JPS588037A - Preparation of eicosapentaenoic acid or its ester - Google Patents

Abstract

PURPOSE:To obtain the titled compound economically with a little amount of wastes on an industrial scale, by distilling a mixture of fatty acids obtained from a natural fat or oil continuously, collecting a main fraction distillate containing the titled compound, and treating the resultant main fraction of ditillate with urea. CONSTITUTION:A natural fat or oil containing a large amount of eicosapentaenoic acid or a derivative thereof, e.g., a fat or oil of an animal marine plankton such as an antarctic krill (Euphausia superba) or a blue skinned fish such as a sardine or saury, is converted into the free fatty acid or an ester thereof by the conventional method, e.g. the saponification or alcoholysis, and the resultant product is then distilled continuously to collect a main fraction of distillate containing 40wt% or more titled substance. The main fraction of distillate is then treated with urea to remove low unsaturated fatty acids. The distillation is preferably carried out by using two packed or spring type rectifying columns in combination having the number of theoretical plates of 3-5 to remove the initial distillate in one of the columns and collect the main fraction of distillate in the other for about 40-60min respectively.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides a novel method for producing eicosapentaenoic acid or its ester, and more specifically, a method for producing eicosapentaenoic acid or its ester in high concentration on an industrial scale from natural fats and oils containing eicosapentaenoic acid or its derivatives. Relating to a method of manufacturing.

It is already known that eicosapentaenoic acid (hereinafter sometimes abbreviated as KX'A) and its esters, amides, etc. are effective in treating and preventing thrombotic diseases such as myocardial infarction and cerebral infarction. (4! Kaisho 55-15444).

1P-human is contained in natural oils and fats, particularly in marine oils and fats such as mackerel, sardines, and cod, either as such or as derivatives such as glycerides, but other contaminating fatty acids are overwhelmingly present. Although 11iPmu has been recognized to have the above-mentioned pharmacological effects, a lot of basic and clinical research must be conducted before it can be marketed as a drug. It is necessary that high EPA be provided in large quantities. However, a method for industrially separating high-concentration 11iPm from natural oils and fats has not yet been found, and this has been a major bottleneck in the development of KPA as a drug.

Conventionally, in order to concentrate a specific fatty acid from a mixture of fatty acids or their esters, dewaxing method, countercurrent distribution method, urea addition method, distillation method,
Liquid chromatography and the like have been used. However, these methods have been used to separate relatively low-molecular-weight fatty acids among fatty acids, or to classify saturated acids and unsaturated acids.

However, EPA is a highly unsaturated fatty acid with 20 carbon atoms and 5 double bonds, and its structure makes it unstable to oxygen, light, heat, etc., and its quantitative method itself requires gas chromatography technology. Due to advances, fatty acids have only recently been established and are difficult to concentrate and separate easily and economically using the existing techniques mentioned above.

Among the existing techniques mentioned above, for example, countercurrent distribution method and liquid chromatography can be used to separate EPA, but these require a large amount of many solvents, have a long processing time, and are not economically practical. From this point of view, this method is completely meaningless.

In view of these circumstances, the present inventor conducted research to industrially advantageously obtain 1ePA or its ester from natural oils and fats, and treated a fatty acid mixture obtained from natural oils and fats containing eicosapentaenoic acid or its derivatives with urea. They discovered a method of removing low unsaturated fatty acids and then performing fractional distillation, and filed a patent application (% Application No. 75168/1983).

According to this method, most of the low unsaturated fatty acids are removed by urea treatment, so it takes almost no time to cut off the pre-tones before fractionating KPA by distillation, and it contains the target MPM at a high concentration. It has the advantage that the main residue can be obtained without deterioration. However, on the other hand, in order to immediately subject the raw fatty acid mixture to urea treatment, it is necessary to use approximately 1.5 times as much urea and approximately 10 times as much alcohol as the raw materials, which increases the size of the fruiting equipment and makes it difficult to operate. One problem was that it was complicated and it was difficult to recycle the large amount of waste generated.

Therefore, as a result of further research, the present inventor found that when the fatty acid mixture is subjected to conventional distillation, especially batch distillation, it takes a long time to remove the foretone, and the residence heating time of the IF system increases. However, if the main distillate containing EPA or its ester is collected using a continuous distillation device that requires a short heating time, and then treated with urea, It has been found that depending on the type of raw fatty acid mixture, a high concentration of KPA or its ester can be obtained. However, in this method, I
In the case of a fatty acid mixture containing a large amount of highly unsaturated fatty acids with a molecular weight similar to that of ICPA, the subsequent urea treatment can only remove the highly unsaturated fatty acids, but cannot increase the concentration of EPA. So, after further consideration, I! Among the natural oils and fats that contain a large amount of iPA, oils and fats from Antarctic krill, horned krill, animal marine plankton from copeboda, and green fish such as sardines, saury, herring, and mackerel contain highly unsaturated fatty acids with a molecular weight close to that of EPA. It has been found that the content is small and it is convenient to apply the above method.

The present invention has been completed based on this new knowledge, and involves subjecting a fatty acid mixture obtained from natural fats and oils containing eicosapentaenoic acid or its derivatives to continuous distillation to obtain eicosapentaenoic acid or its esters of 40% by weight or more. This is a method for producing eicosapentaenoic acid or its ester by collecting the main distillate containing the ester and then treating it with urea.

The above-mentioned raw material fats and oils of the present invention are saponified or alcoholized according to a conventional method, and free fatty acids or fatty acid esters (in this specification, these alone or together) are used to make it possible to separate triglycerides by distillation. hand"
(referred to as "fatty acid mixture").

To carry out the invention, the fatty acid mixture is first subjected to distillation. The distillation must require a short residence heating time for the EPA, and for this purpose a continuous distillation method is used. Continuous distillation can use already known continuous distillation equipment, but among these, two packed or spring-type rectification columns with a theoretical plate number of 6 to 5 are combined, and one of them can remove fore-tones. It is preferable to collect the main distillate elsewhere.@ Distillation is preferably carried out at a vacuum level of 5 degrees or less, preferably 1 degree or less.For example, when the vacuum degree is about 1 Hf, the Removal can be achieved by carrying out at a temperature of 180-200°C for 40-60 minutes.

Then, the part that is distilled at the same degree of vacuum and at a temperature of 200 to 210°C is collected as the main distillate. The main harvest is 40 to 60
Finishes in minutes. It is preferable to shorten the residence time of this distillation as much as possible, and for this purpose, it is sufficient to collect substances with a wide boiling point range as the main distillate, but if the range of the main distillate is too wide, the 11iPA concentration will be low, and the next Even with urea treatment, high concentrations of BPA cannot be obtained. Therefore, the main station is m
It is preferable to collect pm or its ester containing 40% by weight or more (hereinafter referred to as ``chi''), particularly 40 to 609b.

The main distillate thus collected is then subjected to urea treatment. Specifically, a solvent that dissolves urea well,
For example, in addition to methanol, ethanol, etc., if necessary, the urea is dissolved by heating to prepare a urea solution of usually 10 to 20%. Add the fatty acid mixture to this and stir. In this case, the amount of urea in the solution is adjusted to 0.5 parts or more, preferably 1 to 2 parts, per 1 part by weight of the main distillate (hereinafter simply expressed as parts). The urea solution with the main distillate is mixed uniformly.

Next, this urea treatment liquid is cooled. At this time, the low unsaturated fatty acids in the mixed fatty acids are added to the precipitated urea crystals and separated as a kind of complex. ◎The cooling method may be left to cool for a long time, but this may reduce workability. From this point of view, it is preferable to perform forced cooling using a cooling water force, and it is preferable to set the final temperature of the treatment liquid to 50° C. or less, preferably 606° C. to 40° C., to give good results.

The urea crystals to which the low unsaturated fatty acids have been added are separated from each other, and the solution is concentrated to remove most of the solvent.
By adding water and a non-polar port agent such as n-hexane, the remaining urea is transferred to the water layer, and the highly unsaturated fatty acids (referred to as highly unsaturated fatty acids) are transferred to the solvent layer. When the aqueous layer and the solvent layer are allowed to stand, the aqueous layer is separated into the lower layer, so discard this aqueous layer, wash the upper solvent layer thoroughly with water, and distill off the solvent to obtain a high concentration of ll1PA or its ester. If the urea is not completely removed by washing with water, for example, the washed mulch layer may be washed with a dilute aqueous acid solution, or silicic acid, which has a strong affinity with urea, or active Urea can also be adsorbed and removed by a batch method or a column flow method using an adsorbent such as clay, activated alumina, or activated carbon.

As described above, according to the present invention, high-concentration KPA can be produced for 70 seconds or more with simple operation without requiring large-scale equipment.
Process (1) Sardine oil was subjected to alcoholysis using sodium ethylate as a catalyst to obtain a mixture of fatty acid ethyl esters. The composition of the main fatty acids in this mixture was investigated by gas chromatography, and the results were as shown in Table 1(a).

(-) This fatty acid mixture B4t was fed into the first column of a two-column packed continuous distillation apparatus at a rate of 14t/H, and after continuously cutting off the fore-tone by 49.6t (59%), the second
Continuously feed the column to the main distillate 24 t (2B, 5-)
was separated. The number of theoretical plates in the first column is 5, the packing is half-ring, the temperature at the top of the column is 195℃, and the residence time is 45℃.
It was a minute. The number of theoretical plates in the second column was 5, the packing was a spring coil, the temperature at the top of the column was 208°C, and the residence time was 55 minutes. According to gas chromatography, the fatty acid composition of the separated main distillate was as shown in Table 1 ('b).

(-) Next, in the reaction tank, ether/- was heated to 70°C.
After dissolving 128 kg of urea in 680 t of urea, add 85 kg of the pooled main distillate obtained in step II, stir until evenly distributed, cool to 37°C, and dissolve urea and low unsaturation. A complex with fatty acid ethyl ester was precipitated.The precipitated crystals were separated, and the p liquid was concentrated under reduced pressure to remove most of the ethanol, and then 425 tons of water and 425 tons of n-hexane were added to convert urea into water. layer, add ethyl ester to n
- The n-hexane layer was transferred to 850 tons of warm water (40
℃) for 5 times. After dehydrating this hexane layer,
0 cm height 271 silicic acid column - ζ linear velocity 80 clL/
Purified by passing with H. The column eluate was concentrated under reduced pressure and n
- By distilling off hexane, the fatty acid ethyl ester of the present invention 55
I got it. The fatty acid composition of the product thus obtained was analyzed by gas chromatography, and the results are shown in Table 1(C).

The following is a margin of Example 2 (1) A fatty acid mixture was obtained by saponifying the oil extracted with n-hexane from a dried product of Isadeami using a conventional method.According to gas chromatography analysis, the fatty acid composition of this product was shown in Table 2 (a). It was like that.

(Snow) This fatty acid mixture 591 was cut off by 34.2 t (58%) using the apparatus of Example 1 (1).
A main distillate of 9.5 t (16 To) was collected. According to gas chromatography, the fatty acid composition of this product is shown in Table 2.
(1) It was as in 1〇(ml) Next, pooled 100 kg of the main distillate obtained in (1),
After urea treatment and silicic acid column purification in the same manner as in Example 1, the solvent was removed to obtain 63 kg of the fatty acid of the present invention. The fatty acid composition of the product thus obtained was analyzed by gas chromatography, and the results are shown in Table 2(C).

Margin below Table 2

Claims (1)

[Claims] +11 A fatty acid mixture obtained from natural fats and oils containing eicosapentaenoic acid or its derivatives is subjected to continuous distillation to obtain 40% by weight of eicosapentaenoic acid or its ester.
A method for producing eicosapentaenoic acid or its ester, which comprises collecting the main distillate containing the above and then treating it with urea. (2) The method according to claim 1, wherein the main distillate contains 40 to 60% by weight of eicosapentaenoic acid or its ester.