DD147539A5 - PREPARATION OF BENZIMIDAZOLE CARBAMATES SUBSTITUTED IN 5 (6) POSITION - Google Patents

Abstract

The invention relates to a process for the preparation of benzimidazole carbamates substituted in 5 (6) for use in veterinary medicine for the control of parasites of the gastrointestinal tract, liver and bronchial lungs. According to the invention, substituted benzimidazole carbamates of the general formula I are prepared in the 5 (6) position, in which R is a C & ind1! -C &sub4; alkyl group; R & exp1! and R & exp2 !, which may be the same or different, are hydrogen or halogen atoms or a methyl group optionally substituted by one or more halogen atoms; R & exp3! and R & exp4 !, which may be the same or different, are hydrogen or halogen atoms or the methyl group, and X = O, S, SO or SO & ind2! mean.

Description

AP C 07 D / 217 56 603/18,

The invention relates to processes for the preparation of benzimidazole carbamates substituted in 5 (6) -position

The compounds prepared according to the invention are used in veterinary medicine for combating helminths in domestic and breeding animals.

Characteristic of the known technical solutions

Several benzimidazole carbamates which are differently substituted in the 5 (6) position and their antihelminthic effect are already known (compare, for example, DE-PA 2 029 and 2 164 690, PR-PS 1 556 824 and 2 052 983 and US Pat US-PS 3,010,968, 3,915,986 and 4,002,640).

Benzimidazole carbamates having activity against helminths have also been described in DE-PA 2 816 694 and 2 843 308 of the present Applicant.

 Many benzimidazole carbamates substituted at the 5 (6) position have also been commercialized, for example, albendazole, oxibendazole and parbendazole, phenbenedazole, oxphendazole, garbendazole and thiabendazole, and mebendazole.

Object of the invention

The object of the invention is to provide benzimidazo-1-carbamates which are substituted in 5 (6) with improved anti-helical hysteresis and a broad spectrum of effects,

21 7 33 1 -a 18.4.1980

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Explanation of the essence of the invention

The object of the invention is to introduce suitable substituents in the 5 (6) -position of benzimidazole carbamates.

According to the invention, new benzimidazole carbamates having improved helminth activity are prepared, in particular new benzimidazole carbamates which are substituted in the 5 (6) position by a diene chain which is attached to the 5 (6) position by an oxygen or sulfur atom, optionally can be oxidized.

Benzimidazole derivatives are in tautomeric forms such as

With regard to nomenclature, it has been agreed that substituent A, which is in the 5-position in a tautomeric form, occupies the .6-position in the other tautomeric form.

2 1 733 1 -Φ- 18.4.1980

, · AP C 07 D / 217

56 603/18

As a result, a benzimidazole derivative having a substituent in the position corresponding to the substituent A is usually defined as "5 (6) -substituted".

In accordance with the present invention, novel benzimidazole carbamates substituted in the 5 (6) position and the general formula I are now prepared

2 Λ Λ-

I i

H.

possess, in which

₁₄

1 2

R and R (which may be the same or different) are H, halogen or optionally substituted by one or more halogen atoms;

21 733 1 -f- 18.4.1980

AP C 07 D / 217. 331 56 603/18

R and R (may be the same or different) = H, Cl or CH-; and

X = 0, S, SO or SO ₂ .

The compounds of general formula I have one. surprisingly high antihelminthise 'efficacy and a broad spectrum of activity, which is effective both against parasites of the gastrointestinal tract and the bronchial lungs and against parasites of the liver of domestic and breeding animals.

Particularly valuable compounds of the formula I are those in which

1) R is a halogen atom, the methyl or trifluoromethyl

P group, R is a hydrogen or halogen atom or the

Methyl group, R ^ and R are hydrogen atoms or Lie thy 1 groups, wherein at least one of these substituents is a hydrogen atom, mean, and R and X have the meaning mentioned in formula I;

2) R, R, R, R and X have the meaning given under 1) and R is the methyl group;

21 73 3 1 ~ ™ ~ 18.4.1980

AP C 07 D / 217 331 56 603/1 8

3) R and R are halogeners, X is the formula I

has the meaning given, while the remaining substituents have the meaning given under 2);

4) R ¹ = R ² = Cl, R ³ = R ⁴ = H and X = S;

5) R ¹ = R ² = Cl, R ³ = R ⁴ = H and X = SO;

6) R ¹ = R ² = Cl, R ³ = R ⁴ = H and X = SO;

7) R = R = Cl, R and R, which are different from each other, = H, CH, and X = O;

8) R = R = Cl, R ^ and R, which are different from each other, = H, CHo and. X = S are;

9) R = R = Cl, R and R, which are different from each other, = H, CH- and X = SO;

10) R = R = Cl, R and R, which are different from each other = H, CH ₃ and X = SO ₂ ;

11) R = R = Br, R and R, which are different from each other

are, = H, CHo and X = S are; 1 2 3 4

12) R = R = Br, R and R, which are different from each other

are, = H, CH ₃ and X = SO;

21733 1 -14- 18.4.1980

AP C 07 D / 217 331 56 603/18. ,

13) R = R '= I ¹ »R and R, which are different from each other, = H, CH ₃ and X = S;

14) R = R = F, R and R, which are different from each other, = H, CH ₃ and X = SO;

15) R ¹ = CF ₃ , and R ² = H, are halogen, X has the meaning given in formula I and the other substituents have the meaning given under 2);

16) R ¹ = CF ₃ , R ² = H, R ³ and R ⁴ , which are different from each other, = H, CH., And X = S;

17) R ¹ = CF ₃ , R ² = H, R ³ and R ⁴ , which are different from each other, = H, CH ₃ and X = SO;

18) R = CF ₃ , R = F, R ³ and R ⁴ , which are different from each other, = H, CH ₃ and X = S;

19) R = CF ₃ , R = F, R ³ and R ⁴ , which are different from each other, = H, CH ₃ and X = SO;

20) R ¹ = CH ₃ and R ² = H or halogen, X has the meaning given in formula I and the remaining substituents have the meaning given under 2);

21) R ¹ = CH ₃ ,. R ² = Cl, R ³ = R ⁴ = H * and X = S;

22) R ¹ = CH ₃ , 'R ² = Cl, R ³ = R ⁴ = H and X = SO;

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AP C 07 D / 217 331 56 603/18

23) R ¹ = CH ₃ , R ² = Cl, R ³ = R ⁴ = H and X = SO ₂ ; ,

24) R ¹ = CH- ,, R ² = Cl, - Ir and R, which are -from each other

./.

are different, = H, CH ₃ and X = S are;

25) R ¹ = CH ₃ , R ² = Cl, R ³ and R ⁴ , which are different from each other, = H, CH_ and X = SQ;

26) R ¹ = CH ₃ , R = Cl, R ³ and R, which are different from each other, = H, CH ₀ and X = SO ₂ ;

27) R ¹ =. R is CH ₃ , X has the meaning given in formula I and the remaining substituents have the meaning given under 2);

28) R ¹ = R ² = R ⁴ = CH ₃ , R ³ = H and X = S;

29) R ¹ = R ² = R ⁴ = CH ₃ , R ³ = H and X = SO;

Furthermore, the following compounds have antihelminthic activity: special significance:

30) compounds of general formula II

"1·. R ³ R ⁴

R ²

C-GH ₂ -C = C-CH ₂ Z (II)

21733 1 - ^ - '18.4.1980

AP G 07 D / 217 331 56 603/18 ι

11

wherein R = F or one through one or more

Halogen atoms substituted methyl group,

2 »R = halogen, or one by one or more

Halogen atoms substituted methyl group,

3 4 • R and R, which are the same or different

can, = H, CH ^> and

Z and Z ', which may be the same or different,

= .CI or Br;

31) Compounds according to 30) of the formula

CP-CBr ₂ -CH ₂ -G = G-CH ₂ Br

3 4

wherein R and R, which are different from each other,

a hydrogen atom or the methyl group;

32) Compounds according to 30) of the formula

r3 r4

CF ₃ -CFBr-CH ₂ -C = C-CH ₂ Br

wherein R and R, which are different from each other, represent a hydrogen atom or the methyl group;

33) Compounds according to 30) of the formula

Ϋ ? *

ΟΡ, ΟΙ-OOlp-CH-O. = 0-0H ₀ Ol

v / orin R and R _t v / mo which are different from each other, represent a hydrogen atom or the methyl group;

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34) Compounds according to 30) of the formula

OP ₃ -GCl ₂ -GH ₂ -C = C-CH ₂ Cl '

wherein R and R-, which are different from each other, represent a hydrogen atom or the methyl group ";

35) Compounds according to 30) of the formula

CP ₂ Br-CH ₂ -C =C-CH ₂ Br

wherein R and R, which are different from each other, represent a hydrogen atom or the methyl group;

36) Compound according to 30) of the formula CP ₂ Br - CH ₂ - CH = CH - CH ₂ Br;

37) Compound according to 30) of the formula CP ₃ -CBr ₂ -CH ₂ -CH = CH-CH ₂ Br;

38) Compounds of the general formula III

R ¹

2 R ^

worm

C = CII-C = C-CH ₂ -Z (III)

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AP C 07 D / 217 331 56 603/18

1 '

R = P or a methyl group substituted by one or more halogen atoms,

2 «R. a halogen atom or by one or more

R and R, which may be the same or different,

Halogen atoms substituted methyl group, R and R, which are the same or ver = H, CH ₃ and Z = Cl or Br;

39) Compounds according to 38) of the formula

4 R ⁴ Cly - CF = CH - C = C - CHpBr

wherein

R and R, which are different from each other, represent a Y / as s st off atom or the methyl group;

40) Compounds according to 38) of the formula

B? R ⁴ CF ₃ -CBr = CH-C = C-CH ₂ Br

wherein

R and R, which are different from each other, represent a hydrogen atom or the methyl group;

The synthesis of the compounds of the general formula I is carried out by simple process steps, which emerge from the reaction scheme below

12 3 '4 (wherein R, R, R, R and R are those in connection with

of the general formula I, Z and Z ^{ = Cl or Br; and R ⁵ = H or CH ₃ CO):

2 1733

ΛΑ

- 3r6

R ¹ ZR ³ R ⁴

rl Zi it rl

I) C- (A) ₊ CH = C - 'C = CH (B)

R Z

3 "4

ι r

a / I

RZ

C-CH-C = C-CH Z (C)

R ¹ * R ³ R ⁴

Bases \

II) C> -> C = CH-C = C-CH-Z (C) + HZ

NH-R '

in) C ₊ IO! ^N0 2

NH I ²

2 (E) ₊ NaZ

X Na

(X = O, S)

X-Y

R ³ R ⁴

(Y = ^ C = CH-C = C-CH ₀ -)

2 /

IV) C ₊ D

NO.

  »

(E ·) + NaZ 1

R ³ R ⁴

x-y · \ Il

(Y · = C-CH-C = C-CH ₀ -)

2 / I

R Z '

2173

VI) ₈ - ^ i "vrär" V (F) middle k ^

X-Y

VII) F + N = C - NH - COOR - ^ (I) £ "X = 0, S_7

COOR

VIII) I ZTX = S J --- - * + (I) ZJX = SO, SG _7

The first section of the reaction scheme for the preparation of the compounds of formula I (reaction I), i. the reaction between a compound of the general formula

12

£ where R and R are related to

of the general formula I, and Z and Z '(which can be identical or different) denote Cl or Br and a diene of the general formula

f f 3 /

CHp = C C = CHp [where R and R are related '

With the general formula I, meanings are given by "J is free radical intermediates in the presence of suitable catalysts, such as redox transition systems, for example, copper salts and amines, as described in J. Chem. Soc. (London) 1963, page I887, or in the presence of ruthenium complexes, as described more recently in Chemistry Letters, page 115 (1978) for the reaction between CCl ¹ ₊ C (A), R ¹ = R ² = Z = Z ^t = ClJ and isoprene

2 1 733 I

CH ₂ = C CH = CH ₂ [(B), R ^ = CH ₃ , R = H3 in the presence of

Dichloro-tris-triphenyl-phosphine-ruthenium (Ru ¹¹ [P (C ₆ H ₅ ), O ₃ Cl ₂ ] described.

It is important to point out that the implementation I both in the presence of in the presence of. Redox transition systems as well as when carried out in the presence of ruthenium complexes with respect to the substitution site is not selective, therefore, when in the compound B of the substituent ^ of R is different, also mixtures of positional isomers in addition to mixtures of cis-trans isomers due to the presence of the double bond to be obtained.

For example, starting from CCl ₂ . and isoprene, mixtures of the following compounds: CH CH_

CCl-CH-C = CH-CH Cl CCl-CH-CH = C - CH Cl ₀ 3 2 2 3 2 2

ZT (C ¹ ), R ¹ = R ² = Z = Z '= C1; R ³ = CH, R ⁴ = H and R ³ = H, R ⁴ = CH

In general, the mixture of the position isomers can be separated into the individual isomers by fractional distillation.

The compounds of the formula C or C are then reacted with the sodium salt of 2-nitro-4-hydroxyaniline (sodium phenate) [(D), X = O, R ⁵ = HJ or of 2-nitro-iJ-mercapto-aniline ( Sodium mercaptate) [(D), X = S ,. R-Hj reacted according to reactions III and IV.

In some cases, it is preferred to protect the amino group of the compounds (D) by acetylation, starting from the corresponding N-acetylanilines [(P), R-CH.CQ3.

21733 1

After the more convenient process step, the acetyl group can then be easily removed by hydrolysis.

In this way, the nitroanilines of the formulas ¹ E or E ¹ are obtained. The latter, when treated with bases, undergo dehydrohalogenation on their side chain (XY ¹ ) in position 4 with respect to the amino group to give the nitroaniline designated by the letter E (reaction V).

The nitroaniline E is then reduced, for example with sodium hydrosulfite (NapSpOj,) to give the phenylenediamine P (reaction VI).

The phenylenediamine P is then reacted with 1,3-bis-alkoxycarbonyl · S-methylisourea to give the benzimidazole carbamates of general formula I wherein X = O or X = S (Reaction VII).

By reacting the phenylenediamine F with 1,3-bis-methoxy

 ihi'o

carbonyl-S-methyl-isourea, the compounds of general formula I are obtained in which R is the methyl group.

Similarly, reaction of a phenylenediamine F with 1,3-bisethoxycarbonyl-S-methylisourea or 1,3-bis-propoxycarbonyl-S-methylisourea or 1,3-bis-butoxycarbonyl-S-methyl- isothiourea benzimidazole carbamates of general formula I where R is either the ethyl, propyl or butyl group,

Finally, starting from the benzimidazole carbamates of general formula I in which X is S, it is possible to obtain, by ¹ oxidation with peracids, the compounds of general formula I in which X 1 = SO or SO ₂ (reaction VIII) ,

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The reaction VIII is conveniently carried out by dissolving the benzimidazole carbamate I (where X = S) in an inert solvent (or in a mixture of inert solvents) and at a temperature of from -30 C to room temperature a peracid such as e.g. · B. Peracetic acid, perbenzoic acid or 3-chloro-perbenzoic acid, admits.

If the thio group is to be converted to its corresponding sulfinyl group, equimolar amounts of peracids are used. On the other hand, an excess of peracid is used if the thio group is to be converted into its corresponding sulfonyl group, or the sulf-inyl group into its corresponding sulfonyl group.

Examples of compounds of general formula A.

Rl Z

are the following

CHBr ₃ , CHCl ₃ , CBr ₄ , CCl ₄ , CH ₃ -CCl ₃ , CH ₃ -CHCl ₂ , CF ₃ -CHBr ₂ ,

CF ₃ -CHClBr, CF ₃ -CPBr ₂ , CF ₃ -CCl ₃ , CF ₂ Cl-CFCl ₂ , CF ₃ -CBr ₃ ,

CF ₂ Br ₂₇ CF ₂ Cl-CCl ₃ ^ CF ₃ -CBr ₂ -CF ₃ CH ₃ -CClBr-CH.

Examples of compounds of the general formula B

Ϋ t

CH ₂ = CC = CH ₂ (B)

are the following

CH, Cl CH? CH.,

I] J

ι] J

CH ₉ = C-CH = CH ₉ , CH ₉ = CH-CH = CH ₉ , CH ₉ = C-GH = CH ₉ , CH ₉ = CC = CH ₉ ,

^ Cl Cl

I i

CH ₉ = C """ ¹ C = CH ₉ .

21733 1 - "-

Some of the compounds designated by the letters C and C in Reaction Scheme 1 are known, such as the aforementioned adduct of carbon tetrachloride and isoprene or l-bromo-hexa-2,4-diene (sorbyl bromide) of the formula CH ₅ -CH = CH- CH = CH-CH ₂ Br or 5-chloro-l, 3-pentadiene of the formula

CH ₂ = CH-Ch = CH-CH ₂ Cl

which are described in SU-PS 472 926 (see Chemical Abstract, Bd, 83, ref 78559 x (1975).

In the course of the experiments carried out in connection with the synthesis of the benzimidazole carbamates of the general formula I, however, it was found that many of the intermediates designated by the letters C and C in Reaction Scheme 1 are hitherto unknown compounds, therefore the compounds of the following general formula ?! Another object of the present invention are: R ¹ R ³ R ⁴

C-CH ₂ -C = C-CH ₂ Z (II) _and

"I

C = CH-C = C-CH Z (III)

wherein the substituents have the following meanings:

1 ^f R = F or one with one or more halogen atoms

substituted methyl group,

R = halogen or a methyl group substituted with one or more halogen atoms, Z and Z '(which may be the same or different) = Cl

or Br, and

3 4 ^; " ^K "

R and R (which may be the same or different)

H or CH ₃ .

21 733 1 -22- 18.4.1980

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Some of the compounds of general formulas II and III can also be prepared by other processes.

• 3

For example, compounds where R = H,

and R = OH-, are prepared by reacting the corresponding compounds wherein Z = H with N-haloimides, such as. B. II-bromo-succinimide) in the presence of radical reaction promoters.

As already mentioned above, the compounds of the general formula I have a high activity towards: helminths and a broad spectrum of activity; these properties allow successful control of helminth infestation of mammals and birds, such. B. domestic and breeding animals.

Compounds of general formula I are active against gastrointestinal parasites such as Ostertagia spp., Trichostrongylus spp., Strongyloides spp., Trichuris spp., Oesophagostum SPP. Chabertia spp., IJematodirus spp., Ivloniezia spp., Copperia spp., Haernonchus spp., To parasites of the bronchi and lungs, e.g. Dictyocaulus spp. as well as against parasites of the liver, such as. B. Fasciola spp.

The latter property is rarely found in known helminths. The broad field of activity of the compounds I is an important property because the administration of the same to affected animals brings about simultaneous liberation of the animal from parasites of the gastrointestinal tract, liver and bronchial lungs. Compounds of Formula I have been effective against other infarct parasites of the order filarioidea, including brughia pahangi B and Dirofilaria immitis D,

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The activity of the compounds according to the invention was determined in experiments carried out on naturally infected sheep or in the case of Fasciola, on sheep with an artificially induced infestation.

The animals were divided into two groups, one of which (orally) was treated with one dose of the product to be tested, while the other untreated group was used as a control. During 48 to 72 hours after treatment with the compound to be tested, the excrements of the animals were collected to determine the number of parasites or eggs; thereafter, the animals were sacrificed to determine the reduction in infestation compared to the control group. "

For veterinary use, the administration of the connective stomach according to the invention to the animals to be treated may be effected in accordance with the usual veterinary methods for the treatment with antihelminthic agents, namely orally in the form of e.g. Pills, tablets or suspensions, injectable injections or skin absorption (spot on).

It is important to note that the helminth-active compounds of the present invention, unlike known helminths, have good solubility (at about 20% by weight) in H-ethyl-2-pyrrolidone injectable liquid used in the veterinary field. The quantities to be administered depend on several factors, among which are the most important: the weight of the animal to be treated, the species and the severity of the infestation.Suitable doses are up to the veterinarian, but they can range from 0.5 to 100 mg

2.1 73 3 1 - ** -. 18.4.1-980

AP C 07 D / 217 331 56 603/18 ·

the compound of formula I per kg of body weight of the host, preferably 1 to 10 mg / kg.

Small animals require only amounts of a few rags of the antihelminthic drug, while large animals such. B. cattle or sheep, may require quantities of the order of grams per animal.

In practice, the active ingredient is usually formulated with a vehicle (carrier) for veterinary use or directly in animal feed. The active ingredient may be incorporated in or dispersed in one of the components of the putter or in the form of: pills, easily ingestible tablets, capsules,. in the potions, as suspensions, powders, pastes, leaking salt, salt blocks, granules, pellets, and used as feed premixes. The carrier can also be a pharmaceutical excipient or excipient of the type generally used in the formulation of medicaments. Easily accessible products are, for example, corn starch, kaolin, lactose, sucrose, calcium phosphate, gelatin, stearic acid, magnesium stearate, dextrin, agar, pectins, vegetable oils, injectable liquid carriers, such as. For example, propylene glycol and H-LIethy1-2-pyrrolidone. Optionally, other .Wirkstoffe such. For example, other antihelminthics, feed additives and mineral additives can be incorporated.

The administration can be varied considerably and depends on the specific requirements.

Zo

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With respect to antihelminthic activity, preferred compounds are the thio derivatives (X = S) and sulphinyl derivatives (X = SO).

Some samples tested for their antihelminthic efficacy were mixtures of positional isomers (R x different from R).

However, the antihelminthic activity of samples of different composition is practically unaffected by the ratio of the respective positional isomers (cf * Example 21).

Embodiment. '

The following examples serve to explain the invention in more detail.

EXAMPLE 1 '

Preparation of 1, 5> 5-trichloro -3-methylhex-2-ene (A)

and 1, 5, S-trichloro ^ -met hylhex - ^ - en _ (3) _ ^ Gemi sch IT r. 1)

The following compounds were placed under vacuum in an autoclave (type Pfaudler) with a capacity of 2.5 l: 1,1,1-trichloroethane (CH ₃ -CCl ₃ ) 1200 ml

CH ₃ isoprene (CH ₀ = C-CH = CH ₀ ) 500 ml

TT -

Rutlienium tris-triphenylphosphine dichloride Ru L ^^ r ^ 7.5 g. ,

The autoclave contents were then stirred and heated to 90 ° C. At this temperature, an exothermic reaction began, with the temperature rising to 130 ° C.

2 / ί

2 1 73 3 1 - 26 -

The reaction was continued for .2.5 hours, while the temperature was 120-130 ⁰ C held; then the autoclave was allowed to cool to room temperature, the reaction mixture was concentrated by evaporation under reduced pressure (26 mbar, 40 ° C). The residue of about 800 g was diluted with 1200 ml of petroleum ether. The ruthenium complex precipitated and was quantitatively filtered off. The filtrate was concentrated again by evaporation and the residue was distilled under reduced pressure. The fraction boiling between 82 and 85 C at 6.6 mbar was collected (690 g).

Nuclear Magnetic Resonance (NMR-J analysis showed that the fraction collected was a mixture of the following compounds A and B in the ratio of about 85:15:

^CH 3

CH - CCl - CH - C = CH - CH Cl (A)

ij ti L ·, Ct

(ice-trans) CH

C (cis-trans)

CH - CCl. - CH - CH. = C - CH.Cl (B)

EXAMPLE 2

By proceeding in a manner analogous to Example 1, the compounds or mixtures of compounds listed in Table 1 below were obtained.

, "ic.

table

v ₍

3 R

Compounds of the formula ^ c-CH-C = C-CH Z

Compound (or mixture)

formula

(A)

Home (b) products

Kp of the fraction of the position: (C / mbar) isomeric (c

(FROM)

(D)

CH ₃ -CC1 ₂ -CH ₂ -C (CH ₃₎ = CH-CH ₂ CH C1 ₃ -CCl ₂ -CH ₂ -CH = C (CH ₃₎ -CH ₂ Cl

_(B) CH ₃ -CCl ₃ +1.

82-85 / 6.6

85:15

CF-CBr-CH-C (CH J = CH-CH Br CF-CBr-CH-CH = C (CH) -CH Br

CF ₃ -CBr ₃

72 / 2.6

3: 2

CF ₃ -CFBr-CH ₂ -C (CH ₃ ) = CH-CH ₂ Br CF -CFBr-CH-CH = C (CH) -CH Br

O C- O j £ -

(B)

, CF ₃ -CFBr ₂ + I. 62 / 6,6

1: 1

CF ₀ Cl-CCl ₀ -CH ₀ -C (CH) = CH-CH Cl CF Cl -ClC-CH-CH = C (CH) -CH Cl

2C., C., <3 c-

₂ ci-cci ₃ + ι. 90-95 / 9.3

1: 1

CF Br-CH-C (CHJ = CH-CH Br CF ₂ Br-CH ₂ -CH = C (CIi ₃ ) -CH ₃ Br

CFpBr ₂ + I.

90 / 3.9

7: 3

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.21 73 31 - *

(a) Mixture of cis and trans isomers

CH ₃

(b) I = isoprene (CH ₂ = C-CH = CH ₂ ), B = butadiene (CH ₂ = CH-CH = CH ₂ )

(c) approximate ratio, determined by NMR spectroscopy

(d) The preparation of the mixture No. 1 is described in Example 1

(e) Spectroscopic Data of Compound No. 6:

NMR (solvent CDCl ,, internal standard TMS) S _t ppm:

3.1 (dt, 2H, J _HH = 5.66 Hz, J _{H p} = 12.8 Hz) 3.8-4 (m, 2H)

5.3-6.3 (m, 2H)

(d.t. - * doublet of triplet, m = multiplet, J = coupling constant)

(f) The mixture No. 9 was isolated as a residue after distillation from the crude reaction mixture of unreacted CH 2 Cl 2 and isoprene in pure form (gas liquid chromatography).

(g) The NMR spectroscopic data were in agreement with the assigned structure.

(h) An analogous preparation was described by J. Tanaka et al in Nippon Kagaku Zasshi, vol. 90, p. 803 (1969) (100 % isomer A _p ).

- '"to.

1 --54 -

EXAMPLE 3

Preparation of 1,5 ₎ 5,5-tetrachloro-3-methyl "P6nt-2-ene (A) and 1,5j5> 5 ~ tetrachloro-2-m-ethyl-pent-2-ene (B) by redox Transition catalyst .

2g CuCIp. 2HpO were placed in an enamelled autoclave with a capacity of 2.5 liters.

The air was removed from the autoclave and the following compounds were introduced under vacuum:

a solution of n-butyl-amine (n-CnHq-N) (3.65 g) in 300 ml acetonitrile (CH ₃ CN)

a mixture of 600 ml of carbon tetrachloride and 300 ml of isoprene

- 200 ml of carbon tetrachloride.

The autoclave was then within 3 hours at 90 - heated 130 ⁰ C, the inner pressure was maintained by addition of small amounts of isoprene from a small gas bottle to 7-8 bar.

The autoclave was then allowed to cool to room temperature and opened. The autoclave contents were distilled under reduced pressure (about 26 mbar) to remove the volatile components from the reaction mixture (isoprene, CCl j, and CH 2 CN). The residue was distilled under high vacuum to provide all distilled material was collected in a single fraction, which was then again distilled to obtain, caught fraction (570 g), which boiled at 65 ⁰ C (1.7 mbar). An NMR analysis showed that the collected fraction was a mixture of Compound A and B (purity determined by gas-chromatographic chromatography: 97 %) in a ratio of about 7Q-: 30. An analogous preparation was described by P. Piccardi et al. in Agric. and Food Chem., Vol. 25/5, p. 1073 (1977).

2 1733 \

EXAMPLE

Preparation of 1,1 _> 5-trichloro-3-methyl-penta-1,3-diene (A) and of 1,1,5-trichloro-J-methyl-penta-1,3-diene (B ) [Reaction II]

200 g of the mixture, the preparation of which was described in Example 3, were dissolved in 240 ml of benzene. The solution was added to a solution of 1β2 g of NaOH in 210 g of H 2 O in the presence of 1.2 g of tetrabutylammonium iodide (nC 2 H 2 O 3). The reaction mixture was kept under intensive stirring for 5 hours at 25 to 30 ⁰ C.

The organic layer was separated and the aqueous layer, after neutralization with hydrochloric acid, was extracted with 2 portions of diethyl ether of 100 ml each. The organic phases were reunited and dehydrated with anhydrous Na ₂ SO ₄ . The solvents were evaporated in vacuo. The residue was distilled and the fraction which boiled at 50-52 ° C (0.9 mbar) was collected. An NMR analysis showed that the collected fraction was a mixture of compound A and B in the ratio of about 60:40 (purity according to gas-liquid chromatography: 93 %).

EXAMPLE 5

Preparation of 1,1-dichloro-methyl-S-bromo-penta-1,3-diene

CCl ₀ = GH-CH = C-CH Br (A) 2 J d

^CH 3

18 - .53 - -

After an analogous Ver described in Example 1

243 ml of CCl _{11 were added} to 66 g of isopentene CH ₂ -CH-CH (CH ₃ ) ₂ in the presence of 1: 8 g of Ru ^{i: C} [where 45 g of oil were used

CCl-CH-CH-CH-CH

3 2! j 3

Cl CH ₃

received. The product thus obtained was treated by treatment with ή 1,1 ». g (C ₂ H ₅ ) N in DMF dehydrohalogenated at reflux temperature for 10 hours. The reaction mixture was then poured into 100 ml of water and extracted with ethyl ether.

The organic solution was distilled and the fraction boiling at 4 ¹ JC (5j3 mbar) consisting of 1, 1-dichloro-4-methyl-penta-1,3-diene was collected. The NMR spectrum was consistent with the attributed structure

CCl = CH-CH = C-CH.

2 j 3

match.

16.3 g of the product thus obtained were dissolved in 50 ml of CCl ₁ . dissolved and treated with 19.3 g of N-bromosuccinimide in the presence of 100 mg of azobis-isobutyronitrile. The reaction mixture was refluxed for 8 hours. The succinimide was filtered off, the solvent removed under vacuum and the residue was distilled.

The fraction boiling at 93 ~ 96 C / 2.6 mbar (14.6 g) was collected. The NMR data were consistent with the structure attributed to Compound A. .,

217331 -j * -

EXAMPLE 6

Following the procedure of Example 5, starting from 2,5-dimethyl-hexa-2, ^J-i dienjdie compound l-bromo-2,5-

dimethyl-hexa-2 ^,! L-dien of the formula

HC CHBr

H ₃ C

receive; the NMR data agreed with the assigned structure.

EXAMPLE 7

A procedure analogous to the procedure of Example ¹ J was used to prepare the compounds (or mixtures of compounds) listed in Table 2 below:

TABLE

Compounds of the formula ι

3 4

C-CH-C - C-CH Z 2

Compound (mixture)

.No.

formula

(A)

Starting products (see Table 1)

Boiling point the ratio of

Trapped position V'v

Fraction isomeric ^

( ^o C / mbar) (A / B)

18 ^(c) CCl -CH-C (CH J-CH-CHCl 2 3 2 CCl-CH-CH-C (CH J-CH Cl 2 3 2 (A) (B) Mixture of & $ ps.3 50-52 / 0.9 60:40 19 CCl-CH-CH-CH-CHCl 12 63/20 20 CH-C-CH-C (CH J-CH-CHCl 3 1 3 2 Cl CH -C-CH-CH-C (CH J-CH Cl 3 1 3 2 Cl (A) (B) 1 42-45 / 0.26 78:22 21 CF -CF-CH-C (CH J-CH-CH Br 3 3 2 CF -CF-CH-CH-C (CH J-CH Br 3 3 2 (A) (B) 3 . "> 65:35 22 CF -C -CH-C (CH J-CH-CH Br 3 1 3 2 Br CF -C-CH-CHi-C (CH J-CH Br 3 1 3 2 Br (A) (B) 2 Je) 80:20 23 · CCl -CH-CH-C (CH J-CH Br 2 3 2 -cf) 93-95 / 2.6 24 (CH 1 CH-CH-CH-C (CH 3 -CHbr 3 2 3 2 Je) 85-86 / 16th

2173 3 1 -χ-

Note:

(a) Gemi-sch of cis and trans isomers.

(b) approximate ratio, determined by NMR spectroscopy.

(e) The preparation is described in Example 4.

(d) The compounds of the mixture No. 20 decomposed on distillation; Mass spectroscopic data (M ⁺ / e):

248 (10 %) y 246 (10 J6), I67 (80 %) , 147 (56 %), 127 (60 %), 69 (30 56), 53 (100 J6)

(e) The compounds of the mixture No. 21 decomposed upon distillation;

Mass spectroscopic data (M / e):

310 (8'Y), 308 (16 J6), 306 (8 J6), 229 (50 J6)., 227 (50 J6),

148 (45 56), 147 (90 56-), 127 (loo Jt).

(f) The preparation is described in Example 5.

(g) The preparation is described in Example 6.

EXAMPLE 8

Preparation of 4 - [(5,5-dichloro-3-methyl-penta-2,4-dienyl) -thio] -2-nitroaniline (A) and 4 - [(5,5-dichloro 2-methyl-penta-2,4-dien-1-yl) thioj-2-nitroaniline (B) [Reaction 'III,' X = S ₁ R ⁵ = HJ

A solution of 10 g (51.2 mmol) of 2-nitro-4-thiocyanine aniline in 25 ml of dimethylformamide was added to a solution of 2.26 g (51 mmol) of sodium borohydride in 25 ml of dimethylformamide. The reaction mixture was kept under stirring at room temperature for 1 hour, after which 60 mmol of the mixture of the products obtained in Example 3 were added. The reaction mixture was heated to 100 C for 1 hour

21733 1 -w-

heated, after which it was allowed to cool and poured into 200 ml of water. It was extracted with 3 portions of 100 ml of chloroform. The organic extracts were "re-combined, dehydrated with anhydrous Na" _{2 "} SO ₄ , and the solvent was removed in vacuo. A crude product (11.9 g) was obtained which was composed of compounds A and B in a ratio of about 55 : ^ 5 (NMR spectroscopy) and that was obtained in sufficient purity for the subsequent step (Example 9),

EXAMPLE 9

Preparation of * _-? [(5 5 ~ dichloro-3 ~ rnethyl-penta-2, ^f-l-yl dienl>fchig> J-1,2-phenylenediamine (A) and *> - [(5, 5 Dichloro-2-methyl-penta-2, * 1-dien-1-yl) -thio) 3-l, 2-phenylenediamine (B) [Reaction VIj

11.7 g of the crude product obtained in Example 8 were added to a mixture of 200 ml of water and 200 ml of methanol containing 45 g of Na ₂ SpO ₂ .

The reaction mixture was heated at 80 ° C for 15 minutes, after which the inorganic salts were filtered off and a methanol portion was removed under vacuum.

After extracting three times with 100 ml portions of chloroform, the organic phases were re-combined, dehydrated with anhydrous Na ₂ SO 4, and the solvent was removed to give a brown viscous oil consisting of products A and B in a ratio of about 55: 1. ^ 5 (NMR spectroscopy).

3.3 · 1.. -Yes -

EXAMPLE 10

Preparation of 5 (6) - [(5 ₃ 5-dichloro-3-methyl-penta-2,4-dien-1-yl) -thi (DJ-benzimidazole-2-methylcarbamate (A) and from: 5C6) ~ .C (5,5-dichloro-2-methyl-penta-2, ^ - the'n · -! - yl) -thio3-benzimidazole-2-methyl-carbamate (B) [Reaction VII3

8J5 g (29.4 mmol) of the crude oil obtained in Example 9 were dissolved in a mixture of 35 ml of water, 35 ml of ethanol, 2 ml of acetic acid and 6.05 g (29.4 mmol) of 1,3-bis-methoxycarbonyl- Dissolved S-methyl-isothiourea. The reaction mixture was refluxed for 2 hours.

It formed a pesticide, which was filtered off and from methanol and chloroform (mixture in the ratio of 1: 1)

was recrystallized.

In this way, 7 g of a mixture of compounds A and B were obtained in a ratio of about 55:45 (by NMR spectroscopy) with a melting point of 169-170 ° C (decomposition).

EXAMPLE 11

Preparation of 5 (6) - [(5,5-dichloro-3-methyl-penta-2, ^f, -dien-1-yl) -sulfinyl] -benzimidazole-2-methylcarbamate (A) and of 5 (6) [(5,5-dichloro-2-methyl-penta-2, dien-1-yl) -sulfinyl] -benzimidazole-2-methylcarbamate (B) [Reaction VIII-VIII

IQ, 1 mmol of 3-chloro-perbenzoic acid e was added rapidly to a solution of 4 g (10.7 mmol) with vigorous stirring.

SH

of the mixture of products obtained in Example 10 in 400 ml of chloroform, 200 ml of ethanol and 1.5 ml of acetic acid. The reaction mixture was allowed to stand at room temperature for 1 hour, after which it was treated with an aqueous solution of NaHCO3 and then with water until a neutral pH was reached. The organic solution was dehydrated with water / apSON and the solvent was evaporated in vacuo.

The residual oil was washed with methanol and ethyl ether, and the resulting solid was recrystallized from methanol to give 3.5 g of a mixture of products A and B in a ratio of about 55:45, mp = 134-135 ° C (decomposition). receive ^ was.

EXAMPLE 12

Preparation of 4- [5,6,6,6-tetrafluoro-3-methyl-hexa-2,4-dien-1-yl) thioj-2-nitroaniline (A) and 4 ~ [(5,6, 6,6-Tetrafluoro-2-methyl-hexa-2, dienyl-1-yl) thio3-2-nitroaniline (B) [Reaction IV and V]

A solution of 10.5 g of NaBHu in 15 ml of dimethylformamide was added at room temperature to a solution of 5 g (25.6 mmol) of 2-nitro-4-thio-cyano-aniline in 15 ml of dimethylformamide. The reaction mixture was kept under stirring for 1 hour at room temperature, after which 8.85 g (27 mmol) of the mixture No. 2 (see Table 1) were added.

The reaction mixture was heated to 100 C for 1 hour. After cooling, 4.9 ml (35 mmol) of triethylamine

21 7.3 3.1 ·. if.

was added, after which it was heated to 100 C for 2 hours.

The mixture was cooled _} then diluted with 300 ml of water and extracted four times with 100 ml of chloroform each time. The organic phase was dehydrated with anhydrous Na ₂ SO ₁ ^, concentrated in vacuo and chromatographed on silica gel (eluent: mixture of ethyl ether and petroleum ether in the ratio of 1: 1).

There were 5.8 g of a mixture of compounds A and B in the ratio of about 1: 1 (NMR spectroscopy) obtained as a red oil.

EXAMPLE 13

Preparation of 4 - [(5,6,6,6-tetrafluoro-3 ~ methyl-hexa-2, ^2-dien-l l-yl) -thiq) 3-l> 2-phenylenediamine (A) and ^ ~ [(5,6,6 _J 6-Tetrafluoro-2-methyl-hexa-2, dien-1-yl) thia) 3-1,2-Phenylenediamine (B) [Reaction VIj

Starting from 5.7 g of the obtained according to Example 12 mixture of 2-nitro-anilines and according to the method described in Example 9 4.6 g of an intensively colored oil were obtained, which consists of a mixture of compounds A and B in the ratio of about 1: 1 (NMR spectroscopy).

EXAMPLE 14

Preparation of 5 (6) - [(5,6,6-, 6-tetrafluoro-3-methyl-hexa-2,4-dien-1-yl) -thiQJ-benzimidazole-2-methylcarbamate (A) and of 5Q6) t [(5,6,6 6-tetrafluoro-2-methyl-hexa-2,4-dien-1-yl) thio 1 _- benzimidazole-2-methyl-lc Bamat ar (B) [reaction VII]

4.6 g (1.5 mmol) of the mixture obtained according to Example 13 were poured into 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) of 1, 3-bis-methoxycarbonyl-S-methyl-isothiourea dissolved. The reaction mixture was refluxed for 2 hours, after which it was allowed to cool. It formed a pesticide, which was filtered off and from a mixture of methanol and chloroform in the ratio 1: 1

was crystallized, with 3.7 g of a mixture of zn

Compound A and B was obtained in a ratio of about 1: 1; F. = l67-170 ° C.

BEISPIEL.15

Preparation of 5 (6) - [ 5,6,6,6-tetra -l- 3-methyl-hexa- 2,4-di- en-1-yl) -sulfinyl] -benzimidazole-2-methylcarbamate (A) and of 5 (6) - [- (5 _J 6 _> 6 _y 6-tetrafluoro-3-methyl-hexa-2 _> 4- ( dien -1-yl) -sulfinyl] benzimidazole-2-methylcarbamate (B) [Reaction VIII] .

Starting from 1.3 g (3.34 mmol) of the obtained according to Example 14 mixture of benzimidazole carbamates and according to the procedure of Example 11, it was possible to 0.95 g of a mixture of the compounds A and B in a ratio of about 1: 1 (MMR spectroscopy) to obtain; F. = 147-149 ° C.

217331 -

EXAMPLE 16 Preparation of 4 - [(5,5-dichloro-3-methyl-penta-2,4-

dien-1-yl) -oxy3-2-nitroaniline (A) and 4 - [(5,5 ~

Dichloro-2-methyl-penta-2,4-dien-l-yl) -oxy3-2-nitrp-

aniline (B)

[Reaction IU ₃ X = 0, R ⁵ = CH, CQ3

A mixture of 10.2 g (52 mmol) of 3-nitro- ^i- J-acetaminophenol, 20 g of Na-CO, 11.12 g (60 mmol) of mixture No. 18 (see Table 2) and 60 ml of acetone was heated at reflux for 48 hours. The reaction mixture was then allowed to cool, the inorganic salts were filtered off and a portion of the solvent was removed. The resulting crude product was chromatographed on silica gel (eluant: ethyl ether - petroleum ether 1: 1); It was 7.8 g of a brown crystalline substance

tin , which consisted of a mixture of compound A and B in a ratio of about 3: 2 (NMR spectroscopy).

EXAMPLE 17

Preparation of 4 - [(5,5 ~ dichloro-3-methyl-penta-2,4-dien-l-yD-oxyj-l, 2-phenylenediamine (A) and t ^z - [(5 _J 5-dichloro 2-methyl-penta-2,4-dien-1-yl) -oxy3-1,2-phenylenediamine (B) .

[Reaction VI3

Starting from 7.5 g of the mixture of compounds obtained according to Example 16 and following the procedure of Example 9, it was possible to obtain 6.2 g of a thick brown oil which was obtained from a mixture of compounds A and B in a ratio of of about 3 x 2.

2i MA «4 ·

.1 / 841 - ^ -

EXAMPLE 18 Preparation of 5 (6) - [(5,5-dichloro-3-methyl-penta-2-yl)

diene-1-yl) -oxy-3-benzimidazole-2-methylcarbamate (A),

and of 5 (6) - [(5,5-dichloro-2-methyl-penta-2,4-dien-1-yl) -

oxy-3-benzimidazole-2-methyl-2-carbamate (B) [Reaction VI3

Ί, 6 g of 1,3-bis-methoxycarbonyl-S-methyl-isothiourea were added to a solution of 6.2 g (22.7 mmol) of the product mixture obtained according to Example 17 in 30 ml of water, 30 ml of ethanol and 0.8 The reaction mixture was refluxed for 2 hours, after which it was allowed to cool. A solid formed which was filtered off and crystallized from methanol-chloroform to give 5.6 g of a mixture of compound A and B in a ratio of about 3: 2 (NMR spectrum); Mp = 183-185 ⁰ C.

EXAMPLE 19

Table 3 below shows benzimidazole carbamates of the general formula I together with their properties and the method of synthesis.

, "ta

Table 3

/ compounds of the formula ν

R ³ R ⁴

Γ * - Γ * ϊ-ϊ ·· ί ** - {** ·

NH-COOCH.

NH-COOCH-)

formula

(A)

( c ) Initial /, v method of F Ratio Analyst

products ' examples - (C) the pos

isomeric (d) (A / B)

> 5 CCI ₉ = CH-CH = CH-Ch-S-BIAC 19 8-10 188-192 NMR, MS ? 6 CCl = CH-CH = CH-CH-SO-BIAC 25 11 190 (Zers.) NMR ! 7 CCl = CH-CH = CH-CH-SO-BIAC 25 235-40 NMR, EA

: 8 CCl * CH-C (CH2 UCH-CH5-BIAC (A)

<- Δ 2

CCl = CH-CH = C (CH ") - CH _O -S-BIAC _{/ οΛ}

<- -id \O)

8-10

'169-70

55: 5 ^

NMR, EA

'9 CCl = CH-C (CH) = CH-CH-SO-BIAC (A)

έ. Οct

CC1 ₂ = CH-CH = C (CH ₃₎ -CH ₂ -SO-BIAC

11

55: 5 ^

NMR

0 CBr = CH-C (CH) = CH-CH-S-BIAC (A)

C. .ό egg

CBr = CH-CH = C (CH ₃₎ -CH-S-BIAC

12-14

n "d.

55:45

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(a) Mixture of cis and trans isomers.

(b) Me products 1-17 and 18-24 are listed in Table 1 and Table 2, respectively.

(c) Melting points were not corrected. Dec. = Decomposition; n.d. = not determined.

(d) approximate ratio, determined by NMR spectroscopy,

(e) The structures were confirmed by the following analyzes:

NMR = nuclear magnetic resonance spectroscopy IR = infrared spectroscopy MS = mass spectroscopy EA = elemental analysis

(f) Prepared by a procedure analogous to the procedure described in Example but using two equivalents of 3-chloroperbenzoic acid.

(g) The mixture 28/3 is described in Example No. 21.

EXAMPLE 20

Compounds of general formula I were tested for their effectiveness against helminths according to the method described above. Sample Nos. 25, 26, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 39, 40, 44, 45 'and 47 (see Table 3) were added to gut nematodes infected sheep tested; they were fully effective (90-100% reduction in infestation) at a dose of 5 mg / kg body weight. Sample Nos. 28, 29, 35 and 40 were infested with Flukes (Fasciola)

Sheep tested; they were completely effective

(90-100 % reduction in infestation) at a dose of 5 mg / kg body weight. Samples Nos. 32 and 44 were tested .... against lungworms (Dictyocaulus) in affected sheep; they were completely effective (90-100 %

Decrease in infestation) at a dose of 5 and 2.5 mg / kg, respectively. Body weight.

EXAMPLE 21

This example relates to the effectiveness of mixtures of positional isomers of different isomeric composition over helminths.

Sample No. 28 (see Table 3) is a mixture of Compound A and Compound B in the ratio A / B = 55:45.

CCl ₂ = CH-CH = C (CH ₃ ) -CH ₂ -Sj ^ Y ^ ^ C - NH-COOCH ₃ (B)

Sample No. 48 (see Table 3) is Compound B (100 %).

A mixture consisting of. Compounds a and b in the ratio of a / b = 75:25 (NMR spectroscopy) -

CCl = CH-C (CH _) = CH-CH Cl "U)

2 -Λ & \

CCl = CH-GH = C (CH) -CH ₂ Cl · (b.) \

was distilled under reduced pressure.

21733.1 _ £

The following fractions were collected;

Fraction Kd. composition

No. (° C / mbar) - a / b (NMR)

1 50-54 / 0.6 90:10

2. '5 ^ -57 / 0.6 80:20

3 57 / 0.6 70:30

Independently of each other and according to the procedure described in Examples 8 to 10, the corresponding benzimidazole carbamate derivatives (Samples 2,871 and 28/3) were prepared from fractions 1 and 3:

Sample 28/1 Α / Β = 90:10 (NMR) F. = Sample 28/3 A / B = 70:30 (NMR) F. = 16o-5 ° C

Samples 28, 28/1, 28/3 and 48 were separately tested for their antihelminthic activity against gut nematodes in affected sheep.

The efficacy data obtained are given in the following table; they are according to the following rating scale

0 0-10 1-ige 1 11-25 2-ige 2 26-6O2-owned 3 $ 61-90 91-100 2-ige rated.

infestation reduction

2 1 73.3 1

Table 4

sample

Composition of sample (%) dose (mg / kg)

effectiveness

28 A = 55 , B = 45 1.28 A = 90 , B = IO 3.28 A = 70 , B = 30 48 A = O, B = 100

5 5 5 2.5

4 4 3

Claims (3)

Berlin, 18.4.1980 APC 07 D / 217 331 56 603/18 Process for the preparation of benzimidazole carbamates substituted in 5 (6) -position 1 »Process for the preparation of 5 (6) -position of substituted benzimidazole carbamates of the general formula > 3. .N V-WII-C If / R-I wherein R is an (L-C. Alkyl group, R and R2, which may be identical or different, are hydrogen or halogen atoms or a methyl group which is optionally substituted by one or more halogen atoms, R and R, which may be identical or different, are hydrogen or halogen atoms or the methyl group, and X = O, S, SO, or SOp, characterized in that a 2-Nitroaniline of the general formula 04/18/1980 AP C 07 D / 217 56 603/18 3 R ¹ R- ⁵ y * (E) X-CH ₀ -C = C -CH = C ^ά V 2 · ^ R wherein R, R, R "and R have the abovementioned meanings, and X is O or S, is reacted with reducing agents to give the corresponding 1,2-phenylenediamine which is obtained by reaction with 1,3-bis -alkoxycarbonyl-S-methyl ~ isourea in the compounds of formula I in which X = O or X = S, is converted, and that the compounds of the formula I wins by treatment with peracids according to the following reaction scheme in which X = SO or SOp means: reducing agent R ⁴ R ³ -CH ₂ -C =C-CH = Cr ^ ^ (ρ) RP + I = C - HH-- COOR ~ ^ I £ x = 0, SJ COOR peracids H. = s]: ^ ι jx = so,