DE2200648A1 - Process for the preparation of monosubstituted 1-carbamoyl-2-benzimidazolyl carbamates - Google Patents

Description

Anncsircip '»> ·' ■

Frankfurt (Main), d. January 5, 1972

Ohinoin Gyogyszer- es VeT ^ / eszebi Termekek Gyara RT, Budapest TV, To utca 1-B (Hungary ')

7ΕΗΪΑΗΗΕΝ ADDITIONAL POSITION YON MONOSUBSTITÜIEE0 1-0AEBAMOTL-2-BENZIMIDlZOLIL-0ARBAMATEIi

The invention relates to a process for the preparation of monosubstituted 1-0arbamoyl-2-benzimidazolyl- -carbamates of the formula

IJ — NH-OO ₂ -H '

NH

(I)

0ONH-H ^£

176 old. / Ιηέ

QO-mn ¹¹

209 83 3/12 U

wherein R is a lower alkyl group having 1-4 carbon atoms and E represents an alkyl, cycloalkyl or aralkyl group.

Lately, the monosubstituted 1-carbamoyl-2-benzimidazolyl-carbamates have been used as crop protection ■ medium gained great importance. The methyl ester of i-butyl-carbamoyl ^ -benzimidazolyl-carbamic acid is e.g. a systemic agent which is adsorbed in the tissue of the plant and a protection for the whole Plant granted. Another major benefit of this compound is that it can be used to heal already developed plant diseases can be used, i.e. not only as a preventive, but also is effective as a curative agent.

The monosubstituted i-carbamoyl-2-benzimidazolyl -carbamates have a very broad spectrum of activity. Besides the hindrance and destruction of the mushroom mycelia (fungistatic or fungicidal effect) these compounds also prevent mites from multiplying the destruction of their eggs (ovicidal effect).

The monosubstituted i-carbamoyl-2-benzimidazolyl -carbamates can be used, among other things, to combat the following plant diseases:

Il

On sugar beet against Cercospora beticola; on apple and pear against Ifusicladium, apple powdery mildew, and the at the storage of apple-occurring diseases; in the case of grapes against the powdery mildew of the vine, red burner the vine and botritis rotten; on strawberries against botritis rotten; on cucumbers against the powdery mildew of cucumbers, Fusarium and red gooseberry mite; on ornamental plants against flour grapes, Septoria, Fusarium, Botrytis and Penicillium diseases j against cherry cylinderosporios and rice; on celery against Septoria and Oercosporaj against greens Antracnose, Cercospora, powdery mildew ,. Septoria and Botrytis.

The compounds of the formula I are effective even in a very low concentration. You can benefit

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~ 3 -

used in the form of a 0.1% spray liquid will.

From a chemical point of view, the monosubstituted i-carbamoyl-2-benzimidazolyl-carbaiates belong to the group of azolide compounds. This designation is used in the chemical literature (Angew. Chem. £ 4, 407/1962 /) for acid amides in which the acyl group is linked to a ring atom of a quaziaromatic, 5-membered heterojunction containing at least two ring atoms. The azolides show surprisingly high activity towards nucleophilic reagents. Azolides are hydrolyzed to an acid with water. They form esters with alcohols, acid amides with amines and acid anhydrides with acids. The ability of azolides to acylate is close to that of the most reactive acylating agents. The reactivity of azolides is the result of several factors. It can generally be stated that the increase in the number of ring nitrogen atoms (diazole, triazole, tetrazole) increases the reactivity (Chem. Ber. 89 »1927/1956 /; ibid ^, 1320/1957 /). The condensed with a benzene ring derivatives (benzimidazole, benzotriazole), however, exhibit a much smaller reactivity (Chem. Ber, J29-, 13 ^20/1957 /) · ^D i ^e reactivity also depends on the structure of the acyl group from. (Liebigs Ann. Chem. 655 »95 / T962 /, Chem. Ber. <£, 2070/1962 /). The N ^ '- carbonyl-di-azole compounds are particularly reactive (Chem. Ber. _93, 2910/1960 /). The carbamoyl-azoles of the formula

CO-NH-R

can be derived from these compounds in such a way that

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that the N, N ¹ -carbonyldiazole compounds react with 1 mol of primary amine, see reaction scheme 1

CO-

CQ-NH-R *

The preparation of the compounds of the formula IV is made more difficult by the fact that the resulting compound of the formula IV can react further with the amine of the formula RR ^ to form a symmetrical N, N'-disubstituted urea (Liebigs Ann. Chem. 609. 75/1957 / ). _22 ibid 648, 72/1961 / Ang Chem; in solution or by thermal action, the compounds of the formula IV to an isocyanate and an azole (Liebigs Ann 187/1958 /, 622 dissociate 612, 25/1959 /.... »66/1961 /), see reaction scheme 2

¹ 2

00-NH-R ^

Not even the azole-N-carboxylic acid esters of the formula formed from N, N ¹ -carbonyl-di-azoles with Λ mol of alcohol

(V)

COOH

are used to form the compounds of the 'formula IY gseigr.et. When reacted with amines, η 2ht is the cleavage of the OR group but the substitution of the azole ringea instead of « (Liebigs Ann. Chem. 60g, 83/1957 /, J. Am. Chem * Soc * 79 »

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6416/1957 / »see reaction scheme 3

jj + R ¹ NH ₂ > R ¹ - NH - OOOR +

COOR

Although the above reactions of azolides of type IV on derivatives were studied which on the hetero ring do not carry further substituents is the azolide character of the compounds of general formula I based on their following properties:

1) The addition reaction of an izocyanate and of a 2-benzimidazolyl carbamate of the formula

NH-CO ₂ -R

(II)

is a tempera burdependent, leading to balance Process (Belgian patent specification V, 741.429), see Reaction scheme 4

CONH-R ²

CO-NH-H ²

NH-CO ₂ -R

2) The compounds of the formula I hydrolyze under the action of water, with compounds of the formula II and the decomposition products originating from the carbamic acid arise. In the case of thin-layer chromatography Determination of this connection, 2 spots appear, which are methyl 2-benzimidazolyl-carbamate and the

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desired product have been identified. (Journal Agr. Food Chem. J2, 895/1965 /} Phytopathology ^, 705/1969 /).

3) In the implementation of the i-carbomethoxy-2-benzimidazolyl-carbamic acid methyl ester and an amine not a compound of the formula I, but with elimination of the -COOCBL group in position 1 is a compound of the formula II arises. This finding is supported by the fact that the structurally similar 1,2,3,4-tetrahydro- -3-triazino (a) benzimidazole-2,4-dione on hydrolytic action also in the same place (according to the ring numbering along the 4-5 bond). (Weisberger: The Chemistry of Heterocyclic Compounds 1j5, 428/1959 /).

The compounds falling under the general formula I are not among the most reactive azolide derivatives of type IV and, as a result, their practical synthesis by reaction of compounds of formula II (where H is as defined above) and isocyanates are made (British Patent No. 1,193,461 and 1,193,462 and Belgian patent specification No. 7 ^ 1,429). According to the Belgian patents cited, the Compounds of the formula I by reaction before compounds of the formula II with phosgene and subsequent reaction of the carbamic acid chloride derivatives of the formula

Cl

can also be produced with 2 moles of amines. According to the examples of British Patent No. 1,193,461 , this process was not used for the preparation of the compounds falling under the formula I, but in those cases when H ^{2 is} hydrogen or the nitrogen atom of the acid amide group is disubstituted.

The compounds of the formula I can in principle

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by reacting compounds of the formula II with monasubstituted carbamic acid chlorides. According to the literature, the disubstituted derivatives can be prepared by this reaction route. (BED.Patent No. 1.812.100). In contrast to the disubstituted carbamic acid chlorides, the monosubstituted ones are Carbamic acid chlorides unstable substances. According to the literature, they are the first products to be formed in the process of isocyanates leading to phosgenation of primary amines but by splitting off hydrogen chloride they are easily converted into Isocyanates (Houben-Weyl: Methods of Organic Chemistry, J3, 117/1952 /). According to the cited parts of the literature you can these unstable substances are also formed by the addition of isocyanates and hydrochloric acid; one could, however in no way think that through them a nucleophilic agent (e.g. a compound of formula II) without prior Cleavage of the salt acid can be acylated.

On the basis of the literature mentioned above, the successful feasibility of the practical synthesis was not ^{to be expected even from the N, N 1} -carbonyl-bis-derivatives of the compounds of the formula II. By decomposing such a compound with an amine of the formula E -NHo, a mixture of the compounds of the formulas I and II would be formed even in the most favorable case.

It has surprisingly been found that the compounds of general formula I are uniform and very pure state can be produced by a novel process by adding a compound of formula II (where B ^ means an alkyl group with 1-4 carbon atoms) in the presence of a base with a compound of the formula

R ^ -NH-C-OA (III)

converts (where R ^{2 is} an alkyl, cycloalkyl or aralkyl

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(Huppe means and A means an appropriate one, through two or i ^ - their electron-attracting factors β over ;; titled phenyl (ίναρρο represents which the activity dos p-Nitrophenyloite.PB transgressing end eater forms).

A can advantageously e.ino by two or more lialoßtojiatoxne and / or Carbmnoyl "groups substituted Ph e-π. / 1 group, a vorteillioft Pentachlorphenol-, 2,4,5- ~ _'T rrichlorpheayl 2-chloro-6 ~ carbamoylphenyl or pentabromophenyl group no.

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) are used will. According to an advantageous embodiment of the method the bases are calculated in an equivalent amount based on the active carbamic acid ester of the formula III, used. A small excess of the base has also proven advantageous.

The reaction of the compounds of formula II and III is advantageously carried out in an organic solvent accomplished. Hydrocarbons, lower ketones or esters (e.g. acetone, methyl

Il H

ethyl ketone, ethyl a ζ et ate), ether (dioxane, tetrahydrofuran), chlorinated solvents (e.g. chloroform, dichloroethane) lower acid amides (e.g. formamide or acetaraide) are used will. According to an advantageous embodiment of the method, such solvents are used in which both starting materials (the base included) is soluble and the resulting compound of formula I is either is insoluble or can be eliminated from the solution in a pure form, i.e. without impurities. (e.g. with Hexane). When using inorganic bases, the reaction product can, if necessary, be purified in water be flushed out. The organic bases are due

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the solubility of the salts formed from them more favorable, especially in such. Systhemeii, which the resulting Do not dissolve compound of formula T. The reaction can also be carried out in a system. In which we » dec the starting material of Pormol ΓΤ / still from entabandene End product of formula I solvable LMt. With such implementations the grain size and the stirring play a particularly important role.

The N-substituted active carbamic acid esters of Pormol III used as starting material can be prepared by the processes known for the preparation of phenyl or thi.ophenyl esters (Liebigs Ann. Ohem. 562 , 219, 207 / 194-9 / ·; J. Org. Ohem. 28, 658/196? /; HeIv. Chim. A. ^ B, 2005/1965 /).

The new color of the process according to the invention is that to introduce an orarbamoyl group in the 1-position so far only addition reactions (isocyanate) or a two-stage sub-division reaction (phosgene) is known was. According to the latter method, the bond between the nitrogen atom of the bonzimidazole ring and dom. exocyclic carbon dioxide not in the lived stage educated. The inventive method enables the compounds of formula I to be prepared by means of a single-stage substitution reaction. During the implementation splits off the active ester-forming phenol compound, which is in the form of a salt from the compound of the formula T can easily be separated off and returned to the reaction process, i.e. the phenol component can for the formation of the active carbamic acid ester ^ of the formula III can be used again.

Further details of the method according to the invention can be found in the examples, BeJSF) IeI 1

2.2 g (0.006 moles) of n-butyl carbamic acid pentachlorophenyl ester and 0.83 ml (0.60 g, 0.006 moles) of tri-

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auiiylamin are dissolved in 9 ml of acetone with stirring. 0.95 6 (0.005 moles) of 2-benzimidazolyl methyloarbamate is added to the solution. The suspension is stirred at room temperature for 6 hours, filtered, the crystalline product is washed with 1 ml of acetone and dried under reduced pressure. 1.30 g of the in-butyl-carbamoyl--2-benzimidazolyl-methyl-carbamata were obtained. Yield 90%. Mp: 328-334- ° C (the product recrystallized at 220-230 ⁰ C).

Example 2

2.2 g (0.006 moles) of η-butyl-^ carbamic acid pentachlorophenyl ester and 0.83 ml (0.60 g, 0.006 moles) of triethyamine are dissolved in 25 ml of ethyl acetate. To the solution is added 0.95 S (0.005 moles) of 2-benzimidazolyl methyl carbamate, the suspension is stirred for 5 hours at room temperature, filtered and the filtrate is concentrated under reduced pressure. The residue is suspended in 25 ml of methanol, filtered, washed with methanol and dried under reduced pressure. I05 g of 1-n-butyl-carbamoyl-2-benzimidazolyl-methylcarbamate are obtained. Yield 73 %, melting point; 327-334- ⁰ C (the product recrystallized at 224-230 ⁰ C).

Example 3

0.91 g (0.0025 mol) of n-butyl-carbamic acid pentachlorophenyl ester are dissolved in 30 ml of chloroform, after which 0.4-7 S (0.0025 mol) of 2-benzimidazolyl methylcarbamate and 0.35 g ( 0.0025 moles) of potassium carbonate can be added. The suspension is stirred for 5 hours at room temperature, the insoluble solid substance is filtered off and the filtrate is concentrated 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 methyl carbamate is dried under reduced pressure. After recrystallization from methanol, the product melts at 336-340 ° 0 (it recrystallizes

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at 225-230 ⁰ O),

Example 4

2.0 g (0.0055 moles) of n-butyl-carbaiic acid pentachlorophenyl ester and 0.8 ml (0.58 g, 0.0058 moles) of triethylamine are dissolved in 5 ml of anhydrous dimethylformamide. 0.95 g (0.005 mol) of 2-benzimidazolyl-methyl-carbamate are added to the solution with stirring, the reaction mixture is stirred for a further 4 hours at room temperature, cooled to 0 ° 0, the product is suction filtered, washed with methanol and dried under reduced pressure 1.15 g of 1-n-butyl-carbamoyl-2-benzimidazolyl-methylcarbamate are obtained. Yield 80%, Melting point 328-333 ° 0 (the product recrystallizes at 230-237 ° o).

Example 5

1.0 g (0.00275 mol) of n-butyl-carbamic acid pentachlorophenyl ester and 0.4 ml (0.29 S ₅ 0.0029 mol) of triethylamine are dissolved in 3 nil of dimethyl sulphoxide. 0.47 g of ( 0.0025 moles) of 2-benzimidazolyl-methylcarbamate was added and the reaction mixture is gerühifc at room temperature for 5 hours, cooled to 0 ⁰ C, the product is filtered off with suction, washed with methanol and dried under reduced pressure. 0.65 g of n-butyl-carbamoyl-2-benzimidazolyl-methyl-carbamate are obtained. Yield 90 %. The product melts at 328-335 ° 0 (recrystallization occurs at 215-225 ⁰ O on).

Example 6

1.25 B (0.00425 moles) n-butyl-carbamic acid-2,4,5- trichlorophenyl ester and 0.58 ml (0.42 g, 0.0042 moles) of triethylamine are dissolved in 3 ml of anhydrous acetone. 0.76 g (0.004 moles) of 2-benzimidazolyl methyl carbamate are added to the solution with stirring admitted. The suspension is further stirred for 6 hours, after which the insoluble substance removed by filtration and placed on the filter with 3 ml Petroleum ether is washed. That from the acetone petrolatum

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Product precipitated from mother liquor on 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 ⁰ C. (It recrystallized at 216-224 ⁰ O).

Example 7

2.35 g (0.006 moles) of pentachlorophenyl cyclohexylcarbamic acid and 0.83 ml (0.6 g, 0.006 moles) of triethylamine are dissolved in 5 nil of anhydrous acetone with stirring. 0.95 g (0.005 moles) of 2-benzimidazolyl methyl carbamate are added to the solution. The reaction mixture is stirred for 5 hours at room temperature. After addition of petroleum ether the mixture to 0 ⁰ O is cooled. The precipitated product is filtered and the filtrate is concentrated to dryness. The residue is suspended in petroleum ether, suction filtered, washed with acetone, water and methanol and dried under reduced pressure. 0.70 g of the cyclohexyl-carbamoyl-2-benzimidazolyl-methyl-carbamate are 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 moles) of benzylcarbamic acid pentachlorophenyl ester and 0.76 ml (0.55 g, 0.0055 moles) of triethylamine are dissolved in 6 ml of anhydrous acetone with stirring. 0.95 g (0.005 moles) of 2-benzimidazolyl methyl carbamate are added to the solution. The reaction mixture is stirred for 5 hours at room temperature and then cooled ^{to 0 0 O.} The precipitated product is filtered off, washed with methanol and dried under reduced pressure. 1.35 g of 1-benzylcarbamoyl -2-benzimidazolyl methyl carbamate are obtained. Yield 84%. Melting point 339-344 ⁰ O (it recrystallizes at 235-240 ⁰ C).

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Claims (6)

PATENT CLAIMS /. Process for the preparation of compounds of the general formula N ν J = n.co ₂ r ' ¹ (ι) (where R is an alkyl group having 1-4 carbon atoms and H mean an alkyl, cycloalkyl or aralkyl group) characterized in that a compound the general formula (II) (where R has the above meaning) in the presence of a base with a compound of the general formula ₂ Il R-HH-C-OA (III ¹ ο
(wherein R is as defined above and A is a phenyl group which is substituted by two or more electron-withdrawing substituents). 2. The method according to claim 1, characterized that A represents a halogen- and / or carbamoylß-substituted phenyl group. 3. Process according to Claims 1-2, characterized in that A is a pentachlorophenol.-, 2,4,5-trichlorophenyl, 2-chloro-6-carbamoylphenyl or pentabromophenyl group means. 209833/1214 4. The method according to claim!> Thereby g ο k β indicates that the implementation of the compounds the .Formula II and III in the presence of at least one. equivalent amount of base is carried out » ■ ?. Process according to claims 1-4 _i, characterized in that 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 are used, 6. The method according to any one of claims 1-4, characterized in that tertiary amines as the base, advantageously ^ riethylamine or pyridine can be used. 7. Process according to one of Claims 1-6, characterized in that the reaction of the compounds of the formulas II and III is carried out in an organic solvent. 209833 / 12U