CS214847B2 - Method of making the 4-+l +l2.aminoethyl+p-5-methylimidazole - Google Patents

Abstract

The present invention relates to a novel process for preparing 4-¢(2-aminoethyl)thiomethyl!-5-methyl imidazole of the formula <IMG> I and its acid addition salts, characterized as a process for preparing 4-¢(2-aminoethyl)thiomethyl!-5-methyl imidazole of the formula <IMG> and its acid addition salts, characterized in that a compound of the formula <IMG> wherein M represents hydrogen or an alkali metal, is reacted with a 2-haloethylamine, wherein halo represents chloro or bromo, in a system consisting of an aqueous solution or 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.

Description

The invention relates to a process for the preparation of 4 - [(2-aminoethyl) thiomethyl] -5-methylimidazole of the formula I.

CH _3-1 CH = _r SC _from CH _and NH ^{hi i} h ^ SN (I) and its acid addition salts. 4 - [(2-aminoethyl) thiomethyl] -5-methylimidazole is an important intermediate for the production of pharmacologically active substances, such as N-cyano-4-methyl-N '- [(54-methyl-4-imidazolyl) methylthio] ethyl. -guanidine, known as the histamine antibody at the H 2 -receptors under the name "Cimetidine". The intermediate and process for its preparation have been described for the first time in U.S. Pat. file of the United Kingdom 1 338 169.

The known and described methods are based on the reaction of 4-halomethyl, 4-hydroxymethyl or 4-methoxymethyl-5-dimethylimidazole or its hydrohalide of formula Ia wherein Q represents a halogen, hydroxyl or methoxy group with cysteamine or its hydrohalide.

When Q is halogen, the reaction proceeds in a basic medium, such as in the presence of sodium ethanolate or sodium hydroxide. Since cysteamine is the primary amine, it must be protected by an amino group, for example phthalimido, which is removed by acid hydrolysis or hydrazinolysis after completion of the reaction.

When Q is a hydroxyl 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 yields for these reactions are 70 to 90%, the reaction time being 10 to 18 hours at reaction temperatures of 100 to 120 ° C.

SUMMARY OF THE INVENTION The object of the present invention is to provide a process which makes it possible to obtain 4 - [(2-aminoethyl) thiomethyl] -5-methylimidazole in high yield at short reaction times and at room temperature and to isolate the end product simply and with high purity.

The above object is achieved according to the invention by a process for the preparation of 4 - [(2-aminoethyl) thiomethyl] -5-methylimidazole and its acid addition salts, characterized in that the compound of the formula II

Ha)

ch _SM (III wherein M is hydrogen or an alkali metal, is reacted with 2-halogenethylamlnem wherein the halogen is chlorine or bromine, in a system consisting of an aqueous solution of a strong base and an organic phase at room temperature and in the presence of a quaternary ammonium or quaternary phosphonium salts as phase transfer catalysts.

As the catalyst, for example, methylcaprylylammonium chloride, benzyltriethylammonium chloride, benzyltriphenylphosphonium chloride, hexadecyltributylphosphonium bromide and the like can be used.

The reaction is carried out in the presence of a 50% aqueous sodium hydroxide solution.

Suitable solvents are polar organic solvents in which the starting compound is soluble, such as lower alcohols, acetonitrile and the like. The yields of the final compound of the formula I are extremely high and amount to 85 to 90% of theory.

The starting material 4 (S) -mercaptomethyl-5 (4) -methylimidazole as well as the process for its preparation are described in belg. U.S. Pat. file 875 845.

Since thiols are not very stable compounds, the reactions should preferably be carried out under an inert atmosphere.

An alternative procedure is to use 5 (4) -methyl 1-4 (5) -mercaptomethylimidazole in the form of an alkali metal salt, which is a stable compound, as starting material. The reaction conditions are similar to those described above.

In addition to these advantages, another advantage of the process of the invention over the known methods of synthesizing 4 - [(2-aminoethyl) thiomethyl] -5-methylimidazole is that it is not necessary to use cysteamine hydrogen halide in the synthesis of the invention. This expensive compound is replaced by 2-halo-ethylamine, in particular 2-chloroethylamine, which is a cheap and readily available compound, which also does not need to be protected beforehand with an amino group.

The invention is illustrated, but not limited, by the following examples.

He did

6.4 g (0.05 mol) of 5-methyl-4-mercaptomethylimidazole are dissolved in 80 ml of ethanol, 10 ml of a 50% aqueous NaOH solution and 1.16 g (0.0025 mol) of hexadecyltributylphosphonium chloride are added and stirred for 10 min. inert atmosphere at room temperature. Then a solution of 4.0 g of 2-chloroethylamine in 30 ml of ethanol is added over 15 minutes and stirred first at room temperature for 30 minutes and then at 50 ° C for a further 30 minutes. The solvent was evaporated and the residue was extracted with isopropanol. The inorganic salts are filtered off and hydrogen chloride is introduced into the isopropanol phase until pH 1. The reaction mixture is evaporated to dryness and the residue is recrystallized from ethanol. 10.9 g (89.3% of theory) of 4 - [(2-aminoethylthiomethyl) -5-methylimidazole are obtained in the form of the dihydrochloride, m.p. 189-191 ° C.

Example 1 a d 2

The procedure was analogous to Example 1 except that 580 mg (2.5 mmol) of benzyltriethylammonium chloride was used as catalyst. 10.8 g of the desired compound are obtained (88% of theory).

Example 3

The procedure is analogous to Example 1, but using 1.04 g (2.5 mmol) of tricaprylylmethylammonium chloride as the catalyst. 10.9 g (89.3% of theory) of the title compound are obtained.

Example 4

1.5 g (0.01 mol) of 5-methyl-4-mercaptomethylimidazole as the sodium salt are dissolved in 20 ml of water, 70 mg (0.3 mol) of benzyltriethylammonium chloride are added and stirred for 10 minutes at room temperature. 8.0 g of 2-chloroethylamine in 8 ml of ethanol are added dropwise to the reaction mixture over 10 minutes and stirred at room temperature for 1.5 hours. The reaction mixture is evaporated to dryness and worked up as described in Example 1. 2.2 g (90.3% of theory) of the title compound are obtained, m.p. 190-192 ° C.

Claims (4)

A process for the preparation of 4 - [(2-aminoethyl) thiomethyl] -5-methylimidazole of formula I (III --_ C ^ C / I ₂ SCH ₂ CH ₂ NH ₂ (I) and its acid addition salts characterized in that a compound of formula II wherein M is hydrogen or an alkali metal, is reacted with 2-halogenethylaminem wherein halogen is chlorine or bromine, in a system consisting of an aqueous solution of a strong base and an organic phase, at room temperature and in the presence of a quaternary ammonium or phosphonium salt as phase transfer catalysts. 2. A process according to claim 1, wherein the quaternary ammonium or phosphonium salts are methyltricaprylylammonium chloride, hexatributylphosphonium bromide, benzyltriethylammonium chloride. 3. The process of claim 1 wherein the reaction is carried out in the presence of a 50% aqueous sodium hydroxide solution. 4. The process according to claim 1, wherein the reaction is carried out in the presence of lower alcohols or acetonitriles as organic solvents.