC and the overhead temperature of 110-111 degreeC.

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 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 or more 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 performed using a distillation column (41) (42) (10 theoretical plates) having a two-column configuration shown in FIG.

At this time, each distillation column (41) (42) was provided with an independent vacuum system (43) (44) and a condensing system (45) (46), and also provided with reboilers (47) (48).

The first fraction (B ') from the top of the first distillation column (41), the main fraction (D') from the top of the second distillation column (42), and the late fraction (residue) from the bottom (C) ') Was collected. Each of the distillation columns (41) and (42) was set under a reduced pressure of 0.1 Torr. First
An attempt was made to keep the bottom temperature of the distillation column (41) at 195 ° C. or lower, but temperature control was difficult, and the temperature sometimes reached 210 ° C. or higher.

HatsuTomebun, the composition of the main fraction and post-fraction are as shown in Table 2, the separation and purification efficiency to C ₂₀ fraction is inferior far in comparison with the method of the present invention, also, the control of the distillation It became extremely difficult. Moreover, eicosapentaenoic acid ethyl ester of the main fraction recovered as C ₂₀ fraction was only 76%. Even if the bottom temperature of the first distillation column (41) is controlled to 195 ° C. or lower, as is apparent from Table 2, the incorporation of lower carbon number, especially C ₁₈ fatty acids, is inevitable. The product was completely inadequate.

C ₂₀ ethyl ester concentration 99.9 obtained from <Production Example 2> Production Example 1
%, A main fraction (D) having a concentration of eicosapentaenoic acid ethyl ester of 88% was brought into contact with a 15% urea methanol solution in a contact tower (21). The temperature of this solution was 42 ° C, and in the contact tower (21), extraction was performed in an extraction tower (24) using n-hexane cooled to 10 ° C and forcibly cooled to 10 ° C.

The obtained product solvent layer (E) is placed in a methanol rectification column (3
In 2), methanol was removed, and urea was further separated. The product solvent layer (E) contained 12-13% of fatty acid ester, 5% of methanol, 82-83% of hexane, and trace amounts of urea, of which methanol and urea were completely removed.

The treatment solution is then applied to a silica gel adsorption column (36)
Introduced to (37), impurities such as dyes and oxides were removed, and hexane was distilled off in the evaporator (38) to obtain an eicosapentaenoic acid ethyl ester product (F). Its concentration was 93%.

(Effect of the Invention) As described in detail above, the method of the present invention
Eicosapentaenoic acid or an ester thereof having a concentration (purity) of 85% or more, and even 90% or more, can be obtained. In addition, highly efficient manufacturing is realized.

[Brief description of the drawings]

FIGS. 1, 2 and 3 are schematic diagrams showing the structure of an apparatus according to an embodiment of the method of the present invention. FIG. 4 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 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 tower 33 ... Methanol condenser 34 ... Methanol evaporator 35 ... Tank 36,37 ... Adsorption column 38 ... Evaporator 39 ... Hexane condenser A ... Raw material B ... First distillate C ... Last distillate ( Residue) component D: Main fraction E: Product solvent layer F: Product G: Residual solvent layer

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI C07C 67/60 C07C 67/60 69/587 69/587 C11B 3/02 C11B 3/02 3/12 3/12 7/00 7 / 00 C11C 1/08 C11C 1/08 (56) References JP-A-58-8037 (JP, A) JP-A-57-149400 (JP, A) JP-A-64-48898 (JP, A) 57-187397 (JP, A) JP-B 55-11660 (JP, B2) JP-B 53-18011 (JP, B1) (58) Fields investigated (Int. Cl. ⁷ , DB name) C11C 1 / 08-1/10 C11B 7/00 C11B 3/12 C11B 3/02 C07C 57/03 C07C 69/587 C07C 51/44 C07C 51/487 C07C 67/54 C07C 67/60

Claims (7)

(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 rectification column of the first fraction is refluxed to the pre-stage distillation column, and the pressure is reduced to 10 Torr or less and the temperature is reduced to 210 ° C.
The main fraction containing eicosapentaenoic acid or its ester as a main component was contacted with a urea solution to form a urea adduct at the following bottom temperature at the following bottom temperature, followed by extraction using a non-polar solvent. And evaporating the solvent to obtain eicosapentaenoic acid or an ester thereof having a concentration of 85% or more. 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. 6. The method according to claim 1, wherein the urea methanol solution is brought into contact with the main fraction at a temperature not higher than room temperature.
(3) The method for producing eicosapentaenoic acid or an ester thereof according to (4) or (5). 7. The method according to claim 1, wherein the non-polar solvent is hexane (1), (2), (3), (4), (5) or (6).
The method for producing eicosapentaenoic acid or an ester thereof described above.