JPH1171339A - Production of biguanide salts - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject high-purity compound in high yield by subjecting dicyandiamide to heat reaction with an ammonium salt in an organic solvent containing phenol. SOLUTION: (A) Dicyandiamide is subjected to heat reaction with (B) an ammonium salt (e.g. ammonium chloride, ammonium nitrate or ammonium acetate) or (C) an amine salt (e.g. primary amine salt or secondary amine salt), in an organic solvent containing phenols, (preferably at 80-150 deg.C) to provide the object biguanide salt. Phenol alone or a mixed solvent containing phenol and water at a weight ratio of (1:001) to (1:1.50) is preferably used as the organic solvent. The charging amount of the component B or C is preferably 0.8-2.5 mol based on 1.0 mol component A. The objective biguanide salts are simply obtained thereby.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing biguanide salts, and more particularly to a method for producing high-purity biguanide salts in high yield.

[0002]

BACKGROUND OF THE INVENTION As a method for producing biguanide salts, for example, "Journal of American Chemical Society (J. Am. Chem. Soc.)", P. 2342 (192)
2 years) discloses a method for producing an unsubstituted biguanide salt using a melting reaction of dicyandiamide and an ammonium salt.

JP-A-63-264465 discloses that a salt of an alkylbiguanide derivative is prepared by reacting dicyandiamide with a salt of an alkylamine derivative at 80 to 200 ° C. in a solvent-free condition or in a solvent. A method of making is disclosed.

[0004]

In the above method for producing biguanide salts, the yield is generally low. Particularly, in the melting reaction of dicyandiamide and ammonium salt, the reaction is difficult to control because the melting reaction is at a high temperature. In addition, there are problems that the amount of by-products is large and the yield is extremely low.
Therefore, in order to obtain high purity products of biguanide salts,
It must be isolated as a copper complex of biguanide, and there is a problem that the operation becomes complicated.

An object of the present invention is to provide a method for producing high-purity biguanide salts in high yield.

[0006]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems. As a result, the present inventors have found that a dicyandiamide and an ammonium salt or an amine salt are heated and reacted in an organic solvent containing phenol. The present inventors have found that it is possible to synthesize biguanide salts in high yield, and have completed the present invention.

That is, in order to solve the above-mentioned problems, the present invention provides dicyandiamide (A) and ammonium salt (B)
Alternatively, there is provided a method for producing a biguanide salt, which comprises reacting an amine salt (C) with an phenol-containing organic solvent by heating.

[0008]

BEST MODE FOR CARRYING OUT THE INVENTION The dicyandiamide (A) used in the present invention is obtained by treating lime nitrogen with water and an acid to form a cyanamide aqueous solution and subjecting it to a two-stage method of heat polymerization. Is a chemical product that can be produced by a direct method of obtaining leached crystals with hot water, and a synthetic product can be purchased from Nippon Carbide.

The ammonium salt (B) used in the production method of the present invention includes, for example, ammonium chloride,
Ammonium salts of inorganic acids such as ammonium nitrate, ammonium sulfate, ammonium carbonate and ammonium bicarbonate; and ammonium salts of organic acids such as ammonium acetate, ammonium oxalate, ammonium formate and ammonium benzenesulfonate. Among these, ammonium chloride is preferred from the viewpoint of the yield of the target product and the ease of isolation.

The amine salt (C) is a primary amine salt,
Any secondary amine salt can be used without particular limitation. Examples of such amine salts (C) include inorganic amine salts of primary amines whose substituents are aliphatic, such as methylamine hydrochloride, methylamine nitrate, ethylamine hydrochloride, and ethylamine nitrate; methylamine methylsulfonic acid Organic salts of primary amines whose substituents are aliphatic, such as salts, methylamine benzenesulfonate and ethylamine methylsulfonate; primary whose substituents are aromatic, such as aniline hydrochloride and p-toluidine hydrochloride Inorganic acid salts of amines; aniline methyl sulfonate, aniline benzene sulfonate, p
-Organic acid salts of primary amines whose substituents are aromatic, such as toluidine methyl sulfonate and p-toluidine benzene sulfonate; substituents such as diethylamine hydrochloride, diethylamine nitrate, methylethylamine hydrochloride, methylethylamine hydrochloride An inorganic acid salt of a secondary amine, which is aliphatic;

Inorganic acid salts of secondary amines whose substituents are aliphatic and aromatic, such as methylphenylamine hydrochloride, methylphenylamine nitrate and ethylphenylamine hydrochloride;
Secondary amine inorganic acid salts whose substituents are aromatic such as diphenylamine hydrochloride and diphenylamine nitrate; such as diethylamine methylsulfonate, diethylaminebenzenesulfonate, methylethylaminemethylsulfonate, and methylethylamine p-toluenesulfonate; Organic acid salts of secondary amines whose substituents are aliphatic; substituents such as methylphenylamine methylsulfonate, methylphenylamine benzenesulfonate, ethylphenylamine methylsulfonate are aliphatic and aromatic Organic acid salt of a secondary amine; diphenylamine methyl sulfonate;
Organic acid salts of secondary amines whose substituents are aromatic, such as diphenylamine benzene sulfonate, may be mentioned.

The organic solvent used in the production method of the present invention is phenol alone or a mixed solvent of phenol and a solvent which is miscible with phenol and does not affect the reaction. Such organic solvents include, for example, phenol alone, a mixed solvent of phenol and water; a mixed solvent of phenol and alcohols such as methanol, ethanol, n-propanol and iso-propanol; phenol, benzene, toluene, Mixed solvents with aromatic hydrocarbons such as xylene; mixed solvents with phenol and aliphatic hydrocarbons such as n-hexane, cyclohexane and n-heptane; phenol and halogenated hydrocarbons such as chlorobenzene, chloroform and dichloroethane Mixed solvent of hydrogen; mixed solvent of phenol and ether-based hydrocarbon such as diethyl ether, methyl ethyl ether, tetrahydrofuran; mixed solvent of phenol and ketone-based hydrocarbon such as acetone, methyl ethyl ketone, methyl iso-butyl ketone Solvent; mixed solvent of phenol and dimethyl sulfoxide; and a mixed solvent of phenol and dimethylformamide. Among them, the phenol alone or the mixing ratio of phenol and water is 1: 0.01 to 1: 1 by weight, because the yield of the target product is high and the post-treatment after the reaction is easy.
A mixed solvent of phenol and water in the range of 1.50 is preferable, and phenol alone or a mixed solvent in which the mixing ratio of phenol and water is in the range of 1: 0.01 to 1: 0.33 by weight is particularly preferable. preferable. Further, when the mixing ratio of phenol and water exceeds the range of 1: 1.50 by weight, the proportion of water increases, which is not preferable because the reaction rate tends to decrease.

The range of the reaction temperature is from 80 to 15 in that the formation of by-products is suppressed and an appropriate reaction conversion can be obtained.
A range of 0 ° C is preferred, and a range of 100 to 120 ° C is particularly preferred. When the reaction temperature is lower than 80 ° C., the reaction tends to hardly proceed, which is not preferable. On the other hand, when the reaction temperature is higher than 150 ° C., a large amount of by-products such as guanidine salt is generated, and the yield of biguanide salt tends to decrease.

The amount of the ammonium salt (B) or amine salt (C) to be charged is preferably in the range of 0.8 to 2.5 mol per 1.0 mol of dicyandiamide. Within this range, the amount of the ammonium salt (B) or the amine salt (C) charged is 0.9 to 1.5 mol from the viewpoint of suppressing the generation of by-products and obtaining an appropriate reaction conversion. Is suitable. If the amount of the ammonium salt (B) or the amine salt (C) is less than 0.8 mol, the conversion of dicyandiamide tends to decrease, which is not preferable. If the amount of the ammonium salt (B) or the amine salt (C) is more than 2.5 mol, a large amount of by-products such as a guanidine salt tends to be produced, which is not preferable.

The biguanide salts obtained by the production method of the present invention can be isolated and purified using known methods. As a general isolation / purification method, a product precipitated after completion of the reaction is collected by filtration, followed by washing, a solvent in which the product is insoluble is added to the reaction solution, and the precipitate is collected by filtration. A washing method and the like can be mentioned. Further, if necessary, it can be purified by recrystallization from a solvent such as water or alcohol.

[0016]

The present invention will be described below in more detail with reference to Examples and Comparative Examples. In the following Examples and Tables, “%” in “Production rate” and “Isolation yield” means “mol%” of the biguanide salt obtained with respect to the dicyandiamide used unless otherwise specified. It is.

<Example 1> 12.8 g of dicyandiamide
(0.152 mol), 9.8 g of ammonium chloride (0.
183 mol) and phenol (50.8 g) were placed in a 100 ml three-necked flask equipped with a reflux condenser and a stirrer, and heated to 120 ° C. while stirring the contents.
The reaction was performed for 6 hours while maintaining the temperature at 0 ° C. After the reaction, 80
C., and 25 g of iso-propanol was added to the reaction solution with stirring. The dicyandiamide conversion was 91% and the biguanide formation rate was 95%.

The precipitate obtained by filtration is separated into iso-propanol 1
After washing twice with 2.5 g, it was dried to obtain 18.7 g (90% yield) of biguanide hydrochloride.

The melting point of the biguanide hydrochloride thus obtained is shown in Table 1, and the result of elemental analysis is shown in Table 2.

Example 2 Example 1 was repeated except that ammonium chloride was used in an amount of 8.13 g (0.152 mol) and phenol was used in an amount of 47.6 (0.506 mol). In the same manner as in 1, biguanide hydrochloride was obtained.

The yield, isolation yield and melting point of the biguanide hydrochloride thus obtained are shown in Table 1.

<Example 3> In Example 1, 38.1 g of phenol and 1 part of water were used instead of 50.8 g of phenol.
Biguanide hydrochloride was obtained in the same manner as in Example 1, except that a mixed solvent consisting of 2.7 g was used, and the reaction temperature and the reaction time were changed to 100 ° C. and 10 hours.

The yield, isolation yield and melting point of the biguanide hydrochloride thus obtained are shown in Table 1.

<Example 4> 13.5 g of dicyandiamide
(0.160 mol), aniline hydrochloride 20.7 g (0.1
60 mol) and 79.8 g of phenol were charged into a 100 ml three-necked flask equipped with a reflux condenser and a stirrer, and heated to 100 ° C. while stirring the content.
The reaction was carried out for 3 hours while maintaining the temperature. After the reaction, 80 ° C
Then, 40 g of iso-propanol was added to the reaction solution with stirring, and after cooling to room temperature, the precipitate was separated by filtration. The dicyandiamide conversion was 99%, and the N-phenylbiguanide formation was 97%.

The precipitate obtained by filtration is separated into iso-propanol 2
After washing twice with 0 g, it was dried to obtain 31.8 g (yield 93%) of N-phenylbiguanide hydrochloride.

The melting point of the N-phenylbiguanide hydrochloride thus obtained is shown in Table 1, and the result of elemental analysis is shown in Table 2.

Example 5 The procedure of Example 4 was repeated, except that 39.3 g (0.160 mol) of diethylamine toluenesulfonate was used instead of 20.7 g (0.160 mol) of aniline hydrochloride. 4, N, N-
Diethyl biguanide p-toluenesulfonate was obtained.

The production rate, isolation yield and melting point of N, N-diethylbiguanide p-toluenesulfonate thus obtained are shown in Table 1, and the results of elemental analysis are shown in Table 2.

<Example 6> In Example 4, 54.5 g (0.1%) of diphenylamine p-toluenesulfonate was used instead of 20.7 g (0.160 mol) of aniline hydrochloride.
The obtained N, N-diphenylbiguanide p-toluenesulfonate was obtained in the same manner as in Example 4 except that 60 mol) was used.

The production rate, isolation yield and melting point of N, N-diphenylbiguanide p-toluenesulfonate thus obtained are shown in Table 1, and the results of elemental analysis are shown in Table 2.

<Comparative Example 1> 84.1 g of dicyandiamide
(1.0 mol) and 133.7 g of ammonium chloride
(2.5 mol) was charged into a 500 ml four-necked flask equipped with a reflux condenser and a stirrer, and the content was heated to 160 ° C. while stirring and 45 ° C. while maintaining the content at 160 ° C.
Allowed to react for minutes. After the reaction is completed, extract the solubles with hot water,
To the resulting aqueous solution was added a saturated aqueous ammoniacal copper sulfate solution to obtain a pink copper complex solid. After suspending the obtained solid in water, hydrochloric acid was added thereto, and biguanide hydrochloride was used.
0 g was obtained.

The yield, isolation yield and melting point of the biguanide hydrochloride thus obtained are shown in Table 1.

<Comparative Example 2> 12.8 g of dicyandiamide
(0.152 mol), 9.8 g of ammonium chloride (0.
183 mol) and 50.8 g of ethylene glycol were placed in a 100 ml three-necked flask equipped with a reflux condenser and a stirrer, and the contents were heated to 100 ° C. while stirring and reacted for 10 hours while maintaining the temperature at 100 ° C. I let it. After completion of the reaction, the reaction mixture was cooled, and a saturated aqueous solution of ammonium copper sulfate was added to obtain a pink copper complex solid. The obtained solid was suspended in water and hydrochloric acid was added to obtain 1.8 g of biguanide hydrochloride.

The yield, isolation yield and melting point of the biguanide hydrochloride thus obtained are shown in Table 1.

Comparative Example 3 A biguanide hydrochloride was obtained in the same manner as in Comparative Example 2, except that 50.4 g of dimethyl sulfoxide was used instead of 50.8 g of ethylene glycol.

The production rate, isolation yield and melting point of the biguanide hydrochloride thus obtained are shown in Table 1.

Comparative Example 4 In Comparative Example 2, methylcellosolve 5 was replaced with 50.8 g of ethylene glycol.
Biguanide hydrochloride was obtained in the same manner as in Comparative Example 2 except that 0.8 g was used.

The yield, isolation yield and melting point of the biguanide hydrochloride thus obtained are shown in Table 1.

<Comparative Example 5> A biguanide was prepared in the same manner as in Example 1 except that 50.8 g of m-cresol was used instead of 50.8 g of phenol and the reaction temperature was changed to 100 ° C. The hydrochloride was obtained.

The yield, isolation yield and melting point of the biguanide hydrochloride thus obtained are shown in Table 1.

Comparative Example 6 39.3 g (0.160 mol) of diethylamine toluenesulfonate and 13.4 g (0.160 mol) of dicyandiamide were placed in a 100 ml three-necked flask equipped with a reflux condenser and a stirrer. ,
The contents were heated to 140 ° C. with stirring, and reacted for 2 hours while maintaining the temperature at 140 ° C. After the completion of the reaction, a precipitate formed by cooling was separated by filtration. The precipitate collected by filtration was recrystallized from water to obtain N, N-diethylbiguanide p-toluenesulfonate.

The yield, isolation yield and melting point of the N, N-diethylbiguanide p-toluenesulfonate thus obtained are shown in Table 1.

[0043]

[Table 1]

[0044]

[Table 2]

[0045]

According to the production method of the present invention, by using a solvent containing phenol, in the reaction of dicyandiamide with an amine salt or an ammonium salt, not only the amine salt but also the ammonium salt can be highly purified. Biguanide salts can be obtained in high yield,
There is an advantage that post-treatment such as an isolation step is simple.

Claims (4)

[Claims] 1. A process for producing biguanide salts, comprising reacting dicyandiamide (A) with an ammonium salt (B) or an amine salt (C) in an organic solvent containing phenols. 2. An organic solvent comprising: (1) phenol alone or (2) phenol and water having a mixing ratio of phenol and water in a weight ratio of 1.00: 0.01 to 1.00: 1.50. The method for producing a biguanide salt according to claim 1, wherein a mixed solvent comprising: 3. The method for producing biguanide salts according to claim 1, wherein ammonium chloride is used as the ammonium salt (B). 4. The process for producing a biguanide salt according to claim 3, wherein the reaction is carried out at a temperature in the range of 80 to 150 ° C.