JPS6150A - Production of n-acylaminoacid amide - Google Patents

Abstract

PURPOSE:The reaction of N-acylaminoacid with a primary amine is conducted in the presence of a catalyst of a water-soluble acidic boron compound to enable high-yield production of the titled compound which is used as an oil-soluble nonionic surface active agent with reduced skin irritation and good biodegrability. CONSTITUTION:The reaction of an N-acylaminoacid with an amine of the RNH2 (R is H, 1-20C alkyl, alkylene, cycloalkyl, aryl) is carried out in the presence of a water-soluble, acidic boron compound such as boric acid, metaboric acid, boron oxide at a temperature over 100 deg.C, preferably 100-140 deg.C (at 110-125 deg.C, in order to suppress recemization, when an optically active N-acylaminoacid is desired) to give the objective compound. The use of a hydrocarbon boiling at 98- 125 deg.C for azeotropic distillation is suitable for a primary amine of 8 or less carbon atoms and ammonia. USE:Antioxidant, perfume additive, antistatic agent, antifungal, oil coagulant.

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, antibacterial agents, etc. Also, because it has the property of coagulating oils when added to them (Japanese Patent Publication No. 53-134)
3.4 Publication), 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 by a formyl group, an acetyl group, or a benzyloxycarp with a nyl group, and then the cal of the amino acid activates the xyl group in the form of an alkyl ester, phenol ester, acid halide, or acid anhydride. In this method, N-protected amino acid alkylamide and the like are synthesized by reacting with an alkylamine and the like.

Furthermore, a method is known in which an N-acylamino acid amide 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. In other words, the known method involves mixing an N-acylamino acid and an amine having 8 or more carbon atoms, and then directly heating the mixture to 160 to 200°C.
7 is a method for obtaining the desired N-acylamino acid amide by heating under reflux dehydration in the presence of an inert solvent such as xylene, but this method is applied to alkylamines having 7 or less carbon atoms, etc. In this case, since the boiling point of the amine is low, the amine dissipates under conditions of direct heating at 160 to 200°C or heating in the presence of xylene, etc., and the reaction yield decreases. . Also, N
- When the amino acid residue of the acyl amino acid is an acidic amino acid residue and has a plurality of carboxyl groups, one carboxyl group reacts easily, but the other carboxyl group tends to have a markedly low reactivity.

Therefore, in order to obtain a bis- or trisamide substituted product, harsh reaction conditions such as high temperature and long time are essential. Under such reaction conditions, in addition to the desired condensation reaction between carboxyl groups and amines, by-products may be generated due to side reactions such as oxidation of amines, exchange condensation reactions between N-acyl groups and amines, or nitrification. 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.

As a result of intensive studies on an industrially advantageous production method for N-acylamino acid amides, the present inventors have discovered that primary production methods such as alkylamines, alkylene amines, cycloalkylamines, arylamines, etc. can be produced without activating N-acylamino acids. The present invention was completed based on the discovery that the target N-acylamino acid amide can be obtained in high yield by allowing a water-soluble acidic boron compound to coexist as a catalyst during the heating reaction with an amine or ammonia.

The effects of the catalyst according to the present invention are that the reaction proceeds quickly at a relatively low temperature and the target product can be obtained in high yield;
It produces few side reaction products, making purification extremely easy, and because it reacts at low temperatures, racemization can be suppressed even when an optically active N-acylamino acid is used as a raw material. Furthermore, the dissolved catalyst is water-soluble and can be easily separated from the target product by washing the reaction solution with water or a dilute alkali aqueous 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, and functional amino acids such as serine and threonine. Neutral amino acids with substituents, basic amino acids such as lysine and ornithine, glutamic acid, Asno-4
Examples include acidic amino acids such as lagic acid. The acyl component is not particularly limited, but has 1 to 22 carbon atoms.
Single fatty acid acyl groups derived from saturated monounsaturated fatty acids, such as formyl, acetylprogyoyl, caproyl, capryloyl, cabrinoyl, lauroyl, myristoyl, balmitoyl, stearoyl, arachinoyl, pehenoyl, oleoyl, caloyl, etc. In addition to natural mixed fatty acid acyl groups such as Coconut oil fatty acid acyl and hydrogenated beef tallow fatty acid acyl, aromatic carginic acid acyl such as benzoic acid acyl and cinnamic acid acyl can be exemplified.

The general formula of the primary amine or ammonia to be reacted with N-acylamino acid by heating is as follows.

NH2 (However, R is hydrogen and an alkyl group having 1 to 22 carbon atoms,
Examples of such -class amines include methylamine, ethylamine, butylamine, hexylamine, octylamine,
Straight chain or branched aliphatic amines such as 2-ethylhexylamine, laurylamine, cetylamine, sudearylamine, cyclopentylamine, cyclohexylamine,
All examples include alicyclic amines such as 4-isopropylcyclohexylamine, and aromatic amines such as aniline, benzylamine, naphthylamine, and 4-inzolotamine.

As the water-soluble acidic boron compound used as a catalyst to coexist in the reaction system, boric acid, metaboric acid, boron oxide, phenylboric acid, boron trifluoride, etc. are suitable.

These water-soluble acidic boron compounds have the effect of significantly accelerating the reaction, not only shortening the reaction time, but also reducing thermally unstable N2 when these water-soluble acidic boron compounds are present in the reaction system. - The desired dehydration reaction of acylamino acids and general amines proceeds without causing 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; 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. It is possible.

To carry out the present invention, it is only necessary to coexist N-acylamino acids with general amines or ammonia, add a small amount of water-soluble acidic boron compound, and heat in the presence of an azeotropic dehydration medium or in the absence of a medium. It's really simple.

The ratio of the raw material N-acylamino acid to the general amine is generally preferably 1 equivalent of the carboxyl group of the N-acylamino acid and 1.0 to 1.2 equivalents of the -class amine. That is,
The amount of general amine consumed in the reaction is 1 equivalent per equivalent of carboxyl group, but as the reaction progresses, the concentration of free amine is preferably reduced. When the -class amine is methylamine, ethylamine, or ammonia, it is preferable to increase the equivalent ratio of these general amines per carboxyl group of the N-acylamino acid as a raw material. In other words, since these -class 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 general amines are turned into gas and a small amount is released. It is preferable to replenish the general amines in stages so that the equivalent ratio of these general amines to the remaining carboxyl groups in the reaction system becomes 1.0 or more.

The amount of the water-soluble acidic boron compound used as a catalyst is not particularly limited, but it is 1-2% per N-acylamino acid.
0% by weight is preferred. That is, if the amount is less than 1% by weight, the reaction promoting effect as a catalyst will not be sufficient, and if the amount is less than 1% by weight,
If it exceeds %, it is likely to 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 more the reaction is promoted, but in order to suppress side reactions, the heating temperature is most preferably 110 to 140°C.

In particular, when obtaining an optically active N-acylamino acid amide, the temperature is most preferably 110 to 125°C in order to suppress racemization. The reaction without a medium is preferable when using a general amine with a carbon number of 8 or more, and when using a general amine with a carbon number of less than 8 or ammonia, the ability to produce plums such as stirring tends to be poor, so please be careful of the equipment etc. 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 general amines or anthonia with less than 8 carbon atoms are used as raw materials. It is also suitable for use as a The azeotropic dehydration medium is not particularly limited as long as it does not react with the raw material N-acyl amino acid, general amine, or ammonia.
Hydrocarbon compounds are most suitable because they can be easily washed in separate layers with water, an acid, or an aqueous alkali solution after the reaction is completed. The most preferred azeotropic medium is a hydrocarbon compound having a boiling point of 98 to 140°C. That is, when the boiling point is less than 98°C, the temperature of the reaction system is too low to obtain a sufficient reaction rate, and when the boiling point is over 140°C, the reaction is rapid, but the decomposition of N-acyl amino acids and amine This is because undesirable side reactions such as oxidation of Hydrocarbon compounds with a boiling point of 98-15°C are the most preferred azeotropic media, especially when it is necessary to increase the racemization temperature, such as heptane, isooctane, methylcyclohexane, cyclohezotane, methylcyclohexene, diisobutylene. Preferred examples include mixtures in which high-boiling hydrocarbon compounds such as toluene, octane, and octenene are appropriately mixed to have a boiling point of 125° C. or higher.

The time required for the reaction varies depending on the raw materials used for the reaction, the heating temperature, the type and amount of catalyst added, etc., but is approximately 1 to 35 minutes.
The reaction completes in time.

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. After that, it is cooled and recrystallized to obtain the desired N-
Acyl amino acid amides can be obtained. Depending on the type of N-acylamino acid amide, it may gel not only oils but also organic solvents such as ethyl acetate, and in such cases, the entire product will not crystallize when cooled, so
The desired N-acylamino acid amide can be obtained by repeatedly slurry washing the reaction composition with water, acid or aqueous alkali solution, etc. to remove the catalyst, unreacted raw materials or side reaction products.

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 reaction is completed, 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 solution of mineral acid or a dilute alkali solution, unreacted general amines, N-acylamino acids, side reaction products, etc. are extracted and removed.

By repeating this operation, the target N-acylamino acid amide can be purified as a mixture with the azeotropic dehydration medium. When carrying out this method, the presence of a hydrocarbon compound used as an azeotropic dehydration medium facilitates phase separation and facilitates 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 Since it floats as a granular 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 desired N-acylamino acid amide is obtained, which is subjected to solid-liquid separation,
The target product is isolated by drying. 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 I 329 g (1 mol) of N-lauceyl L-glutamic acid, 149 g of n-butylamine. ! Li' (2.04 mol) and 30 g of boric acid were added to 11 toluene, and an H-tube was attached and heated under reflux for 24 hours.
mol).

The reaction solution was mixed with 0.5N sulfuric acid aqueous solution 21.0.5N caustic soda aqueous solution 821. After washing by successively extracting and separating layers with 21 parts of water, 2 parts of water was added and heated while stirring to distill toluene 11 together with water to obtain an aqueous slurry. This was filtered and dried to obtain 430 g (yield: 98%) of the target N-lauroyl-L-glutamic acid bis-n-butylamide. m
p148~15゛0℃ Elemental analysis value C (%) H (correspondence) N (chi) Calculated value 68.29 11.23 9.56 Actual value 68
．． 37 11.18 9.58 Also, the optical rotation of this product matched that of the standard product as shown below, and there was no racemization.

Sample Optical rotation (250nrn: 19 & ethanol solution) Example -305° Control -308° Comparative example ) or toluene 17
(referred to as Comparative Example 2), and a heating reaction was performed for 8 hours in Comparative Example 1 and 45 hours in Comparative Example 2. In the same manner as in Example 1, the reaction solution was extracted and separated into layers with an aqueous sulfuric acid solution, an aqueous caustic soda solution, and water in order and washed. The solvent was azeotropically removed, and N-lauroylglutamic acid bis-n-butylamide was obtained by filtration and drying. Obtained. The results are shown in Table-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 extraction phase washing with an aqueous caustic soda solution. . A comparison with a standard product obtained by a known method shows that the main component of the solid substance 318#Fi'N-uraloylglutamic acid mono-n-butyramide is obtained by adding sulfuric acid to the symptomatic fluid and neutralizing it to pH 2. Confirmed by.

Example 2 As shown in Table 2, various N-diacylinutamic acids 0
．． 5.Put each of the various -grade amine 1.1 cells in 500 m of azeotropic dehydration medium, add 10 f of a water-soluble acidic boron compound to each, then attach an H-shaped tube and heat under reflux at the specified temperature for 24 hours. However, 1 mole of water (1
8 m) were placed in the bottom of each H-tube.

The reaction solution was extracted and washed sequentially with 0.5 N sulfuric acid aqueous solution IJ, 0.5 N aqueous anthonia solution 17 and water 17, and then water 17. was added, heated steam was blown in, and the azeotropic dehydration medium 500- was removed by steam distillation to obtain an aqueous slurry. This was filtered and dried to obtain N-acylglutamic acid bisamide. The amount and yield of the obtained bisamide are collectively shown in the same table.

Example 3 N-casoloyl asparayanic acid 217y- (1 mol) and 2-ethylhexylamine 266 fF (2.06 mol) were mixed in 1 toluene! In addition, 20 f/metaboric acid was added, an H-tube was attached, and the mixture was heated under reflux for 20 hours, yielding 36 d (2 moles) of water.

The reaction solution was mixed with 0.5 N hydrochloric acid aqueous solution (27) and 0.5 N caustic potassium aqueous solution (2!). , After washing the extracted layers in sequence with 2j of water, 2j of water! Add and heat while stirring to make toluene! was distilled off with water to obtain an aqueous slurry. This was filtered and dried to produce the desired N-caproylalpartic acid bis-2-ethylhexylamide 439p (yield 97g).
I got it.

mp, 137-140°C Elemental analysis value C (excellent) H (%) N (chi) Calculated value 68.83 11.33 9.26 Actual value 68.74 11.38 9.20 Example 4 N-Capryloyl Glutamic acid 273% (1 mol), laurylamine 40OFF (2.16 mol) and metaboric acid 201 were placed in a reaction vessel equipped with a stirrer, a nitrogen blowing tube and a dehydrator, heated to 120°C, and nitrogen and fs were added. 1 every minute! The reaction was carried out for 6 hours while stirring at a speed of . 18 ml of water distilled out at the bottom of the dehydrator.

After cooling, the contents of the reactor were diluted with ethyl acetate 3! The mixture was heated and dissolved. After removing insoluble metaboric acid by filtration, it is cooled and N
-Capryloylglutamic acid bislaurylamide was precipitated to obtain white crystals 577FF (yield: 95%). m
p, 12'8~130℃ elemental analysis value C (chi)
f((chi) N(chi) Calculated value 73.09
12.10 6.91 Actual value 73.18 12
．． I5 6.85 Example 5 As shown in Table 3, each mN-acylamino acid 0.5
mole and each m-9 amine 0.6 mole toluene 5001n
In addition to t and 10F of metaboric acid, H
After attaching a cross tube and heating and refluxing for 24 hours, water 9.
td (0.5 mol) was placed at the bottom of each H-shaped tube.

The reaction solution was sequentially extracted and washed with 0.5N hydrochloric acid, 0.5N aqueous potassium hydroxide solution and 500% water, and then 1% water. was added, and 500% of toluene was removed by steam distillation to obtain an aqueous slurry. This was filtered and dried to obtain N-acylamino acid amide. The amount and yield of the N-acyl amino acids obtained are shown in the same table.

Example 6 NN'-Cicaprinoyl lysine 229z and metaboric acid 20p were added to 500 dK of toluene, an H-tube was attached, and while heating and refluxing was carried out with stirring, 15% of dry anthonia gas was added. 500+7 per minute! The mixture was injected into the bottom of the reaction vessel. Furthermore, while blowing dry ammonia gas from the bottom of the reaction vessel at a rate of 50 d/min, heating and refluxing was carried out for 5 d/min.
After continuing for a while, 9-ounces of water was collected at the bottom of the H-shaped tube.

The reaction solution was extracted and washed with 500 d each of 0.5 N hydrochloric acid, 0.5 N sodium hydroxide, and water, and then 500 ml of water was added and toluene 500 ml was removed by distillation while blowing in steam. Thus, an aqueous slurry 90C)- was obtained. This was filtered and the solid material was dried to obtain NN'-Cicaprinoyl lysine amide 224i (yield: 98h).

Claims (2)

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