DE1201354B - Process for the preparation of cyanomethyl substituted heterocyclic compounds - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Number.
File number:

Exhibition day;

German KI .: l2p-9

B67956IVb / 12p

July 7, 1962

September 23, 1965

The preparation of 2-cyanomethylbenzimidazole by the condensation of 1,2-diaminobenzene with ethyl cyanoacetate in boiling aniline is known (Journal of the American Chemical Society, Vol. 65 [Ϊ943], pp. 1072-1075), because of the danger of handling large Amounts of ether _s required to precipitate the condensation product and additional purification by primary crystallization, this process is difficult to carry out on an industrial scale. If the corresponding methyl ester is used instead of the ethyl cyanoacetate, a sticky condensation product is obtained from which 2-cyanomethylbenzimidazole can be isolated in yields of only about 10% of theory. Compounds substituted on a nitrogen atom of the 1,2-diaminobenzene or 1,2-diamines substituted in the aromatic nucleus by radicals such as phenyl, methyl or chlorine cannot be converted into the corresponding 2-cyanomethylbenzinidazoles by the known process.

The invention relates to a process for the preparation of cyanomethyl-substituted heterocyclic compounds the general formula

Ri

, S.

CH ₂ -CN

If A is a benzene or benzene which is optionally substituted by halogen atoms, alkyl or alkoxy groups Naphthalene radical means which is substituted by the two nitrogen atoms in the ortho or peri position and Ri is a hydrogen atom, optionally substituted by the hydroxyl or cyano group Means alkyl groups or aryl groups, by reacting compounds of the general formula

Ri

a:

NH
NH ₂

II

with alkyl cyanoacetates of the general formula

_: O

NC-CH ₂ -C

III

ORs

in which R _{2 is} alkyl radicals having 1 to 8 carbon atoms Process for the preparation of cyanomethyl-substituted heterocyclic compounds

Applicant:

Aniline & Soda Factory in Baden

Aktiengesellschaft, Ludwigshafen / Rhein

Named as inventor:

Mr. Günter Hansen,

Dr. Johannes Dehnert, Ludwigshafen / Rhine -

means at temperatures of 160 to 22O ⁰ C and in the presence of inert solvents, which is characterized in that one carries out the reaction in the presence of aromatic sulfonic acids.

Examples of compounds of the formula II are in particular: 1,2-diaminobenzene, 1 - amino - 2 - phenylaminobenzene, 1,2 - diamino - 4 - methylbenzene, 1 - amino - 2 - methylaminobenzene, 1,2 - diamino - 4 - chlorobenzene, 1 - amino-2 - Yy? - cyanäthylamino] - benzene, Ϊ - amino - 2 - methylamina4-methylbenzöi, 1,2-, 2,3- or 1,8-diaminonaphthalene.

Examples of starting materials of the formula III are named: methyl cyanoacetate, ethyl cyanoacetate, n-propyl cyanoacetate, I-propyl cyanoacetate, n-butyl cyanoacetate, cyanoacetic acid - η> octyl ester, isobutyl cyanoacetate.

The reaction of compounds of the formula II with compounds of the formula III in the presence of preferably 0.5 to 5% of an aromatic sulfonic acid, such as p-toluenesulfonic acid, naphthalene-2-sulfonic acid or benzenesulfonic acid, takes place at temperatures of 160 to 220 ^° C., with the volatile products formed during the reaction are distilled off. Cyanoacetic acid esters of the formula III with R ₂ = C3H7 - to CeHi7 - give the highest yields of cyanomethyl-substituted heterocycles; Compounds of the formula III with R ₂ = CH ₃ - and C ₂ H ₅ - are therefore appropriately transesterified to give the higher esters, which can be further reacted as crude product. Suitable inert solvents are those which remain unchanged under the reaction conditions and whose boiling points are between 160 and 220.degree

509 6S8 / 456

lie. Chlorinated benzenes, such as o-dichlorobenzene and trichlorobenzene, are particularly suitable.

The reaction products, which are obtained in good yields and high purity, can finally be converted into are usually isolated.

The compounds obtainable according to the invention are intermediates for the preparation of Dyes and pharmaceuticals.

The parts and percentages given in the following examples are, unless otherwise noted, Weight units. Parts of space relate to parts by weight like liters to kilograms Normal conditions.

example 1

A mixture of 110 parts of methyl cyanoacetate, 108 parts of powdered o-phenylenediamine, 4 parts p-toluenesulfonic acid and 100 parts of o-dichlorobenzene is heated to about 170 ⁰ C. After 135 parts of liquid have been distilled off, the mixture is stirred until it cools to room temperature, left to stand for a few hours, and the residue is filtered off with suction, washed with a little o-dichlorobenzene and dried. 98 parts of 2-cyanomethylbenzimidazole with a melting point of 202 ^° C. are obtained.

Example 2

In an enamelled iron kettle, a mixture of 1200 parts of methyl cyanoacetate, 1000 parts of isobutanol and 20 parts of p-toluenesulfonic acid is refluxed for 2 hours with stirring, then 925 parts of solvent are distilled off and 1080 parts of powdered 1,2-diaminobenzene are added to the hot solution. The mixture is heated to 180 to 190 ^° C., 1530 parts of liquid are distilled off, ^{1000 parts of o-dichlorobenzene are added to the reaction mixture at about 150 °} C. and the mixture is stirred until it has cooled to room temperature. After suction filtration, washing with a little o-dichlorobenzene and drying at 8O ⁰ C under reduced pressure to obtain 1,100 parts of 2-CyanmethylbenzimidazoI a melting point of 201 ⁰ C.

Example 3

A mixture of 108 parts of 1,2-diaminobenzene, 140 parts of cyanoacetic acid - η - propyl ester, 2 parts of p-toluenesulfonic acid and 100 parts of 1,2-dichlorobenzene is heated ^{to 180 to 190 ° C. with stirring.} 185 parts of liquid are removed by distillation to about 150 ° C hot reaction mixture of 100 parts of 1,2-dichlorobenzene, the mixture was stirred until cooled to room temperature, suction filtered, the product washed with a little of 1,2-dichlorobenzene and 8O ⁰ C under reduced Print dried. 144 parts of 2-cyanomethylbenzimidazoI with a melting point of 2O6 ° C. are obtained.

Proceed as indicated above and use n-propyl cyanoacetate in place of 140 parts 156 parts of n-butyl cyanoacetate and, instead of 2 parts of p-toluenesulfonic acid, 2 parts Naphthalene-2-sulfonic acid, 153 parts of 2-cyanomethylbenzimidazole are obtained after work-up.

In the same way, the following 2-cyanomethyl compounds are made manufactured:

example Diamine component Cyanoacetic acid ester Condensation product Melting point yield 4th l-amino-2-methyl-
aminobenzene Cyanoacetic acid
n-propyl ester l-methyl-2-cyano
methylbenzimidazole 129 ° C 61% of theory 5 I, 2-diamino
4-chlorobenzene Cyanoacetic acid
n-butyl ester 2-CvanmethyI-
5 (6) -chlorobenzimide-
azole > 300 ° C 11% of theory 6th l-amino-2-methyl-
amino-5-methyl-
benzene Cyanoacetic acid iso-
butyl ester 1-methyl-2-cyano
methyl-5-methyl- 147 ° C 25% of theory 7th 1,2-diamino
4-methoxybenzene Cyanoacetic acid iso-
butyl ester 2-cyanomethyl
5 {6) -methoxybenz-
inudazole > 300 ° C 31% of theory 8th l-amino-2 - [/? - cyano-
ethylamino] -
benzene Cyanoacetic acid iso-
butyl ester 1-IS-cyanoethyI] -
2-cyanmetfaylbenz-
imidazole 239 ° C 27% of theory 9 l-amino-2 - [/ S-hy-
droxyäthylamino] -
benzene Cyanoacetic acid iso-
butyl ester 1-f ^ -hydroxyethyl] -
2-cyanomethylbenzene
imidazole 17l ° C 15% of theory 10 1,8 diamino
naphthalene Cyanoacetic acid iso-
butyl ester 2-cyanomethylper-
imidine 153 ° C 97% of theory

Example 11 distills off 125 parts of liquid, gives 100 parts

A mixture of 108 parts of o-phenylene oxide, 65 o-dichlorobenzene, cools and isolates the

217 parts of n-octyl cyanoacetate, 100 parts of precipitated product. After washing with o-dichloro-dichlorobenzene and 2 parts of p-toluenesulfonic acid benzene and drying gives 119 parts of 2-cyano

is heated to 190 to 200 ^{0 C with stirring.} One methylbenzimidazole of melting point 204 ⁰ C.

Claims (1)

Claim: Process for the preparation of cyanomethyl-substituted heterocyclic compounds of general formula Ri in which A denotes a benzene or naphthalene radical optionally substituted by halogen atoms, alkyl or alkoxy groups, which is substituted by the two nitrogen atoms in the ortho or peri position, and Ri denotes a hydrogen atom, alkyl groups or aryl groups optionally substituted by the hydroxyl or cyano group, by reacting compounds of the general formula
Ri a: -NH
NH ₂ with alkyl cyanoacetates of the general formula " • - m "- r ν NC - CH ₂ - C OR ₂ in which R2 denotes alkyl radicals with 1 to 8 carbon atoms, at temperatures from 160 to 220 ^° C. and in the presence of inert solvents, characterized in that the reaction is carried out in the presence of aromatic sulfonic acids. Considered publications:
Chemisches Zentralblatt, 1960, pp. 17446 and 17447. 5OT688M56 9.65 θ Bundesdruckerei Berlin