NO133231B - - Google Patents

Description

The present invention relates to a process for the production of monosubstituted 1-carbamoyl-2-benzimidazolyl carbamates with the formula where R means a lower alkyl group with 1-4 carbon atoms and R 2 an alkyl, cycloalkyl or aralkyl group.

In recent times, the monosubstituted 1-carbamoyl-2-benzimidazolyl carbamates have achieved great importance as plant protection agents. The methyl ester of l-butyl-carbamoyl-2-benzimidazolyl-carbamic acid is, for example, an agent with a systemic effect, which is adsorbed in the plant's tissue and thus provides protection for the entire plant. A further significant advantage of this compound is that it can be used to cure already developed plant diseases, i.e. are not only effective as preventive agents, but also as curative agents.

The monosubstituted 1-carbamoyl-2-benzimidazolyl carbamates have a very broad spectrum of action. In addition to preventing and destroying fungal mycelia (fungistatic or fungicidal effect), these compounds also prevent the reproduction of mites by destroying their eggs (ovicidal effect).

The monosubstituted l-carbamoyl-2-benzimidazolyl carbamates can i.a. used to combat the following plant diseases: In sugar beet against Cercospora beticola; in apples and pears against Fusicladium, apple powdery mildew and diseases occurring during the storage of apples; in grapes against the true powdery mildew of grapes, root fire on the vine and Botritis faule; in strawberries against Botritis foule; in cucumbers against true powdery mildew in cucumbers, Fusarium and root gooseberry mite; in ornamental plants against powdery mildew, Septoria, Fusarium, Botrytis and penicillin diseases; against cherry cylindrosporios and rice; in celery against Septoria and Cercospora; in vegetables against Anthracnose, Cercospora, powdery mildew, Septoria and Botrytis.

The compounds of formula I are effective in very low concentrations. They can advantageously be used in the form of a 0.1% spray liquid.

In chemical terms, the monosubstituted l-carbamoyl-2-

benzimidazolyl carbamates to the group of azolide compounds.

This term is used in the chemical literature (Angew.

Chem. 74' 407 /1962/) for such acid amides, in which the acyl group is bound to a ring atom in a quasi-aromatic, 5-membered, at least 2 ring atom containing hetero ring. The azolides show a surprisingly high activity towards nucleophilic reagents. Azolides are hydrolyzed with water to an acid.

They form with alcohols esters, with amines acid amide and with

acids acid anhydride. The acylating ability of azolides comes close to that of the most reactive acylating agents. The reactivity for the azolides is a consequence of several factors. It can generally be established that increasing the number of ring nitrogen atoms (diazole, triazole, tetrazole) increases the reactivity (Chem. Ber. 89, 1927 /1956/; ibid 90, 1320 /1957/). On the other hand, derivatives condensed with a benzene ring (benzimidazole, benztriazole) show a significantly lower reactivity (Chem. Ber. 90, 1320 / 1957/). The reactivity also depends on the structure of the acyl group. (Liebig's Ann. Chem. 655, 95 /1962/, Chem. Ber. 95, 2070/1962/). The N,N<1->carbonyl-diazole compounds

are particularly reactive (Chem. Ber. 93, 2910 /1960). The carbamoyl azoles of the formula

can be derived from these compounds so that the N,N<1->carbonyl-diazole compounds react with 1 mol of primary amine, see reaction scheme 1

The preparation of compounds of formula IV is made difficult

in that the resulting compound of formula IV can further

react with the amine of the formula R-Nt^ to form a symmetrical N,N'-disubstituted urea (Liebig's Ann. Chem. 609, 75 / 1957/). In solution or by thermal action, the compounds of formula IV dissociate into an isocyanate and an azole,

(Liebig's Ann. 612, 187 /1958/, 622, 23 /1959/; ibid 648, 72 / 1961/ Ang. Chem. 73, 66 /1961/), see reaction scheme 2

Neither did the azole-N-carboxylic acid esters with the formula formed from N,N<1->carbonyl-diazoles with one mole of alcohol. is suitable for the formation of compounds of formula IV. When reacting with amines, the removal of the OR group does not take place, but the substitution of the azole ring. (Liebig's Ann. Chem. 609, 83 /1957/, J. Am. Chem. Soc. 79, 6416 /1957/, see reaction scheme 3

Although the above reactions of azolides of type IV were studied on derivatives which do not carry additional substituents in the heteroring, the azolide character of the compounds of the general formula I is justified by their following properties:

1) The addition reaction of an isocyanate and a 2-benzimidazolyl carbamate with the formula is a temperature-dependent process leading to equilibrium (Belgian patent V, 741 429), see reaction scheme 4 2) The compounds of formula I hydrolyse under the influence of water, whereby compounds of formula II and the cleavage products originating from the carbamic acid are produced. In the thin-layer chromatographic determination of this compound, 2 spots appear, which were identified as 2-benzimidazolyl-carbamic acid methyl ester and the desired product. (Journal Agr. Food Chem. 17, 895 /1965/; Phytopathology .59, 705 /1969/) . 3) In the reaction of the 1-carbomethoxy-2-benzimidazolylcarbamic acid methyl ester and an amine, no compound of formula I occurs, but during cleavage of the -C00CH3~ group in the 1-position a compound of formula II. This fact is supported by the fact that the structurally similar structured 1,2,3,4-tetrahydro-3-triazino(a)benzimidazol-2,4-dione is also split up at the same place during hydrolytic action (following the ring numbering along the 4-5 bond ). (Weisberger: The Chemistry of Heterocyclic Compounds 13, 428 /1959/).

The compounds falling under the general formula I do not belong to the most reactive azolide derivatives of type IV and, as a result, their practical synthesis can be carried out by reacting compounds of formula II (where R<1> has the preceding meaning) and isocyanates ( British Patent Nos. 1,193,461 and 1,193,462 and Belgian Patent No. 741,429). According to the cited Belgian patent, the compounds of formula I can also be prepared by reacting compounds of formula II with phosgene and subsequent reaction of the obtained carbamic acid chloride derivatives with the formula

with 2 moles of amines. Following the examples in British patent no.

1 193 461, this method was not used for the preparation of compounds falling under the formula I, but used in cases where R 2 means hydrogen or the nitrogen atom in <«>acid- the amide group is doubly substituted.

The compounds of formula I can in principle be prepared by reacting compounds of formula II and monosubstituted carbamic acid chlorides. According to the literature, the disubstituted derivatives can be prepared via this reaction route. (BRD. patent document no. 1 812 100). In contrast to the disubstituted carbamic acid chlorides, the monosubstituted carbamic acid chlorides are unstable substances. According to the literature, they are formed as the first product by the phosgenation of primary amines leading to isocyanates, but by splitting off chlorine hydrogen they can easily be converted into isocyanates (Houben-Weyl: Methoden der organischen Chemie, 8, 117 /1952/). According to the cited literature, can these unstable substances also be formed by the addition of isocyanates and hydrochloric acid? however, one could not imagine that with these a nucleophilic agent (e.g. a compound of formula II) could be acylated without prior cleavage of the hydrochloric acid.

Due to the aforementioned literature, the somewhat favorable feasibility of the practical synthesis was not even to be expected from the N,N'-carbonyl-bis-derivatives of the compounds of formula II. Cleavage of such compounds with an amine of the formula R^-NHj will in the most favorable case only a mixture of the compounds of formula I and II occurs.

It was surprisingly found that the compounds of the general formula I can be prepared uniformly and in a very pure state according to a new method, reacting a compound of the formula II (where S?~ means an alkyl group with 1-4 carbon atoms) in the presence of a base with a compound of the formula

(where R 2 means an alkyl, cycloalkyl or aralkyl group and A is a phenyl group substituted with two or more halogen atoms, preferably chlorine atoms, forming an ester.)

As a base, inorganic bases (advantageously alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, alkaline earth metal hydroxides, alkaline earth metal carbonates or alkaline earth metal bicarbonates) or tertiary amines (advantageously triethylamine or pyridine) can be used. According to an advantageous embodiment of the method, the bases are used in an equivalent amount calculated for the active carbamic acid ester of formula III. A small excess of the base has also proved beneficial.

The reaction of the compounds of formula II and III is advantageously carried out in an organic solvent. As reaction medium, hydrocarbons, lower ketones or esters (e.g. acetone, methyl ethyl ketone, ethyl acetate), ether (dioxane, tetrahydrofuran), chlorinated solvent (e.g. chloroform, dichloroethane)

lower acid amides (e.g. formamide or acetamide) are used.

According to an advantageous embodiment of the method, such solvents are used in which both starting substances (including the base) are soluble and the resulting compound with the formula I is either insoluble or can be separated from the solution in pure form, i.e. without impurities, (e.g. with hexane). When using inorganic bases, the reaction product can be slurried if necessary for purification in water. Due to the solubility of the salts formed from these, the organic bases are more favorable, particularly in such systems where the resulting compound of formula I does not dissolve. The reaction can also be carried out in a system in which neither the starting compound with formula II nor the resulting final product with formula I dissolves. In such turnovers, grain size and agitation play a significant role.

The N-substituted active carbamic acid esters of formula III used as starting materials can be prepared according to the method known for the preparation of phenyl or thiophenyl esters (Liebigs Ann. Chem. 562, 219, 207 /1949/; J. Org. Chem. 28, 658 /1963/; Heiv. Chim. A. 48, 2005 /1965/).

The novelty of the method according to the invention is that for the introduction of a carbamoyl group in the 1-position only addition reactions (isocyanate) or a two-step substitution reaction (phosgene) were known. According to the latter method, the bond between the nitrogen atom in the benzimidazole ring and the exocyclic carbon atom is not formed in the last step. The method according to the invention enables the preparation of the compounds of formula I by means of a one-step substitution reaction. During the reaction, the active ester-forming phenolic compound splits off, which is easily separated in the form of a salt of the compound of formula I and can be fed back into the course of the reaction, i.e. the phenolic components can again be used to form the active carbamic acid ester with formula III.

Further details of the method according to the invention will appear from the following examples.

EXAMPLE 1

2.2 g (0.006 mol) of n-butyl-carbamic acid pentachlorophenyl ester and 0.83 ml (0.60 g, 0.006 mol) of triethylamine are dissolved in 9 ml of acetone while stirring... The solution is added to 0.95 g (0.005 mol ) 2-benzimidazolyl methyl carbarnate. The suspension is stirred for 6 hours at room temperature, filtered, the crystalline product

washed with 1 ml of acetone and dried under reduced pressure. 1.30 g of 1-n-butyl-carbamoyl-2-benzimidazolyl-methyl-carbamate are obtained. Yield 90%. Melting point: 328-334°C (the product recrystallises at 220-230°C).

EXAMPLE 2

2.2 g (0.006 mol) of n-butyl carbamic acid pentachlorophenyl ester and 0.83 ml (0.60 g, 0.006 mol) of triethylamine are dissolved in 25 ml of ethyl acetate. To the solution is added 0.95 g (0.005 mol) of 2-benzimidazolyl methyl carbarnate, the suspension is stirred for 5 hours at room temperature, filtered and the filtrate is evaporated under reduced pressure. The residue is suspended in 25 ml of methanol, filtered, washed with methanol and dried under reduced pressure. 1.05 g of 1-n-butyl-carbamoyl-2-benzimidazolyl-methyl carbarnate is obtained. Yield 73%. Melting point: 327-334°C (the product recrystallises at 224-230°C).

EXAMPLE 3

0.91 g (0.0025 mol) n-butyl carbamic acid pentachlorophenyl ester

dissolve in 30 ml of chloroform, after which 0.47 g (0.0025 mol) of 2-benzimidazolyl methylcarbamate and 0.35 g (0.0025 mol) of potassium carbonate are added. The suspension is stirred for 5 hours at room temperature, the insoluble solid substance is filtered off and the filtrate is evaporated under reduced pressure. The residue is suspended in 20 ml of petroleum ether, filtered, washed with petroleum ether and the 1-n-butyl-carbamoyl-2-benzimidazolyl-methylcarbamate obtained is dried under reduced pressure. After recrystallization from methanol, the product melts at 336-340°C (it recrystallizes at 225-230°C).

EXAMPLE 4

2.0 g (0.0055 mol) n-butyl-carbamic acid pentachlorophenyl ester and 0.8 ml (0.58 g 0.0058 mol) triethylamine are dissolved in 5 ml anhydrous

dimethylformamide. The solution was added with stirring 0.95 g (0.005 mol) of 2-benzimidazolyl-methyl-carbamate, the reaction mixture is stirred for a further 4 hours at room temperature, cooled to 0°C, the product is filtered off, washed with methanol and dried under reduced pressure. 1.15 g of 1-n-butylcarbamoyl-2-benzimidazolyl-methylcarbamate is obtained. Yield 80%, melting point 328-333°C (the product recrystallizes at 230-237°C).

EXAMPLE 5

1.0 g (0.00275 mol) of n-butylcarbamine urea pentachlorophenyl ester and 0.4 ml (0.29 g, 0.0029 mol) of triethylamine are dissolved in 3 ml of dimethylsulfoxide. 0.47 g (0.0025 mol) of 2-benzimidazolyl methyl carbarnate is added to the solution and the reaction mixture is stirred for 5 hours at room temperature, cooled to 0°C, the product is filtered off, washed with methanol and dried under reduced pressure. 0.65 g of 1-n-butyl-carbamoyl-2-benzimidazolyl-methyl-carbamate is obtained. Yield 90%. The product melts at 328-335°C

(recrystallization occurs at 215-225°C)

EXAMPLE 6

1.25 g (0.00425 mol) of n-butyl-carbamic acid-2,4,5-trichlorophenyl-ester and 0.58 ml (0.42 g, 0.0042 mol) of triethylamine are dissolved in 3 ml of anhydrous acetone. 0.76 g (0.004 mol) of 2-benzimidazolyl methyl carbarnate is added to the solution while stirring. The suspension is stirred for a further 6 hours, after which the insoluble substance is removed by filtration and the filter is washed with 3 ml of petroleum ether. The product separated from the acetone-petroleum ether mother liquor after cooling is filtered, washed with petroleum ether and dried under reduced pressure. The obtained 1-n-butyl-carbamoyl-2-benzimidazolyl-methylcarbamate melts at 324-330°C. (It recrystallizes at 216-224°C).

EXAMPLE 7

2.35 g (0.006 mol) of cyclohexylcarbamic acid pentachlorophenyl ester and 0.83 ml (0.6 g, 0.006 mol) of triethylamine are dissolved with stirring in 5 ml of anhydrous acetone. To the solution is added 0.95 g (0.005 mol) of 2-benzimidazolyl-methyl-carbamate. The reaction mixture is stirred for 5 hours at room temperature. After the addition of

petroleum ether, the mixture is cooled to 0°C. The separated product is filtered and the filtrate is evaporated to dryness. The residue is suspended in petroleum ether, filtered off, washed with acetone, water and methanol and dried under reduced pressure. 0.70 g of cyclohexyl-carbamoyl-2-benzimidazolyl-methyl-carbamate is obtained. Yield 44%. After recrystallization from methanol, the product melts at 352-357°C (it recrystallizes at 228-235°C).

EXAMPLE 8

2.2 g (0.0055 mol) of benzylcarbamic acid pentachlorophenyl ester and 0.76 ml (0.55 g, 0.0055 mol) of triethylamine are dissolved with stirring in 6 ml of anhydrous acetone. To the solution is added 0.95 g (0.005 mol) of 2-benzimidazolyl-methyl-carbamate. The reaction mixture is stirred for 5 hours at room temperature and then cooled to 0°c. The separated product is filtered, washed with methanol and dried under reduced pressure. 1.35 g of 1-benzyl-carbamoyl-2-benzimidazolyl-methyl-carbamate is obtained. Yield 84%. Melting point 339-344°C (it recrystallizes at 235-24o°C).

Claims (1)

Process for the preparation of compounds of the general formula where R1 means an alkyl group with 1-4 carbon atoms and R<2> an alkyl, cycloalkyl or aralkyl group, characterized by reacting a compound with the general formula where R"*" has the above meaning, in the presence of a base with a compound of the general formula where R 2 has the above meaning and A denotes a phenyl group which is substituted with two or more halogen substituents, preferably chlorine substituents.