KR850001699B1 - Process for the preparation of aryl amidino urea derivative - Google Patents

Abstract

Amidino urea derivative, substisuted with aryl gp. (I) and used as diarrhea remedy, is prepared from 2,6-dimethyl phenyl urea(II) by condensation reaction with sulfuric acid salt of Nmethyl guanidine(III) in the presence of inorganic acid, e.g., sulfuric acid or nitric acid. (II) is prepared from 2,6-dimethyl aniline by treating with an aqueous soln. of sodium cyanate in a mixed solvent, e.g., water, acetic acid, dimethyl formamide, tetrahydrofuran, dioxane, methyl isobutyl ketone, ethyl acetate or acrylonitrile.

Description

Method for preparing aryl-substituted amidino urea derivatives

FIG. 1 Infrared Absorption Spectrum Graph of Hydrochloride Crystalline Form of Final Target

The present invention relates to a novel process for preparing an aryl substituted amidinourea derivative represented by the following structural formula (I).

The compound of formula (I) is a known compound has excellent branching action and the preparation method is US Patent 4.285.972, 4.117.165, 4.150.154, 4.216.229, 4.216.230, 4.060.635, 3.784 .582, 3.539.616, Japanese Patent Laid-Open Nos. 50-40544, 50-40545, 50-40546, Belgian Patent 844,832 and Arzneimittel Fhorscung 28 (II) p1433-1480 (1978) and the like.

The types of known production methods are as follows.

The first way is

However, R ₁ : lower alkyl group

R ₂ : hydrogen or lower alkyl group

R ₃ : lower alkyl group.

The 2,6-disubstituted aniline derivative is refluxed while passing through an excess of phosgene gas, followed by distillation under reduced pressure to obtain a 2,6-disubstituted phenyl isocyanate compound.

Thus obtained 2,6-disubstituted phenyl isocyanate compound. Condensation with N-alkylsubstituted guanidine yields the desired alkylsubstituted amidino urea derivative.

Second way

However, R ₁ , R ₂ , R ₃ are as described above. R ₄ : hydrogen or lower alkyl)

Treatment of 2,6-disubstituted phenyl alkylamine derivatives with excess phosgene gas to form 2,6-disubstituted phenyl carbamoyl chloride compounds and reaction with N-alkylsubstituted guanidines to produce the desired N-alkylamidino urea derivatives Or 2,6-disubstituted phenyl carbamoyl chloride compounds obtained by treating with phosgene gas after saturation of 1,2-substituted amines with excess hydrochloric acid.

Therefore, the known methods all use phosgene gas which is toxic to the human body, and therefore requires a special ventilation system for industrial mass production, and may cause serious concern on air pollution. In addition, even if the intermediate 2,6-dimethyl phenyl isocyanate is synthesized and used industrially, this material is a highly hygroscopic compound, so it is unstable, difficult to handle in large quantities, and has a great effect on yield. This is necessary.

Therefore, the present inventors have applied for a patent because they have invented a new method for preparing a compound of formula (I), which solves this problem and enables industrial mass production.

The present invention is shown schematically as follows.

In the mechanism of the present invention, a compound of formula (I) is produced as the primary amine of N-methylguanidine sulfate, which is a compound of formula (III), attacks the carbon of the carbonyl group of 2,6-dimethylphenyl urea and the ammonium sulfate is released. This reaction has been introduced as a very common method of synthesizing urea derivatives and is described in detail in organofunctional group preparations p.135. In more detail, the compound of formula (II) is a mixed polar solvent, i.e., water, acetic acid, glacial acetic acid, dimethyl formamide, tetrahydrofuran, dioxane, methyl isobutyl It can be easily obtained by treating with a solution of sodium cyanate in water in a mixed solvent such as ketone, ethyl acetate, acrylonitrile and the like. By condensing N-methyl guanidine, which is a compound of formula (III), to the compound of formula (II) thus obtained in the presence of an inorganic acid, the target substance can be easily obtained in high yield. Inorganic acids are sulfuric acid and nitric acid.

Method for preparing N-methyl guanidine, sulfate, which is a compound of formula (III)

1) Ber. 3,896 (1870)

2) J. Chem. Soc. 45, 1755 (1923)

3) J. Am. Chem. Soc. 45, 1755 (1923)

4) Ber. 60.2120 (1927)

5) J. Am. Chem. Sec. 59, 2144 (1937)

Etc. are described in detail.

In order to more specifically describe the present invention, examples are as follows.

Example 1

Preparation of 2,6-dimethyl phenyl urea

60.6 g (0.5 mol) of 2,6-dimethyl aniline is dissolved in 240 ml of glacial acetic acid and 480 ml of water at 35 ° C.

The solution is treated with a solution of 65 g of sodium cyanate dissolved in 450 ml of water at 20 ° C.

Add approximately 50 ml of sodium cyanate solution with gentle stirring, then add the remaining solution at high speed with vigorous stirring. When the temperature is raised to 30-40 ℃, the target is separated, and the material thus formed is stirred for 10 minutes and left at 0 ℃ for 2-3 hours and diluted with 200 ml of water.

After filtration, washing with water and drying thoroughly, 75.5 g of white crystalline powder was obtained (yield 92%), and recrystallized with water-soluble ethanol to obtain pure 2,6-dimethyl phenyl urea.

Elemental Analysis C ₉ H ₁₂ N ₂ O

C 65.8 H 7.4 N 17.1 O 9.7

C 65.7 H 7.5 N 17.0 O 9.8

Example 2

Preparation of 1- (2,6-methylphenyl) -3-methyl amidino urea, hydrochloride.

A mixture of 2,6-dimethylphenyl urea 3,284 g (20 mol), N-methyl guanidine and 1,221 g (5 mol) sulfate was added to a 12 liter round bottom flask, followed by 2 liters of water, shaking well, and boiling.

Boil the resulting solution vigorously for 45-90 minutes until the reaction is complete. The mixture in the reaction port is cooled to room temperature, stirred by adding 1.5 L of water, filtered, washed with cold water and dried.

This free base is dissolved in a mixed solution of saturated hydrochloric acid in methanol, and reacted for 2 hours while maintaining the temperature of 30-40 ℃.

The mixed solution was concentrated and diethyl ether was added to filter the resulting crystals to obtain 4618 g of the target substance 1- (2,6-dimethylphenyl) -3-methyl amidinourea hydrochloride. (Yield 90%)

C ₁₁ H ₁₇ N ₄ OCI

m.p: 194-197 ℃

I.R: see drawing I

Elemental Analysis Values:

Theoretic value: C 51.44 H 6.68 N 21.82 O 6.24 CI 13.82

Found: C 51.42 H 6.67 N 21.85 O 6.24 CI 13.82

Claims (1)

A method for preparing a compound of formula (I) and a hydrochloride thereof by condensing a compound of formula (II) with a compound of formula (III).

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