JPS6125706B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a completely new process for producing hexamethylene bis-dicyandiamide in high purity and yield without using toxic substances.

1:6-di(N ⁵ -p-chlorophenyl-N ¹ -diguanide)hexane (common name: chlorhexidine) is a strong bactericidal disinfectant that is effective against both Gram-positive and Gram-negative bacteria. It is a useful compound used as a raw material or intermediate for.

This hexamethylene bis-dicyandiamide [] is produced by reacting dicyanimide alkali salt with hexamethylene diamine dihydrochloride.
Since alkaline salts are produced by reacting cyanamide alkali salts such as sodium cyanamide with cyanogen halides such as cyanogen bromide, they have the following extremely serious defects.

That is, first of all, cyanogen halides are extremely poisonous and therefore extremely difficult to handle and highly dangerous, making it extremely difficult to obtain dicyanimide alkali salts. Secondly, during the reaction between cyanamide alkali salt and cyanogen halide, alkali halide salt is produced as a reaction by-product in addition to dicyanimide alkali salt, but it is difficult to separate and remove this by-product. It is extremely difficult. In other words, it is extremely difficult to produce dicyanimide alkali salts that do not contain alkali halides.
In other words, it is extremely difficult to obtain highly pure dicyanimide alkali salt. Therefore, thirdly, because the purity of the dicyanimide alkali salt is low, the yield of hexamethylene bis-dicyandiamide [] decreases, and as a result, the yield of chlorhexidine decreases.

The present invention was made to overcome these drawbacks, namely lack of safety, difficulty in obtaining raw materials, and low yield, and is fundamentally different from conventional methods and has many of the above-mentioned drawbacks. This method is characterized in that it does not use dicyanimide alkali salt, which has the disadvantages of dicyanimide, as a raw material compound, but uses a completely different compound as a raw material.

As a result of earnestly searching for a compound that has never been used as a raw material that can replace the raw material compound in the conventional method, the inventor discovered that cyanamide dithiocarbonate S
-We obtained the new knowledge that methylpotassium salt can be used, and based on this we researched the reaction conditions, and finally arrived at a completely new and effective production method that was previously unknown, and completed the present invention. .

That is, the present invention is a method for producing hexamethylene bis-dicyandiamide by the method shown by the following reaction formula.

The raw material compound S-methylpotassium cyanamide dithiocarbonate [ ] is a compound that is easily available, safe, and easy to handle.
The compound represented by this formula [] is reacted with ammonia and an ammonium compound, but the ammonium compound can be a volatile or weakly acidic substance, such as NH ₄ OH, (NH ₄ ) ₂ CO ₃ ,
and/or using ( _NH4 ) _HCO3 . The reaction is preferably carried out at a relatively high temperature, preferably in the temperature range of 80 to 120°C, with 105°C being particularly preferred.

As the reaction solvent, water, other organic solvents, or mixtures thereof are appropriately used, but depending on the raw materials, no solvent may be used.

In this way, N-cyanoisothiourea potassium salt [] is obtained, which is then treated with an alkylating agent to form an N-cyano-S-(alkyl)isothiourea represented by the formula []. "Alkyl" represents an alkyl group having 1 to 10 carbon atoms). The alkylation of the compound of formula [] is carried out by a conventional method, and as the alkylating agent, alkyl halides, alkyl sulfates, and other ordinary alkylating agents are used as appropriate, and in particular, alkyl iodides, alkyl bromides, alkyl chlorides, and dialkyl sulfates are useful, and in the case of methylation, for example, methyl iodide and dimethyl sulfate are particularly preferred.

Next, the N-cyano-S-alkylisothiourea represented by the formula [] is reacted with hexamethylene diamine to obtain hexamethylene bis-dicyandiamide [], but this reaction is carried out at room temperature to
The temperature is preferably 170°C, preferably 50 to 130°C.

The reaction time varies depending on each reaction step, but 1
~24 hours is appropriate. Although a wide variety of solvents can be used as the reaction solvent, particularly preferred solvents are water and alcohols.

Next, Examples of the present invention will be described, and as a further reference example, hexamethylene bis-dicyandiamide [ ] obtained by the method of the present invention will be described.
A method for producing chlorhexidine mineral salt by reacting with chloraniline mineral salt will also be described as a reference example.

The reaction between hexamethylene bis-dicyandiamide [] and p-chloroaniline mineral salt (generally hydrochloride) is carried out by a conventional method, but according to this method, as mentioned above, hexamethylene bis-dicyandiamide is reacted with p-chloroaniline mineral salt (generally hydrochloride). The production of dicyandiamide is extremely superior to conventional methods in terms of safety, availability, and purity, making it possible to obtain chlorhexidine mineral salt in high yield and purity. A great effect is produced. This mineral salt is treated with alkali to produce free chlorhexidine, which is generally converted into water-soluble chlorhexidine digluconate and used as a disinfectant.

Example 1 (i) S-methyl potassium cyanamide dithiocarbonate salt
After adding 60 ml of concentrated ammonia water to 34.0 g, react in a sealed tube at 105°C for 3 hours. Next, the solvent was distilled off under reduced pressure, a small amount of ethanol was added to the residue, and the precipitated crystals were separated and dried to obtain 26.8 g of N-cyanoisothiourea potassium salt (yield 96.4
%) was obtained.

(ii) After dissolving 26.8 g of N-cyanoisothiourea potassium salt in 100 ml of water and 100 ml of acetone, 28.7 g of methyl iodide was added dropwise under ice cooling.
The reaction is stirred at room temperature for 3 hours. Next, the solvent is distilled to dryness under reduced pressure, a small amount of water is added to the residue, the precipitated crystals are separated and dried, and N-cyano-
S-methylisothiourea 9.1g (yield 40.9%)
I got it.

(iii) N-cyano-S-methylisothiourea9.1
Dissolve 4.7 g of hexamethylene diamine in 80 ml of water and react in a sealed tube at 105°C for 19 hours. Next, the solvent is distilled off to dryness under reduced pressure, a small amount of water is added to the residue, the mixture is dispersed under heating, and the mixture is cooled to separate the precipitated crystals. At this time, the crystals are washed with cold alcohol. When the separated crystals are dried, hexamethylene bis-dicyandiamide (melting point 202-203) is produced.
℃) 8.7g (yield 88.0%) was obtained.

Example 2 (i) S-methyl potassium cyanamide dithiocarbonate salt
34.0g and ammonium carbonate (NH ₃ = 30%) 17.0
Dissolve g in 30 ml of water and react in a sealed tube at 105°C for 3 hours. Next, the solvent was distilled off under reduced pressure, a small amount of ethanol was added to the residue, and the precipitated crystals were separated and dried to obtain 25.9 g (yield: 93.2%) of N-cyanoisothiourea potassium salt.

(ii) After dissolving 25.9 g of N-cyanoisothiourea potassium salt in 100 ml of water and 100 ml of acetone, 27.8 g of methyl iodide was added dropwise under ice cooling.
The reaction is stirred at room temperature for 3 hours. Next, the solvent is distilled to dryness under reduced pressure, a small amount of water is added to the residue, the precipitated crystals are separated and dried, and N-cyano-
S-methylisothiourea 9.7g (yield 45.3%)
I got it.

(iii) N-cyano-S-methylisothiourea9.7
Dissolve 4.9 g of hexamethylene diamine in 80 ml of water and react in a sealed tube at 105°C for 19 hours. Next, the solvent is distilled off to dryness under reduced pressure, a small amount of water is added to the residue, the mixture is dispersed under heating, and the mixture is cooled to separate the precipitated crystals. At this time, the crystals are washed with cold alcohol. When the separated crystals are dried, hexamethylene bis-dicyandiamide (melting point 202-203
℃) 9.5g (yield 90.3%) was obtained.

Example 3 Ammonium bicarbonate instead of ammonium carbonate
Hexamethylene bis-dicyandiamide was prepared in the same manner as in Example 2 except that 23.7 g was used.
Obtained in an amount of 13.4g (yield 53.6%).

Example 4 The method of Example 1 was repeated using 26.5 g of dimethyl sulfate instead of methyl iodide, and 11.0 g of hexamethylene bis-dicyandiamide (yield 43.9) was obtained.
%) was obtained.

Example 5 The method of Example 1 was repeated except that 32.8 g of ethyl iodide and 35.7 g of propyl iodide were used in place of methyl iodide, and N-cyano-S-ethyl (or propyl) isothiourea was used. After obtaining (yield 54.2% and 56.5%), hexamethylene diamine was reacted to obtain hexamethylene bis-dicyandiamide (yield 40.3% and 42.7%).

Reference Example Hexamethylene obtained by the method of Example 1
19.1 g of bis-dicyandiamide, 25.0 g of P-chloroaniline hydrochloride and 2-ethoxyethanol
After heating and dissolving in 180 ml, stir and reflux and react for 3 hours. Next, the reactant is cooled, the precipitated crystals are separated and dried, and chlorhexidine hydrochloride (melting point
260-262°C) was obtained in a yield of 88.6%. This matched the standard product based on melting point and IR.

Claims (1)

[Claims] 1. A compound represented by the following formula [], A compound represented by the following formula [] is obtained by reacting an ammonia compound selected from the group consisting of aqueous ammonia, ammonium carbonate, and ammonium bicarbonate, Then, this is treated with an alkylating agent to obtain a compound represented by the following formula [], (However, in the formula, R represents an alkyl group having 1 to 10 carbon atoms.) Hexamethylene bis-dicyandiamide represented by the formula [], which is then reacted with hexamethylene diamine. manufacturing method.