PROCESS FOR PREPARING IMIDAZOLE DERIVATIVE

METHODE DE PREPARATION D'UN DERIVE D'IMIDAZOLE

English Abstract

Abstract of the Disclosure


The present invention relates to a novel process for preparing
4-[(2-aminoethyl)thiomethyl]-5-methyl imidazole of the formula


Image
I
and its acid addition salts, characterized as a process for
preparing 4-[(2-aminoethyl)thiomethyl]-5-methyl imidazole of
the formula

Image

and its acid addition salts,
characterized in that a compound of the formula

Image


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.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing 4-[(2-aminoethyl)thiomethyl]-5-methyl
imidazole of the formula

Image

and its acid addition salts,
characterized in that a compound of the formula,

Image

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
of a strong base and of an organic phase, at room temperature
in the presence of quaternary ammonium or quaternary phosphon-
ium salts as phase transfer catalysts.

2. A process according to claim 1, characterized in that methyl-
tricaprylyl ammonium chloride, hexadecyltributyl phosphonium
bromide, benzyltriethyl ammonium chloride are used as quater-
nary ammonium or quaternary phosphonium salts.

3. A process according to claim 1, characterized in that the
reaction is carried out in the presence of a 50 % aqueous
sodium hydroxyde solution.




4. A process according to claim 1, characterized in that the
reaction is carried out in the presence of lower alcohols or
acetonitrile as organic solvents.

Description

~540~

A PROCESS FOR PREPARING IMIDAZOLE DERIVATIVE

The present invention relates to a novel process for preparing
4- ~(2-aminoethyl)thiomethyl~-5-methyl imidazole of the formula




3 ¦ - ~ CH2SC~2CH2NH2
HN



and its acid addition salts~


4-~(2-aminoethyl)thiomethyl~-5-methyl imidazole is an important
intermediate in the preparation of pharmacologically active com-
pounds, such as N-cyano-N'-me~hyl-N"-~2-[(5-methyl-4-imidazolyl)-
methylthio]ethyl3-guanidine, which acts as an active histamine
antagonist on H2 receptors and is known under the generic name of
"cimetidin". The intermediate and processes for the preparation
thereof were disclo.sed and described for the first time in the
British patent 1,338,169.


The known and described processes arelbased on the reaction of
4-halomethyl-, 4-hydroxymethyl- or 4-methoxymethyl-5-methyl
imidazole or its hydrohalide of the ormula



CH3 ~ _ I CH2Q
H ~ N



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



-- 1 --
,~

l~S9~ 3

When Q represents a halogen, the reaction is carried out in a basic
medium, e.g. in the prssence of sodium ethoxyde or sodium hydroxydeO
Since cysteamine is a primary amine, it is necessary to protect
the amino group, ~.g. with a phthalimide group, which is removed
after completion of the reaction by acid hydrolysis or hydrazinoly-
sis. When Q represents a hydroxy or a 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 of these re-
actions are between 70 and 90 ~, the reaction times from 10 to 18
hours and the reaction temperature from 100 to 120C.


The aim of the present invention is to provide a process for pre-
paring 4-~(2-aminoethyl)thiomethyl~-5-methyl imidazole with high
yields, short reaction times and at room temperature, which would
make it possible that the final product I is isolated easily and
with high purity.


The aim is achieved by selective alkylation of 4(5)-thiomethyl-
5(4)-me~hyl imidazole of the formula

CH3 1- ¦ 2 H




HN ~ ~ N



with a 2-haloethylamine, wherein halo means chloro or bromo, at
room temperature in a system consisting of a 50 % aqueous solution
of a strong base and an organic phase using quaternary ammonium
or quaternary phosphonium salts as phase transfer catalysts. As
catalysts there can be used e.g. methyltricaprylyl ammonium
chloride, benzyltriethyl ammonium chloride, benzyltriphenyl
phosphonium chloride, hexadecyltributyl phosphonium bromide etc.
2 -


i

~i54()2;~

Another advantage of the process of the invention over knownprocesses for synthetizing 4-[(2-aminoethyl)-thiomethyl~-5-methyl
imidazole i5 that the use of cysteamine hydrohalide is avoided.
Instead of this expensive chemical, a 2-haloethylamine, preferably
2-chloroethylamine, which is a cheaper and readily available com-
pound, is used. Furthermore, there is no need for a preliminary
protection of the amino group in this compound.


As organic solvents there can be used polar organic solvents in
which the starting reactant is soluble, such as lower alcohols,
acetonitrile and the like. The yields of the final compound of
the formula I are extraordinarily high and amount to 85 to 90 % of
the theoretical yield.


The starting 4(5?-thiomethyl-5(4)-methyl imidazole and the process-
es for preparing the same are disclosed in our Belgian patent
875 845.


Since 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, which is a stable compound, is used as
the starting substance. The reaction conditions are similar to
those of the previous case.


The invention is illustrated but not limited by the following

Examples.


Example 1
S-methyl-4-thiomethyl imidazole (6.4 g, 0.05 mole) is dissolved in
-- 3 --
t`-
~




. ' ','

1154(;~

ethanol (80 ml). Thereto a 50 % aqueous NaOH solution (10 ml) is
added, followed by the addition of hexadecyltributyl phosphonium
chloride (1.16 g, 0.0025 mole) and stirring for 10 minutes in an
inert atmosphere at room temperature. Over a period of 15 minutes,
a solution of 2-chloroethylamine (4.0 g) in ethanol (30 ml) is
added and the resùlting mixture is stirred for 30 minutes at room
temperature and then for 30 more minutes at 50C. The solvent is
removed by evaporation and the residue is extracted with isopropan-
ol.


The inorganic salts are filtered off and hydrogen chloride is pass-
ed into the isopropanolic solution until pH 1 is reached.


The reaction mixture is evaporated to dryness and the residue is
recrystallized from ethanol. There is obtained 3-C(2-aminoethyl)
thiomethyl]-5-methyl imidaæole (10.9 g, 89.3 %) in the form of its
dihydrochloride, mnp. 189-191C.


ExamPle 2
The procedure of the previous Example is followed, using, however,
benzyltriethyl ammonium chloride (TEBA, 580 mg, 2.5 mmole) as the
catalyst. There are obtained 10.8 g (88 %) of the desired com-
pound.


Example 3
The procedure of Example 1 is followed, using, however, tricaprylyl-
methyl ammonium chloride (Aliquat 336, 1.04 g, 2.5 mmole) as the

catalyst. There are obtained 10.9 g (89.3 %) of the desired
compound.


~1~46) '~


5-methyl-4-thiomethyl imidazole (1.5 g, 0.01 mole) in ~he form of
its sodium mercaptide is dissolved in water (20 ml). Thereto
benzyltriethyl ammonium chloride (70 mg, 0.3 mmole) is added. 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 1.5 hours at room temperature, evaporated
to dryness and the rest of the procedure of Example 1 is followed.
There are obtained 2.2 g (90.3 %) of the desired compound, m.p.
190-1~2C.