CS242859B2 - Method of benzimidazole-carbamates production - Google Patents

Abstract

Benzimidazole-carbamates endowed with anthelmintic activity have the general formula: <IMAGE> in which: R represents an alkyl group having 1 to 4 carbon atoms, R<1> and R<2> independently represent a hydrogen or halogen atom or a methyl group optionally substituted with one or more halogen atoms, R<3> and R<4> independently represent a hydrogen or chlorine atom or a methyl group, and X represents O, S, SO or SO2.

Description

The present invention relates to benzimidazole carbamates exhibiting anthelmintic activity, in particular to novel benzimidazole carbamates substituted at the 5 (6) position by a diene chain attached at the 5 (6) position via an oxygen atom or sulfur atom, optionally oxidized, and to their use as anthelmintic.

Benzimidazole derivatives exist in tautomeric forms, as in the following tautomeric forms:

In terms of nomenclature convention, substituent A which occupies position 5 in one tautomeric form occupies position 6 in the other tautomeric form.

Thus, benzimidazole derivatives bearing a substituent at a position corresponding to residue A are generally defined as 5 (6) -substituted.

Several benzimidazole carbamates differently substituted in the 5 (6) position, as well as their anthelmintic activity, are known (see, for example, German Patent Applications Nos. 2,029,637 and 2,164,690, French Patent Nos. 1,556,824 and 2,052,988). , and U.S. Patent Nos. 3,010,968, 3,915,986, and 4,002,640).

Anthelmintically active benzimidazole carbamates are also disclosed in German Patent Application Publication Nos. 2,816,694 and 2,843,308.

Numerous benzimidazole carbamates substituted at the 5 (6) position are already on the market, such as Albendazole, Oxibendazole and Parbendazole manufactured by Smith Kline Co., Phenbendazole manufactured by Hoechst, Oxphendazole manufactured by Syntex, Cambendazole and Thiabendazole manufactured by Merck, and Mebendazole manufactured by Janssen.

In accordance with the invention, novel benzimidazole carbamates substituted in the 5-position (6) corresponding to the general formula (I) have now been found.

NH-COOR (I) wherein

R is C 1 -C 4 alkyl,

2 each of R and R, which may be the same or different, represents a hydrogen atom, a halogen atom or a methyl group optionally substituted by one to three halogen atoms, each of the symbols R 6 and R 6, which may be the same or different, represents a hydrogen atom or a methyl group; and

X is oxygen, sulfur, SO or S0 _second

The compounds of the formula I exhibit a high anthelmintic activity and a broad spectrum of activity, since they are active against both gastrointestinal and broncho * -pulmonary parasites and against hepatic parasites of domestic and breeding animals.

The compounds of formula I are prepared by simple reaction steps as shown in the following reaction scheme wherein R, R, R, R and R have the same meaning as in formula I, Z and Z are chlorine or bromine and R ⁸ is a hydrogen atom or an acetyl group.

(II)

(III)

R (V)

(VI) (VII)

(d) IV + VI --- ---->

(VII ')

f) a reducing agent

VII -----------------------

S-CH ³

g) VIII + N = C-NH-COOR ---- ^ (2)

AND

COOR

LX = 0, s' i

(h)

I LX = S ^{is a} peracid

-----> (i) [X = SO, SO ₂ ']

The individual reactions a) to h) shown schematically above will now be described in more detail. It should be noted here that process a) -> d) - * e) - »f) - tg) - + h) is the subject of the invention itself, while process a) - b) -) -) -> f) - g) -> h) is a possible alternative. .

The first part of the sequence of reactions leading to the formation of compounds of formula I (reaction a), i.e. the reaction between the compound of formula II

(II) wherein R and R are as defined in formula I and each of Z and Z, which may be the same or different, is chlorine or bromine, and a diene of formula III

R ³ R ⁴

I I

CHr = C-C = CH (III)

Wherein R and R are as. in the formula I, is carried out by means of radical-type intermediates in the presence of suitable catalysts, such as electron transfer redex systems, for example, copper salts and amines, as described above. M. Asscher et al. £ j. Chem. Soc., P. 1887 (1963), or in the presence of complex ruthenium compounds, as most recently described by H. Matsumoto et al. [Chemistry Letters, p .115 (1978)] for the reaction between carbon tetrachloride ^CH 3 [(IIb R ¹ = R ² = Z = Z'-C ¹ | and ^I sopron of formula CH 2 C-CH ^- ^ ² [(ШЬ) R ^{j 3} = CH, ^R4 = ^Hj, execution ^{pMtomnos-Dichloro-r i} s ^t r ^{-t IF} en ^YLF axis ^{fI t} hen NRU ^I and / LP R4 ^Ir (C ₆ H _{5) 3} l ³ C1 ² /.

It should be pointed out that reaction a, whether carried out in the presence of electron transfer redox systems or in the presence of complex ruthenium compounds, is not ttereosseed, so that in the case of the compound of formula (III), the

4, o x

R, other than the R @ 1 subsection, is obtained in addition to the cis and trait tsomers exissing as a result of the double bond, as well as from the positional isomers.

For example, starting from tetzachormethane and isoprene, the following compounds are obtained:

CCl ₃ -CH ₂ -C = CH-CH ₂ Cl

CC1 ₃ -CH ₂ -CH = C-CH ₂ Cl [( ^IV H R ¹ = R ² = Z 2; s' = C1; R ³ = CH ^3, R ⁴ = H and R ³ = HR ⁴ = CH ³ _ ]

In general, mixtures of the positional isomers can be separated into individual traction disturbances.

Compounds of formula (V) or (IV) are then reacted with the sodium salt of 2-nitrohydroxylamine f (VI), X = O. ^{R 1} = ^h] or 4-nitro-mercapto [(VI) ^{, X} = ^{S. R} 5 = hJ in accordance with the above reaction. c) and d).

In some cases it is advantageous to protect the amino group of compound VI AGO ^ ^ IAC pulling the ^p and ^{k y} c of ^hook September tdpot ⁱⁿ mar gin ^I CH N ^^ N AAC irrn ^{[(VI), R 5} = ^{CH 3 ct ]} .

The acetyl group can then be readily cleaved by hydrolysis which can be carried out at any suitable stage in the process. \

The process described above yields the formula VII or VI. The latter product undergoes dehydrohalogenation in the side chain at the 4-position relative to the amino group (X-Y ') under the action of the base, thereby obtaining a corresponding reaction to general formula VII (reaction e).

The nitrothiazilium (VII) is then reduced, isptithead dithonium salt, to give the phenalondiaiin (VII) (reaction f).

Phenylenediamine of formula VIII is then reacted with ^1,3-net-S-y alkoxakzrSon ieSylisohhtoπюčovintt to afford benzimidazol-karbamátr of formula I wherein X represents either oxygen or sulfur (reaction g).

Fonyiondiaminu reacting VIII with 1,3-net-iettxχatabstya S-metslisot] hiomcotovinou zítкají the compounds of formula I, wherein R is ^Y ltvot MIO group. In an analogous manner by reacting fonalsndiaiint of formula VIII with a 1,3-net-sttxaкarS ^(sn-s? S ^s IEO lisohhSimtčovinot or 1,3 - proptxakarStnyl Sit-S-metyltsohhtimočtvintu or 1,3-net-buSox karSonal ^y-S- The benzimidazole carbamates of the general formula I in which r represents an ophthalmic, trttyl and Sutal group, respectively, are obtained.

Finally, it may be a benzimidazole-carbamates of the formula I wherein X is S by oxidation-acid compounds of formula I in which X denotes ^Y tulfin Owl or tulfoiylovot group (reaction h).

Reaction h) is carried out so that the benzimidazole-carbamate of the formula I wherein X is sulfur rtztuttí in an inert solvent (or in inert solvents Smee) and ^{tetrabutylammonium} s te ^ ^d cleaved with about -30 ° C to ^t epLtt room ^and i ^ ^s added Terk seSiia such as peracetic acid, perSennoová acid or 3-chloro ^p esbenztová acid.

If a thio group is to be converted to a sulfinyl group, an equimolar amount of acid is used. If the thio group is to be converted to a sulfooyl group or a sulfinyl group to a sulfonyl group, an excess of peracid is used.

As examples of compounds of formula II

(II). her:

tribrmimetan trihhlrrmetao tetabromnmethane t et r a c hibrm »et a n

1- trlchlolettn

1.1- didiilhrotan

1, 1-diium- ² , 2,

1- chloro-l-boom- ^2, 2,2-trifluoro ^ o ^ tan

1,1-dihydro-1,2,2,2-trifluorofuran

111-trichloro-1,2,3-trichloro-4-ol

112-trichine-1,2,2-trifluoroethyl

1,1'-Trifluoro-2,2,2-trifluoro-diaminomethylmethane

1112- tltralhlrr-2, l · ^ ι ^ i.fL · Jr- ^ lt ^ an

2,2-dibrdine-1,1,1,3,3,3-hexadipropao

2-chloro-2-boompropane.

As examples of compounds of formula III

R ³ R ⁴

I I

CH2 = C-C = _CH2 may be UVES substances successors formulas:

(iii) _Г з.

CH ₂ = C-CH = CH ₂ ,

CH 2 = CH-CH = CH 2

Cl

CH 2 = C-CH = CH 2

CKk CH «

II ³ .

_CH2 = C - C = _CH2

Cl Cl Ϊ / CH ₂ = CC = CH 2

Some of the compounds represented in the above reaction scheme by V and IV are known as the above mentioned adduct of carbon tetrachloride and isoprene or 1-bromo-2,4-hexadiene of the formula CH ₃ -CH = CH-CH = CH-CH 2 Br or 5-chloro-1. 3-pentadiene of the formula CH 2 = CH-CH = CH-CH ₂ Cl (see Soviet Patent Specification No. 472,926, Chemica 1A-83, 78559x (1975)).

However, during the study of the synthesis of the benzimidazole carbamates of Formula I,

Numerous of the intermediates of formulas V and IV are not yet known. These compounds, within the scope of the invention, may be described by the following general formulas (V ') and (IV'). rV \ I I

C = CH _O -C = C-CH 2.

²

R Z (E *)

(IV ')

in which

R ¹ represents a fluorine atom or a methyl group substituted by one or more halogen atoms, represents a halogen atom or a methyl group substituted by one or more halogen atoms, each of Z and Z ', which may be the same or different, represents a chlorine or bromine atom and

Each of R and R, which may be the same or different, represents a hydrogen atom or a methyl group.

Some of the compounds of formulas V 'and IV' may also be prepared by methods other than those described above. For example, those compounds in which R @ 1 is hydrogen and R @ ⁴ is methyl may be prepared by reacting the corresponding compounds in which Z is hydrogen with N-halimides (e.g., N-bromosuccinimide and the like) in the presence of radical promoters reaction.

As mentioned above, the compounds of the formula I are distinguished by a high anthelmintic activity and a broad spectrum of activity, which allows them to be used successfully in combating parasites in mammals and birds, for example domestic and breeding animals.

The compounds of formula I are effective against gastrointestinal parasites such as Ostertagia spec, Trichostrongylus spec, Strongyloides spec, Trichuris spec. Oesophagostomum spec, Chabertia spec, Nematodirus spec, Moniezia spec, Cooperia spec and Haemonchus spec, against broncho-pulmonary parasites such as Dictyocaulus spec, and pulmonary hepatic parasites such as Fasciola spec.

The latter combination of effects is very difficult to find in known anthelmintics. The broad spectrum of activity of the compounds of formula (I) is extremely important since it makes it possible to rid an infected animal by administering a compound of formula (I) simultaneously with gastrointestinal, hepatic and bronchopulmonary parasites.

The activity of the compounds according to the invention is determined by tests carried out on naturally infected sheep or, in the case of fluke (Fasciola), on artificially infected sheep.

The animals are divided into two groups. Animals from one of these groups are orally administered the test compound, while animals from the other group are left untreated as controls. Within 48 to 72 hours after treatment with the test compound, the faeces of the animals are collected and counted for the number of parasite or their eggs. The animals are then sacrificed and the extent to which the infestation was suppressed compared to that of the control animals is examined.

For use in veterinary medicine, the compounds of the invention may be administered to treated animals using conventional veterinary techniques and anthelmintic agents, namely orally in the form of boluses, tablets, suspensions and the like, by injection in the form of an injectable liquid or by spot absorption. .

It should be noted that the anthelmintically active compounds of the present invention, in contrast to known anthelmintics, have good solubility (up to about 20% by weight) in N-methyl-2-pyrrolidone, an injectable liquid used in veterinary medicine.

The doses of active substances to be administered depend on various factors, among which the weight of the animal to be treated, the nature and the severity of the infestation are important. Although suitable dosages are at the discretion of the veterinarian, they may range from 0.5 to 50 mg of the compound of formula I per kilogram of body weight of the host, preferably from 1 to 10 mg / kg.

For the treatment of small animals, only a few milligrams of anthelmintically active compound is required, while for the treatment of large animals such as cattle, sheep and the like, the active ingredient may be used in an amount of the order of one or several grams per animal.

In practice, the active ingredient is usually formulated into a formulation using a carrier or introduced directly into the animal feed. The active ingredient may be mixed or dispersed in any of the feed ingredients or may be used as boluses, tablets or capsules, beverages, suspensions, powders, pastes, saline licks, granules, pellets or feed premixes. The carrier may also be a pharmaceutically acceptable diluent or excipient usually used in the manufacture of dosage forms in human medicine. Easily available materials of this type are, for example, corn starch, kaolin, lactose, sucrose, calcium phosphate, gelatin, stearic acid, magnesium stearate, dextrin, agar, pectins, vegetable oils, carriers for injectable liquids such as propylene glycol, N-methyl-2 -pyrrolidone and the like

Optionally other active ingredients such as other anthelmintics, nutritional and mineral additives may also be included in the above compositions.

The method of application of the active agents can vary greatly and depends on the particular requirements.

With respect to anthelmintic activity, the preferred compounds of the invention are the corresponding thioderivatives (X = S) and sulfinyl derivatives (X = SO). Some of the compounds tested for

The anthelmintic activities consisted of mixtures of positional isomers (R different from R). However, the anthelmintic activity of individual formulas of different compositions was virtually unaffected by the relative ratio of the positional isomers (see Example 21).

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

Example 1

Preparation of 1,5,5-trichloro-3-methylhex-2-ene (A) and 1,5,5-trichloro-2-methylhex-2-ene (BJ (Mix No. 1)

The autoclave (type Pfaudler., 2.5 liter) is charged with 1200 ml under vacuum

1,1,1-trichloroethane, 500 ml of isoprene and 7,5-tris-ruthenium trifenylfosfindichloridu / Ru R ¹¹ (36H ^{5 3 P]} 2 ^l c /. O ^b is ^H and ^t o vu ^monastery pa ^k. Behind the ball ^hook it again to ⁹⁰ ° C. at theta ^t e ^pl of ^thee a ^No No ^P robíhat exothermic ^s rea ^for marking and ^t e ^p lo ^t and outp ^pi to ¹³⁰ ° C. Rea ^to CE NEC ^{hook P} rob ^IH and ^t for ^2, 5 hr while maintaining ny ^{and even} the ^pl Ota between. ¹²⁰ and ¹³⁰ ° C, NAM car ^KLA do not read cool to room te ^p lot. Rea ^CZK it was .zahus ^those from ^p and ^r tions for Reducing ^E it t ^ ^k at ⁽⁴⁰ ° C ^{/ 2,} 6, ⁷ mbar and the residue weighing about 800 g was diluted with 1,200 ml of petroleum ether to precipitate a ruthenium complex which quantitatively filtered off. the filtrate was again concentrated by evaporation and the residue was ^p o ^{d is running d} es ro ^t ILAC ^even sn ^iz it en ^é ^ ^PRICE em pressure ^Ps is ^d Eber vroud fraction ^{at 82-85} ° ^{C /} / 667 Pa. the yield was 690 g.

According to NMR spectra, this fraction consists of a mixture of compounds of the formulas below

A and B, in the ratio of about 85:15 c н ₃

CH ₃ - CC 12 -CH ₂ -C = CH-CH ₂ Cl (cis-trans) (A) (B)

CH ..

T-CC-C ^-C ^-C Cl (cis-trans)

Example 2

By analogy to Example 1, the following table 1 is given:

to give compounds or smmss. compounds,

Taboo 1 k and 1. R ^ _R v 1 | Compounds of formula C-CH; 1 1 -OC-CH 2 / 1 ² of ^r < ^{2 Z} ' Merge- "(A) Formula nina č. or mixture no. χ (d) СНз-СС12-СН2-С (СНз) = С ^н -СН2С1 (AND) СНз-а ^] _ 2 ^СН 2 ^{СН = С} (СНз) - СН ₂ С1 (B) 2 CF3-CBr2-CH2-C (C1-4CH-CH3r) (AND) CF3-CB? 2-CH2-CH = C (CH3) - _CH2-Br (B) 3 CP 1 -CFBr-C 1 -C (C 1 -C CH-CbBr (AND) CF 3 'CFBr - CH 2 --CH = C (CH 3) -C 1 Br (B) 4 СР ₂ С1-СС _{1 2} -СН ₂ -С (СН3) = СН-СН2 < Cl (A | CF ₂ C1-CC12 ~ CH2 ~ CH = C (CH3) -СН2 ' Cl (B) 5 CF ₂ Br-CH 2 -C (CH 3) = CH-CH ₂ Br (AND) CF ₂ Br-CH ₂ -CH = C (CH 3) -CH 3 Br (B) 6 CF ₂ Br-CH 2 -CH = CH-CH ₂ Br ^(e) 7 Ср3-С12-СН ₂ -С (СН3) = СН-СН ₂ С1 (AND) СР3-СС12-СН ₂ -СН = С (СN3) -СН _Э С1 (B) 8 CF 3 - CH ₂ -CH ₂ -C (CH 3) = CH-CH ₂ Cl (AND) СР3 _{СНС1-2-СН} -СН = С (СН3) -СН ₂ С1 (B) 9 CHCl ₂ -CH ₂ -C (CH 3) = CH-CH ₂ Cl (AND) CHCl ₂ -CH ₂ -CH = C (CH 3) -CH ₂ Cl (B) 10 CIlB4-Cl-CH3H-CH3r ^(g *

Defaults (b) Temperature of the fraction of the collected fraction (° C / Pa) Position isomer ratio (A / B) ^(C) СН3-СС13 + I 82 to 85/667 85:15 CF3-CB173 + 1 72/267 3 - 2 CF3 ^p CFBr ₂ + 1 62/667 1 - 1 СР ₂ С1-СС13 + I 90 to 95/933 1 - 1 CF ₂ B; ₂ + I 90/400 7: 3 CF + ^ + B CF3-CG3 + I 60/267 3 - 2 CF3-CHCl.Br + I 56/133 5: 2 mc ^ + 1 _(F) 2 - 1 CH B + + B 140/67

Table 1 continued

Compound Formula Starting materials Boiling point Position ratio C. or (b) removed isomers mixture no. fraction (° C / Pa) (A / B) ^> 1 1 CHBr CH -C (CH _Q = CH-CH? Br (AND) CHBr - + I 115/400 5: 2 CHBr ₂ -CH ₂ -CH = C (CH ₃ ) -CH ₂ Br (B) □ 12 CC1 ₃ -CH ₂ -CH = CH-CH ₂ Cl ^(g) CC1 ₄ + в 69/200 13 CBr ₃ -CH ₂ -CH = CH-CH ₂ Br ^(g) CBr ₄ + В 135/133 14 CH ₃ -CCl ₂ -CH ₂ -CH = CH-CH ₂ Cl ^(g) _{3-CH 3} CC1 + в 67/667 15, CF ₃ -CBr ₂ -CH ₂ -CH ₂ -CH = CH-CH ₂ Br (g> CF ₃ + ₃ -CBr в 75/400 16 (h) CCl ₃ -CH ₂ -C (CH ₃ ) = CH-CH ₂ Cl (AND) CC1. + I 61 to 63/133 9: 1 CCl ₃ -CH ₂ -CH = C (CH ₃ ) -CH ₂ Cl (B) 4 17 CBr ₃ -CH ₂ -C (CH ₃ ) = CH-CH ₂ Br CBr ₃ -CH ₂ -CH = C (CH ₃ ) -CH ₂ Br (AND) (B) CBr ₄ + 1 140 to 145/133 60:40

Legend:

(a) (b) (c) (d) (e) (f) (g) (h) a mixture of cis and trans isomers

I = isoprene (CH- = C-CH = CH-) _t

I ^CH 3

= = Butadiene (CH ₂ = CH-CH = CH ₂ ) approximate ratio determined by NMR spectroscopy The preparation of mixture No. 1 is described in Example 1 spectroscopic data of compound No. 6:

NMR: (deuterochloroform, tetramethylsilane as internal standard, ppm values):

3.1 (doublet of triplets, 2H, J _HH = 5.66 Hz, J _H = 12.8 Hz) 3.8 to 4 (multiplet, 2H),

5.3 to 6.3 (multiplet, 2H) mixture # 9 was isolated in pure state (by gas chromatography) as the residue after distillation of unreacted trichloromethane and isoprene from the crude reaction mixture NMR spectra consistent with the above structure analogous to that described by J. Tanaka et al. [Nippon Kagaku Zasshi 90, 803 (1969) J (100% isomer A).

Example 3

Preparation of 1,5,5,5-tetrachloro-3-methylpent-2-ene (A) and 1,5,5,5-tetrachloro-2-methylpent-2-ene (B) using a redox system which proceeds transmission of electrons

A 2.5 liter enamel autoclave was charged with 2. g of copper (II) chloride dihydrate, removed from the autoclave and introduced under vacuum: a solution of 3.65 g of n-butylamine in 300 ml of acetonitrile, a mixture of 600 ml of carbon tetrachloride and 300 ml. isoprene, and 200 ml of carbon tetrachloride. The autoclave was then heated to 90-130 ° C for 3 hours, maintaining the pressure inside the autoclave at 0.7 to 0.8 MPa by adding small amounts of isoprene from the pressure steel cylinder.

x

The autoclave was allowed to cool to room temperature, opened and the contents of the autoclave distilled under reduced pressure (ca. 2.67 kPa) to remove volatile components from the reaction mixture (isoprene, carbon tetrachloride and acetonitrile). The residue is then distilled under high vacuum, whereby all the distilling material is collected in a single fraction, which is then redistilled.

In this redistillation, a fraction boiling at 65 ° C / 173 Pa was collected. The weight of this fraction was 570 g.

The NMR spectrum shows that the fraction collected consists of a mixture of compounds A and V (purity by gas chromatography 97%) in a ratio of about 70:30. An analogous preparation has been described by P. Piccardi et al. '.Agric. and Food Chem. 25/5, 1073 (1977)].

Example 4

Preparation of 1,1,5-trichloro-3-methylpenta-1,3-diene (A) and 1,1,5-trichloro-4-methylpenta-1,3-diene (B) (reaction II)

200 g of the compound mixture prepared as described in Example 3 are dissolved in 240 ml of benzene and added to a solution of 162 g of sodium hydroxide in 210 g of water containing 1.2 g of tetrabutylammonium iodide. The reaction mixture was stirred vigorously at 25-30 ° C for 5 hours.

The organic layer was separated, the aqueous layer was neutralized with hydrochloric acid and extracted twice with 109 ml of diethyl ether. The organic phases are combined, dried over anhydrous sodium sulphate, the solvents are evaporated off under vacuum and the residue is subjected to distillation, collecting the fractions boiling at 50-52 ° C / 1 mmHg. According to the NMR spectrum, the collected fraction consists of a mixture of compounds A and V in a ratio of about 60:40 (purity according to gas chromatography 93%).

Example 5

СН _Э ^{1 3} ;

Preparation of 1,1-dichloro-4-methyl-5-bromopenta-1,3-diene (A) of formula CCl ₂ = CH-CH = C-CH ₂ fBr

In analogy to Example 1, 243 ml of carbon tetrachloride were reacted with 66 g of isopentene in the presence of 1.8 g of ruthenium-tris-triphenylphosphine dichloride. 45 g of 1,1,1,3-tetrachloro-4-methylpentane of the formula are obtained

CC1 _O -CH -CH-CH-CH.

2 . 3

I I

Cl CH ₃

The product thus obtained is dehydrohalogenated under reflux for 10 hours with 41.4 g of triethylamine in dimethylformamide. The reaction mixture was then poured into 100 ml of water and extracted with ethyl ether.

The organic solution was distilled to collect a fraction boiling at 44 ° C / 533 Pa consisting of 1,1-dichloro-4-methylpenta-1,3-diene. (The NMR spectrum corresponds to the expected structure СС1 _Э = СН-СН = С-СН-,).

^{2 3 CH} 3

16.3 g of the product thus obtained are dissolved in 50 ml of carbon tetrachloride and 19.3 g of N-bromosuccinimide are added to the solution in the presence of 100 mg of azobis-isobutyronitrile. The reaction mixture is refluxed for 8 hours, the succinimide is filtered off, the solvent is evaporated off under vacuum and the residue is subjected to distillation to remove the fractions boiling at 93 to 96 ° C / 267 Pa. Yield 14.6 g.

The NMR spectrum was consistent with the structure attributed to compound A.

Example 6

By analogy to Example 5, starting from 2,5-dimethylhexa-2,4-diene as starting material, 1-bromo-2,5-dimethylhexa-2,4-diene having the formula:

HQC CHoBr ³ \ / ²

C = CH-CH = C whose structure is confirmed by NMR spectrum.

Example?

Using the procedure analogous to Example 4, the compounds or mixtures of compounds shown in Table 2 below are prepared:

Table 2

Compounds of formula

c = ch-c = .c-ch ₂ z

Compound No. Formula (mixture - no. .) 18 * ^{* * C) *} CC = CH-C _(CH3) = CH-CH2C1 (AND) CCl 2 = C 1 -C -CH = C (CH ₃ ) 1 CH 2 Cl (B) 19 Dec CC 11. = CH-CH = CH-CH of 2 20 May CH-C-CH-C (CH = CH-CH_C1 3 i 3 z (AND) 1 ci CH ₃ -C = CH-CH = C (CH 3) -CH ₂ Cl (B) ¹ Cl 21 CF 3 -CF = CH-C (CH ₃ ) = CH-CH ₂ Br (AND) CF.-CF = CH-CH = C (CH ₃ ) -CH ₂ Br (B) 22nd CF ₃ -C = CH-C (CH ₃ ) = CH-CH ₂ Br (AND) AND Br CF ₀ -C = CH-CH = = (CCH / -CH ²⁾ (B) 1 Br 23 CCl ₂ = CH-CH = C (CH ₃ ) -CH ₂ Br 24 (CH 3) ₂ C = CH-CH = C (CH 3) -CH ₂ Br

Legend:

Starting materials (see Table 1) Boiling point of fraction collected (° C / Pa) Ratio of positional isomers (A / B) mixture of kladu 3 50 to 52/93 60:40 12 63/2 000 1 42 to 45/27 78:22 3 _ (d) 65:35 2 _(E) 80:20 _ (f) 93 to 95/267 _ (g) 85 to 86/1 600

(a) (b) (c) (d) mixture of cis- and trans-isomers approximate ratio determined by NMR speetroscopy The preparation described in Example 4 of Compound # 21 was decomposed at distillation;

mass spectrum (M ⁺ / e):

248 (10%), 246 (10%), 167 (80%), 147 (56%), 127 (60%), 69 (30%), 53 (100%) of Compound No 22 at dissociation decompose?

Potential with ^p ectruo ( ^{м + /} е): *

310 (8%), 308 (16Μ, 306 (8%), 229 (50%), 227 (50%), 148 (45%), 147 (90%),

127 (100%) (f) (g) Preparation of ^POPs on the ^IKA ACLU ^EXAMPLE 5 preparation described in Example 6th

Example 8

Preparation of 4- [(5,5-dichltr-3-2,4-oetylpenta diee-yl) 2-thitj nitrsanilinu (A) and 4 - ^[(5,5-d ichltr 2-OEt ^YIp Enta -2,4-L-diee ^Iy l) thit ^ J ^ -ni tanil-yne ^(B) (reaction II ^ X = S, R ⁵ - H)

A solution of 2.26 g (51 mmol) in 125 ml natrúuoborohydridu dioetyltromamidu solution of 10 g '(51.2 enol) 2 ^nitrs-4-yl hhikk anoal isoquinoline-ol in 25 d0metyfSormaoidu. The reaction mixture was stirred at room temperature for 1 hour and then 60 mol. Of products obtained as described in Example 3 were added.

The resultant ^a SOCS 1 hour ^also play V, ^{and 1} 00 ° C, is not read out ser ^ howling ije-ol 200 into the water. The aqueous extract is extracted three times with 100 l of chlorine each time, the organic extracts are combined and, after drying over anhydrous sodium sulphate, the solvent is evaporated off under vacuum.

11.9 g of crude product are obtained which, according to the NMR spectrum, is composed of compound II

A and B in a range of about 55:45, and which is sufficiently pure for the next reaction (Example 9).

Example 9

Preparation of 4 - [(5,5-Dichloro-3-oethylpenta-2,4-diin-1-yl) hiot-1,2-phenylenediamine

4- ^f (S ^ -dich ^ r - ^ - ^ oetyl nta- ^{2, 4} - п ^^ ^- 1 ^ 1 ^ 1 ° ^-1.2 - ^L ^ n ^ ^yl ^ n ^d n; ^ s of mill ⁽ B) (A) and (reaction VI)

11.7 g of crude product prepared by the procedure described in Example 8 were added. 200 [mu] l and 200 [mu] l of oleate containing 45 g of sodium dithisinacetate. The mixture was heated for 15 minutes at 80 ° C, after which the inorganic salts were filtered and the methanol was removed in vacuo. The residue is extracted three times with 100 l of chloroform each, the organic phases are separated and after drying over anhydrous sodium sulphate, the solvent is evaporated off. A brown, viscous oily residue is obtained which is obtained from products A and B at a ratio of about 55:45 (according to NMR spectrum).

injects into

The reaction of the SOEs ^d pa ^aí

Example 10

Preparation 5 (6) - [(5,5-Dichloro-3-oethylpenta-2,4-dien-1-yl) -benzoyl] benzioidazole-2-oethylcarbaoate (A) and 5 (6) -L (5,5- Dichloro-2-methyl-chloro-2,4-dien-llyl) this] benzioidazole-2-ontylcarbaoate (B) (reaction VII)

8.5 g (29.4%) of the crude oil obtained by the procedure described in Example 9 were dissolved in the salt. 35 l of water, 35 l of ethanol, 2 o of acetic acid and 6.05 (29.4 onol) of 1,3,1-benzo-methoxycarblyl-5-methacrylate (cyanates). The solid product precipitates, which is filtered and crystallized from an equal volume of chloroform and equal parts.

prig heats and pr242859

7 g of a mixture of compounds A and V in a ratio of about 55:45 (according to NMR spectrum), melting with decomposition at 169-170 ° C, is obtained.

Example 11

Preparation of 5 (6) - 35,5-dichloro-3-methylpentan-2,4-dienyl-1-sulfinyl] benzimidazole-2-methylcarbamate (A) and 5 (6) - [(5,5- dichloro-2-methylpenta-2,4-dien-1-yl) sulfinyl] benzimidazole-2-methylcarbamate (B) (reaction VIII)

To a solution of 4 g (10.7 mmol) of the product mixture obtained in Example 10 in 400 ml of chloroform, 200 ml of ethanol and 1.5 ml of acetic acid is added rapidly, with vigorous stirring, 10.1 mmol of 3-chloroperbenzoic acid, The reaction mixture was allowed to react for 1 hour at room temperature, then washed with aqueous sodium bicarbonate solution and washed successively with water until neutral pH. The organic solution was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo.

The oily residue was washed with methanol and ethyl ether, and the resulting solid material was recrystallized from methanol. There are obtained 3.5 g of a mixture of products A and V in a ratio of about 55:45, melting with decomposition at 134-135 ° C.

Example 12

Preparation of 4- [(5,6,6,6-tetrafluoro-3-methylhexa-2,4-dien-1-yl) thio] -2-nitroaniline (A) and 4-L (5,6,6,6) 6-tetrafluoro-2-methylhexa-2,4-dien-1-yl) thio) -2-nitroaniline (B) (reaction IV and V)

To a solution of 5 g (25.6 mmol) of 2-nitro-4-thiocyananiline in 15 ml of dimethylformamide at room temperature was added a solution of 10.5 g of sodium borohydride in 15 ml of dimethylformamide. The reaction mixture was stirred at room temperature for 1 hour, then 8.85 g (27 mmol) of mixture # 2 was added (see Table 1).

The resulting mixture was heated at 100 ° C for 1 hour, after cooling 4.9 ml (35 mmol) of triethylamine was added, the mixture was heated at 100 ° C for 2 hours, then cooled with 300 ml of water and extracted four times each time. 100 ml of chloroform. The organic phase is dried over anhydrous sodium sulphate, concentrated in vacuo and the residue is chromatographed on silica gel using a mixture of equal parts of ethyl ether and petroleum ether as eluent.

5.8 g of a red oily product consisting of a mixture of compounds A and V in a ratio of about 1: 1 (according to NMR spectrum) are obtained.

Example 13

Preparation of 4- (5,6,6,6-tetrafluoro-3-methylhexa-2,4-dien-1-yl) thio] -1,2-phenylenediamine (A) and 4-f (5,6,6,6,6-tetrafluoro-2,4-dien-1-yl) thio] - 6,6-Tetrafluoro-2-methylhexa-2,4-dien-1-yl) thio] -1,2-phenylenediamine (B) (Reaction VI)

Using the procedure described in Example 9, using 5.7 g of the 2-nitroaniline mixture obtained in Example 12, 4.6 g of a brightly colored oil consisting of a mixture of compounds A and V in a ratio of about 1: 1 (according to NMR spectrum) are obtained.

Example 14

Preparation of 5 (6) - E (5,6,6,6-Tetrafluoro-3-methylhexa-2,4-dien-1-yl) thio benzimidazole-2-methylcarbamate (A) and 5 (6) - [5] 6,6,6-tetrafluoro-2-methylhexa-2,4-dien-1-yl) thio] benzimidazole-2-methylcarbamate (B) (reaction VII)

4.6 g (1.5 mmol) of the compound mixture obtained as described in Example 13 are dissolved in a mixture of 20 ml of water, 20 ml of ethanol and 0.5 ml of acetic acid containing 3.1 g (1.5 mmol). 1,3-bis-methoxycarbonyl-5-methylisothiourea. The reaction mixture was heated under reflux for 2 hours and then allowed to cool. The precipitated solid material was filtered off and crystallized from a mixture of equal parts of methanol and chloroform to give 3.7 g of a 1: 1 mixture of Compounds A.A., m.p. 167-170 ° C.

Example 15

Preparation of 5 (6) - [(5,6,6,6-Tetrafluoro-3-methylhexa-2,4-dien-1-yl) sulfinyl] benzimidazole-2-methylcarbamate (A) and 5 (6) ) - [* (5,6,6,6-Tetrafluoro-3-methylhexa-2,4-dien-1-yl) sulfinyl] benzimidazole-2-methylcarbamate (B) (Reaction VIII)

Following the procedure described in Example 11, from 0.9 g (3.34 mmol) of the benzimidazole carbamate mixture obtained in Example 14, 0.95 g of a 1: 1 (by NMR spectrum) mixture of compounds A and V are obtained. at 147-149 ° C.

Example 16

Preparation of 4-f (5,5-dichloro-3-methylpenta-2,4-dien-1-yl) oxy] -2-nitroaniline (A) and 4 - [(5,5-dichloro-2-methylpenta-2) (4-dien-1-yl) oxyl] -2-nitroaniline (B) (reaction III, X = O, R ⁵ = CH ₃ CO)

A mixture of 10.2 g (52 mmol) of 3-nitro-4-acetaminophenol, 20 g of sodium carbonate, 11.12 g (60 mmol) of mixture No. 18 (see Table 2) and 60 ml of acetone is heated under reflux for 48 hours. under reflux. The reaction mixture was allowed to cool, the inorganic salts were filtered off and some of the solvent was evaporated. The crude product obtained after chromatography on silica gel using a mixture of equal parts of ethyl ether and petroleum ether as eluent gave 7.8 g of a brown crystalline solid, consisting of a mixture of compounds A and V in a ratio of about 3: 2 (according to NMR spectrum).

Example 17

Preparation of 4-f (5,5-dichloro-3-methylpenta-2,4-dien-1-yl) oxy] -1,2-phenylenediamine (A) and 4 - [(5,5-dichloro-2-methylpenta- 2,4-Dien-1-yl) oxy-1,2-phenylenediamine (B) (Reaction VI)

Using the procedure of Example 9, using 7.5 g of the compound mixture prepared as described in Example 16 as starting material, 6.2 g of a thick brown oil is obtained consisting of a mixture of compounds A and V in a ratio of about 3: 2.

l 6

Example 18

Preparation of 5 (6) -? (5, S-dichloro-S-methylpenta, 4-dienyl) oxy, benzimidazole-2-methylcarbamate (A) and 5 (6) - [(5,5-iichloro) -2-methylpenta-2,4-ditn-1-yl) oxybenzimidazole-2-methylcarbamate (B) (reaction VI)

To a solution of 6.2 g (22.7 mmol) of the product mixture obtained in Example 17 in 30 ml of water, 30 ml of ethanol and 0.8 ml of acetic acid was added 4.6 g. 3-bls-methoxy-cyclon-1-S-methylisothioureas. The reaction mixture was refluxed for 2 hours, then allowed to cool, the precipitated solid material was filtered off and crystallized from methanol / chloroform. 5.6 g of a mixture of compounds A and B in a ratio of about 3: 2 (according to NMR spectrum) ^of the temperature T ^and the ^183-185 ° C.

Example 19

Further benzimidazole carbamates of general formula (I) are summarized in Table 3 below, together with their chaacaketistic properties and methods of preparation.

N> 1

CA X X Ы - _v Honors honors Honors X WITH WITH with WITH OF OF of OF

what

X

kJ OT ω H X Honors Dí X X WITH WITH with with of of of of

1 0 1 o X < r — 1 Q 0 • <4 Ch Ό x: —- P O > φ • С2 G > P 0 0 Φ Ch X E

IA in

LIMB

1 'ua -í *

LA LA

UA «5ΤA in

UA vT

UA iA

ti o · at O r-i Ή Ch С j φ 'ti O Η P -

Ό ti

CM <HO cr <3 T rH NCM o

> N P> N titles

O c00 OLA

CACO — t rHCM> N ti σ> kD la un

c 'ti c 'ti in > > what  O O > > o ' O > N C C ti ti ti P p ’З · w ω cn OJ Φ rH C C

'ti> O> O c u ω Φ c

Compounds of general formula

Φ

TJ O Ch a

U ω

O Ch> o

J «J r-4

Μ> P

Ch

o r — I> N ti «5 *> NJ

OJ

CM

M 'N

CM

XI> 1 Xť u 'ti

About LA aa rH CM CM

what

CM το cn

UA

CQ

CQ

CQ

CJ CJ CJ CJ O CJ < < CJ CJ < H H < 1-1 H O O -and H X CQ H H X X O < CQ CQ 1 1 X X 1 1 CJ < H 1 1 O O 1 1 O O CQ < H CQ ω cn cn cn .cn ω cn cn 1 H CQ 1 1 1 1 1 1 1 1 1 cn CQ CM CM cm cm CM CM CM CM CN 1 1 0 O x X X X X X X X CM ω cn cn O O CJ CJ CJ CJ AND CJ CJ 1 X CM CM CM x X X X 1 x X X O m CJ m CJ what CJ C-· X CJ CJ O II X II X II X II X CJ 1 ' 1 O CJ CJ CJ II x x x what cn what what CJ at O x CJ X CJ X υ X CJ WHAT II II II at II CJ II CJ II CJ II X X X X x X X X CJ CJ CJ O at O CJ CJ O CJ CJ CJ X X x X x X X X X X X CJ I at CJ O CJ Ό CJ CJ CJ CJ CJ CJ X II II 11 II II II II II if II II CJ CM CM CM CM CM cm CM CM CN CM CN II i — 1 r-1 r — 1 r-l i — i r-l r-l P P P P CN at O. CJ O CJ at O X X X X X O O CJ O CJ CJ CJ CJ CJ CJ CJ CJ

1A kO

CM CM CM

ΟΟ

CC σ>

CC about cn co

CM CO

CF ₂ = CH-CH = C (CH ₃ ) -CH ₂ -S-BIAC

ω 0) of it O what N H X rH d CX CA 5 я with < of of • d Φ 1 6 0 r-ι ω - .0 · Η X CX Λ < μ и ~ O O > Ф>, M ' un g> - o 0 no O O cu kD un

O un o

un

KJ M (A я from un on un k0 o

un on un k0 o

«3 ·

About k0 un un oo

o ft > O o> CN he un 0 C-· M * kO r- oo ;> г — 1 г — 1 í — i T— < "Yeah 0 J - Д > N > N > N > N > N O (0 <d <OJ Ф <XJ (6 <—I Ή -—— · 4J tX C u (Л Г ' r- 00 un he o mJ o Ф ко properties Sp un kD oo E-i 4+ C * - < г — 1 f — 1 r — 1 ^1-1

un> N OJ 'T un

Φ r-1 · 'd > u o ÍX d cu Ό β d rH j ω 'rl O Λ ÍX

> N <TS

CN and «3 *> N tJ

CN

oo O <-1 > N > N β d k0 oo

CN on

M * on oo

CN

he

3 rt 3 X < 03 / < rt 3 X < m 2 rt O at O CJ O O at no < O O < < < < H H H H H H U <; H H what X H H rt rt CJ CJ rt rt CJ oo « AND 0 ( rt AND O AND < AND AND H 4! AND AND O O AND AND O H H X 03 / oa | H CQ | ω AND ω AND on I CO I oa I ω I CO I w I rt I X AND CN í (N O ω | CN CN <N he CN CN CN CN O O rt rt O X X X X rt rt rt rt AND AND CJ (J ω í at O CJ CJ CJ AT O O (N CN AND HE J AND AND 1 AND AND AND AND rt rt X ÍE CN X X rt. rt -in CJ CJ CJ m CJ OF CJ he o> m O he no he AND AND II rt AND CJ AND II X II X ' II X II rt X CJ W O at -TO CJ - at J he . he (j he he he he m II rt X CJ II W X υ CC at rt O rt O —К CJ υ II (j CJ II O II O II oj II he rt he X X rt rt rt CJ CJ O к CJ C? O CJ O at at oi O CJ II AND □ II AND AND AND AND AND AND AND AND rt X X X X X X rt X rt rt CJ CJ CJ O CJ O CJ at at at oj CJ CJ CJ AND AND II II | AND II II II II II II II E and rH w OF Ix IX ÍX ÍX w X rt ® CJ CJ CJ CJ CJ II CN no o f O AND CJ AND и I o í O I o I CJ 1 II CN II CN u I AT 1 I) f4 he he he he he he he he r — l •-AND he m | I ix Uo ÍX ÍK bf rt rt rt CJ υ rt rt AT O O oj CJ CJ no AT CJ (J O CJ CJ

he m «on he un on k £) (- · he on oo he on '1 f · (б N

(0 q X X WITH WITH of OF <О Я Ф i е 0 0 -N <Л - 0 -н Д. CU \ х: < м υ ~> ф '> 1 сП ш g> - <—1 гЧ 0 0 Ό х х; - Ш U0 00 00 'Т 00 rd U Р - о > ГЧ > N гЧ Ή χ— Ф <б леи ф чб о 00 00 Н Р - со Г ^1-1 е-1 — Г — 1 · тз> υ 0 СЦ 2 Ό CU Ф Р гЧ Р 44 ЧЧ ω м 0> Р Д съ гЧ

TJ Гб 1Л ш СЧ со гЧ со 00 44 (М см AND Д N гб О > N > N > гч > Ν <4 Р Oh oj (б Oh 44 СО СХ) _! 6 N 0 сч СО 00 Р о ГЧ сч гм о <—1 о гН > N (б > м ЧЧ Oh - 00 г-Н оо г — Г гН СО г-Ч гЧ • -Ч

no

>

сп со

СП

СО СЧ

ГЧ ^ г м ·

О СО

О го о сч> N <б u *> ΟΊ чч сл

СО оо сч о

> N fO

ГГО> N rd со

Lf

< д д < д о о no о < no < н нч no < н 1—! X д < н о no Д д 1 1 н д no < <3 1 сч сч д | no н ич no о о О О 1 о о < н д д < ω (Л ω со ω ω н д 1 1 н 1 1 1 1 1 AND н д ( сч сч д сч сч сч сч сч сч д 1 сч о о 1 Д д Д Л д д о О ω ω (Л О no О no о no ω ω ω 1 1 1 Ή rj 1 X 1 д 1 1 1 сч 1 сч 1 сч сч X сч X сч X чб no со no СО СО со д Д д no no о > (б II д II Д д д no О о 1 1 t о no no no no 1 1 1 X > о СО со д д д no СО СО (б д о д О ω no no о о II X X ц □ no II о II II II II II II ω о 44 ф д д д д д д X со 0 р no no о о о о о no о X no о Л 0 1 д 1 д 1 д 1 д 1 д д 1 д 1 д 1 X no II X II X > no о о no о ω о no no no no no II II II II II || II II II 1 1 со гЧ Г-Н г — 1 гЧ no о гЧ «—1 гЧ X X X о о о о сч сч no о no о о no о о no no - no no no II II II 1 1 1 1 со СО 1 1 1 сч сч сч со со со СО д д со со со i — 1 гЧ <б д X X д no о X д X no о no о о no no - ' no no no о no о 44 гЧ а > 0 л <б 44 гб Р Еч чб о »—1 сч СО ш со Г- ' 00 • ч * ЧТ ’З · чг м ·

mixture of cis- and trans-isomers of the compound respectively. mixtures 1 to 17 and 18 to 24 are shown in Table 1 and Table 1 respectively. in Table 2, the melting points are not corrected.

approximate ratio determined by NMR spectroscopy of the structure confirmed by the following methods:

Legend:

(a) (b) (c) (d) (e)

NMR = nuclear magnetic resonance spectroscopy

IC = infrared spectroscopy

HS = mass spectroscopy

EA = Elemental Analysis The product was prepared in a manner analogous to that described in Example 11, but using 2 equivalents of 3-chloroperbenzoic acid mixture 28/3 is described in Example 21.

Example 20

The anthelmintic activity of the compounds of formula I was tested as described above.

Substances No. 25, 26, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 39, 40, 44, 45, and 47 (see Table 3) were shown in a test on sheep infested with intestinal nematodes when administered at a dose of 5 mg / kg body weight as totally effective (90-100% infestation control).

In the test on fluke infested sheep (Fasciola), substances 28, 29, 35 and 40 proved to be totally effective (90-100% infestation control) when administered at a dose of 5 mg / kg body weight.

In the test on sheep infested with pulmonary disease (Dictyocaulus), substances 32 and 44 proved to be totally effective (90-100% infestation control) at 5 and 2.5 mg / kg body weight.

Example 21

This example illustrates the anthelmintic activity of mixtures of positional isomers of different compositions.

Compound No. 28 (see Table 3) is a mixture of Compound A and Compound B in an A / B ratio of 55:45. Compounds A and B have the following structure (A) cci ₂ = ch-c (ch ₃ ) = ch-ch ₂ -s

CCl ₂ = CH-CH = C (CH ₃ ) -CH ₂ -S

NH-COOCH ₃

NH-COOCH ₃

Compound No. 48 (see Table 3) consists of 100% Compound B.

The mixture consisting of compounds a and b, corresponding to the formulas below, in the ratio a / b = 75:25 (by NMR spectroscopy) is distilled under reduced pressure cci ₂ = c 1 -c (ch ₃ ) = ch-ch ₂ ci (a)

CC1 ₂ = CH-CH = C (CH ₃ ) -CH ₂ Cl (b)

The following fractions are removed:

Fraction no. Boiling point (° C / Pa) Composition a / b. (NMR) 1 50 to 54/67 90:10 2 54 to 57/67 80:20 3 57/67 70:30

The corresponding benzimidazole carbamates (28/1 and 28/3), having the following composition and properties, were independently prepared from fractions Nos. 1 and 3 as described in Examples 8-10.

compound 28/1 A / B = 90:10 (NMR) melting point 163-165 ° C compound 28/3 A / B = 70:30 (NMR) melting point 160-165 ° C «

Compounds No. 28, 28/1, 28/3 and 48 were separately tested for althelmintic activity on sheep infested with intestinal nematodes. The efficacy values obtained are given in Table 4 below, which is given on a scale of 0 to 4, where each value has the following meaning:

= 0 to 10% infestation suppression

1 = 11 to 25% suppression contamination 2 = 26 to 60% suppression contamination 3 = 61 to 90% suppression contamination 4 = 91 to 100% > suppression contamination

Table 4 Substance no. Ingredients (%) 28 A = 55, , В = 45 28/1 A = 90, , V = 10 28/3 A = 70, , в = 30 48 A = 0, , в = 100

Dose (mg / kg) Efficiency ♦ 5 4 5 4 5 4 2,5 ' 3

SUBJECT OF THE INVENTION

Claims (3)

SUBJECT OF THE INVENTION Process for the preparation of the benzimidazole carbamates of the general formula I (I) R is C 1 -C 4 alkyl, Each of R and R, which may be the same or different, represents a hydrogen atom, a halogen atom or a methyl group optionally substituted by one to three halogen atoms, each of the symbols R 1 and R 2 which may be the same or different represents an atom hydrogen or methyl; and X is oxygen, sulfur, SO or SO ₂ , characterized in that the compound of formula (II): 1 2 R and R are as defined above, and each of Z and Z ', which may be the same or different, is chlorine or bromine, reacted in an autoclave, in the presence of an electron transfer redox system, or a complex ruthenium compound, with a compound of formula III ch ₂ = cc = ch ₂ (III) in which they are as defined above, to give a compound of formula IV (IV) in which 12 3 4 R, R, R, R, Z and Z are as defined above, which are reacted with a 2-nitroaniline of formula VI 'in which: X is oxygen or sulfur, the resulting compound of formula VII wherein nh ₂ x-ch ₂ -c = R ⁴ R ¹ C-CH ² -CR ² AND, From '(VII') R ¹ , R ² , R 3, R ⁴ and Z are as defined above and are oxygen or sulfur are dehydrohalogenated in the presence of a base to form a compound of formula VII X-CH ₂ -C · c-ch = g (VII) in which R @ ¹ , R @ ² , R @ ³ and R ^{@ 4} have the meanings given above and are oxygen or sulfur which are reduced to the corresponding radicals; 1,3-phenylaidia, which, by reaction with 1,3-bis-alkoxycarbthiyl-S-methylStothyme, provides a compound of formula I wherein X is oxygen or sulfur, and which compound wherein X is sulfur is optionally reacted with a peracid tdpotídající converted to the compound of formula I wherein X is SO or S0 ₂ · 2. A process according to claim 1, wherein the following starting materials are used to form compounds of formula (I) in which: 3 4 R, R, R and X are as defined in 1a Each of R and R, which may be the same or different, represents a halogen atom or a methyl group optionally substituted by one to three halogen atoms. 3. The method of claim 1 vyznnačuící in that the tjijí tdpotídající ^a starting material, to give compounds of the formula I wherein 3 4 R, R, R and X are as defined in 1a Each of R and R, which may be the same or different, represents a hydrogen atom, a halogen atom or a methyl group, or a substituent of one to three halogen atoms, provided that at least one of the symbols 12- ' R and R represent a hydrogen atom;