DE2041324A1 - New benzimidazole derivatives and a process for their preparation - Google Patents

Description

AG FA-G EVAERT AG 204132 *

PATENT DEPARTMENT

LEVERKUSEN 1 9 AUG. 1970

New benzimidazole derivatives and a process for their preparation

The invention relates to new mercapto- or thioether-substituted benzimidazole derivatives, and a process for their preparation. In the previously customary method for preparing benzimidazoles, one starts from a suitably substituted o-nitrobenzene, which is usually reacted at elevated temperature with ammonia or primary amines Formation of the corresponding o-nitroaniline. This is reduced, for example catalytically, and the diamine obtained is converted into the benzimidazole by ring closure reactions in the known manner, for example by reaction with acetic acid to form 2-methylbenzimidazole or by reaction with carbon disulfide or thiophosgene to form 2-mercaptobenzimidazole. In the first step of this reaction sequence 2,4,5-trichloronitrobenzene, for example, can be reacted with methylamine in propanol by heating for 2 hours at 80 ⁰ C for 2-methylamino-4,5-dichloronitrobenzene implement. So only one chlorine atom reacts.

It has now been found that nitrobenzenes holgenated several times after reaction with ammonia or primary amines with mercapto compounds, preferably in an alkaline medium, can be further implemented. For example, arises from

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the above-mentioned 2-methylamino-4,5-dlchloronitrobenzene the reaction with thiophenol 2-methylamino-4-chloro-5-phenyl ■ thionitrobenzene. This opens up access to new benzimidazole derivatives.

The invention therefore relates to new mercapto and thioether-substituted benzimidazole derivatives of the following formula:

where mean:

R and R = identical or different radicals, namely hydrogen, lower alkyl with 1-3 carbon atoms, e.g. methyl, ethyl, propyl or isopropyl, aralkyl such as benzyl or phenylethyl, aryl such as phenyl, halogen such as fluorine, chlorine or bromine, -CF ,, -CN, -SO ₂ R, -SOR, -SO ₂ NR ₂ , -COOR or -CONR ₂ where R is alkyl or aryl;

R and R = identical or different radicals, namely Hydrogen, alkyl, e.g. methyl, ethyl, propyl, isopropyl, dodecyl, octadecyl, alkenyl such as Allyl, alkynyl, cycloalkyl such as cyclohexyl, aralkyl such as benzyl or phenylethyl. Aryl, e.g.

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Phenyl, naphthyl or biphenyl, or heterocyclic Radicals such as ^ L-pyridyl, where the groups mentioned, in particular the alkyl or aryl groups, continue can be substituted, e.g. by halogen or hydroxy, alkoxy, acetoxy, carboxy, sulfo, SuIfato-, amino-, N-sulfonylcarbamyl-, N-aylsulfamyl- or N-sulfonylsulfamyl groups.

R ⁵ = hydrogen, alkyl, e.g. methyl, ethyl, propyl, isobutyl, tert-amyl, dodecyl or octadecyl, olefinically unsaturated alkyl, e.g. allyl, cycloalkyl such as cyclohexyl, aralkyl such as benzyl or ™ phenylethyl, aryl, e.g. phenyl, naphthyl or Biphenyl, or a heterocyclic aromatic group such as furyl, thienyl, pyridyl or carbazolyl, it being possible for the groups mentioned, in particular the alkyl or aryl groups, to be further substituted, for example by halogen or hydroxy, alkoxy, acetoxy, carboxy, sulfo -, sulfato or amino groups;

R- * can also be -OH, -SH, -OR, -SR or -NR ₂ , where R is alkyl.

Substituted alkyl groups are to be understood as meaning, for example : Chloroalkyl, hydroxyalkyl, alkoxyalkyl, acetoxyalkyl or aminoalkyl, e.g., dimethylaminoethyl. As substituted Aryl group should be mentioned, for example: chlorophenyl, metho>: yphenyl, p-tolyl, garboxyphenyl or sulfophenyl.

As an example + -, for the mercapto or thioethi ¹ ubsti + aiertcii benzimidazoles according to the invention, the following may be mentioned:

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Nv
S-SH

247-259 ° C

Cl

f \

CH, Pp 142-143 C

Cl N

HO-CH ₂ -CH ₂ -S

CH,

(CH ₂

Mp 84-87 C.

N
V-SH

N
CH, Pp 209-212 ⁰ C.

204132 *

NaOOC-CH ₂ -S

Pp> 290 ^° C

C ₁₂ H ₂₅ -S

Pp 104 ⁰ C

Cl

HO-CH ₂ -CH ₂ -S

CE,

160 to 161 ⁰ C

0-CO-CH, Pp 108-110 ⁰ C.

CH ₂ -CH = CH ₂ pp 152-158 ⁰ C.

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Cl

Mp 235 ° C

Cl

Mp 157-160 ⁰ C

N CH, 193-194 ° C

HO-CHo-GHo-S

CH ₂ -S

CH-O-COCH ₃

CH ₂ -O-GOGH ₅ mp 179-180 ⁰ C, mp 126 ° C

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ORIGINAL INSPECIH)

The invention also relates to a method for production of the mentioned mercapto- and thioether-substituted benzimidazoles, which is characterized by the following process steps:

a) Implementation of o-Nltranilinen of the following formula:

NH-R ⁵

Shark

where Hai denotes a halogen atom, e.g. chlorine or bromine and R, R and Ir have the meaning already given, with a mercaptan of the formula R-SH, in which R ^ has the meaning already given;

b) reduction of the nitro group in a known manner and

c) cyclization in a likewise known manner with formation of the mercapto or thioether-substituted Benzimide zole.

The reaction of the halogenated nitranilines with mercaptans is expediently carried out in solution at elevated temperatures. Possible solvents are, for example: alcohols such as methanol, ethanol, propanol or butanol, ketones such as diethy! Ketone or cyclohexanone, aromatic or cycloaliphatic hydrocarbons such as benzene, toluene, xylene or cyclohexane, cyclic or open-chain nitrogenous organic bases such as pyridine, quinoline, Dimethylaniline, triethylamine or triethanolamine, but also water or mixtures of the solvents mentioned.

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The reaction is preferably carried out in the presence of acid-binding reagents in order to bind the split off hydrogen halide. Inorganic bases are mainly used for this purpose or basic salts used, e.g. sodium or potassium hydroxide, soda, potash, tertiary potassium phosphate, Sodium acetate, oxides of magnesium, calcium, aluminum or zinc, possibly also silver and mercury oxide, or potassium fluoride. In the case of the basic organic solvents already mentioned, the acid-binding effect can be taken over by the solvents.

Instead of the nercapto compound used in the reaction, its metal salts, e.g. alkali or alkaline earth salts, can also be used. In this case, it is not necessary Use of another acid-binding agent.

The 2-nitroanilines obtained, mercapto- or thioether-substituted in the 5-position, then become one in a known manner subjected to reducing treatment, wherein the nitro group is reduced to a primary amino group. This can be done catalytically using, for example Raney nickel can be done or by treatment with zinc and hydrochloric acid.

The o-phenylenediamine obtained is then cyclized by likewise known methods to form the corresponding one Benzimidazoles. For example, when the o-phenylenediamines are reacted with aliphatic, or isocyclic or heterocyclic, one obtains aromatic carboxylic acids, such as acetic acid, propionic acid, benzoic acid, furan, thiophene, pyridine or carbazole carboxylic acid, the mercapto- or thioether-substituted benzimidazoles with the corresponding substituents in the 2-position. Another known method consists in the reaction with carbon disulfide, phosgene or thiophosgene, with 2-hydroxy or 2-mercaptoben-bimidazole, which in turn are converted into the (thio) ether compounds by known methods can be. . ,

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^0RiG ^ INSPECTED

The new benzimidazole derivatives can be used in pharmacy or in the field of plant protection use, there they e.g. have fungicidal effects or by simple Reaction can be converted into fungicidal active ingredients.

The following is an example of the manufacture of some thioether-substituted benzimidazoles described.

example 1
i-Phenylamino ^ -nitro ^ -chloro-S-phenylthiobenzene

28.5 g of i-phenylamino - ^ - nitroH-tS-dichlorobenzene are dissolved in 200 ml of alcohol and 50 ml of benzene at an oil bath temperature of 100 ° C. To this end, 12 ml of thiophenol and, with stirring, a solution of 22 g of soda in 50 ml of water are added. The reaction is allowed to continue for 4 1/2 hours and then cooled. Bas which has crystallized out is filtered off with suction and boiled with 300 ml of water. Yield 35.4 g, Pp. 165 - 167 ⁰ C. After recrystallization from 25o ml of methanol and 15o ml of chloroform there was obtained yellow crystals. Yield 34.8 g, pp. ^{164-167 C} i -phenylamino ^ -nitro ^ -chloro-S-phenylmercaptobenzene.

i-Phenyl ^ -mercapto-S-chloro-e-phenylthiobenzimidazole

35 g of the above-mentioned nitroaniline are dissolved in 250 ml of methanol and 2oo ml of benzene and using Raney nickel reduced at 60 ° C to the diamine, which - after filtering off the Raney nickel without isolation - with 30 ml of CSg and 20 ml 50 # sodium hydroxide solution to boil for 5 hours on the steam bath is heated. The solution is cooled with 10 ml of glacial acetic acid added and the precipitate filtered off with suction. It is dissolved in 400 ml of water and 50 ml of 20% sodium hydroxide solution, the solution Clarified with activated charcoal and again with 2o ml of glacial acetic acid

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failed. The precipitate which is suctioned off is recrystallized from 800 ml of acetone and a little activated charcoal. Yield 21.5 g, Pp 247 -. 259 ⁰ C fine white needles.

Example 2

2-nitro-4-chloro-5-phenylthio-N-methylaniline

A solution of 66 g of 2-nitro-4,5-dichloro-N-methylaniline and 33 g of thiophenol in 650 ml of ethanol was heated on the P steam bath and a solution of 39 g of sodium carbonate in 120 ml of water was left with stirring over the course of 15 minutes drip. The mixture was then heated to boiling for a further 4 hours while stirring on the steam bath and then poured into 1000 ml of ice water. The reaction product was filtered off with suction and recrystallized first from isopropanol and then again from alcohol. Yellow crystals; Yield 39 g, Pp 155 -. 157 ⁰ C.

2-Amino - ^ - chloro-S-phenylthio-N-methylaniline

37 g of 2-nitro-4-chloro-5-phenylthio-N-methylaniline were dissolved in 500 ml of dimethylformamide and hydrogenated in an autoclave using Raney nickel as a catalyst. The reaction solution freed from the catalyst was stirred into 2 l of ice water, the amine precipitating. It was filtered off with suction, washed with water and dried. Yield 34 g of white crystals; Mp. 97 - 98 ⁰ C.

1,2 ~ Dimethyl-5-chloro-6-phenylthiobenzimidazole

33 g of 2-amino-4-chloro-5-phenylthio-N-methylaniline and 12o ml Acetic anhydride was refluxed for 3 hours and then the liquid was distilled off

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(Bath temperature 2oo ° C). The solid residue was recrystallized from 120 ml of n-propanol. Yield 18 g of colorless crystals; Mp 142 -. 145 ⁰ C

Example 3

1- ( Oi -Dimethylaminopropylamino) -2-nitro-4,5-dichlorobenzene

226 g of 2,4,5-tri-chloronitrobenzene are heated with 1 l of propanol, 110 g of 3-amino-O-dimethylaminopropane and 10.6 g of soda for 6 hours on the steam bath. After filtering off with suction, the filtrate is precipitated with 100 ml of concentrated hydrochloric acid. The precipitate is boiled with benzene and triturated cold with acetone. Yield 175 g of yellow crystals, Pp 202 -. 208 ⁰ C.

(-Dimethylaminopropylamino) -2-nitro-4-chloro-5- (ß-hydroxyethylthio) benzene

39 g of 1 - * (ω-dimethylaminopropylamino) -2-nitro-4,5-dichlorobenzene are dissolved in 175 ml of alcohol on the steam bath and 8.5 ml of 2-hydroxy-ethy-mercaptan are added. To this end, 21 g of soda in 40 ml of water are added dropwise over the course of 15 minutes. After a further four hours of boiling, the mixture is cooled and filtered off with suction. The filtrate is mixed with water and the deposited precipitate is filtered off with suction. It is recrystallized from 70 ml of ethyl acetate. Yield 30 g, mp 96-98 ⁰ g of yellow crystals.

(-Dimethylaminopropyl) -2-methyl-5-chloro-6- (ß-hydroxyethylthio) benzimidazole

30 g of this intermediate are in 50 ml of benzene and 1oo ml Dissolved methanol and in a known manner with hydrogen on Raney nickel contact reduced at 60 ° C. The solution will be

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filtered and treated with 10 ml of acetic anhydride. After the methanol has been distilled off, a further 40 ml of acetic anhydride are added and then all solvents are distilled off up to a bath temperature of 200 ° C. The residue is dissolved in 750 ml of cyclohexane, clarified with activated charcoal and evaporated. Yield 20 g, Pp. 84 - 87 ⁰ C cream-white crystals.

Example 4

1-chloro-3-methylamino-4-nitrobenzene

^ 192 g (1 mol) of 2,4-dichloroitrobenzene are dissolved in 800 ml of methanol. The solution is heated on the steam bath. While stirring, 2oo ml of methylamine solution (approx. 35%) are allowed to run in slowly in 3 fortions. The mixture is left to react on the steam bath for a total of 8 hours. The product crystallizes out overnight and is filtered off with suction. The crude product is recrystallized from 1.3 l of methanol. Yield 79 g, mp. 109 - 111 ⁰ C.

1-phenylthio-3-methylamino-4-nitrobenzene

75 g of 4-nitro-3-methylamino-1-chlorobenzene, 300 ml of toluene and 48 ml of thiophenol are heated to an oil bath temperature of 120.degree. 2oo ml of 5% sodium ethylate solution are added dropwise with stirring. fiB same time, the alcohol is distilled off within about 2 hours. The oil bath temperature is then increased to 150 ° C. The reaction mixture is allowed to react for 4 hours under reflux cooling. The toluene is then distilled off in vacuo. The remaining product is boiled three times with 500 ml of cyclohexane each time. The solution is treated with activated charcoal, filtered and concentrated to about 2oo ml. 50 ml of ethyl acetate are added to the warm solution and the mixture is cooled in ice water. Crude yield 55 g, mp. 94 - 96 ⁰ C. The product is dissolved in 13o ml of ethyl acetate, filtered and concentrated to half. The product crystallized out overnight is filtered off with suction. Yield 50 g, m.p. 95-95 C.

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1-methyl-2-iiiercapto-6-phenylthiobenzimidazole

25 g of 1-phenylthiQ-3-methylamino-4-nitrobenzene are dissolved in 1oq ml of toluene and 90 ml of methanol and hydrogenated using Raney nickel in an autoclave at 5o ° C. and 5o atm. The Raney nickel is separated off. 30 ml of concentrated sodium hydroxide solution and 20 ml of carbon disulfide are added to the solution. The mixture is heated on the steam bath with stirring for 6 1/2 hours. The solution is cooled and adjusted to pH 5 with glacial acetic acid. The product is filtered off with suction and washed with methanol. Raw yield 17g. The product obtained is dissolved in 300 ml of water, 100 ml of methanol and 5 ml of concentrated sodium hydroxide solution, treated with activated charcoal, filtered off with suction and the solution filtered once more through a hard filter. The product is precipitated again with glacial acetic acid, filtered off with suction, washed with water and then a little methanol. Yield 12g. This product is recrystallized from 90 ml of methanol using fuller's earth. Yield 7 g, Pp 209 -. 212 ⁰ O.

Example 5

1-nitro-2-methylamino-4-carboxymethyrthio-5-chlorobenzene

44 g of 4,5-dichloro-2-methylamino-1-nitrobenssol are dissolved in 150 ml of benzene and 600 ml of ethyl alcohol. 17 ml of thioglycolic acid and 90 ml of water are added and the mixture is warmed to an oil bath temperature of 100.degree. 62 g of sodium carbonate are added in portions with stirring. This reaction gel is allowed to react for 5 hours at an oil bath temperature of 100.degree. The product, which crystallizes out overnight, is dissolved in 3 l of water, filtered and precipitated with 50 ml of constant hydrochloric acid. The precipitated product is filtered off with suction, washed with water, then with methanol and air-dried. Yield 70 g; Ep. 282 - 284 ⁰ O.

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1,2-Dimethyl-5-chloro-6-carboxymethylthio-benzimidazole sodium salt

45 g of i-Ni.tro ^ -methylamino ^ -carboxymethylthio-S-chlorobenzene are dissolved in 65o ml of methanol and 65 ml of water and 70 ml of 10% sodium hydroxide solution. (The pH value is approx. 7). This solution is hydrogenated using Raney nickel in an autoclave at a temperature of up to 50 ° C. and atti. The Raney nickel is separated off and 15 ml of acetic anhydride are added to the solution. A temperature increase of up to 37 ^° C. is recorded. The solvent is distilled off in a rotary evaporator under vacuum. Another 40 ml of acetic anhydride are added to the product and the mixture is heated to an oil bath temperature of 160 ° C. for 2 hours. Acetic acid is distilled over. Finally, excess acetic anhydride should still be distilled off. The oil bath temperature is increased to 200 ° C. for a further hour. The product is then dissolved in 1 l of methanol, treated with activated charcoal, filtered and concentrated to about 2oo ml. 8 g of sodium hydroxide are dissolved in this solution and allowed to crystallize. Yield 11 g, pp. Over 290 ^° C.

Example 6

i-Nitro ^ -methylamino ^ -dodecylthio-S-chlorobenzene

22 g of 4,5-DiChIOr ^ -methylamino-1-nitrobenzene are dissolved in 75 ml of benzene and 3oo ml of ethyl alcohol. 24 ml of dodecyl mercaptan are added, whereupon the mixture is heated to an oil bath temperature of 100 ° C. and a solution of 21 g of soda, dissolved in 45 ml of water, is added with stirring. It is allowed to react for 4 hours at an oil bath temperature of 100.degree. The product that crystallizes out overnight is filtered off with suction and recrystallized from 170 ml of ethyl alcohol. Yield 27 g, pp. 94 ^° C.

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1,2-Dimethyl-5-chloro-6hlodeeylthio-benziniidazole

54 g of i-lfitro ^ -methylaraino ^ Hlodeeylthio ^ -ehlorbenzol are dissolved in 34o ml of benzene and 170 ml of methanol. Using Raneyniekel, this solution is in the autoclave at 50 ° C and 50 atu. hydrogenated. The Raney nickel is separated off and 30 ml of acetic anhydride are added to the solution. The solvent is distilled off in a rotary evaporator under vacuum. 50 ml of acetic acid and the excess of acetic anhydride are added to the product. The oil bath temperature is increased to 200 ° G. The product is left to react for a further hour at this temperature. The product is dissolved in 250 ml of cyclohexane and 100 ml of acetone, treated with activated charcoal, filtered, and then the acetone is distilled off. The product which has crystallized out is filtered off with suction and washed with cyclohexane. Yield: 51 g, melting point 104 ^° C.

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Claims (3)

Patent claims: Benzimidazole derivatives represented by the following formula where mean: 2
R and R = identical or different radicals, namely Hydrogen, lower alkyl with 1-3 C atoms, aralkyl, aryl, halogen, -CF ,, -CN, -SO ₂ R, -SOR or -SO ₂ NR ₂ where R is alkyl or aryl; R and R = identical or different radicals, namely Hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl. Aralkyl, aryl or a heterocyclic radical; R = hydrogen, alkyl, olefinically unsaturated ftf alkyl, cycloalkyl, aralkyl, aryl, or a heterocyclic aromatic group; R ^ can also be -OH, -SH, -OR, -SR or -NR ₂ , where R is alkyl. A-G 671 - 16 - 209809/1636 2. Benzimidazole derivatives according to. Claim 1, characterized in that 1 2
R and R = hydrogen or halogen, R ⁵ and R ⁴ = hydrogen, alkyl, alkenyl, aryl or heterocyclic radicals and one alkyl, one alkylt] Mean mercapto group. R = an alkyl, an alkylthio or a 3. Process for the preparation of benzimidazole derivatives according to Claim 1, characterized by the following process steps: a) Implementation of o-mtranilines of the following formula: Shark 1 wherein Hai is a halogen atom, and R, R and R ^ have the meaning already given, aiit a mercaptan of the formula R ^4- -SH, in which R has the meaning already given; b) reduction of the nitro group in a known manner and o) Cyclization in a likewise known manner with the formation of the mercapto or thioether-substituted benzimidazoles -G 671 ■ - 17 - ■ 209309/1636