NO810083L - PROCEDURE FOR THE PREPARATION OF IMIDAZOLD DERIVATIVES - Google Patents

Description

The invention relates to a new process for the production of 4-[(2-aminoethyl)thiomethyl]-5-methyl imidazole with the formula:

and its acid addition salts.

4-[(2-aminoethyl)thiomethyl]-5-methyl imidazole

is an important intermediate in the production of pharmacologically active compounds, such as N-cyano-N'-methyl-N"-[ 2-[(5-methyl-4-imidazolyl)-methylthio]ethyl)-guanidine, which acts as an active histamine antagonist on H2-receptors, and is known under the generic name: "cimitidine". The intermediate product and process for its preparation were first described in British patent 1,338,169.

The known and the mentioned processes are based on the reaction of 4-halomethyl-, 4-hydroxymethyl- or 4-methoxymethyl-5-methyl imidazoles or their hydrocal gelide by formula:

wherein Q represents a halogen, hydroxy or methoxy group, with cysteamine or its hydrohalogenides.

When Q means halogen, the reaction is carried out in a basic medium, e.g. in the presence of sodium ethoxide or sodium hydroxide. As cysteamine is a primary amine, it is necessary to protect the amino group, e.g. a phthalimide group is removed after termination reaction, acid hydrolysis or hydrazinolysis. When Q means a hydroxy or methoxy group, the reaction is carried out in an acidic medium in the presence of a 48% aqueous HBr solution :or in glacial acetic acid/ The yield of these reactions is between 70 and 90%, and the reaction time from 10 to 18 hours, and the reaction temperature from

■ 100 to 120°C.

The purpose of the invention is to provide

a process for the production of 4-[(2-aminoethyl)-thiomethyl]-5-methyl imidazole with high yields, shorter reaction time and at room temperature which will enable the final product I to be easily isolated, at high purity.

The purpose is achieved by selective alkylation of 4(5)-thiomethyl-5(4)-methylimidazole by formula:

with a 2-haloethylamine, in which halo means chlorine or bromine, at room temperature in a system consisting of a 50% aqueous solution of a strong base and an organic phase, quaternary ammonium or quaternary phosphonium salts were used as phase transfer catalysts. Catalysts can be used e.g. methyltricaprylyl ammonium chloride, benzyltriethyl ammonium chloride, benzyltriphenyl phosphonium chloride, hexadicyltributyl phosphonium bromide, etc.

Other advantages of the method according to the invention, in relation to known methods for the production of 4-[(2aminoethyl)-thiomethyl]-5-methyl imidazole,

is that the use of cysteamine hydrohalide is avoided. Instead of this expensive chemical, a 2-haloethylamine, preferably 2-chloroethylamine, is used, which is a cheaper and easily available compound. Furthermore, there is no need for a preliminary protection of the amino group in that connection.

As an organic solvent, polar organic solvents can be used, where the starting reaction participant is soluble, such as lower alcohols, acetonitrile, etc. The yields of the final compound of formula I are extraordinarily high and go up to 85 to 90% of the theoretical yield.

The starting compound 4(5)-thiomethyl-5(4)-methyl imidazole and. the method for producing this is mentioned in Belgian patent 875 845.

As thiols are not very stable compounds, the reactions are preferably carried out in an inert atmosphere.

In an alternative method, an alkali mercaptide of 5 (4)-methyl-4,(5)-thiomethyl imidazole is used which is a stable compound as starting material. The reaction conditions are similar to those mentioned above.

The invention will be explained by some examples.

Example 1. 5-methyl-4-thiomethyl imidazole (6.4 g, 0.05 mol) is dissolved in ethanol (80 ml.). A 50% aqueous NaOH solution (10 ml.) was added, followed by the addition of hexadecyltributylphosphonium chloride (1.16 g, 0.0025 mol),

and stirring for 10 minutes in an inert atmosphere at room temperature. After a period of 15 minutes, a solution of 2-chloroethylamine (4.0 g) in ethanol (30 ml) is added,

and the resulting mixture is stirred for 30 minutes at room temperature, and then, 30 more minutes at 50°C. The solvent is removed by evaporation and the residue is extracted with isopropanol.

The organic salts are filtered off and hydrogen chloride is introduced into the isopropanol solution until pH 1 is reached.

The reaction mixture is evaporated to dryness and the residue crystallizes from ethanol. 3-[(2-aminoethyl)thiomethyl]-5-methyl imidazole (10.9g, 89.3%) is obtained

in the form of the hydrochlorides, melting point 189-191°C.

Example 2.

The procedure according to the previous example is repeated using benzyltriethylammonium chloride (TEBA, 580 mg, 2.5 mol) as catalyst. 10.8 g (88%) of the desired compound are obtained.

Example 3.

The procedure according to example 1 is then repeated

however, tricaprylmethyl ammonium chloride (Aliquat 336, 1.04 g, 2.5 mmol) is used as catalyst. 10.9 g (89.3%) of the desired compound are obtained.

Example 4.

5-methyl-4-thiomethyl imidazole (1.5g, 0.01 mol)

in the form of sodium mercaptide is dissolved in water (20 ml).

Benzyltriethylammonium chloride (70 mg, 0.3 mol) is added there. The resulting solution is stirred for 10 minutes at room temperature. Over a period of 10 minutes, 2-chloroethylamine (8.0 g): in ethanol (8 ml) is added dropwise to the reaction mixture. The reaction mixture is stirred for ±h hour at room temperature, evaporated to dryness, and the rest of the procedure according to example 1 is followed.

2.2 g (90.3%) of the desired compound is obtained, with a melting point of 190-192°C.

Claims (4)

1. Method for the production of 4-[(2-aminoethyl)thiomethyl]-5-methyl imidazole with formula: and its acid addition salts, k:ar,acter ices t in that a compound of formula:. in which M means hydrogen or an alkali metal, is reacted with 2-halogenethylamine, in which halo means chlorine or bromine, in a system consisting of an aqueous solution of a strong base, and of an organic phase, at room temperature in the presence of quaternary ammonium or quaternary phosphonium salts as phase transfer catalysts. 2. Method according to claim 1, characterized in that methyltricaprylylammonium chloride, hexadecyltributylphosphonium bromide, benzyltriethylammonium chloride and the like are used as quaternary ammonium or quaternary phosphonium salts. 3. Method according to claim 1, characterized in that the reaction is carried out in the presence of a 50% aqueous sodium hydroxide solution. 4. Method according to claim 1, characterized in that the reaction is carried out in the presence of lower alcohols or acetonitrile as organic solvents.