JP3326700B2 - Method for producing amide group-containing guanidine derivative or salt thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a high-purity guanidine derivative containing an amide group or a salt thereof for applying a guanidine derivative having a strong basicity to a wide range of uses.

[0002]

2. Description of the Related Art Compounds having a guanidine group have been used in the fields of pharmaceuticals, agricultural chemicals, bactericides, insecticides, useful metal collectors, chelating agents, etc., taking advantage of their strong basicity and antibacterial properties. However, there are only a few examples of applications as surfactants that make use of their basicity, such as arginine derivatives and amide group-containing guanidine derivatives.

The first reason is that when a compound having a structure in which a linear alkyl group is a lipophilic group and a guanidine base is a hydrophilic group is used as, for example, a fabric softener or a hair rinsing agent, the compound has a cationic property. Although excellent in the adsorptivity to fiber or hair, it has a sticky or heavy finish and has difficulty in finish performance.

[0004] The second reason is that the purification method of guanidine derivatives is generally complicated. Conventionally, after the reaction, purification methods such as preparative liquid chromatography, column chromatography, solvent extraction, and recrystallization are used in combination as necessary.

An arginine derivative or an amide group-containing guanidine derivative is disclosed in JP-B-51-22055,
-80667, JP-A-2-243614, JP-A-4-3
The finishing performance is good as described in No. 4080, and it has more excellent performance as compared with general-purpose quaternary ammonium type cationic surfactants. However, the purification method is still complicated, and even when purified by the above-described purification method, insolubles may be generated when a water and / or alcohol solution is used. For example, when these derivatives are used as hair cosmetics, stability may be problematic due to the presence of a trace amount of impurities.

[0006] Therefore, of the high-performance arginine derivatives and amide-containing guanidine derivatives, amide-containing derivatives which are considered to have a variation in structure and can be produced at lower cost and have excellent solubility in water and / or alcohol. It has been desired to develop a rational production method for guanidine derivatives.

[0007]

SUMMARY OF THE INVENTION The present invention provides a method for advantageously producing an amide group-containing guanidine derivative or a salt thereof having high purity and excellent solubility and stability in water and / or alcohol. With the goal.

[0008]

According to the present invention, there is provided a compound represented by the following general formula (I):

Embedded image (Wherein, R ¹ is a linear or branched alkyl or alkenyl group having 1 to 22 carbon atoms. R ² , R ^2
3 is a hydrogen atom or a linear or branched alkyl group or a hydroxylalkyl group having 1 to 4 carbon atoms, which may be the same or different. A is a linear or branched alkylene group or alkenylene group having 1 to 10 carbon atoms. Immediately after the heat treatment under reduced pressure or heated nitrogen bubbling, or after storage in a carbon dioxide-free atmosphere, the amidoamine represented by the formula (1) is converted into guanidine using a guanidination reagent and then the impurities are removed. Characteristic general formula (II) below:

Embedded image (Wherein, R ¹ is a linear or branched alkyl or alkenyl group having 1 to 22 carbon atoms. R ² , R ^2
3 is a hydrogen atom or a linear or branched alkyl group or a hydroxylalkyl group having 1 to 4 carbon atoms, which may be the same or different. A is a linear or branched alkylene group or alkenylene group having 1 to 10 carbon atoms. The present invention provides a method for producing an amide group-containing guanidine derivative represented by the formula (1) or a salt thereof, in particular, when performing the guanidination reaction of the amidoamine, in the presence of a small amount of alcohols or ethers, The means for removing is crystallization, and
In the crystallization step, especially the crystallization and filtration temperatures are:
A method for producing the amide group-containing guanidine derivative or a salt thereof, characterized in that the solubility of bisamide by-produced in the guanidination reaction step in a crystallization solvent is at least 0.1% or more. .

That is, in the present situation, the present inventors have conducted intensive studies, and as a result, the amidoamine was immediately heated or decompressed or heated with nitrogen bubbling, or under an atmosphere free from carbon dioxide (for example, nitrogen atmosphere). After storage under (2), guanidine is formed by a usual method while controlling the reaction temperature, and the insoluble matter in water and / or alcohol solution is clarified. Further, they have found that an amide group-containing guanidine derivative having excellent solubility in water and / or alcohol can be produced, and thus completed the present invention.

Hereinafter, the present invention will be described in more detail. The reaction in the production method of the present invention is represented by the following reaction formulas (I) and (II) in Table 1. In the present invention, an amidoamine (for example, obtained by reacting a diamine having a primary and / or secondary amino group with a general acylating agent) is subjected to the pretreatment of the present invention, and then a small amount of alcohol or ether is added. The reaction temperature is controlled by a method such as adding a solvent such as guanidine, while suppressing side reactions, in the presence of a general inorganic or organic acid, guanidination with a normal reaction reagent such as cyanamide or S-methylisothiourea. Performing the reaction to obtain an amide group-containing guanidine derivative crude reactant,
A water and / or alcohol solution was obtained by removing a small amount of unreacted amidoamine, unreacted guanidine reagent, bisamide of by-produced diamine and by-produced urea derivative contained in the crude reaction product in a single purification step. In this case, the present invention relates to a method for obtaining a high-purity amide group-containing guanidine derivative excellent in stability without generating a precipitate over time.

[Table 1] (Wherein R ¹ , R ² , R ³ and A are the same groups as described above. R ⁴ is a linear or branched alkyl group having 1 to 4 carbon atoms. HX is an inorganic acid or an organic acid. Represents an acid.
Y is S or O. )

The amidoamine used in the present invention can be synthesized by a known method. The diamine portion of the amidoamine is a diamine having a primary and / or secondary amino group, and can be represented by the following general formula (III).

Embedded image ^{R 2 -NH-A-NH-} R 3 ··· (III) ( wherein, R ^2, R ³ is a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, a hydroxyalkyl group. A is a linear or branched alkylene group or alkenylene group having 1 to 10 carbon atoms.) Specific examples of the diamine include diaminomethane, ethylenediamine, N-methylethylenediamine, N, N'-dimethylethylenediamine, N -Ethylethylenediamine, N, N'-diethylethylenediamine, N-propylethylenediamine, N, N'-dipropylethylenediamine, N-butylethylenediamine, N, N'-dibutylethylenediamine, N-tert-butylethylenediamine, N, N ' -Di-tert-butylethylenediamine, N-methyl-N'ethylethylenediamine, 1,2-diaminopropa 1-methylamino-2-aminopropane, 1
-Amino-2-methylaminopropane, 1,3-diaminopropane, 3-methylaminopropylamine, 1,3
-Di (methylamino) propylamine, 3-ethylaminopropylamine, 3-propylaminopropylamine, 3-butylaminopropylamine, 3-tert-butylaminopropylamine, 3- (2-hydroxyethylamino) propylamine , 1,2-diaminobutane, 1,
4-diaminobutane, 1,3-diamino-1-methylpropane, 1,3-diamino-2-methylpropane, 1,
4-diamino-1-methylbutane, 1,4-diamino-
2-methylbutane, 1,6-diaminohexane, 1,8
-Diaminooctane, 1,10-diaminodecane and the like. These can be used alone or in combination of two or more.

The acyl moiety of the amidoamine is a linear or branched short or long chain fatty acid residue, such as acetic acid,
Propionic acid, butyric acid, isobutyric acid, caproic acid, octanoic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, oleic acid,
Examples include elaidic acid, linoleic acid, linolenic acid, arachidic acid, behenic acid, coconut oil fatty acid, palm kernel oil fatty acid, palm oil fatty acid, and tallow fatty acid. These can be used alone or in combination of two or more.

The guanidination reagent used in the present invention includes cyanamide, S-methylisothiourea, S-ethylisothiourea, O-methylisourea, O-ethylisourea and the like.

The amide group-containing guanidine or a salt thereof in the method of the present invention can be obtained by pretreating an amidoamine, followed by a guanidination reaction and purification, as described above. Pretreatment conditions, reaction conditions and purification conditions are as follows:
Although it depends on the physical properties of the reaction reagents and the like, here, the reaction conditions are shown below, taking as an example the case where monolauroylethylenediamine (abbreviated as amidoamine) is converted into guanidine with cyanamide.

First, the amidoamine is stored in a heated and reduced pressure treatment, a heated nitrogen bubbling treatment or a carbon dioxide-free atmosphere (eg, a nitrogen atmosphere). When the heating and decompression treatment or the heating nitrogen bubbling treatment is not performed, or when the mixture is stored in an atmosphere containing carbon dioxide, the amidoamine absorbs the carbon dioxide, and is subjected to the following general formula (IV) during the subsequent guanidination reaction. When the urea derivative shown in (Chem. 4) is by-produced and used as a water and / or alcohol solvent after purification, precipitation may occur with the passage of time, and the mixture may be heated and reduced in pressure, heated with nitrogen bubbling, or free of carbon dioxide. Storage under an atmosphere (for example, under a nitrogen atmosphere)
Required.

Embedded image (In the formula, R ¹ , R ² , R ³ and A are the same groups as described above.)

Usually, the heating and depressurizing treatment is performed at an internal pressure of 10-700.
Under reduced pressure of about hPa, at 60 ° C. to 150 ° C. for 10 minutes to 3
Time, heating nitrogen bubbling treatment is performed at 60 ° C. to 150 ° C. for 10 minutes to 3 hours while blowing nitrogen,
In addition, storage in a carbon dioxide-free atmosphere is performed at room temperature in an atmosphere of an inert gas such as nitrogen, helium, neon, argon, or the like, until just before the reaction preparation.

Next, the pretreated amidoamine is neutralized with an inorganic acid such as hydrochloric acid or an organic acid such as acetic acid, etc., and the cyanamide in powder form or heated to a temperature higher than the melting point, or isopropyl alcohol having a solubility greater than the saturation solubility. , Etc. or an ether solvent such as tetrahydrofuran, and added all at once or dropwise. In the case of cyanamide dropwise addition, the addition time is not particularly limited, but is preferably in the range of 0.1 to 3 hours from the viewpoint of production efficiency. The reaction temperature is from 60C to 120C, preferably from 80C to 100C.
Range. Below 60 ° C., the reaction rate is slow,
At 0 ° C. or higher, undesired side reactions such as the polymerization reaction of cyanamide occur, and any case is inappropriate. When cyanamide is added without a solvent, attention must be paid to the reaction temperature control because of an exothermic reaction, but it is preferable to perform the reaction in the presence of alcohols or ethers because the reaction temperature control is easy.

The thus obtained crude reaction product of the amide group-containing guanidine derivative is purified by a purification method described below. The crude reaction product of the amide group-containing guanidine derivative can be purified by a conventional purification method to remove impurities considerably.
When a product is formulated after preparing an aqueous solution or emulsion for other uses, the presence of a small amount of impurities greatly affects the storage stability of the product. .

The impurities are unreacted starting compounds and by-products. It can be easily predicted that the impurities include unreacted amidoamine, unreacted cyanamide, and dicyandiamide, but these three compounds are sufficiently removed,
Even when the content is practically 0, a slight amount of precipitate may be formed in the case of a water and / or alcohol solution. The present inventors have collected, separated, and analyzed the precipitate, and found that the compounds represented by the following general formulas (V) and (VI) are responsible for the precipitation. All of these have low solubility in water and / or alcohol, and thus precipitate as precipitates.

Embedded image

Embedded image )

As described above, various methods can be used for removing impurities such as bisamides. For example, when purification is performed by crystallization, it is preferable to perform the following conditions. The solubility of a guanidine derivative, such as tetrahydrofuran or methyl ethyl ketone, in an amide group-containing guanidine derivative crude reaction product,
A solvent which greatly changes depending on the temperature is added 2 to 10 times (weight ratio), heated to the boiling point, and, if necessary, filtered while hot, and then gradually cooled. The solubility of the bisamides and the like shown in the general formulas (V) and (VI) in the crystallization solvent has a temperature dependence, and the solubility changes abruptly at a certain temperature. The solubility of the compound having a lower solubility of bisamide shown in (VI) is kept at a constant temperature of not less than 0.1%, and after sufficiently crystallizing the target substance, filtration is carried out, and the crystals are dried under vacuum. To remove the solvent. If the amount of the solvent to be added is less than 2 times, there are disadvantages such as high viscosity during the crystallization operation or insufficient removal of impurities. If the amount of the solvent is more than 10 times, the yield is low, and any case is not preferable. When the solubility of the compound having a lower solubility at the inner crystallization temperature of the bisamide represented by the general formulas (V) and (VI) in the crystallization solvent is less than 0.1%, the purified product is treated with water. And / or when an alcohol solution is used, a minute amount of precipitate may be observed over time, which is not preferable.

By the above operation, an amide group-containing guanidine or a salt thereof having high purity, excellent solubility in water and / or alcohol, and excellent stability in a solution state can be produced.

[0022]

The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the invention is limited thereto. %
Is based on weight.

Example 1 Synthesis of lauroylamidoethylguanidine hydrochloride (1) Pretreatment of monolauroylethylenediamine 500 ml equipped with a stirrer, thermometer, vacuum / nitrogen inlet tube
In a four-necked flask, 121 g of monolauroylethylenediamine (abbreviated as amidoamine, purity: 97.2%, unreacted lauric acid: 0.8%, bisamide: 2.0%)
(0.5 mol), and maintain at 80 ° C. while depressurizing.
Nitrogen introduction was repeated three times, and the atmosphere was replaced with nitrogen.

(2) Synthesis of lauroylamidoethylguanidine hydrochloride 48.2 concentrated hydrochloric acid (36%) was added to the pretreated amidoamine.
g (0.475 mol) was added dropwise and neutralized while being careful not to exceed 100 ° C. in the system. Separately, 31.5 g (0.75 mol) of cyanamide was dissolved in 31.5 g of isopropyl alcohol, and added dropwise to 95% hydrochloride of amidoamine over 1 hour while maintaining the system temperature at 80 to 90 ° C. After dropping, aged at the same temperature for 3 hours,
2.5 g (0.025 mol) of concentrated hydrochloric acid (36%) was added,
After complete neutralization, the solvent was distilled off under reduced pressure. Yield: 170
g, by liquid chromatography and thin layer chromatography, conversion from amidoamine: 93.5%, purity: 88.1%, unreacted amidoamine: 2.6%, by-product dicyandiamide: 7.0%, bisamide 1.4%,
By-product urea derivative: trace.

(3) Purification of lauroylamidoethylguanidine hydrochloride (1) Four-necked flask equipped with a stirrer and a thermometer was charged with (2)
100 g of the crude product obtained in
00 g was added and heated to 80 ° C. to completely dissolve the crude product. The mixture was cooled to 40 ° C. at a rate of 1 ° C./min over 40 minutes, and kept at 40 ° C. for 1 hour after the crystal was precipitated, to sufficiently precipitate the crystal. The crystals were separated by filtration and dried in vacuo at 40 ° C. for 2 hours to obtain purified lauroylamidoethylguanidine hydrochloride. Yield: 75 g, purity by liquid chromatography and thin layer chromatography analysis: 99.5%, unreacted amidoamine: 0.5%, by-product dicyandiamide: 0.01
%, Bisamide: 0.01% or less, by-product urea derivative: not detected. 50 g of this purified product was dissolved in 30 g of ethanol and 20 g of water.
It was a clear solution for months. The solubility of by-product bisamide in tetrahydrofuran was 0.5% at 40 ° C.

Example 2 Synthesis of lauroylamidobutylguanidine acetate (1) Pretreatment of monolauroylbutylene diamine 500 ml equipped with a stirrer, thermometer, vacuum / nitrogen inlet tube
In a four-necked flask, 135 g of monolauroyl butylenediamine (abbreviated as amidoamine, purity: 98.4%, unreacted lauric acid: 1.0%, bisamide: 0.6%)
(0.5 mol), and maintain at 80 ° C. while depressurizing.
Nitrogen introduction was repeated three times, and the atmosphere was replaced with nitrogen.

(2) Synthesis of Lauroylamidobutylguanidine Acetate 30 g (0.5 mol) of acetic acid was added to the pretreated amidoamine.
Was added dropwise and neutralized while being careful not to exceed 100 ° C. in the system. Separately, 25.2 g of cyanamide (0.6
Mol) is dissolved in 25.2 g of isopropyl alcohol,
The solution was added dropwise to the amidoamine acetate over one hour while maintaining the temperature in the system at 80 to 90 ° C. After completion of the dropwise addition, the mixture was aged at the same temperature for 3 hours, and then the solvent was distilled off under reduced pressure. yield:
189 g, conversion by amidoamine: 93.8 by liquid chromatography and thin layer chromatography analysis.
%, Purity: 92.4%, unreacted amidoamine: 1.9
%, By-product dicyandiamide: 2.9%, bisamide:
0.4%, acetylated amidoamine: 1.6%, by-product urea derivative: trace.

(3) Purification of lauroylamidobutylguanidine acetate In a 1 l four-necked flask equipped with a stirrer and a thermometer, (2)
100 g of the crude product obtained in
00 g was added and heated to 80 ° C. to completely dissolve the crude product. After cooling to 50 ° C. over 30 minutes at a rate of 1 ° C./min, the temperature was kept at 50 ° C. for 1 hour after the crystals had precipitated to sufficiently precipitate the crystals. The crystals were separated by filtration and dried in vacuo at 40 ° C. for 2 hours to obtain purified lauroylamidobutylguanidine acetate. Yield: 80 g, purity by liquid chromatography and thin layer chromatography analysis: 99.5%, unreacted amidoamine: 0.4%, by-product dicyandiamide: 0.0
1% or less, bisamide: 0.01% or less, acetylated amidoamine: 0.1%, by-product urea derivative: not detected. Take 50 g of this purified product, 30 g of ethanol,
When dissolved in 20 g of water, it was a clear solution at 25 ° C. for 6 months. The solubility of bisamide by-produced in methyl ethyl ketone was 0.1% at 50 ° C.

Example 3 (1) Synthesis of Lauroylamidoethylguanidine Acetate 30 g (0.5 mol) of acetic acid was added to monolauroylethylenediamine pretreated in the same manner as in Example 1 (1), and the temperature in the system was 100 ° C. And neutralized, taking care not to exceed. To this, 25.2 g (0.6 mol) of cyanamide was added and dissolved, and the mixture was reacted for 5 hours with occasional cooling so that the reaction temperature did not exceed 90 ° C. Yield: 176 g, conversion by amidoamine: 93.2%, purity: 91.1 by liquid chromatography and thin layer chromatography analysis.
%, Unreacted amidoamine: 2.7%, by-product dicyandiamide: 3.1%, bisamide: 1.4%, acetylated amidoamine: 1.5%, and by-product urea derivative: trace.

(2) Purification of Lauroylamidoethylguanidine Acetate (1) In a 1-l four-necked flask equipped with a stirrer and a thermometer, (1)
100 g of the crude product obtained in
00 g was added and heated to 80 ° C. to completely dissolve the crude product. After cooling to 50 ° C. over 30 minutes at a rate of 1 ° C./min, the temperature was kept at 50 ° C. for 1 hour after the crystals had precipitated to sufficiently precipitate the crystals. The crystals were separated by filtration and dried in vacuo at 40 ° C. for 2 hours to obtain purified lauroylamidoethylguanidine acetate. Yield: 79 g, purity by liquid chromatography and thin layer chromatography analysis: 99.6%, unreacted amidoamine: 0.4%, by-product dicyandiamide: 0.0
1% or less, bisamide: 0.01% or less, acetylated amidoamine: 0.01% or less, by-product urea derivative: not detected. Take 50 g of this refined product and add ethanol 3
When dissolved in 0 g and 20 g of water, it was a transparent solution at 25 ° C. for 6 months. The solubility of by-product bisamide in methyl ethyl ketone was 0.2% at 50 ° C.

Example 4 (1) Synthesis of lauroylamidobutylguanidine acetate Example 2 (2) In the synthesis of lauroylamidobutylguanidine acetate, the procedure was the same except that tetrahydrofuran was used instead of isopropyl alcohol as a solvent for dissolving cyanamide. Was reacted. Yield: 189 g, conversion by amidoamine: 93.8%, purity: 92.4%, by liquid chromatography and thin layer chromatography analysis.
Unreacted amidoamine: 1.9%, by-product dicyandiamide: 2.9%, bisamide: 0.4%, acetylated amidoamine: 1.6%, by-product urea derivative: trace.

(2) Purification of Lauroylamidobutylguanidine Acetate (1) In a 1-l four-necked flask equipped with a stirrer and a thermometer, (1)
100 g of the crude product obtained in
00 g was added and heated to 80 ° C. to completely dissolve the crude product. The mixture was cooled to 25 ° C. at a rate of 1 ° C./min over 55 minutes, and kept at 25 ° C. for 1 hour after the crystal was precipitated, to sufficiently precipitate the crystal. The crystals were separated by filtration and dried in vacuo at 40 ° C. for 2 hours to obtain purified lauroylamidoethylguanidine acetate. Yield: 85 g, purity by liquid chromatography and thin layer chromatography analysis: 99.4%, unreacted amidoamine: 0.5%, by-product dicyandiamide: 0.0
1% or less, bisamide: 0.01% or less, acetylated amidoamine: 0.1%, by-product urea derivative: not detected. Take 50 g of this purified product, 30 g of ethanol,
When dissolved in 20 g of water, it was a clear solution at 25 ° C. for 6 months. The solubility of by-produced bisamide in tetrahydrofuran was 0.1% at 25 ° C.

Comparative Example 1 Example 2 (1) In pretreatment of monolauroyl butylene diamine, amidoamine was allowed to stand in the air at room temperature for 3 days, and then reacted and crystallized without performing nitrogen replacement under reduced pressure. : 82 g, purity by liquid chromatography and thin layer chromatography analysis: 98.5%, unreacted amidoamine: 0.7%, by-product dicyandiamide: 0.0
1% or less, bisamide: 0.05% or less, acetylated amidoamine: 0.4%, and by-product urea derivative: 0.3%. When 50 g of the purified product was taken and dissolved in 30 g of ethanol and 20 g of water, a precipitate was formed after 2 days at 25 ° C.

[0034]

The amide group-containing guanidine derivative and its salt obtained by the production method of the present invention have high purity and excellent stability in a water and / or alcohol soluble solution state. According to the production method of the present invention, the target amide group-containing guanidine derivative or a salt thereof can be industrially advantageously produced.

────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-48-56640 (JP, A) JP-A-2-243614 (JP, A) JP-B-45-23328 (JP, B1) JP-B-44-44 5374 (JP, B1) JP-B-38-9268 (JP, B1) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07C 277/00-277/08 C07C 279/00-279/26

Claims (4)

(57) [Claims] 1. A compound represented by the following general formula (I): (Wherein, R ¹ is a linear or branched alkyl or alkenyl group having 1 to 22 carbon atoms. R ² , R ^2
3 is a hydrogen atom or a linear or branched alkyl group or a hydroxylalkyl group having 1 to 4 carbon atoms, which may be the same or different. A is a linear or branched alkylene group or alkenylene group having 1 to 10 carbon atoms. Immediately after the heat treatment under reduced pressure or heated nitrogen bubbling, or after storage in a carbon dioxide-free atmosphere, the amidoamine represented by the formula (1) is converted into guanidine using a guanidination reagent and then the impurities are removed. The following general formula (II) (Chemical formula 2) (Wherein, R ¹ is a linear or branched alkyl or alkenyl group having 1 to 22 carbon atoms. R ² , R ^2
3 is a hydrogen atom or a linear or branched alkyl group or a hydroxylalkyl group having 1 to 4 carbon atoms, which may be the same or different. A is a linear or branched alkylene group or alkenylene group having 1 to 10 carbon atoms. The method for producing an amide group-containing guanidine derivative represented by the formula or a salt thereof. 2. The method for producing an amide group-containing guanidine derivative or a salt thereof according to claim 1, wherein the guanidination reaction of the amidoamine is carried out in the presence of a small amount of alcohols or ethers. 3. The method for producing an amide group-containing guanidine derivative or a salt thereof according to claim 1, wherein the means for removing the impurities is crystallization. 4. In the crystallization step, the temperature for crystallization and filtration is not lower than the temperature at which the solubility of bisamide by-produced in the guanidination reaction step in the crystallization solvent is at least 0.1%. The method for producing an amide group-containing guanidine derivative or a salt thereof according to claim 3.