JPH0353297B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an improved method for producing N-acylamino acid amides. N-acylamino acid amide is an oil-soluble nonionic surfactant with low toxicity, low skin irritation, and good biodegradability, and is used for applications such as antioxidants, cosmetic additives, antistatic agents, and antibacterial agents. Furthermore, since it has the property of coagulating oils when added to oils (Japanese Patent Publication No. 13434/1983), its industrial utility value as an oil coagulant is attracting attention. Conventionally, many N-acyl amino acid amides have been synthesized as intermediates for amino acid amide synthesis by a type of peptide synthesis method. That is, the amino group of an amino acid is protected with a formyl group, acetyl group, or benzyloxycarbonyl group, and then the carboxyl group of the amino acid is protected with an alkyl ester,
This is a method for synthesizing N-protected amino acid alkylamides, etc. by reacting activated phenol esters, acid halides, acid anhydrides, etc. with alkylamines, etc. In addition, a method is known in which an N-acylamino acid having an acyl group having 1 to 22 carbon atoms is directly heated and reacted with an alkylamine having 8 or more carbon atoms to obtain an N-acylamino acid amide (Japanese Patent Publication No. 52 −
18691), it is difficult to apply this method when the alkylamine has 7 or fewer carbon atoms or is ammonia. That is, the known method is N-
After mixing an acylamino acid and an amine having 8 or more carbon atoms, the desired N-acylamino acid amide can be obtained by directly heating the mixture to 160 to 200°C or by heating and dehydrating it under reflux in the presence of an inert solvent such as xylene. However, when applying this method to alkylamines having 7 or more carbon atoms, etc., the boiling point of the amines is low, so under the conditions of direct heating at 160 to 200 ° C or heating in the presence of xylene etc. This method has the disadvantage that the amine escapes and the reaction yield decreases. In addition, when the amino acid residue of the N-acyl amino acid is an acidic amino acid residue and has multiple carboxyl groups, one carboxyl group easily reacts, but the other tends to have low reactivity. Significant. Therefore, in order to obtain bis- or trisamide-substituted products, harsh anti-agricultural conditions such as high temperatures and long hours are required. Under such reaction conditions, in addition to the desired condensation reaction between the carboxyl group and the amine, oxidation of the amine and N-
By-products are generated due to exchange condensation reactions between acyl groups and amines, or side reactions such as nitrification.
Alternatively, when an optically active N-acylamino acid amide is used as a raw material, racemization proceeds at the same time, resulting in problems such as not being able to obtain the desired optically active N-acylamino acid amide. The present invention was developed as a result of intensive studies on industrially advantageous production methods for N-acylamino acid amides.
The purpose is to coexist with a water-soluble acidic boron compound as a catalyst when acylamino acids are heated to react with primary amines such as alkylamines, alkylene amines, cycloalkylamines, arylamines, etc. or ammonia without any activation. The present invention was completed based on the discovery that the N-acylamino acid amide can be obtained in high yield. The effects of the catalyst according to the present invention are that the reaction proceeds quickly at a relatively low temperature and the desired product can be obtained in high yield, that there are few side reaction products, and therefore purification is extremely easy. Even when an optically active N-acyl amino acid is used as a raw material for reaction, racemization can be suppressed. Furthermore, the catalyst is water-soluble and can be easily separated from the target product by washing the reaction solution with water or a dilute aqueous alkali solution after the reaction is completed, so it has the characteristic that it does not adversely affect the purification process. The amino acid components of the N-acyl amino acids used as raw materials in the present invention are not particularly limited, but include neutral amino acids such as glycine, alanine, valine, and leucine, nucleated amino acids such as phenylalanine, serine, threonine, etc. Examples include neutral amino acids having functional substituents, basic amino acids such as lysine and ornithine, and acidic amino acids such as glutamic acid and aspartic acid. The acyl component is not particularly limited, but has 1 to 1 carbon atoms.
Acyl groups derived from 22 saturated or unsaturated fatty acids, such as formyl, acetylpropioyl,
Caproyl, capryloyl, caprinoyl, lauroyl, myristoyl, palmitoyl, stearoyl, arachinoyl, behenoyl, oleoyl,
Examples include single fatty acid acyl groups such as linoleoyl, natural mixed fatty acid acyl groups such as coconut oil fatty acid acyl, hydrogenated beef tallow fatty acid acyl, and aromatic carboxylic acid acyl groups such as acyl benzoate and acyl cinnamate. . The general formula of the primary amine or ammonia to be reacted with N-acylamino acid by heating is as follows. RNH ₂ (wherein R represents hydrogen and an alkyl group having 1 to 22 carbon atoms, an alkylene group, a cycloalkyl group, or an aryl group) Such primary amines include methylamine, ethylamine, butylamine, hexylamine, octylamine, Linear or branched aliphatic amines such as 2-ethylhexylamine, laurylamine, cetylamine, stearylamine, alicyclic amines such as cyclopentylamine, cyclohexylamine, 4-isopropylcyclohexylamine, and aniline, benzylamine, naphthylamine, 4 Examples include aromatic amines such as -isopropylaniline. Preferred examples of the water-soluble acidic boron compound used as a catalyst to coexist in the reaction system include boric acid, metaboric acid, boron oxide, phenylboron, and boron trifluoride. These water-soluble acidic boron compounds have curing properties that significantly accelerate the reaction, and not only shorten the reaction time, but also reduce heat-labile N2 when these water-soluble acidic boron compounds coexist in the reaction system. - The desired dehydration reaction of acylamino acids and primary amines proceeds without side reactions such as decomposition. When an N-acyl acidic amino acid is selected as a raw material, a monoamide compound is the main product when the water-soluble acidic boron compound is not coexisting in the reaction system as a catalyst, whereas the reaction of the water-soluble acidic boron compound is When coexisting in the system, bisamide compounds can be obtained in high yield. Furthermore, when an optically active N-acylamino acid amide is used as a raw material, a sufficiently practical reaction rate can be obtained even at a low reaction temperature, making it possible to obtain the desired optically active N-acylamino acid amide without causing racemization. is possible. In carrying out the present invention, N-acylamino acids and primary amines or ammonia are allowed to coexist, and a small amount of a water-soluble acidic boron compound is added.
The operation is extremely simple, as it only requires heating in the presence of an azeotropic dehydration medium or in the absence of a medium. The ratio of the raw material N-acylamino acid to the primary amine is generally preferably 1.0 to 1.2 equivalents of the primary amine per equivalent of the carboxyl group of the N-acylamino acid. That is, the primary amine consumed in the reaction is 1 equivalent per 1 equivalent of carboxyl group, but as the reaction progresses, the concentration of free amine decreases, and in order to avoid taking a long time to complete the reaction, an economically advantageous range is set. It is advisable to use a slight excess of primary amine. When the primary amine is methylamine, ethylamine and ammonia, the raw material N-
It is preferable to increase the equivalent ratio of these primary amines per carboxyl group of the acylamino acid. In other words, since these primary amines are substances with extremely low boiling points, they tend to escape from the reaction system during the heating reaction, and during the course of the reaction, these primary amines are turned into gas and are gradually released. A preferred method is to replenish the primary amine so that the equivalent ratio of these primary amines to the remaining carboxyl groups in the reaction system is 1.0 or more. The amount of the water-soluble acidic boron compound used as a catalyst is not particularly limited, but is preferably 1 to 20% by weight based on the N-acylamino acid. That is, if it is less than 1% by weight, the reaction promoting effect as a catalyst will not be sufficient, and if it exceeds 20% by weight, it will likely be disadvantageous economically and in the catalyst removal operation after the reaction is completed. The heating temperature during the reaction is generally preferably 100°C or higher in order to remove water generated by the reaction in the case of no medium.The higher the heating temperature, the faster the reaction, but in order to suppress side reactions, , 110-140°C is most preferred. Particularly when obtaining optically active N-acylamino acid amides, in order to suppress racemization,
110-125°C is most preferred. Reaction without a medium is preferable when using a primary amine with 8 or more carbon atoms, but when using a primary amine with less than 8 carbon atoms or ammonia, operability such as stirring tends to be poor, so Some effort is needed. On the other hand, when a heating reaction is carried out in the coexistence of an azeotropic dehydration medium, the water produced by the reaction is easily removed from the reaction system by azeotropy, so primary amines or ammonia with less than 8 carbon atoms are used as raw materials. It is also suitable for use as a There are no particular restrictions on the azeotropic dehydration medium as long as it does not react with the raw material N-acylamino acids, primary amines, or ammonia, but carbonization is preferred because it can be easily washed in separate layers with water, acid, or alkaline aqueous solution after the reaction is completed. Hydrogen compounds are most suitable. The most preferred azeotropic medium is a hydrocarbon compound with a boiling point of 98 to 140°C. In other words, the boiling point
If the temperature is less than 98°C, the temperature of the reaction system is too low to obtain a sufficient reaction rate, and if the boiling point exceeds 140°C, the reaction may be rapid but may cause decomposition of N-acylamino acids, oxidation of amines, etc. This is because undesirable side reactions proceed. Hydrocarbon compounds with a boiling point of 98-125°C are the most preferred azeotropic media, especially when racemization needs to be suppressed, such as heptane, isooctane, methylcyclohexane, cycloheptane, methylcyclohexene, diisobutylene, toluene, octane, etc. , compounds such as octene and dimethylcyclohexane, and mixtures thereof, or mixtures of these compounds and high-boiling hydrocarbon compounds such as xylene as appropriate to raise the boiling point to 125°C.
Suitable examples include mixtures prepared below. The time required for the reaction varies depending on the raw materials used for the reaction, the heating temperature, the type and amount of the catalyst added, etc., but the reaction is completed in about 1 to 35 hours. After the reaction is completed, the desired N-acylamino acid amide can be isolated by heating and dissolving it in an organic solvent such as ethyl acetate after the reaction, and removing insoluble substances such as the catalyst when the reaction is carried out without a medium. Thereafter, the desired N-acylamino acid amide can be obtained by cooling and recrystallizing. Depending on the type of N-acylamino acid amide, not only oils but also organic solvents such as ethyl acetate may be gelled. In such cases, the entire gelation occurs without crystallization upon cooling, so the reaction is slow. By repeatedly slurry washing the composition with water, acid or aqueous alkali solutions, the catalyst, unreacted raw materials or side reaction products can be removed to obtain the desired N-acylamino acid amide. When a hydrocarbon compound or the like is used as the azeotropic dehydration medium, it is also possible to remove the azeotropic dehydration medium by distillation after the completion of the reaction and then recrystallize it from an organic solvent such as ethyl acetate as described above. The following method can be used by utilizing the property that N-acylamino acid amide is sparingly soluble in water. That is, water is added to the reaction mixture, thoroughly stirred, and then separated into layers, and the catalyst is extracted and removed from the aqueous layer. Similarly, by using a dilute aqueous mineral acid solution or a dilute alkali aqueous solution, unreacted primary amines, N-acylamino acids, side reaction products, etc. are extracted and removed. By repeating this operation, the desired N
- Acyl amino acid amides can be purified as a mixture with an azeotropic dehydration medium. When carrying out this method, the presence of a hydrocarbon compound used as an azeotropic dehydration medium facilitates phase separation and simplifies the operation. In particular, when the target N-acylamino acid amide has the property of gelling oils, it often gels the hydrocarbon compound used as the azeotropic dehydration medium, and during phase separation, the hydrocarbon compound layer is Since it floats as a granular gel-like composition, the aqueous layer can be easily separated and removed. After the purification is completed, water is added to the mixture of the azeotropic dehydration medium and the N-acylamino acid amide, and the azeotropic dehydration medium is distilled off by steam distillation or azeotropic distillation with water while stirring. As a result, an aqueous slurry of the target N-acylamino acid amide is obtained, which is subjected to solid-liquid separation and dried to isolate the target product. According to this method, solid-liquid separation only needs to be performed once in the final step, and everything from reaction to purification can be carried out in one reaction apparatus, which simplifies the production apparatus and greatly simplifies process operations. Hereinafter, the present invention will be explained in detail with reference to Examples, but it goes without saying that the present invention is not limited thereto. Example 1 329 g of N-lauroyl-L-glutamic acid (1
149 g (2.04 mol) of n-butylamine and 30 g of boric acid were added to 1 mol of toluene, an H-tube was attached, and the mixture was heated and refluxed for 24 hours.
molar). The reaction solution was extracted and separated in sequence with 2 parts of a 0.5N sulfuric acid solution, 2 parts of a 0.5N caustic soda solution, and 2 parts of water, and then washed. Two parts of water was added and heated with stirring to distill out one part of toluene together with water to form an aqueous slurry. I got it. This is overdried to obtain the desired N-lauroyl-L-glutamic acid bis-n-butylamide.
430g (yield 98%) was obtained. mp148～150℃ Elemental analysis value C(%) H(%) N(%) Calculated value 68.29 11.23 9.56 Actual value 68.37 11.18 9.58 Also, the light intensity of this product matches that of the standard product as shown below, and there is no racemization. was not accompanied. Sample Light intensity (250 nm: 1% ethanol solution) Example -305° Control -308° Comparative example 329 g of N-lauroyl-L-glutamic acid (1
mol) and n-butylamine 149 g (2.04 mol)
were added to xylene 1 (comparative example 1) or toluene 1 (comparative example 2), respectively.
8 hours in Comparative Example 1, and 8 hours in Comparative Example 2.
A heating reaction was carried out for 45 hours. Similar to Example 1,
The reaction solution was extracted and separated into layers and washed successively with an aqueous sulfuric acid solution, an aqueous caustic soda solution, and water, and then the solvent was removed azeotropically and overdried to obtain N-lauroylglutamic acid bis-n-butylamide. Table the results.
Shown in 1. As shown in Table 1, in Comparative Example 1, racemization was found to have progressed significantly. Comparative Example 2 had an extremely low yield, but this was due to the fact that most of the product was extracted and removed during the extraction phase washing with an aqueous caustic soda solution. Solid substance obtained by adding sulfuric acid to the extract and neutralizing it to PH2 318
It was confirmed by comparison with a standard product obtained by a known method that N-lauroylglutamic acid mono-n-butylamide was the main component of g.

[Table] Example 2 As shown in Table 2, 0.5 mol of various N-acyl glutamic acids and 1.1 mol of various primary amines were each placed in 500 ml of azeotropic dehydration medium, and 10 g of each water-soluble acidic boron compound was added. When an H-shaped tube was attached and each sample was heated and refluxed at a specified temperature for 24 hours, 1 mole (18 ml) of water was collected at the bottom of each H-shaped tube. After extracting and washing the reaction solution sequentially with 1 part of 0.5N sulfuric acid solution, 1 part of 0.5N ammonia solution, and 1 part of water, 1 part of water was added, heated steam was blown in, and 500 ml of azeotropic dehydration medium was removed by steam distillation. An aqueous slurry was obtained. This was overdried and N-
Acylglutamic acid bisamide was obtained. The amount and yield of the obtained bisamide are collectively shown in the same table.

[Table] * Cocoyl: Coconut oil fatty acid acyl Example 3 217 g (1 mol) of N-caproyl aspartic acid and 266 g (2.06 mol) of 2-ethylhexylamine were added to 1 toluene, 20 g of metaboric acid was added, and H When a tube was attached and the mixture was heated and refluxed for 20 hours, 36 ml (2 moles) of water was produced. The reaction solution was washed with 2 parts of 0.5N hydrochloric acid solution, 2 parts of 0.5N caustic potassium solution, and 2 parts of water, and then 2 parts of water was added and heated with stirring to distill 1 part of toluene together with water to form an aqueous slurry. I got it. This is then dried and the desired N
-439 g (yield 97%) of caproylalpartic acid bis-2-ethylhexylamide was obtained. mp.137~
140℃ Elemental analysis value C(%) H(%) N(%) Calculated value 68.83 11.33 9.26 Actual value 68.74 11.38 9.20 Example 4 273g (1 mol) of N-capryloylglutamic acid, 400g (2.16 mol) of laurylamine, and metabolous 20g of acid was placed in a reaction vessel equipped with a stirrer, nitrogen suction pipe and dehydrator, heated to 120℃,
Stir while passing nitrogen gas at a rate of 1 min.
The reaction was carried out for 6 hours. 18 ml of water was distilled out at the bottom of the dehydrator. After cooling, the contents of the reactor were heated and dissolved in 3 ml of ethyl acetate. After excessively removing insoluble metaboric acid, it was cooled to precipitate N-capryloylglutamic acid bislaurylamide, yielding 577 g of white crystals.
(yield 95%). mp.128-130℃ Elemental analysis value C(%) H(%) N(%) Calculated value 73.09 12.10 6.91 Actual value 73.18 12.15 6.85 Example 5 As shown in Table-3, 0.5 mol of various N-acyl amino acids and 0.6 mol of various primary amines in toluene.
After adding 500 ml and 10 g of metaboric acid to each, an H-shaped tube was attached and heating and reflux was performed for 24 hours, resulting in 9 ml (0.5 mol) of water collecting at the bottom of each H-shaped tube. After extracting and washing the reaction solution with 500 ml each of 0.5N hydrochloric acid, 0.5N potassium hydroxide aqueous solution, and water in sequence, 1 portion of water was added, and 500 ml of toluene was removed by steam distillation to form an aqueous slurry. Obtained. This was overdried to obtain N-acylamino acid amide. The amount and yield of the obtained N-acyl amino acids are shown in the same table.

[Table] Example 6 229 g of NN'-dicaprinoyllysine and 20 g of metaboric acid were added to 500 ml of toluene, an H-tube was attached, and while heating and refluxing with stirring, dry ammonia gas was added at 15 ml per minute. 500ml each was injected from the bottom of the reaction vessel. Furthermore, when heating and refluxing was continued for 5 hours while blowing dry ammonia gas from the bottom of the reaction vessel at a rate of 50 ml per minute, 9 ml of water accumulated at the bottom of the H-shaped tube. After sequentially extracting and washing the reaction solution with 500 ml each of 0.5N hydrochloric acid, 0.5N sodium hydroxide, and water, 500 ml of water was added, and 500 ml of toluene was distilled off while blowing in steam to form an aqueous slurry.
Obtained 900ml. After this, dry the solid matter.
224 g of NN'-dicaprinoyllysinamide (yield
98%).

Claims (1)

[Claims] 1. An N- acyl amino acid, characterized in that a water-soluble acidic boron compound is allowed to coexist in the reaction system when producing an N-acyl amino acid amide by heating the N-acyl amino acid and a primary amine or ammonia. A method for producing acylamino acid amide. 2. The method for producing an N-acylamino acid amide according to claim 1, in which a hydrocarbon compound or hydrocarbon mixture having a boiling point of 98 to 125°C is used as the azeotropic dehydration medium.