CS207658B2 - Method of making the derivatives of the amidazole - Google Patents

Description

(54) A method for producing imidazole derivatives

The invention relates to a process for the preparation of novel imidazole derivatives of the general formula I,

in which

R ^{* 1} represents a hydrogen atom or a straight or branched alkyl group having 1 to 10 carbon atoms, or a straight or branched alkenyl or alkynyl group containing from 2 to 10 carbon atoms and each of R ² , R ³ and R ⁴ , which may be the same or different, is hydrogen or halogen (i.e., chlorine, fluorine, bromine or iodine), trifluoromethoxy or methyl, ethyl, propyl or isopropyl optionally substituted by one or more fluorine atoms, for example trifluoromethyl, or one of R R ² , R ³ and R ⁴ are methoxy and at least one of R ² , R ³ and R ⁴ is halogen, trifluoromethoxy or methyl, ethyl, propyl or isopropyl, optionally substituted with one or more fluorine atoms, wherein at least one of R, R, Ir and R is other than hydrogen.

It will be appreciated that the compounds of formula (I) above may exist in the form of optical isomers, i.e., stereoisomers. The invention encompasses a process for the preparation of all isomeric forms of the compounds of formula I as well as mixtures thereof, including racemic mixtures.

2Q7658

The compounds produced by the process of the invention exhibit herbicidal activity. To control weed growth (i.e. undesirable vegetation) at a particular site, the imidazole derivatives of formula I are normally used in the form of herbicidal compositions (i.e. in combination with compatible diluents or carriers suitable for use in herbicidal compositions). ), for example in the form of compositions described below.

The compounds of formula (I) above have activity against monocotyledonous weeds (e.g. grasses) and dicotyledonous weeds (e.g. broadleaf weeds), both in pre-emergence and post-emergence application.

The term pre-emergence _r ..i.ace is meant application to the soil in which they are present in seeds or seedlings weeds before emergence of the weeds above the soil surface. By post-emergence application is meant the application of the above-ground part of the weeds or the part of the weeds exposed to the herbicide, ground above the soil surface.

For example, the compounds of formula (I) may be used to inhibit the growth of annual grass weeds such as various species of deaf oats (Avena spp., E.g., Avena fatua), feathers (Alopecurus spp., E.g. Alopecurus myosuroides), venus (Setaria spp. Setaria viridis), hedgehogs (Echinochloa spp., For example Echinochloa crus-galli), Elusine spp., For example Elusine indica, sundews (Digitaria spp., For example Digitaria sanguinalis) and meadow-grasses (Poa spp. For example Poa annua), perennial grass weeds such as creeping wheatgrass (Agropyron repens), various bentgrass species (Agrostis spp., for example Agrostis stolonifera), and roundnose (Cynodon dactylon), annual Broadleaf weeds, such as abutilon (Abutilon theophrasti), Amsinkia intermedia, Anthemis arvensis), Ipomoea purpurea, various goosefoot (Chenopodium spp., For example Chenopodium album) ·, amaranth ( Amaranthus spp., For example Amaranthus retroflexus), cotton (Polygonum spp., For example Polygonum lapathifolium, Polygonum convolvulus, Polygonum persicaria and Polygonum avioulare), Chickweed (Stellaria spp., For example Stellaria media), Bedstraw (Galium spp.), For example Galium aparine , dead-nettle (Lamium spp., for example Lamium nurptireum), chamomile (Matricaria spp., for example Matricaria inodora), Sruch (Portulaoa spp., for example Portulaca oleracea), mustard (Sinapis spp., for example Sinapis arvensis), longer radish (Raphanus) raphanistrum), various types of speedwell (Veronica spp., for example, Veronica persica and Veronica hederifolia), Daisy (Chrysanthemus segetum), Cucumber Durman (Datura stramonium), Descurainea sophia, Emex eustralis, Cheir's Wallflower (Erysimum oheirecides) (Euphorbia helioscopa), Common Hemp (Ge leopsis tetrahit), Forget-me-not (Myosotis arvensis), Field Knee (Spergula arvensis), Kick Urtica urens, Viola arvensis, Viola trioolor, Anagallis arvensis, Capsella bursapastoris, Papaver rhoeas, Solanum nigrum Beetle Durkoman (Xanthium strumarium), and perennial Broadleaf weeds, such as pike (Rumex obtusifolius), Coltsfoot (Tussilago farfara) and Thistle (Cirsium arvense), and crayfish, such as the lily (Cyperus rotundus), and pre-emergence and post-emergence applications.

The compounds of formula I also exhibit herbicidal activity against aquatic weeds, such as Monochoria vaginalis and Rotala indica, when applied to both the leaves of the plants and the water in which the plants grow, and can therefore be used accordingly to suppress the growth of these weeds.

The rates of application of the compounds of formula X vary depending on the nature of the weeds, the compositions used, the time of application, the climatic and soil conditions, and the nature of the crop, if weed growth is suppressed.

When applied to areas where crops are or will be grown, the compounds of the invention should be applied at a dose sufficient to control weed growth and do not cause significant permanent damage to the crops.

Taking into account these factors, good results are generally obtained at dosages of between 0.25 kg and 20 kg of active ingredient per hectare. It will be appreciated, however, that the compounds of the invention may be applied at higher or lower doses, depending on the particular circumstances associated with the weed control problem.

The compounds of formula (I) may be used to selectively control the growth of weeds, for example to control the growth of the aforementioned weeds by pre-emergence or post-emergence, directed or unmounted application, e.g. used or will be used for the cultivation of useful crops such as grassy crops such as wheat, barley, oats, rice, maize, rye and sorghum, soybean, field beans, peas, sugar beet, fodder beet and beetroot, cotton, peanuts oilseed, potato, Iru, onion, carrot, herbaceous seed and fodder (pasture), before or after sowing of the crop, or before or after the emergence of the crop.

For the selective control of weeds in areas infested with weeds, which are areas which are used or will be used for cultivation of useful plants, for example of the aforementioned useful plants, application rates ranging from 0.25 kg to 8.0 kg of active substance per hectare.

Compounds of formula I, in particular 1- (3,4-dichlorobenzyl) imidazole-N, N * -dimethyl-4,5-dicarboxamide, 1- (3,4-dibromobenzyl) imidazole-N, N * -dimethyl-4 , 5-dicarboxamide and 1- (4-trifluoromethylbenzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide, can be used to selectively suppress the growth of annual broadleaf weeds, for example the growth of the aforementioned annual broadleaf weed species, and by post-emergence application in a non-directional manner, such as non-directional spraying, to an area used to grow grassy crops such as wheat, barley, oats, rice, rye, corn and sorghum, sugar beet, fodder beet, beetroot, onion, herbaceous seed plants and fodder plants (pasture), before or after emergence of crops.

For this purpose, i.e. to selectively control annual broadleaf weeds by post-emergence application to the area used to grow the crop plants mentioned immediately above, application rates of between 0.25 kg and 4.0 kg of active ingredient per hectare are particularly suitable.

Compounds of formula I, in particular 1- (4-trifluoromethylbenzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide and 1- 1- (3,4-dichlorophenyl) ethyl imidazole-4,5-N, N -dimethyl-4,5-dicarboxamide, are useful for selectively controlling the growth of annual grass weeds and broadleaf weeds, e.g., to suppress the growth of annual grass weeds and broadleaf weeds listed above, by pre-emergence non-directional application, e.g. crop plants, such as wheat, barley, oats, rye, corn, rice and sorghum, and broadleaf crop plants, such as cotton, soybean and potato, before emergence of the crop plants above the soil surface.

For this purpose, i.e. to selectively control annual grass weeds and broadleaf weeds by pre-emergence application to the area used to grow the crop plants mentioned immediately above, application rates of between 0.25 and 4.0 kg of active ingredient per hectare are particularly suitable.

Compounds of formula I, in particular 1- (4-trifluoromethylbenzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide, 1- [1- (4-trifluoromethylphenyl) ethyl] imidazole-N, N'-dimethyl -4,5-dicarboxamide and 1- (3,4-dichlorobenzyl) imidazole-N, N * -dimethyl-4,5-dicarboxamide may also be used to control the growth of weeds, in particular the weeds mentioned above, by pre-emergence or post-emergence application in orchards and in areas where trees are grown, such as in forests, groves and parks, in plantations such as sugar beet, bananas, pineapples and rubber trees, and in bushes (including areas used to grow fruit shrubs such as black and red) currant).

For this purpose, the substances may be applied, directed or unmounted (for example by directing or unmounted spraying), to weeds or to the soil on which they are expected to occur, before or after planting trees, plunger plants or shrubs, at doses between 0, 25 and 10.0 kg of active substance per hectare, in the case of sugar cane, in particular at doses between 0.25 and 8.0 kg of active substance per hectare (preferably between 0.25 and 4.0 kg of active substance per hectare), to control annual broadleaf weeds by post-emergence application.

The compounds of formula (I) may also be used to control the growth of weeds, in particular the weeds mentioned above, in places where the crop plants are not grown, but where it is nevertheless desirable to control the weeds. Examples of such areas are airports, open areas of industrial enterprises, railways, roadsides, river banks, irrigation canals and other waterways, shrubbery, eels or uncultivated land. This is particularly the case in areas where it is desirable to control the growth of weeds in order to reduce the risk of fire.

When used for this purpose, where a total herbicidal effect is often desired, the active ingredients are usually applied at doses higher than those used to treat the crops on the crops as described above.

The exact dosage depends on the nature of the vegetation to be treated and the effect desired. Preemergent or post-emergence application, preferably pre-emergence application, carried out in a directed or non-directed manner (for example by a directed or non-directed spray) at doses of between 2.0 and 20.0 kg of active ingredient per hectare is particularly suitable for this purpose.

When used to control weed growth by pre-emergence application, the compounds of formula (I) may be incorporated into the soil on which weeds are expected to emerge. It is understood that when compounds of formula I are used to control weed growth by post-emergence application, i.e. by application to above-ground or unprotected parts of emerging weeds, the compounds of formula I normally also come into contact with soil where they may have a pre-emergence effect on later germinating weeds found in the soil.

Where particularly prolonged weed control is desired, for example in areas not intended for crop cultivation, weed infestation and crop plantations, the application of the compounds of formula I may be repeated if necessary.

The utility of the compounds of formula I as herbicides is further enhanced by the fact that these compounds are relatively harmless to warm-blooded animals, as evidenced by the following test:

Mice are orally administered one of the compounds of Formula I at a certain dose, and individual groups of mice each given a given compound at a certain dose are observed until at least three days in the study group no experimental mice die.

The values of Ιιϋϋ θ (dose lethal for 50% of treated mice) range from 500 to more than 1000 mg / kg body weight of test animals.

Preferred compounds of the invention are those compounds of formula (1) wherein:

R ¹ represents a hydrogen atom or a straight alkyl group having 1 to 8 carbon atoms,

3

R and R are as defined above and

R is hydrogen, chlorine or trifluoromethyl, or one of R ^2, R and R is methoxy and at least one of these symbols has a meaning other than hydrogen and especially those compounds of formula I wherein

R ¹ represents a hydrogen atom or a methyl, ethyl, propyl or butyl group;

3 each of R and R is hydrogen, halogen, trifluoromethoxy, methyl, ethyl, isopropyl or trifluoromethyl; and

R ⁴ . represents a hydrogen atom, a chlorine atom or a trifluoromethyl group, or one of R ² , R ³ and R ⁴ represents a methoxy group and at least one of them has a meaning other than a hydrogen atom.

Particularly interesting compounds of formula I are the following:

1- (4-chlorobenzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide,

- [1- (4-chlorophenyl) ethyl] imidazole-Ν, Ν'-dimethyl-4,5-dicarboxamide,

1- [1- (4-iodophenyl) ethyl] imidazole-N, N'-dimethyl-4,5-dicarboxamide, N - (4-trifluoromethoxyphenyl) ethyl] imidazole-N, N'-dimethyl-4,5 -dicarboxamide,

- [1- (3,4-Dichlorophenyl) propyl] imidazole-Ν, Ν'-dimethyl-4,5-dicarboxamide,

-O- (3,4-dichlorophenyl) butyl] imidazole-Ν, Ν'-dimethyl-4,5-dicarboxamide,

- [1- (3,4-dichlorophenyl) pentyl] imidazole-Ν, Ν'-dimethyl-4,5-dicarboxamide,

- [1- (3,4-dibromophenyl) ethyl] imidazole-N, N'-dimethyl-4,5-dicarboxamide,

- (4-bromo-3-chlorobenzyl) imidazole-Ν, Ν‘-dimethyl-4,5-dicarboxamide,

- (3-chlorobenzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide, - [1- (3-chlorophenyl) ethyl] imidazole-N, N'-dimethyl-4,5-dicarboxamide,

- (3-fluorobenzyl) imidazole-Ν, Ν-dimethyl-4,5-dicarboxamide,

- (3-Trifluoromethylbenzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide,

- [1- (3-Trifluoromethylphenyl) ethyl] imidazole-Ν, Ν'-dimethyl-4,5-dicarboxamide,

- (3,5-dichlorobenzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide and - {1- [3,5-bis (trifluoromethyl) phenyl] ethyl} imidazole-N, N'- dimethyl-4,5-dicarboxamide, and in particular

- (4-bromobenzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide,

- (4-iodobenzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide,

- (4-trifluoromethoxybenzyl) imidazole-Ν, Ν'-dimethyl-4,5-dicarboxamide,

- (4-Trifluoromethylbenzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide,

-O- (4-trifluoromethylphenyl) ethyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide,

- (3,4-dichlorobenzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide,

- [1- (3,4-dichlorophenyl) ethyl] imidazole-Ν, Ν'-dimethyl-4,5-dicarboxemide,

- (3,4-dibromobenzyl) imidazole-Ν, Ν'-dimethyl-4,5-dicarboxamide,

- (4-chloro-3-methylbenzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide,

- (3,4-diiodobenzyl) imidazole-Ν, Ν'-dimethyl-4,5-dicarboxamide, and 1- (3,4,5-trichlorobenzyl) imidazole-Ν, Ν'-dimethyl-4,5-dicarboxamide.

Other interesting compounds of formula I are the following:

- (4-fluorobenzyl) imidazole-Ν, Ν'-dimethyl-4,5-dicarboxamide,

- (3-bromobenzyl) imidazole-Ν, Ν'-dimethyl-4,5-dicarboxamide,

- (3-i-benzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamides,

- (3-methylbenzyl) imidazole-Ν, Ν'-dimethyl-4,5-dicarboxamide,

- (4-methylbenzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide,

- (4-ethylbenzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide,

- (4-Isopropylbenzyl) imidazole-Ν, Ν'-dimethyl-4,5-dicarboxamide,

- (3,4-dimethylbenzyl) imidazole-Ν, Ν'-dimethyl-4,5-dicarboxamide,

1- (3-chloro-4-methoxybenzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide,

- (3-bromo-4-methylbenzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide,

- (3-chloro-4-methylbenzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide,

- [3,5-bis (trifluoromethyl) benzyl] imidazole-N, N'-dimethyl-4,5-dicarboxamide,

- [1- (3,4-dichlorophenyl) hexyl] imidazole-Ν,--dimethyl-4,5-dicarboxamide,

- (Ί- (3,4-dichlorophenyl) heptyl] imidazole-N, Ν'-dimethyl-4,5-dicarboxamide and 1- [1- (3,4-dichlorophenyl) nonyl] imidazole-Ν, Ν'-dimethyl -4,5-dicarboxamide.

The results of the herbicidal activity tests of representative compounds of the formula I are given in our related Czechoslovak patent specification 207,657.

In accordance with the process of the invention, the compounds of formula (I) above are prepared by the preparation of a compound of formula (II), (II)

R ¹ -CH

R ⁴ in which

X represents a halogen atom, preferably chlorine

R, R, ^RJ and R * are as defined above,

Or bromine and reacted with an alkali metal salt, preferably a sodium salt, of the imidazole-N, N'-dimethyl-4,5-caricamide of formula III.

O

II (III) ch ₃ nhc

CHqNHC4 ii N

This reaction may be carried out in the presence of an inert organic solvent such as dimethylformamide or tert-butanol at a temperature between 50 and 150 ° C, preferably at a temperature between 60 and 110 ° C,

The compound of formula III can be prepared by reacting imidazole-4,5-dicarboxylic acid of formula IV

O

with thionyl chloride and then reacting the resulting product with methylamine.

The reaction of imidazole-4,5-dicarboxylic acid with thionyl chloride can be carried out using an excess of thionyl chloride, optionally in the presence of an inert organic solvent and optionally in the presence of a catalytic amount of dimethylformamide or pyridine, under reflux.

The reaction of the intermediate product with methylamine can be carried out in the presence of an acid binding agent, which is preferably an excess of methylemine, and in the presence of an organic solvent such as toluene, at a temperature between 0 and 30 ° C, preferably at room temperature. ,

Alternatively, a compound of formula (III) may be prepared by reacting a compound of formula (III).

r ⁵ oc

II o

H in which

R ^ represents a straight or branched alkyl group having 1 to 6 carbon atoms, with methylamine in the presence of an inert organic solvent such as toluene or ethanol, at a temperature between 0 and 100 ° C.

Compounds of formula V may be prepared by reacting a compound of formula XV with a C 1 -C 6 alkanol, for example ethanol, in the presence of an acid catalyst such as hydrogen chloride.

The reaction may conveniently be carried out by introducing hydrogen chloride gas into an alkanolic, for example ethanolic, solution of the compound of formula IV under reflux.

The alkali metal salts of the compound of formula III can optionally be prepared in situ using known methods. For example, the sodium salt may be prepared by reacting a compound of formula III with sodium hydride in the presence of dimethylformamide.

As used herein, known methods refer to methods previously used or described in the chemical literature.

An alternative process for the preparation of imidazole derivatives of the general formula I, as well as herbicidal compositions containing these compounds as active ingredients, are described and protected in our co-pending Czechoslovak patent specification 207,657.

The invention is illustrated by the following non-limiting examples.

Example 1

1.8 g of imidazole-N, N'-dimethyl-4,5-dicarboxamide [see Vinogradova and Chromov-Borisov,

Žur. Obšč. Chim., 31, 1446 (1961)] is partially dissolved with stirring in 10 ml of dry dimethylformamide and 0.24 g of sodium hydride is added to the mixture at 60 ° C.

This temperature was maintained by external heating until all components were completely dissolved for 15 minutes, 1.95 g of 3,4-dichlorobenzyl chloride was added to the resulting solution, the reaction mixture was heated at 70 ° C for 6 hours, then cooled, diluted. 50 ml of chloroform, the solution was washed with 100 ml of water, dried over magnesium sulphate and evaporated to a colorless oily residue which solidified upon trituration with water.

This solid material was dried and recrystallized from 15 ml of toluene and 15 ml of hexane to give 2.0 g of 1- (3,4-dichlorobenzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide as colorless crystals of m.p. mp 128-129 ° C.

Example 2

By analogy to Example 1, the following compounds can be obtained by substituting 3,4-dichlorobenzyl chloride with the appropriate benzyl halides:

from 4-bromo-3-chlorobenzyl bromide 1- (4-bromo-3-chlorobenzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide, melting after crystallization from ethanol at 127 to 128 ° C, from 3-bromo -4-methylbenzyl chloride 1- (3-bromo-4-methylbenzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide, melting after crystallization from ethanol at 121.5 to 122 ° C, from 3-chloro-4 methylbenzyl chloride [see Stephen et al., J. Chem. Soo. 117. 524 (1920)] 1- (3-chloro-4-methylbenzyl) imidazole-N, N ^, -dimethyl-4,5-dicarboxamide, melting after crystallization from a mixture of toluene and light naphtha (boiling point 60-80 ° C) ) at 110.5 to 111 ° C, from 4-chloro-3-methylbenzyl chloride [see Horvath, U.S. Patent 2,965,682 (1960)] 1- (4-chloro-3-methylbenzyl) imidazole-N, N 1'-dimethyl-4,5-dicarboxamide, melting after crystallization from ethanol at 149-151 ° C, from (S) -1- (3-chlorophenyl) ethyl chloride [see Usui et al., Japanese Kokai 73-67 228 (1973)]. (I) -1- [1- (3-chlorophenyl) ethyl] imidazole-N, N * -dimethyl-4,5-dicarboxamide, melting after crystallization from ethanol at 86-88 ° C, from (1) - 1- (4-chlorophenyl) ethyl chloride [see Protwa et al., Collection Czech. Chem. Commun 22> 2 102 (1962)] (i) -1- [1- (4-chlorophenyl) ethyl] imidazole-N, N'-dimethyl-4,5-dicarboxamide, melting after crystallization from ethanol at 29 to 29 , 30 ° C, from (1) -1- (3,4-dibromophenyl) ethyl chloride (i) -1- [1- (3,4-dibromophenyl) ethyl] imidazole-N, N'-dimethyl-4, 5-dicarboxamide, melting after crystallization from cyclohexane at 118 to 120 ° C, from (S) -1- (3-trifluoromethylphenyl) ethyl bromide (1) -1- [1- (3-trifluoromethylphenyl) ethyl] imidazole-N, N -dimethyl-4,5-dicarboxamide, boiling point 197-199 ° C / 40 Pa, from (±) -1- (4-trifluoromethylphenyl) ethyl bromide (s) -1- [1- (4-trifluoromethyl) thylphenyl) ethyl] imidazole-Ν, Ν-dimethyl-4,5-dicarboxamide, melting after crystallization from cyclohexane at 95 to 97 ° C, from (i) -1- (3,4-dichlorophenyl) propyl chloride (s) - 1- [1- (3,4-dichlorophenyl) propyl] imidazole-N, N-dimethyl-4,5-dicarboxamide, melting after crystallization from cyclohexane at 91-93 ° C, and (±) -1- (3, (4) -1- [1- (3,4-diohlorophenyl) butyl] imidazole-4 ', 4'-dimethyl-4,5-dicarboxamide After crystallization from toluene at 134-135 ° C.

The benzyl halides used as starting materials in the reactions described above are prepared by the following procedures a) to c).

a) In an analogous manner to that described in Example 4 below for the preparation of 3,4-dibromobenzyl chloride, except that the 3,4-dibromobenzyl alcohol is replaced by the corresponding substituted benzyl alcohol. The following compounds were prepared in this way:

from 3-bromo-4-methylbenzyl alcohol 3-bromo-4-methylbenzyl chloride as a clear moving oil, from (1) -1- (3,4-dibromophenyl) ethanol [see Koton et al., Sur. Example. Chim., 26666 (1953)] (I) -1- (3,4-dibromophenyl) ethyl chloride, bp 90-100 ° C / 33 Pa, from (±) -1- (3,4-dichlorophenyl) propanol [See Shell Oil Co., U.S. Patent 3,840,579 (1974)] (±) -1- (3,4-dichlorophenyl) propyl chloride, boiling point 82-85 ° C / 33 Pa, az (-1) -1 - (3,4-dichlorophenyl) butanol (±) -1- (3,4-dichlorophenyl) butyl chloride as a light brown oil.

b) To a mixture of 38 g of (±) -1- (3-trifluoromethylphenyl) ethanol [see Overberger et al., Org. Synth. Coll. 200 (1955)], 56 g of triphenylphosphine and 200 ml of dry dimethylformamide are added, under stirring, under nitrogen atmosphere, over a period of 15 minutes, 32.5 g (10.4 ml) of bromine while maintaining the temperature of the mixture by external ice cooling at 40-50 ° C. .

Additional bromine was added until the orange color persisted, the reaction mixture was stirred for 15 minutes, then poured into a mixture of 1 liter of ice water and 500 ml of hexane.

The mixture was filtered and the solid was washed thoroughly with hexane. The hexane solutions were combined, washed four times with 100 ml of water each time, dried over sodium sulfate and distilled. There was obtained (R) -1- (3-trifluoromethylphenyl) ethyl bromide as a clear mobile oil having a boiling point of 98-105 ° C / 2000 Pa.

The following product is prepared in an analogous manner by substituting (I) -1- (3-trifluoromethylphenyl) ethanol with the corresponding benzyl alcohol derivative:

from (R) -1- (4-trifluoromethylphenyl) ethanol [see Novotny et al., J. Pharm. Sciv, 1973,

62. 910] (R) -1- (4-trifluoromethylphenyl) ethyl bromide, boiling point 8 to 84 ° C / 1733 Pa.

♦

o) 31.8 g of 4-bromo-3-chlorotoluene [see Cohen and Raper, J. Chem. Soc., 85 1267 (1904)] was refluxed with 27.5 g of N-bromosuccinimide and 3.6 g of benzoyl peroxide in 75 ml of carbon tetrachloride for 10 hours.

The cooled solution was filtered, washed with aqueous ferrous sulfate solution, dried over magnesium sulfate, filtered and evaporated to dryness. 44 g of 4-bromo-3-chlorobenzyl bromide are obtained in the form of a pale orange oil.

The benzyl alcohols used as starting materials in reactions a) and b) above were prepared by one of the following processes i) and ii).

(i) In an analogous manner to that described in Example 4 below for the preparation of 3,4-dibromobenzyl alcohol, except that 3,4-dibromobenzoic acid is replaced with 3-bromo-4-methylbenzoic acid [see Jannasch and Dieckmann, Ann., 171. 83 (1874)], 3-bromo-4-methylbenzyl alcohol is obtained as a clear orange oil, sufficiently pure for the next reaction.

(ii) To a solution of 65.3 g of 3,4-dichlorobutyrophenone [see Foerster et al., GDR Patent No. 45,721 (1966)] with stirring at 0 to 10 ° C was added portionwise over 30 minutes 14.9 sodium borohydride.

The reaction mixture was heated to reflux for 2 hours, cooled, 300 ml of 2N sodium hydroxide solution was added, and the resulting mixture was heated under reflux for 30 minutes.

The methanol was evaporated and the aqueous solution was extracted five times with 200 ml of diethyl ether each time. The combined extracts were washed with 200 ml of water, 200 ml of 2N hydrochloric acid and five times with 200 ml of water each, dried over magnesium sulfate and evaporated to dryness. 65 g of (i) -1- (3,4-dichlorophenyl) butanol are obtained in the form of a brownish oil of sufficient purity for the next reaction.

Example 3

The following compounds were prepared in an analogous manner to that described in Example 1, except that 3,4-dichlorobenzyl chloride was replaced by the corresponding benzyl halide in each case:

from 3,4-diiodobenzyl bromide 1- (3,4-diiodobenzyl) imidazole-N, N-dimethyl-4,5-dicarboxamide, melting after crystallization from ethanol at 155-156 ° C, from 3,4,5- triohlorobenzyl chloride [see Chiavarelli, Gazz. chim. Italian. 85. 1,405 (1955)]

1- (3,4,5-trichlorobenzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide, melting after crystallization from ethanol at 128-130 ° C, from 3,5-bis (trifluoromethyl) benzyl bromide [see] Ambrus, U.S. Patent 3,625,970] 1- [3,5-bis (trifluoromethyl) benzyl] imidazole-N, N ^from -dimethyl-4,5-dicarboxamide, melting after crystallization from cyclohexane at 142-144 ° C from (1) -1- (4-iodophenyl) ethyl bromide (i) -1- [1- (4-iodophenyl) ethyl] imidazole-N, N'-dimethyl-4,5-dicarboxamide, melting after crystallization from aqueous of ethanol at 132-134 ° C, from (i) -1- (4-trifluoromethoxyphenyl) ethyl bromide (1) -1- [1- (4-trifluoromethoxyphenyl) ethyl] imidazole-N, N'-dimethyl-4,5 -dicarboxamide, melting after crystallization from light petroleum (b.p. 60-80 ° C) at 78-79 ° C, from 1- [3,5-bis (trifluoromethyl) phenyl] ethyl bromide (±) -1- {1- [ 3,5-bis (trifluoromethyl) phenyl] ethyl} imidazole-N, N'-dimethyl-4,5-dicarboxamide, melting after crystallization from cyclohexane at 132-134 ° C, from (i) -1- (3,4) -dichlorophenyl) pentylbromide (s) -1- [1- (3,4-dichlorophenyl) pentyl] imidazole-N, N'-dimethyl-4,5-dicarboxamide, melting after crystallization from light gasoline (boiling point 60 to 80 ° C) at 142 to 143 ° C, (I) -1- (3,4-dichlorophenyl) hexylbromide of (I) -1- [1- (3,4-dichlorophenyl) hexyl] imidazole-N, N'-dimethyl-4,5-dicarboxamide, melting after crystallization from light gasoline (boiling point 60 to 80 ° C) at 114 to 115 ° C, from (±) -1- (3,4-dichlorophenyl) heptyl chloride (s) -1- [1- (3,4) -dichlorophenyl) heptyl] imidazole-N, N ^from -dimethyl-4,5-dicarboxamide, melting after crystallization from light naphtha (boiling point 60-80 ° C) at 97.5-99 ° C, az (±) -1- (±) -1- [1- (3,4-Dichlorophenyl) nonyl] imidazole-N, N'-dimethyl-4,5-dicarboxamide (3,4-dichlorophenyl) nonyl chloride, m.p. 60 to 80 ° C) at 79 to 79.5 ° C.

The benzyl halides used as starting materials in the above reactions are prepared by the following procedures a) to c).

a) In analogy to the procedure described in Example 4 below for the preparation of 3,4-dibromobenzyl chloride, substituting (I) -1- (3,4-dichlorophenyl) heptanol for 3,4-dibromobenzyl alcohol with (I) -1- (3) 4-dichlorophenyl) heptyl chloride as a colorless oil.

b) In analogy to the procedure described in Example 2 (b) for the preparation of (I) -1- (3-trifluoromethylphenyl) ethyl bromide, substituting (I) -1- (3-trifluoromethylphenyl) ethanol with the appropriate alcohol each yields the following compounds:

from (1) -1- (4-iodophenyl) ethanol (I) -1- (4-iodophenyl) ethyl bromide as an orange oil, from (I) -1- (4-trifluoromethoxyphenyl) ethanol (I) -1- ( 4-trifluoromethoxyphenyl) ethyl bromide in the form of an orange oil, from (±) -1- [3,5-bis (trifluoromethyl) phenyl] ethanol [see McBee and Sanford, JACS 72. 4,054 (1950)] (i) -1- [3,5-bis (trifluoromethyl) phenyl] ethyl bromide, boiling point 97-98 ° C / 1333 Pa, from (I) - 1- (3,4-dichlorophenyl) pentanol (I) -1- (3, 5-methylphenyl) pentanol 4-Dichlorophenyl) pentyl bromide as a light orange oil, from (I) -1- (3,4-dichlorophenyl) hexanol (1) -1- (3,4-dichlorophenyl) hexyl bromide as a yellow oil, and (a) - 1- (3,4-dichlorophenyl) nonanol (±) -1- (3,4-dichlorophenyl) nonyl bromide as a yellow oil.

c) In an analogous manner to that described in Example 2c) for the preparation of 4-bromo-3-chlorobenzyl bromide, substituting 3,4-diiodotoluene for 4-bromo-3-chlorotoluene [see Willgerodt and Simonis, Ber. 32, 279 (1906)] gives 3,4-diiodobenzyl bromide, m.p. 85-87 ° C.

Some of the benzyl alcohols used as starting flights in the above reactions are prepared in an analogous manner to that described in Example 2ii) for the preparation of (±) -1- (3,4-di-chlorophenyl) butanol, except that 3, 4-Dichlorobutyrophenone is always replaced by the corresponding alkanophenone. The following compounds are obtained in this way:

from 4-iodoacetophenone [see Campaigne et al., J. Org. Chem., 24, 1229 (1959)] (I) -1- (4-iodophenylenethenol as an orange oil, from 3 '>4'-dichlorvalerophenone (+) - 1- (3,4-diohlorophenyl) pentanol, z S, N, N -dichlorohexanophenone (I) -1- (3,4-dichlorophenyl) hexanol as a pale yellow oil, from 3 *, 4 ^, -dichloroheptanophenone (I) -1- (3,4-dichlorophenyl) heptanol as nearly colorless oil from 3 ', 4 ^/ -dichlornonanofenonu (±) -1- (3,4-dichlorophenyl) nonanol as an almost colorless oil.

(±) -1- (4-Trifluoromethoxyphenyl) ethanol was prepared as follows:

Methylmagneeium iodide (prepared from 3.5 g magnesium and 20.5 g methyl iodide in 50 ml diethyl ether) was treated with a solution of 20 g 4-trifluoromethoxybenzaldehyde [see Jagupolsky and Troickaya, Zur. Občejch Chim., 30. 3 129 (1960)] in 25 ml diethyl ether.

After the latter solution was added, the reaction mixture was refluxed for 6 hours, cooled, and a solution of 35 g of ammonium chloride in 100 ml of water was added at 0-5 ° C.

The organic layer was separated and the aqueous layer was washed three times with 50 ml of diethyl ether each time.

The ether solution was combined with the wash liquids, and the organic phase was washed twice

100 ml of water, dried over sodium sulphate and evaporated to dryness.

20.3 g of (1) -1- (4-trifluoromethoxyphenyl) ethanol are obtained in the form of a clear colorless oil which is sufficiently pure for the next reaction.

3,4-Dichlorvalerophenone, used in one of the above reactions, is prepared as follows:

To a solution of 70 g of aluminum chloride in 73.5 g of o-dichlorobenzene was added, with vigorous stirring, 60.3 g of valeryl chloride, raising the temperature from 25 to 47 ° C. The resulting solution was gently heated on a steam bath for 3 hours, then cooled and poured into a mixture of 500 g of ice and 100 ml of concentrated hydrochloric acid. The layers were separated and the aqueous layer was extracted three times with 250 ml of diethyl ether each time.

The organic phase is combined with the ether extracts, washed twice with 250 ml of water each, then four times with 100 ml of saturated aqueous sodium carbonate solution and finally with three times 250 ml of water each, dried over sodium sulfate and evaporated to dryness. After crystallization from 150 ml of light petroleum (b.p. 60-80 ° C), the solid residue gives 41 g of 3 ', 4'-dichlorvalerophenone as brownish crystals, m.p. 40-41 ° C.

In an analogous manner, the following compounds are substituted for valeryl chloride with the corresponding alkanoyl chlorides:

3'4'-dichlorhexanophenone hexanoyl chloride, boiling point 115-150 ° C / 27 Pa, melting below 35 ° C; 4'-dichlorononanophenone, boiling point 155-157 ° C / 33 Pa.

Example 4

The following compounds can be prepared in analogy to Example 1 by replacing 3,4-dichlorobenzyl chloride with the appropriate benzyl halide:

from 3-fluorobenzyl chloride [see Jerumanis and Bruylants, Bull. Soc. Chim. Belges, 69, 312 (1960)] 1- (3-fluorobenzyl) imidazole-N, N ^, -dimethyl-4,5-dicarboxamide, melting after crystallization from ethanol at 103.5-104 ° C, from 4-fluorobenzyl chloride [ kiz Olah, Pavlath and Kuhn, Acta. Chim. Acad. Sci. Hung., 2, (1955)] 1- (4-fluorobenzyl) imidazole-N, N ^, -dimethyl-4,5-dicarboxamide, melting after crystallization from hexane at 94-95 ° C, from 3-chlorobenzyl chloride [see Franzen] and Rosenberg, J. Prakt. Chem., [2] 101. 334 (1867) 3 1- (3-chlorobenzyl) imidazole-N, N ^, -dimethyl-4,5-dicarboxamide, melting after crystallization from ethanol at 121 to 121.5 ° C, from 4-chlorobenzyl chloride [see Olivier, Rec . Trav. Chim., 41 308 (1922)] 1- (4-chlorobenzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide, melting after crystallization from ethanol at 131-132 ° C, from 3-bromobenzyl chloride [see Olivier , Rec. Trav. Chim., 41, 649 (1922) 1- (3-bromobenzyl) -. imidazole-N, N ^from -dimethyl-4,5-dicarboxamide, melting after crystallization from ethanol at 114-115 ° C, from 4-bromobenzyl chloride [see Boeseken, Rec. Trav. Chim., 23 99 (1904)] 1- (4-bromobenzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide, m.p. 149-150 ° C, from 3-iodobenzyl bromide [see Olivier, Rec. Trav. Chim., 42 520 (1923) 11- (3-iodobenzyl) imidazole-N, N ^from -dimethyl-4,5-dicarboxamide, melting after crystallization from ethanol at 112-114 ° C, from 4-iodobenzylbromide [see Olivier , Rec. Trav. Chim., 42; 519 (1923)] 1- (4-iodo-benzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide, melting after crystallization from ethanol at 150-151 ° C, from 3,4-dibromobenzyl chloride 1- (3, 4-dibromobenzyl) imidazole-N, N ^from -dimethyl-4,5-dicarboxamide, melting after crystallization from ethanol at 118-119 ° C, from 3,5-dichlorobenzyl chloride [see Fuchs and Carlton, JACS §5, 107 (1963) 1-] - (3,5-dichlorobenzyl) imidazole-N, N-dimethyl-4,5-dicarhoxamide, melting after crystallization from ethanol at 135-136 ° C, from 3-methylbenzyl chloride [see Olivier, Rec. Trav. Chim., 41, 307 (1922)] 1- (3-methylbenzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide, melting after crystallization from ether at 84-85 ° C, from 4-methylbenzyl chloride (see Olivier, Rec. Trav. Chim., 41, 405 (1922)] 1- (4-methylbenzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide, melting after crystallization from aqueous ethanol at 115-116 ° C , from 4-ethylbenzyl chloride [see Membrane, Bull. Soc. Chim., [4], g., 317 (1923)] 1- (4-ethylbenzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide, m.p. after crystallization from cyclohexane at 68 to 69 ° C, from 4-isopropylbenzyl chloride [see Membrane, Bull. Soc. Chim., [4], 32, 317 (1923) 1- (4-isopropylbenzyl) imidazole-N, N'- dimethyl-4,5-dicarboxamide, melting after crystallization from hexane at 54 to 56 ° C, from 3,4-dimethylbenzyl chloride [see Sommelet, Compte Rendu, 157, 1445 (1913)] 1- (3,4-dimethylbenzyl) imidazole-N, N ^- dimethyl-4,5-dicarboxamide, melting after crystallization from a mixture of toluene and petroleum ether (b.p. 60-80 ° C) at 168-170 ° C, from 3-trifluoromethylbenzyl alcohol; chloride [see Pecherer Benjamin, U.S. Pat. No. 3,465,051 (1966)] 1- (3 'trifluoromethylbenzyl) imidazole-N, ^{<-dimethyl-4,5-dikarboxemid} after crystallisation from a mixture of hexane and ethanol 108-110 ° C, from 4-trifluoromethylbenzyl chloride [see Sarett and Shen, U.S. Patent 3,196,162 (1959)] 1- (4-trifluoromethylbenzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide, m.p. after crystallisation from cyclohexane at 13> 132 ° C, from 4-trifluormethoxybenzylohloridu 1- (4-trifluoromethoxybenzyl) imidazole-N, N ^/ -dimethyl-4,5-dicarboxamide, after crystallisation from ethanol at 110.5 ° C from 3-chloro-4-methoxybenzyl chloride [see Naik and Wheeler, JCS 1938. 1780] 1- (3-Chloro-4-methoxybenzyl) imidazole-N, N'-dimethyl-4,5-dicarboxamide, melting after crystallization from a mixture of toluene and cyclohexane at 122-123 ° C, and (R) -1- (3,4-dichlorophenyl) ethyl chloride [see Manuel et al., JACS, 68 861 (1946)] (R) -1- [1- (3,4-dichlorophenyl) ethyl] imidazole-N, N * -dimethyl-4,5-dicarboxamide, m.p. after crystallization from methanol at 124 to 126 ° C,

The 3,4-dibromobenzyl chloride used in one of the reactions described above was prepared as follows:

g of 3,4-dibromobenzoic acid [see Miller, JCS 61. 1033 (1892)] was suspended in 150 ml of toluene with stirring at 50 ° C and 52 ml of 70% (50 ml) was added over 30 minutes at 50 ° C ( weight / volume) of a toluene solution of sodium dihydro-bis (2-methoxyethoxy) aluminum.

The mixture was heated on a steam bath for 1 hour, then cooled to 20 ° C and hydrolyzed by the addition of 150 ml of 6N hydrochloric acid under cooling. The phases are separated and the aqueous phase is extracted with 100 ml of diethyl ether.

The combined organic extracts were washed with saturated sodium bicarbonate solution and water, dried over sodium sulfate and evaporated after filtration. 19 g of 3,4-dibromobenzyl alcohol are obtained in the form of a light red colored oil.

The alcohol thus obtained was dissolved in 60 ml of chloroform without purification, the solution was heated to reflux and 20 ml of thionyl chloride was added portionwise over 10 minutes.

The reaction mixture was refluxed for 1 hour, evaporated to a light oily residue, which was diluted three times with 50 ml of chloroform each time and the combined chloroform solutions were evaporated. The residue was dissolved in diethyl ether, washed with saturated sodium bicarbonate solution, dried over sodium sulfate and evaporated.

20 g of .alpha., 4-diboffoffenzyl chloride are obtained in the form of a clear mobile oil, sufficiently pure for the next reaction.

In an analogous procedure to substituting 3,4-dibromobenzoic acid for 4-trifluoromethoxybenzoic acid, see Sheppard, J. Org. Chem., 29.1 (1964) gives 4-trifluoromethoxybenzyl chloride as a clear mobile oil which is also used as a starting material in one of the above reactions.

Claims (7)

OBJECT OF THE INVENTION2U A process for the preparation of imidazole derivatives of the general formula I, wherein: R ¹ represents a hydrogen atom or a straight or branched (C 1 -C 10) alkyl group or a straight or branched (C 2 -C 10) alkenyl or alkenyl group, each of R ² , R ² and R 2 which may be the same or different , represents a hydrogen or halogen atom, a trifluoromethoxy group or a methyl, ethyl, propyl or isopropyl group, optionally substituted by one or more fluorine atoms, or one of R ² , R 6 and represents a methoxy group and at least one of the remaining R ² , R 6 and R 1 represents a halogen atom, a trifluoromethoxy group or a methyl, ethyl, propyl or isopropyl group, optionally substituted by one or more fluorine atoms, provided that at least one of R ¹ , R ² , R 4 and R 4 is other than an atom hydrogen, characterized in that the compound of formula (XX) wherein: R ² (II) X represents a halogen atom and R ^1, R ^2, R 3 and are as defined above, is reacted with a salt of imidazole-N, N'-dimethyl-4,5-dicarboxamide alkali metal. 2. The process according to claim 1, wherein the reaction is carried out in the presence of an inert organic solvent, at a temperature between 50 and 150 [deg.] C. 3. Process according to claim 1 or 2, characterized in that the compounds of the above general formula (II) in which: R @ 1 represents a hydrogen atom or a straight or branched alkyl group having from 1 to 6 carbon atoms and R ² , r 1, R ^{3 4} and X are as in point 1. 4. Process according to claim 1 or 2, characterized in that the compounds of the above-mentioned general formula (II) are used as starting materials, in which R ¹ represents hydrogen or a straight alkyl group having 1-8 carbon atom, 2 3 R and R are as in 1 a R ⁴ represents hydrogen, chlorine or trifluoromethyl, or one of R, R ^J and R is methoxy and at least one of the remaining symbols R ^2, R ³ and R ⁴ is halogen, trifluoromethoxy or methyl, ethyl, propyl, or an isopropyl group optionally substituted by one or more fluorine atoms, and X my meaning as in point 1. 5. Process according to claim 1 or 2, characterized in that the compounds of the above-mentioned general formula (II) are used as starting materials R ¹ represents a hydrogen atom or a methyl, ethyl, propyl or butyl group; R 3 and R 3 are each hydrogen, halogen, trifluoromethoxy, methyl, ethyl, isopropyl or trifluoromethyl; and R ⁴ is hydrogen, chlorine or trifluoromethyl, or one of R ^2, R ³ and R ⁴ is methoxy, and at least one of the remaining symbols R ^2, R ³ and R ⁴ is halogen, trifluoromethoxy or methyl, a propyl or isopropyl group optionally substituted by one or more fluorine atoms; and X is as in point 1. 6. The process of item 1 or 2, for the preparation of imidazole derivatives of the above formula I wherein either R ³ is bromine and R ¹ , R ² and R ⁴ are hydrogen, or R ³ is iodine and R ¹ , R ² and R ⁴ represent hydrogen atoms, or R ³ is trifluoromethoxy and R ¹ , R ² and R ⁴ are hydrogen, or R ³ represents a trifluoromethyl group and R ¹ , R ² and R ⁴ represent hydrogen atoms, or R ² and R ³ represent chlorine atoms and R ¹ and R ⁴ represent hydrogen atoms, or R ¹ is methyl, R ² and R ³ are Cl and R ⁴ is hydrogen, or R ² and R ³ are bromine atoms and R ¹ and R ⁴ are hydrogen atoms, characterized in that compounds of the above-mentioned general formula (II) in which R ¹ , R ² , R ³ and R ⁴ have a and X is as in 1. 7. A method according to claim 1 or 2 for the manufacture of imidazole derivatives of the general pattern ce I in which BU3 ^R1 represents a methyl group, R ³ is trifluoromethyl and R and R ⁴ are hydrogen atoms, or κ is methyl, R ^J is chlorine and R ¹ and R ⁴ are hydrogen, or R ² and R ³ are iodine and R ¹ and R ⁴ are hydrogen, or R ² , R ³ and R ⁴ are chlorine and R ¹ is a hydrogen atom, characterized in that the compounds of the above general formula (II) in which R @ ¹ , R @ ² , R ^{@ 3} and R ^{@ 4} are as defined above and X are as defined in point 1 are used as starting materials.