JP2003096039A - Production method of high-purity n-long chain acylamino acid salt - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a production method of N-long chain acylamino acid salt that can efficiently remove or reduce impurities such as long chain fatty acids, long chain fatty acid salts and so on which are by-products in a usual N-long chain acylamino acid production and difficult to remove. SOLUTION: The production method of a high-purity N-long chain acylamino acid salt comprises a step of adding a basic substance and water to a crude N-long chain acylamino acid containing the impurities such as fatty acids or salts thereof to neutralize the crude acylamino acid to a neutralization degree of at most 1 (0 is not included), a step of adding a hydrophilic organic solvent to the neutralized solution thus obtained and then warming it, a step of dissolving the whole reaction system and then cooling it to precipitate the crystal of the N-long chain acylamino acid salt, and a step of filtrating the precipitated crystal to recover to give the high-purity N-long chain acylamino acid salt having remarkably reduced impurities.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a high-purity N-long-chain acylamino acid salt, and more specifically, it has a low content of impurities, particularly long-chain fatty acids or salts thereof, high purity, low irritation, and The present invention relates to a method for producing an N-long chain acylamino acid salt having high solubility in a solvent.

[0002]

2. Description of the Related Art N-long-chain acylamino acids and salts thereof have excellent surface-active properties, bacteriostatic properties, etc. and are mildly stimulating, and are therefore used in various fields. Conventional N-
As a method for producing a long-chain acylamino acid, a Schotten-Baumann reaction of reacting a fatty acid halide with an alkaline solution of an amino acid, an improved method thereof using an aqueous solvent containing a hydrophilic organic solvent, and the like are known (JP-A-50-5305). Japanese Patent Laid-Open No. 5-112796). Further, as another method, there is also a method of synthesizing it by hydrolysis of nitrile using amide nitrile as a raw material (JP-A-7-247254). The use of the acylamino acid produced by these methods is a surfactant, and when the salt is dissolved in water, the purity is such that precipitates derived from phosphorus compounds, which are impurities in the raw material fatty acid halide, are not seen. If so, it is sufficient as a surfactant.
There are the following methods for purifying the acylamino acid produced by these methods. That is, a method in which an acid is added to the reaction solution to make it strongly acidic, and an inorganic salt is removed by heating and separating layers (JP-A-11-180938), and a method in which an odor component derived from an acid chloride is decomposed with an oxidizing agent to deodorize (Japanese Patent Laid-Open No. 4-91066). The above method is effective for removing inorganic salts, phosphorus compounds, nitriles, etc., but cannot remove free fatty acids. As a method for removing free fatty acids, there is a method of washing a partially neutralized slurry with an organic solvent (Japanese Patent Laid-Open No. 9-40624), but this method is for washing the slurry and removing impurities in crystals. I can't cut it. When it is used for pharmaceutical products, it is necessary to purify it to a higher purity.

[0003]

An object of the present invention is to effectively remove hard-to-remove impurities such as long-chain fatty acids and long-chain fatty acid salts, which are by-produced in the conventional method for producing N-long-chain acylamino acids. Another object is to provide a method for producing an N-long chain acylamino acid salt that can be reduced.

[0004]

As a result of intensive studies, the present inventors have found that the amount of residual fatty acid can be remarkably reduced by purifying a crude N-long chain acylamino acid by a specific method. Completed the invention.

That is, the present invention includes the following (1) to
The present invention relates to a method for producing a high-purity N-long chain acylamino acid salt shown in the item (7). (1) Crude N containing fatty acid or its salt as an impurity
-A basic substance and water are added to a long-chain acylamino acid to neutralize it to a neutralization degree of 1 or less (0 is not included), and a hydrophilic organic solvent is added to this to heat it, and after dissolving the whole system High purity characterized by cooling and precipitating crystals of N-long-chain acylamino acid salt, filtering and collecting the precipitated crystals to obtain N-long-chain acylamino acid salt in which the impurities are significantly reduced. N-
Method for producing long-chain acylamino acid salt. (2) The method for producing a high-purity N-long chain acylamino acid salt according to (1) above, wherein the degree of neutralization is in the range of 0.2 to 1. (3) The crude N-long chain acylamino acid has 10 to 1 carbon atoms.
The linear saturated fatty acid halide of 8 was reacted with an amino acid in the presence of an alkali, and after the reaction was completed, the obtained crude N-
The method for producing a high-purity N-long chain acylamino acid salt according to (1) or (2) above, which is produced by warming a synthetic reaction solution containing a long chain acylamino acid salt and acidifying it with an inorganic acid. . (4) The basic substance is a compound selected from the group consisting of sodium hydroxide, potassium hydroxide, triethylamine, triethanolamine, aminomethylpropanol, arginine, ornithine and threonine (1).
~ The method for producing a high-purity N-long chain acylamino acid salt according to any one of (3). (5) The method for producing a high-purity N-long chain acylamino acid salt according to any one of (1) to (4) above, wherein the hydrophilic organic solvent is acetone, ethyl acetate, or tetrahydrofuran. (6) The high-purity N according to any of (1) to (5) above, wherein the amino acid is a neutral amino acid or an acidic amino acid.
-A method for producing a long-chain acylamino acid salt. (7) The fatty acid halide is a fatty acid chloride, the alkali is sodium hydroxide or potassium hydroxide,
The method for producing a high-purity N-long chain acylamino acid salt according to (3) above, wherein the inorganic acid is hydrochloric acid or sulfuric acid.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in more detail below. According to the present invention, the amount of residual fatty acid can be remarkably reduced by purifying a crude N-long chain acylamino acid synthesized by a conventional method by a specific method.
The long-chain acylamino acid can be obtained from a reaction product obtained by subjecting a saturated or unsaturated fatty acid halide having 10 to 22 carbon atoms and an amino acid to a condensation reaction in the presence of an alkali. The fatty acid halide has 10 to 22 carbon atoms,
It is preferable to use saturated or unsaturated fatty acid chloride having 10 to 18 carbon atoms.

The amino acid used as a raw material for the crude N-long chain acylamino acid is preferably a neutral amino acid or an acidic amino acid, for example, neutral amino acids such as valine, leucine, isoleucine, phenylalanine and methionine, and acidic amino acids such as glutamic acid and aspartic acid. Is used. These amino acids may be synthetic products or natural products.
Examples of the alkali used in the reaction include sodium hydroxide and potassium hydroxide. Examples of the solvent used in the reaction include water and a mixed solvent of water and a hydrophilic organic solvent.
Examples of the hydrophilic solvent include acetone, methanol, ethanol, propanol, butanol and the like. After completion of the reaction between the fatty acid halide and the amino acid, the system is acidified with an inorganic acid such as hydrochloric acid or sulfuric acid and heated, and the precipitated organic layer is recovered to obtain a crude N-long chain acylamino acid. In the present invention, a recrystallization method is used.

"Recrystallization" is the Iwanami-Rikagaku Dictionary (19
According to Iwanami Shoten Co., Ltd., Oct. 20, 1981, 3rd edition, supplementary edition, p. 487), "refers to an operation of dissolving a crystalline substance in a solvent and precipitating it as crystals again by an appropriate method. , And also in a chemical dictionary (1996 1
Published by Tokyo Kagaku Doujin Co., Ltd., 1st edition, 50th
Pp. 5), "Recrystallization refers to the dissolution of a crystalline substance containing impurities in a suitable solvent, the difference in solubility due to temperature, the decrease in solubility due to concentration of the solution or the addition of another solvent, or the common ion. It refers to an operation of utilizing the effect and precipitating crystals again. " Therefore, in the present invention,
"Recrystallization" is an operation of "dissolving a crystalline substance N-long-chain acylamino acid or a salt thereof in a solvent for recrystallization with heating, dissolving with heating and then cooling to precipitate crystals again." The content of the present invention will be further described.

The method of the present invention is carried out by treating the crude N-long-chain acylamino acid by the procedures of neutralization, dissolution-cooling, precipitation-filtration. Examples of the basic substance used for neutralization by this method include sodium hydroxide, potassium hydroxide, triethylamine, triethanolamine, organic amines such as aminomethylpropanol, arginine, ornithine, threonine and the like. As the hydrophilic organic solvent, acetone, ethyl acetate, tetrahydrofuran, etc. are preferably used. Especially, the use of acetone is most suitable.

The neutralization and dissolution will be described below. Neutralization,
The dissolution is performed by neutralizing the basic substance in water to a neutralization degree of 1 or less, then mixing the solution with the hydrophilic organic solvent and heating. If the degree of neutralization exceeds 1, the fatty acid as an impurity is also neutralized, and the removal efficiency is significantly reduced.
When the neutralization degree is 0.2 or less, the ratio of the acid type N-long chain acylamino acid is large, the solubility in the recrystallization solvent is high, and the yield may be significantly deteriorated. Further, since the proportion of the acid type increases, the filterability of the precipitated crystals becomes poor. The amount of the solvent may be 5 ml or more, preferably 10 ml or more per 1 g of the crude N-long chain acylamino acid so that a good slurry can be obtained. As for the solvent / water ratio, when the amount of water increases, two layers separate when dissolved. If it is too small, it will not dissolve. Therefore, the solvent / water ratio is 5/1 to 50 by volume.
The range of / 1 is desirable.

Cooling and precipitation will be described below. The cooling may be performed with stirring or with standing. If the cooling rate is too fast, a good slurry cannot be obtained. If it is too late, it is not economical. The cooling temperature is
It may be at a temperature at which a sufficient amount of slurry can be obtained,
It is about -25 ° C. The deposition time is, after reaching the predetermined temperature,
It should be longer than the time to reach equilibrium. Next, the filtering will be described. The filtration can be carried out by a method such as centrifugation or vacuum filtration according to a conventional method. The crystals after filtration may be washed with a solvent if necessary. In short, the preferable manufacturing method of the present invention is the manufacturing method shown in the gist (1) shown in the above-mentioned "Means for solving the problem".

[0012]

EXAMPLES The present invention will be described in more detail with reference to Examples and Comparative Examples. Example 1 50 g of crude N-decanoyl-L-aspartic acid having a free fatty acid content of 2.8% by weight, 6.96 g of sodium hydroxide and 7 parts of water.
Add 5 ml and 1275 ml of acetone and heat to 40 ℃.
It was neutralized and dissolved in. This degree of neutralization is 0.5. After dissolution, 0.
Cooling was started at a cooling rate of 2 ° C./min and cooled to 0 ° C. After cooling to 0 ° C. and holding for 2 hours, the precipitated crystals were filtered off. After drying the crystals, 51.8 g of purified N-decanoyl-L-aspartic acid sodium salt was obtained.
The amount of free fatty acid was 0.2% by weight. Example 2 Tetrahydrofuran 1 instead of 1275 ml of acetone
The same operation as in Example 1 was performed except that 275 ml was used, to obtain 47.8 g of purified N-decanoyl-L-aspartic acid sodium salt. The amount of free fatty acid was 0.2% by weight. Example 3 1275 ml of ethyl acetate instead of 1275 ml of acetone
Using the same procedure as in Example 1 except that 1 was used, 47.8
g of purified N-decanoyl-L-aspartic acid sodium salt was obtained. The amount of free fatty acid was 0.1% by weight. Comparative Example 1 Hexane 127 instead of 1275 ml of acetone
Although the same operation as in Example 1 was tried to be performed using 5 ml, recrystallization could not be performed due to an insoluble content at the time of neutralization and dissolution.

Example 4 Crude N-tridecanoyl-L having a free fatty acid content of 2.8% by weight
-Leucine 50g sodium hydroxide 1.22g, water 25
0 ml and 2000 ml of acetone were added and neutralized and dissolved at 40 ° C. This degree of neutralization is 0.2. After the dissolution, cooling was started at a cooling rate of 0.2 ° C / min and cooled to 0 ° C. After cooling to 0 ° C. and holding for 2 hours, the precipitated crystals were filtered off. After drying the crystals, 42.0 g of purified N-tridecanoyl-L-leucine sodium salt was obtained. The amount of free fatty acid was 0.2% by weight. Example 5 Purification of 41.4 g was carried out by the same procedure as in Example 4 except that sodium hydroxide (3.02 g) was used instead of sodium hydroxide (1.22 g) so that the degree of neutralization was 0.5. N-tridecanoyl-L-leucine sodium salt was obtained. The amount of free fatty acid was 0.2% by weight. Example 6 Purification of 42.6 g was performed by the same procedure as in Example 4 except that 6.11 g of sodium hydroxide was used instead of 1.22 g of sodium hydroxide so that the degree of neutralization became 1.0. N-tridecanoyl-L-leucine sodium salt was obtained. The amount of free fatty acid was 0.8% by weight.

Comparative Example 2 The same operation as in Example 4 was carried out except that the basic substance was not used, and 4.0 g of purified N-tridecanoyl-L-leucine was obtained. The amount of free fatty acid was 0.2% by weight. The yield was not always sufficient. Comparative Example 3 The same operation as in Example 4 was carried out except that sodium hydroxide (7.32 g) was used instead of sodium hydroxide (1.22 g) so that the degree of neutralization was 1.2. Purification of N-
Tridecanoyl-L-leucine sodium salt was obtained. The amount of free fatty acid was 2.7% by weight. Example 7 Crude N-palmitoyl-L- having a free fatty acid content of 2.6% by weight
50 g of isoleucine, 2.71 g of sodium hydroxide and 7 parts of water
5 ml and 1275 ml of acetone were added and neutralized and dissolved at 40 ° C. This degree of neutralization is 0.5. After the dissolution, cooling was started at a cooling rate of 0.2 ° C / min and cooled to 0 ° C. After cooling to 0 ° C. and holding for 2 hours, the precipitated crystals were filtered off. After drying the crystals, 47.4 g of purified N-palmitoyl-
L-Isoleucine sodium salt was obtained. The amount of free fatty acid was 0.2% by weight.

Example 8 43 g of the same procedure as in Example 7 was carried out except that 3.80 g of potassium hydroxide was used instead of 2.71 g of sodium hydroxide so that the degree of neutralization was 0.5. Purified N-palmitoyl-L-isoleucine potassium salt was obtained. The amount of free fatty acid was 0.3% by weight. Example 9 The same operation as in Example 7 was performed except that 6.84 g of triethylamine was used instead of 2.71 g of sodium hydroxide so that the degree of neutralization became 0.5, and 49.5 g of purified N- was used. Palmitoyl-L-isoleucine triethylamine salt was obtained. The amount of free fatty acid was 0.4% by weight. Example 10 Purification of 52.5 g was carried out by the same procedure as in Example 7 except that 11.78 g of L-arginine was used instead of 2.71 g of sodium hydroxide so that the degree of neutralization became 0.5. An N-palmitoyl-L-isoleucine arginine salt was obtained. The amount of free fatty acid was 0.3% by weight.

[0016]

EFFECTS OF THE INVENTION According to the present invention, impurities such as long-chain fatty acids and long-chain fatty acid salts are low (low free fatty acid content), high purity, low irritation, and high solubility in solvents. Therefore, a good quality N-long chain acylamino acid salt can be easily produced.

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Claims (7)

[Claims] 1. A crude N-long-chain acylamino acid containing a fatty acid or a salt thereof as an impurity is neutralized to a neutralization degree of 1 or less (0 is not included) by adding a basic substance and water to make it hydrophilic. After adding an organic solvent and heating to dissolve the whole system, the system was cooled to precipitate N-long chain acylamino acid salt crystals, and the precipitated crystals were separated by filtration and collected to obtain N in which the impurities were significantly reduced. -A method for producing a high-purity N-long-chain acylamino acid salt, which comprises obtaining a long-chain acylamino acid salt. 2. The method for producing a highly pure N-long chain acylamino acid salt according to claim 1, wherein the degree of neutralization is in the range of 0.2 to 1. 3. A crude N-long-chain acylamino acid is obtained by reacting a linear saturated fatty acid halide having 10 to 18 carbon atoms with an amino acid in the presence of an alkali, and after the reaction is completed, the obtained crude N-long-chain amino acid is obtained. The synthetic reaction solution containing a chain acyl amino acid salt is heated and acidified with an inorganic acid to produce the compound.
Alternatively, the method for producing the high-purity N-long chain acylamino acid salt according to 2 above. 4. The basic substance is a compound selected from the group consisting of sodium hydroxide, potassium hydroxide, triethylamine, triethanolamine, aminomethylpropanol, arginine, ornithine and threonine. A method for producing a high-purity N-long-chain acylamino acid salt according to (1). 5. The method for producing a high-purity N-long chain acylamino acid salt according to claim 1, wherein the hydrophilic organic solvent is acetone, ethyl acetate, or tetrahydrofuran. 6. The method for producing a highly pure N-long chain acylamino acid salt according to claim 1, wherein the amino acid is a neutral amino acid or an acidic amino acid. 7. The method for producing a high-purity N-long chain acylamino acid salt according to claim 3, wherein the fatty acid halide is fatty acid chloride, the alkali is sodium hydroxide or potassium hydroxide, and the inorganic acid is hydrochloric acid or sulfuric acid. .