DE2062265A1 - Process for the preparation of substituted benzimidazoles - Google Patents

Description

DR. BERG DIPL-ING. STAPF

PATENTANWÄLTE 8MUNCHENS ₁ HILBL ₁ ESTRASSEZo

Dr. Berg Dipl.-Ing. Stapf, 8 Munich 2, HllblestraBe 20 Our sign 20 345 ^date '^' ΟβΖι 1970

Attorney file 20 345

Martino FINOTTO, Milano / Italy

Process for the preparation of substituted benzimidazoles

The present invention "relates to a method of manufacture of substituted benzimidazoles, in particular of benzimidazoles with a heterocyclic substituent in the 2-position, such as 2- (4'-thiazolyl) -benzimidazoles

So far, these substituted benzimidazoles have been used, for example, in accordance with Swiss patent specification 423 789 by condensation of 4-i'hiazolcarboxylic acid or their

V / My - 2 -

209821/1051

BAD ORJQfNAt

Analogues, such as their esters or amides with o-phenylenediamine in polyphosphoric acid at 200 to 35O ⁰ C for three hours or more prepared. The process conditions of this method are very strict in terms of duration, temperature and substances used, which leads to considerable destruction of the reactants and the formation of undesired by-products. The presence of the latter makes the cleaning of the end product very difficult, cumbersome and expensive.

According to another method, which is described for example in Swiss patent specification 423 791, can these Benzimi.dazole derivatives from the chloride of 4-thiazolecarboxylic acid or their analogues by condensation with o-nitroaniline or similar nitrophenylamines and then Reduction and cyclization of the product obtained can be produced. This procedure therefore points Disadvantages because the halides of thiazole acids are not easy to prepare and to purify and the reduction must be carried out in such a way that the heterocyclic nuclei are protected, which must be done with great care is possible.

According to another method, for example, in the Swiss patent 423 790 is described, the same compounds from o-phenylenediamine and thiazole

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aldehydes are produced; however, the production of these aldehydes is particularly high on an industrial scale difficult.

The disadvantages indicated above are according to the present invention by a process for the preparation of substituted benzimidazoles and in particular the 2- (4'-Thiazolyl) -benzimidazoles of the formula (i)

(D

fixed, which is characterized by the fact that one is on cold Clean the mixed anhydride from 4-thiazolecarboxylic acid and ethyl chloroformate with o-phenylenediamine for reaction brings and cyclizes the intermediate product obtained under really weak and operationally convenient conditions. The mixed anhydride is not isolated »

In the following the present invention is based on the The following reaction schemes and the subsequent description are explained in more detail:

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-A-

K *

COOH

'2 ⁿ 5

(II)

+ Cl-C- OC ₂ H ₅

(in)

ν-I-CO-O-Co-OC ₂ H ₅

(V)

(VI)

^NH NH

N; —CO - NH 

• ^ Jl ^ j) > (ι)

H ₂ N (VII)

The 4-thiazolecartonic acid of the formula (II), prepared according to Helv.Chim.Acta _# 25, 362 (1945), is reacted at room temperature with ethyl chloroformate (III) in an inert solvent such as, for example, benzene.

The conditions are of the same kind as for trimethoxybenzamide in Ber. 82_, 859 (1959), and it is deposited in the presence of a tertiary amine (IV), which absorbs the hydrogen chloride formed during the reaction. A solution of the mixed anhydride (V) an equivalent of o-phenylenediamine (VI) is added, and

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it becomes the corresponding one, in each case at room temperature Mono amide (VII). with yields of about 50% of theory, based on acid and amine used, received,

It is obvious that the distinctive, new and advantageous feature of the process according to the invention in the production means taking place under mild conditions the easily prepared or accessible monothiazolyl or derivatives of o-phenylenediamine analogous to it lies.

These compounds crystallize from the benzene Reaction solution in pure form and can be used directly for the cyclization to benzimidazoles.

The cyclization is preferably carried out by heating the amides in the course of a few minutes to the melting point or to 150 ⁰ C in 85 $ strength by weight phosphoric acid or in the presence of j ^ ntwässerungsmitteln such as potassium hydrogen sulfate *

iöin feature of economic importance of the invention Process is the production of monoamides between thiazole acids and o-phenylenediamine under really mild conditions «

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example

2- (4'-thiazolyl) -benzimidazole acid "

In a 2 liter flask with a stirrer and droplet separator 32.5 (0.25 mol) of thiazole carboxylate, 1000 ecm of benzene anhydride and 27 g of triethylamine are entered. After an hour Stirring at room temperature, 37.5 g of ethyl chloroformate are added dropwise.

The mixture is stirred for about a further two hours and then a benzene solution of o-phenylenediamine (27 g) is added dropwise. The mixture is then stirred at room temperature for three hours and the precipitate is filtered off. After drying in air, it is shaken with cold water in a glass, the amide formed is filtered off and dried in an oven at 100 ° C .; it has a melting point of 203-204 ⁰ G.

The triethylamine is recovered from the water. A 25% solution of this product in 85% H ₅ PO ₄ is heated to 150 to 170 ° C. for 15 minutes with stirring and, after cooling, poured into ground ice.

The precipitated product is filtered, washed and dried at 100 ⁰ G. It is then recrystallized from acetic acid. Pp 304 to 305 ⁰ C.

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Although only one exemplary embodiment of the method according to the invention has been described, it will be easy for a person skilled in the art fall to work out numerous changes and modifications, all of which fall within the scope of the invention are to be considered.

Patent claims:

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Claims (5)

Patent claims: 1.11 Process for the preparation of substituted benzimidazoles, especially of benzimidazoles with a heterocyclic substituents in the 2-position, characterized in that that one thiazole-4-carboxylic acid or a carboxylic acid analogous to it mixed with a chloroform ester Reacts anhydride, then brings this to reaction with o-phenylenediamine and the resulting monoamide cyclized under mild conditions. 2. The method according to claim 1, for the preparation of
2- (4'-Thiazolyl) -benzimidazole and analogous compounds, characterized in that the mixed anhydride of 4-thiazolecarboxylic acid and ethyl chloroformate is reacted with ο-phenylenediamine by a cold route and the intermediate product obtained under mild conditions is then cyclized. 3. The method according to any one of the preceding claims, characterized in that the reaction between the mixed anhydride (V) and ο-phenylenediamine with formation of the corresponding monamide (VII) executes at room temperature . 4. The method according to any one of the preceding claims, characterized in that the cyclization of the Mon- 209821/1051 _ ₉ _ COPY amids (VII) within a few minutes by heating the melting point or to about 150 ° C. in 85% phosphoric acid; ^ 'also in the presence of dehydrating Means, carries out. 5. As new intermediates obtained by reaction between shiazolic acids and o-phenylenediamine Monoamides ο 20 982 1/1051 COPY BAD ORiGiNAL