HK1032588A - Method for producing triazolinthion derivatives - Google Patents

Description

Process for preparing triazolinethione derivatives

The present invention relates to a novel process for preparing triazolinethione derivatives which are active compounds having microbiocidal, in particular fungicidal, activity.

It is known that triazolinethione derivatives can be prepared by the following method: the corresponding triazole derivatives are reacted with a strong base and sulfur in sequence and then hydrolyzed, or the triazole derivatives are reacted directly with sulfur at elevated temperature and then treated with water (see WO-A96-16048). However, this process has the disadvantage that the desired product is obtained only in relatively low yields or that the desired reaction conditions are difficult to maintain on an industrial scale.

Furthermore, it is described in the literature that certain 1, 2, 4-triazoline-5-thiones substituted in the 3-position can be prepared by reacting N-chlorothioformyl-N- (1-chloro-1-alkene) -amines with carbohydrazide derivatives (cf. DE-A19601032, DE-A19601189 and EP-A0784053). However, no mention is made of the synthesis of the corresponding substances without substituents in the 3-position.

Furthermore, Bull. chem. Soc. Japan 46, 2215(1973) discloses that triazolinethione compounds substituted in the 3-position can be synthesized by reacting phenylhydrazine with sodium thiocyanate and a ketone or aldehyde in the presence of hydrochloric acid and treating the triazolinethione compounds formed which are substituted in the 3-position with an oxidizing agent. The disadvantage of this process is that the reaction times required are very long and triazolinethione compounds which are unsubstituted in the 3-position cannot be prepared by this process.

Finally, it is known that when [1- (2-chloro-phenyl) -2- (1-chloro-cyclopropan-1-yl) -2-hydroxy ] -propyl-hydrazine is reacted with formamidine acetate, 2- (1-chloro-cyclopropan-1-yl) -1- (2-chloro-phenyl) -3- (1, 2, 4-triazol-1-yl) -propan-2-ol is obtained (see, DE-a-4030039). However, this method cannot produce a thione derivative of triazole.

It has now been found that triazolinethione derivatives of the formula (I)Wherein

R¹And R²The same or different, each represents an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted aralkyl group, an optionally substituted arylalkenyl group, an optionally substituted aryloxyalkyl groupOptionally substituted aryl or optionally substituted heteroaryl,

can be prepared by the following method:

a) in a first step, a hydrazine derivative of the formula (II)

Wherein

R¹And R²Each of which is as defined above, respectively,

with formaldehyde and a thiocyanate of the formula (III) in the presence of a diluent and, if appropriate, in the presence of an acid,

X-SCN (III)，

wherein

X represents sodium, potassium or ammonium, and

b) in a second step, the triazolidinethione compound of the formula (IV) formed is reacted

Wherein

R¹And R²Each of which is as defined above, respectively,

alpha) with an oxidizing agent, if appropriate in the presence of a catalyst and in the presence of a diluent, or

Beta) with formic acid of the formula (V)

HCOOH (V)。

It is extremely surprising that the process of the present invention makes it possible to prepare the triazolinethione derivatives of the formula (I) in much higher yields or under much simpler conditions than the processes of the prior art.

The process of the present invention has many advantages. As mentioned above, the triazolinethione derivatives of formula (I) can be synthesized in high yields. In addition, the required starting materials and reactants can be prepared by simple processes and are available in large amounts. Another advantage is that the individual reaction steps and the isolation of the reaction products can be carried out without difficulty.

If [1- (2-chloro-phenyl) -2- (1-chloro-cycloprop-1-yl) -2-hydroxy is used]Propyl-1-hydrazine as starting material and reacted in a first step with paraformaldehyde and ammonium thiocyanate, and the product formed is then reacted in a second step with oxygen in the presence of potassium hydroxide and sulfur, the course of the process according to the invention can be illustrated by the following reaction scheme.

The formula (II) is a general definition of the hydrazine derivatives required as starting materials for carrying out the process according to the invention. Preference is given to using compounds of the formula (II) in which

R¹Represents straight-chain or branched alkyl of 1 to 6 carbon atoms, where these alkyl radicals may each be mono-to tetrasubstituted by identical or different substituents from the group consisting of halogen, alkoxy of 1 to 4 carbon atoms, alkoxyimino of 1 to 4 carbon atoms in the alkoxy moiety and cycloalkyl of 3 to 7 carbon atoms,

or

Represents straight-chain or branched alkenyl of 2 to 6 carbon atoms, where these alkenyl radicals may in each case be mono-to trisubstituted by identical or different substituents from the group consisting of halogen, alkoxy of 1 to 4 carbon atoms and cycloalkyl of 3 to 7 carbon atoms,

or

Denotes cycloalkyl having 3 to 7 carbon atoms, wherein the cycloalkyl radicals may each be mono-to trisubstituted by identical or different substituents from the group consisting of halogen, cyano and alkyl having 1 to 4 carbon atoms,

or

Represents an aralkyl group having 6 to 10 carbon atoms in the aryl moiety and 1 to 4 carbon atoms in the straight-chain or branched alkyl moiety, wherein the aryl moiety may be mono-to trisubstituted by identical or different substituents selected from the group consisting of halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, haloalkyl having 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, haloalkoxy having 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, haloalkylthio having 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, cycloalkyl having 3 to 7 carbon atoms, phenyl, phenoxy, alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy moiety, alkoxycarbonyl, and amino, alkoxyiminoalkyl having 1 to 4 carbon atoms in the alkoxy moiety and 1 to 4 carbon atoms in the alkyl moiety, nitro and cyano,

or

Denotes arylalkenyl having 6 to 10 carbon atoms in the aryl moiety and 2 to 4 carbon atoms in the alkenyl moiety, wherein the aryl moiety may be mono-to trisubstituted by identical or different substituents from the group consisting of halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, haloalkyl having 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, haloalkoxy having 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, haloalkylthio having 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, cycloalkyl having 3 to 7 carbon atoms, phenyl, phenoxy, alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy moiety, phenyloxy, Alkoxyiminoalkyl having 1 to 4 carbon atoms in the alkoxy moiety and 1 to 4 carbon atoms in the alkyl moiety, nitro and cyano,

or

Represents an aryloxyalkyl group having 6 to 10 carbon atoms in the aryl moiety and 1 to 4 carbon atoms in the straight or branched oxyalkyl moiety, wherein the aryl moiety may be mono-to trisubstituted by identical or different substituents selected from the group consisting of halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, haloalkyl of 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, haloalkoxy of 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, haloalkylthio of 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl, phenoxy, alkoxycarbonyl of 1 to 4 carbon atoms in the alkoxy moiety, Alkoxyiminoalkyl having 1 to 4 carbon atoms in the alkoxy moiety and 1 to 4 carbon atoms in the alkyl moiety, nitro and cyano,

or

Represents an aryl group of 6 to 10 carbon atoms, wherein each of these groups may be mono-to trisubstituted by identical or different substituents from the group consisting of halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, haloalkyl containing 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, haloalkoxy containing 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, haloalkylthio containing 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl, phenoxy, alkoxycarbonyl of 1 to 4 carbon atoms in the alkoxy moiety, alkoxyiminoalkylalkylcarbonyl of 1 to 4 carbon atoms in the alkoxy moiety and 1 to 4 carbon atoms in the alkyl moiety, A nitro group and a cyano group,

or

Represents a 5-or 6-membered heteroaromatic radical containing 1 to 3 heteroatoms, such as nitrogen, sulfur and/or oxygen, which is optionally fused to a benzene ring, where these radicals may be mono-to trisubstituted by identical or different substituents from the group consisting of halogen, alkyl having 1 to 4 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkynyl having 3 to 8 carbon atoms, alkoxy having 1 or 2 carbon atoms, alkylthio having 1 or 2 carbon atoms, haloalkyl, haloalkoxy and haloalkylthio each having 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, such as fluorine or chlorine atoms, formyl, dialkoxymethyl having 1 or 2 carbon atoms in each alkoxy moiety, acyl having 2 to 4 carbon atoms, alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy moiety, Alkoxyiminoalkyl having 1 to 4 carbon atoms in the alkoxy moiety and 1 to 3 carbon atoms in the alkyl moiety, nitro and cyano,

R²represents straight-chain or branched alkyl of 1 to 6 carbon atoms, where these alkyl radicals may each be mono-to tetrasubstituted by identical or different substituents from the group consisting of halogen, alkoxy of 1 to 4 carbon atoms, alkoxyimino of 1 to 4 carbon atoms in the alkoxy moiety and cycloalkyl of 3 to 7 carbon atoms,

or

Represents straight-chain or branched alkenyl of 2 to 6 carbon atoms, where these alkenyl radicals may in each case be mono-to trisubstituted by identical or different substituents from the group consisting of halogen, alkoxy of 1 to 4 carbon atoms and cycloalkyl of 3 to 7 carbon atoms,

or

Denotes cycloalkyl having 3 to 7 carbon atoms, wherein the cycloalkyl radicals may each be mono-to trisubstituted by identical or different substituents from the group consisting of halogen, cyano and alkyl having 1 to 4 carbon atoms,

or

Denotes an aralkyl group having 6 to 10 carbon atoms in the aryl moiety and 1 to 4 carbon atoms in the straight-chain or branched alkyl moiety, wherein the aryl moieties may all be mono-to trisubstituted by identical or different substituents from the group consisting of halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, haloalkyl having 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, haloalkoxy having 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, haloalkylthio having 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, cycloalkyl having 3 to 7 carbon atoms, phenyl, phenoxy, alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy moiety, alkoxycarbonyl, and amino, amino, Alkoxyiminoalkyl having 1 to 4 carbon atoms in the alkoxy moiety and 1 to 4 carbon atoms in the alkyl moiety, nitro and cyano,

or

Denotes arylalkenyl having 6 to 10 carbon atoms in the aryl moiety and 2 to 4 carbon atoms in the alkenyl moiety, wherein the aryl moieties may all be mono-to trisubstituted by identical or different substituents from the group consisting of halogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, haloalkyl having 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, haloalkoxy having 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, haloalkylthio having 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, cycloalkyl having 3 to 7 carbon atoms, phenyl, phenoxy, alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy moiety, alkoxycarbonyl, Alkoxyiminoalkyl having 1 to 4 carbon atoms in the alkoxy moiety and 1 to 4 carbon atoms in the alkyl moiety, nitro and cyano,

or

Represents an aryloxyalkyl group having 6 to 10 carbon atoms in the aryl moiety and 1 to 4 carbon atoms in the straight or branched oxyalkyl moiety, wherein the aryl moiety may be mono-to trisubstituted by identical or different substituents selected from the group consisting of halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, haloalkyl of 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, haloalkoxy of 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, haloalkylthio of 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl, phenoxy, alkoxycarbonyl of 1 to 4 carbon atoms in the alkoxy moiety, Alkoxyiminoalkyl having 1 to 4 carbon atoms in the alkoxy moiety and 1 to 4 carbon atoms in the alkyl moiety, nitro and cyano,

or

Represents an aryl group of 6 to 10 carbon atoms, wherein each of these groups may be mono-to trisubstituted by identical or different substituents from the group consisting of halogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, haloalkyl containing 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, haloalkoxy containing 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, haloalkylthio containing 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, cycloalkyl of 3 to 7 carbon atoms, phenyl, phenoxy, alkoxycarbonyl of 1 to 4 carbon atoms in the alkoxy moiety, alkoxyiminoalkylalkylcarbonyl of 1 to 4 carbon atoms in the alkoxy moiety and 1 to 4 carbon atoms in the alkyl moiety, A nitro group and a cyano group,

or

Represents a 5-or 6-membered heteroaromatic radical containing 1 to 3 heteroatoms, such as nitrogen, sulfur and/or oxygen, which is optionally fused to a benzene ring, where these radicals may be mono-to trisubstituted by identical or different substituents from the group consisting of halogen, alkyl having 1 to 4 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, hydroxyalkynyl having 3 to 8 carbon atoms, alkoxy having 1 or 2 carbon atoms, alkylthio having 1 or 2 carbon atoms, haloalkyl, haloalkoxy and haloalkylthio each having 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, such as fluorine or chlorine atoms, formyl, dialkoxymethyl having 1 or 2 carbon atoms in each alkoxy moiety, acyl having 2 to 4 carbon atoms, alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy moiety, Alkoxyiminoalkyl having 1 to 4 carbon atoms in the alkoxy moiety and 1 to 3 carbon atoms in the alkyl moiety, nitro and cyano.

Particular preference is given to using hydrazine derivatives of the formula (II) in which

R¹Represents a straight-chain or branched alkyl group of 1 to 4 carbon atoms, where these alkyl groups may each be mono-to tetrasubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, alkoxyimino having 1 to 2 carbon atoms in the alkoxy moiety, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,

or

Represents straight-chain or branched alkenyl of 2 to 5 carbon atoms, where these alkenyl radicals may in each case be mono-to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,

or

Represents cycloalkyl having 3 to 6 carbon atoms, wherein the cycloalkyl radicals may each be mono-to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl and tert-butyl,

or

Represents phenylalkyl having 1 to 4 carbon atoms in the straight-chain or branched alkyl moiety, in which the phenyl moiety may be mono-to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, chlorodifluoromethoxy, difluoromethoxy, chlorodifluoromethylthio, methoxycarbonyl, ethoxycarbonyl, methoxyiminomethyl, 1-methoxyiminoethyl, nitro and cyano,

or

Denotes phenylalkenyl having 2 to 4 carbon atoms in the alkenyl moiety, wherein the phenyl moiety may be mono-to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, chlorodifluoromethoxy, difluoromethoxy, chlorodifluoromethylthio, methoxycarbonyl, ethoxycarbonyl, methoxyiminomethyl, 1-methoxyiminoethyl, nitro and cyano,

or

Represents a phenoxyalkyl group having 1 to 4 carbon atoms in the straight or branched oxyalkyl moiety, wherein the phenyl moiety may be mono-to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, chlorodifluoromethoxy, difluoromethoxy, chlorodifluoromethylthio, methoxycarbonyl, ethoxycarbonyl, methoxyiminomethyl, 1-methoxyiminoethyl, nitro and cyano,

or

Represents phenyl which may be mono-to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, chlorodifluoromethoxy, difluoromethoxy, chlorodifluoromethylthio, methoxycarbonyl, ethoxycarbonyl, methoxyiminomethyl, 1-methoxyiminoethyl, nitro and cyano,

or

Represents pyrazolyl, imidazolyl, 1, 2, 4-triazolyl, pyrrolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, quinazolinyl, indolyl, benzothienyl, benzofuryl, benzothiazolyl or benzimidazolyl, wherein these radicals may be mono-to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, chlorodifluoromethoxy, chlorodifluoromethylthio, hydroxymethyl, hydroxyethyl, hydroxyalkynyl containing 4 to 6 carbon atoms, methoxycarbonyl, ethoxycarbonyl, methoxyiminomethyl, 1-methoxyiminoethyl, nitro and cyano, formyl, Dimethoxymethyl, acetyl and propionyl, and a pharmaceutically acceptable salt thereof,

R²denotes straight-chain or branched alkyl of 1 to 4 carbon atoms, where the alkyl radicals may each be mono-to tetrasubstituted by identical or different substituents, the radicalsThe substituents are selected from the group consisting of fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, alkoxyimino having 1 to 2 carbon atoms in the alkoxy moiety, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,

or

Represents straight-chain or branched alkenyl of 2 to 5 carbon atoms, where these alkenyl radicals may in each case be mono-to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,

or

Represents cycloalkyl having 3 to 6 carbon atoms, wherein the cycloalkyl radicals may each be mono-to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, cyano, methyl, ethyl, propyl, isopropyl and tert-butyl,

or

Represents phenylalkyl having 1 to 4 carbon atoms in the straight-chain or branched alkyl moiety, in which the phenyl moiety may be mono-to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, chlorodifluoromethoxy, difluoromethoxy, chlorodifluoromethylthio, methoxycarbonyl, ethoxycarbonyl, methoxyiminomethyl, 1-methoxyiminoethyl, nitro and cyano,

or

Denotes phenylalkenyl having 2 to 4 carbon atoms in the alkenyl moiety, wherein the phenyl moiety may be mono-to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, chlorodifluoromethoxy, difluoromethoxy, chlorodifluoromethylthio, methoxycarbonyl, ethoxycarbonyl, methoxyiminomethyl, 1-methoxyiminoethyl, nitro and cyano,

or

Represents a phenoxyalkyl group having 1 to 4 carbon atoms in the straight or branched oxyalkyl moiety, wherein the phenyl moiety may be mono-to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, chlorodifluoromethoxy, difluoromethoxy, chlorodifluoromethylthio, methoxycarbonyl, ethoxycarbonyl, methoxyiminomethyl, 1-methoxyiminoethyl, nitro and cyano,

or

Represents phenyl which may be mono-to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, chlorodifluoromethoxy, difluoromethoxy, chlorodifluoromethylthio, methoxycarbonyl, ethoxycarbonyl, methoxyiminomethyl, 1-methoxyiminoethyl, nitro and cyano,

or

Represents pyrazolyl, imidazolyl, 1, 2, 4-triazolyl, pyrrolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, quinazolinyl, indolyl, benzothienyl, benzofuryl, benzothiazolyl or benzimidazolyl, wherein these radicals may be mono-to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, chlorodifluoromethoxy, chlorodifluoromethylthio, hydroxymethyl, hydroxyethyl, hydroxyalkynyl containing 4 to 6 carbon atoms, methoxycarbonyl, ethoxycarbonyl, methoxyiminomethyl, 1-methoxyiminoethyl, nitro and cyano, formyl, Dimethoxymethyl, acetyl and propionyl.

Very particular preference is given to using hydrazine derivatives of the formula (II) in which

R¹Represents n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, where these radicals may each be mono-to tetrasubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, methoxyimino, ethoxyimino, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,

or

Represents straight-chain or branched alkenyl of 2 to 5 carbon atoms, where these alkenyl radicals may in each case be mono-to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,

or

Represents 1-methyl-cyclohexyl, 1-chloro-cyclopropyl, 1-fluoro-cyclopropyl, 1-methyl-cyclopropyl, 1-cyano-cyclopropyl, 1-methyl-cyclopentyl or 1-ethyl-cyclopentyl,

or

Represents phenylalkyl having 1 to 2 carbon atoms in the straight-chain or branched alkyl moiety, in which the phenyl moiety may be mono-to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, chlorodifluoromethoxy, difluoromethoxy, chlorodifluoromethylthio, methoxycarbonyl, ethoxycarbonyl, methoxyiminomethyl, 1-methoxyiminoethyl, nitro and cyano,

or

Denotes phenylalkenyl having 2 to 4 carbon atoms in the alkenyl moiety, wherein the phenyl moiety may be mono-to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, chlorodifluoromethoxy, difluoromethoxy, chlorodifluoromethylthio, methoxycarbonyl, ethoxycarbonyl, methoxyiminomethyl, 1-methoxyiminoethyl, nitro and cyano,

or

Represents a phenoxyalkyl group having 1 to 4 carbon atoms in the straight or branched oxyalkyl moiety, wherein the phenyl moiety may be mono-to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, chlorodifluoromethoxy, difluoromethoxy, chlorodifluoromethylthio, methoxycarbonyl, ethoxycarbonyl, methoxyiminomethyl, 1-methoxyiminoethyl, nitro and cyano,

or

Represents phenyl which may be mono-to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, chlorodifluoromethoxy, difluoromethoxy, chlorodifluoromethylthio, methoxycarbonyl, ethoxycarbonyl, methoxyiminomethyl, 1-methoxyiminoethyl, nitro and cyano,

or

Represents pyrazolyl, imidazolyl, 1, 2, 4-triazolyl, pyrrolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, quinazolinyl, indolyl, benzothienyl, benzofuryl, benzothiazolyl or benzimidazolyl, wherein these radicals may be mono-to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, chlorodifluoromethoxy, chlorodifluoromethylthio, hydroxymethyl, hydroxyethyl, hydroxyalkynyl containing 4 to 6 carbon atoms, methoxycarbonyl, ethoxycarbonyl, methoxyiminomethyl, 1-methoxyiminoethyl, nitro and cyano, formyl, Dimethoxymethyl, acetyl and propionyl, and a pharmaceutically acceptable salt thereof,

R²represents n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, where these radicals may each be mono-to tetrasubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, methoxyimino, ethoxyimino, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,

or

Represents straight-chain or branched alkenyl of 2 to 5 carbon atoms, where these alkenyl radicals may in each case be mono-to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl,

or

Represents 1-methyl-cyclohexyl, 1-chloro-cyclopropyl, 1-fluoro-cyclopropyl, 1-methyl-cyclopropyl, 1-cyano-cyclopropyl, 1-methyl-cyclopentyl or 1-ethyl-cyclopentyl,

or

Represents phenylalkyl having 1 to 2 carbon atoms in the straight-chain or branched alkyl moiety, in which the phenyl moiety may be mono-to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, chlorodifluoromethoxy, difluoromethoxy, chlorodifluoromethylthio, methoxycarbonyl, ethoxycarbonyl, methoxyiminomethyl, 1-methoxyiminoethyl, nitro and cyano,

or

Denotes phenylalkenyl having 2 to 4 carbon atoms in the alkenyl moiety, wherein the phenyl moiety may be mono-to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, chlorodifluoromethoxy, difluoromethoxy, chlorodifluoromethylthio, methoxycarbonyl, ethoxycarbonyl, methoxyiminomethyl, 1-methoxyiminoethyl, nitro and cyano,

or

Represents a phenoxyalkyl group having 1 to 4 carbon atoms in the straight or branched oxyalkyl moiety, wherein the phenyl moiety may be mono-to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, chlorodifluoromethoxy, difluoromethoxy, chlorodifluoromethylthio, methoxycarbonyl, ethoxycarbonyl, methoxyiminomethyl, 1-methoxyiminoethyl, nitro and cyano,

or

Represents phenyl which may be mono-to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, chlorodifluoromethoxy, difluoromethoxy, chlorodifluoromethylthio, methoxycarbonyl, ethoxycarbonyl, methoxyiminomethyl, 1-methoxyiminoethyl, nitro and cyano,

or

Represents pyrazolyl, imidazolyl, 1, 2, 4-triazolyl, pyrrolyl, furyl, thienyl, thiazolyl, oxazolyl, pyridyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, quinazolinyl, indolyl, benzothienyl, benzofuryl, benzothiazolyl or benzimidazolyl, wherein these radicals may be mono-to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, tert-butyl, methoxy, ethoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, chlorodifluoromethoxy, chlorodifluoromethylthio, hydroxymethyl, hydroxyethyl, hydroxyalkynyl containing 4 to 6 carbon atoms, methoxycarbonyl, ethoxycarbonyl, methoxyiminomethyl, 1-methoxyiminoethyl, nitro and cyano, formyl, Dimethoxymethyl, acetyl and propionyl.

The hydrazine derivatives of the formula (II) are known or can be prepared by processes known in principle (cf. DE-A-4030039).

Accordingly, the hydrazine derivative of formula (II) can be prepared by the following method: reacting a 1-chloro-2-hydroxyethane derivative of the formula

Wherein

R¹And R²As defined above, the above-mentioned,

in the presence of an acid-binding agent such as potassium tert-butoxide, sodium methoxide or potassium carbonate in the presence of a diluent such as dimethylformamide, methanol, n-butanol, tetrahydrofuran or methyl tert-butyl ether at a temperature of from 20 to 60 ℃ and then the resulting oxirane derivative of the formula (VII) is reacted

Wherein

R¹And R²As defined above, the above-mentioned,

with hydrazine hydrate, if appropriate in the presence of diluents such as methanol, n-butanol, tetrahydrofuran, methyl tert-butyl ether, dioxane or nitriles such as acetonitrile, at temperatures of from 30 to 120 ℃.

It is particularly preferred to react the 1-chloro-2-hydroxyethane derivative of formula (VI) with an excess of hydrazine hydrate, in which case hydrazine hydrate acts both as a reactant and as a base and as a diluent.

The 1-chloro-2-hydroxyethane derivatives of the formulｃA (VI) are known or can be prepared by processes known in principle (cf. DE-A-4030039 and EP-A-0297345).

The formaldehyde reactant required for carrying out the first step of the process of the invention may be in the form of paraformaldehyde, gaseous formaldehyde or a formalin solution (═ aqueous formaldehyde solution).

Furthermore, in carrying out the first step of the process of the invention, the thiocyanate of the formula (III) is used as reactant. Thiocyanates of the formula (III) are known.

Suitable diluents for carrying out the first step of the process of the present invention may be various inert organic solvents commonly used in the reaction. Preference is given to using alcohols, for example n-butanol and tert-butanol, furthermore ethers such as dioxane, methyl tert-butyl ether, and also nitriles such as acetonitrile, hydrocarbons such as toluene or chlorobenzene, if appropriate mixtures of the abovementioned solvents with water.

Suitable acids for carrying out the first step of the process of the present invention may be various conventional inorganic and organic acids. Hydrochloric acid, sulfuric acid, p-toluenesulfonic acid and sodium hydrogensulfate are preferably used in the presence of water.

The first and second reactions of the process of the invention are generally carried out at atmospheric pressure. However, it is also possible to carry out the reaction under elevated pressure or, if no gaseous components are involved in the reaction, under reduced pressure.

When carrying out the first step of the process of the invention, it is usual to use from 1 to 2 mol of formaldehyde and from 1 to 2 mol of the thiocyanate salt of the formula (III) and, if appropriate, equivalent amounts of acid or sodium hydrogensulfate and water per mole of hydrazine derivative of the formula (II), the amount of water also being able to be in excess. The work-up is carried out by conventional methods. If the reaction is carried out without water, the reaction mixture, if appropriate after dilution with a slightly water-miscible organic solvent, is generally washed with an aqueous solution of a base, and the organic phase is then dried and concentrated. If the reaction is carried out in the presence of water and sodium bisulfate, the reaction mixture is generally diluted with a slightly water-miscible organic solvent, filtered and concentrated under reduced pressure. Impurities still present can be removed by conventional methods such as recrystallization or chromatography.

Formula (IV) is a general definition of the starting triazolidinethione compound required for carrying out the second step of the process of the present invention. In the formula, R¹And R²Preference is given to having the preferred meanings mentioned in connection with the hydrazine derivatives of the formula (II).

The triazolidinethione compounds of the formula (IV) have never been disclosed. They can be prepared by the first reaction step of the process of the present invention.

According to variant (. alpha.), the oxidizing agents used in carrying out the second step of the process of the invention are preferably oxygen, sulfur and potassium peroxide. If the oxidant used is oxygen, it is preferably added in the form of air.

According to variant (. alpha.), the catalyst used in carrying out the second step of the process of the invention is preferably a mixture of potassium hydroxide and sulphur powder. When oxygen is used as the oxidizing agent, the catalyst is preferably used.

According to scheme (. alpha.), suitable diluents for carrying out the second step of the process of the invention may be the various inert organic solvents customarily used in the reactions. Preference is given to using aliphatic, cycloaliphatic and aromatic hydrocarbons, such as pentane, hexane, cyclohexane, benzene, toluene and xylene, and furthermore ethers such as methyl tert-butyl ether and esters such as n-butyl acetate.

According to variant (. alpha.), the reaction temperature can be varied within a relatively wide range when carrying out the second step of the process of the invention. Typically, the reaction is carried out at a temperature of from 0 ℃ to 120 ℃. If the oxidant used is oxygen, the reaction is preferably carried out at a temperature between 20 ℃ and 80 ℃. If the oxidizing agent used is sulfur, the reaction is preferably carried out at a temperature between 50 ℃ and 110 ℃. If the oxidizing agent used is potassium peroxide, the reaction is preferably carried out at a temperature of between 20 ℃ and 80 ℃.

According to scheme (. alpha.), in carrying out the second step of the process of the present invention, an excess of oxidizing agent is generally used per mole of triazolidinethione compound of formula (IV). If the oxidizing agent used is sulfur or potassium peroxide, it is preferred to use 1.5 to 2 moles of oxidizing agent per mole of the triazolidinethione compound of formula (IV). If the oxidant used is oxygen in the form of air, a stream of air is preferably passed through the reaction mixture until the end of the reaction. The work-up is carried out by conventional methods. In general, the reaction mixture, if appropriate after dilution with a slightly water-miscible organic solvent, is extracted with aqueous saline solution, and the organic phase is then dried and concentrated. Impurities still present can be removed by conventional methods such as recrystallization or chromatography. The product can also be isolated as the potassium salt and then released by addition of an acid.

According to scheme (. beta.), the reaction temperature can be varied within certain limits when carrying out the second step of the process of the invention. Typically, the reaction is carried out at a temperature of from 50 ℃ to 100 ℃.

According to scheme (. beta.), formic acid serves as both reactant and diluent in carrying out the second step of the process of the invention. Thus, for each mole of triazolidinethione compound of formula (IV), a large excess of formic acid is generally used. Likewise, the work-up is carried out by customary methods. Typically, the reaction mixture is concentrated under reduced pressure and the product is then separated from the residue by recrystallization and/or chromatography.

In one embodiment, the process of the invention may be carried out as follows: the 1-chloro-2-hydroxyethane derivative of formula (VI) is reacted with hydrazine hydrate and the resulting hydrazine derivative of formula (II) is then subjected to further reaction without isolation. Accordingly, the triazolinethione compounds of formula (I) can also be prepared by the following process:

1-chloro-2-hydroxy-ethane derivatives of formula (VI)

Wherein

R¹And R²As defined above, the above-mentioned,

with hydrazine hydrate if appropriate in the presence of a diluent,

the hydrazine derivative of formula (II) formed

Wherein

R¹And R²As defined above, the above-mentioned,

directly without separation from formaldehyde and the thiocyanate of the formula (III)

X-SCN (III)

Wherein

X represents sodium, potassium or ammonium,

in the presence of a diluent and, if appropriate, in the presence of an acid, and then reacting the resulting triazolidinethione compound of the formula (IV)

Wherein

R¹And R²Each of which is as defined above, respectively,

alpha) with an oxidizing agent, if appropriate in the presence of a catalyst and in the presence of a diluent, or

Beta) with formic acid of the formula (V)

HCOOH (V)。

Suitable diluents for carrying out the first reaction step of the scheme according to the process of the present invention may be various inert organic solvents commonly used. Preference is given to using alcohols, for example n-butanol, and furthermore ethers such as dioxane or methyl tert-butyl ether, and nitriles such as acetonitrile. However, the reaction can also be carried out without addition of a solvent. In this case, an excess of hydrazine hydrate is used, so that the hydrazine hydrate acts both as a reactant and as a diluent.

According to the process of the present invention, the reaction temperature can be varied within a certain range when carrying out the first reaction step of the scheme. Generally, the reaction is carried out at a temperature of from 60 ℃ to 120 ℃, preferably from 70 ℃ to 100 ℃.

According to the process of the invention, in carrying out the first reaction step of this variant, from 3 to 20 mol, particularly preferably from 4 to 15 mol, of hydrazine hydrate are used per mole of 1-chloro-2-hydroxy-ethane derivative of the formula (VI), the mixture is then diluted with a slightly water-miscible organic solvent, such as methyl tert-butyl ether, the aqueous phase is separated off, the organic phase is washed and dried and then used directly for the subsequent reaction without work-up.

According to the method of the invention, the other steps of the protocol are carried out in the manner described above.

The triazolinethione derivatives which can be prepared according to the process of the invention can be present in the form of "thiones" of the formula

Or in the form of a tautomeric "thiol" of the formula

For the sake of simplicity, only the "thione" form is given in each case.

Triazolinethione derivatives which can be prepared according to the process of the present invention are active compounds having microbicidal, in particular fungicidal, activity (cf. WOA 96-16048).

The process of the present invention is illustrated by the following examples.

Preparation examples

Example 1

a) Preparation of the Compounds of the formula

A mixture of 5.48g (20mmol) [2- (1-chloro-cycloprop-1-yl) -3- (2-chlorophenyl) -2-hydroxy ] -propyl-1-hydrazine, 40ml methyl tert-butyl ether, 0.9g (30mmol) paraformaldehyde and 1.84g (24mmol) ammonium thiocyanate was heated at 60 ℃ for 3 hours with stirring. After cooling to room temperature, the reaction mixture was diluted with methyl tert-butyl ether and washed with saturated aqueous sodium carbonate solution. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. 6.1g of product are obtained, which contains 86.9% 2- (1-chloro-cycloprop-1-yl) -1- (2-chlorophenyl) -2-hydroxy-3- (1, 2, 4-triazolidin-5-thione-1-yl) -propane, according to HPLC analysis. After addition of a small amount of dichloromethane, 2- (1-chloro-cycloprop-1-yl) -1- (2-chlorophenyl) -2-hydroxy-3- (1, 2, 4-triazol-ane-5-thione-1-yl) -propane precipitated as a crystalline solid.

Melting point: 152 ℃ and 154 DEG C

¹H NMR Spectrum (CDCl)₃，TMS，250MHz)：δ＝0.8-1.3(m，3H)；3.1(d，J＝14Hz，1H)；3.65(d，J＝14Hz，1H)；4.2(s，2H)；4.45-4.65(m，3H)；5.1(t，NH)；7.15-7.6(m，4H)ppm

b) Preparation of the Compounds of the formula

To a mixture of 1.72g (5mmol) of 2- (1-chloro-cycloprop-1-yl) -1- (2-chlorophenyl) -2-hydroxy-3- (1, 2, 4-triazolidin-5-thione-1-yl) -propane, 10ml of anhydrous toluene, 0.34g (6mmol) of potassium hydroxide powder and 10mg of sulfur powder heated to 70 ℃ was blown air with stirring for 3.5 hours. The progress of the reaction was monitored by HPLC analysis. After cooling to room temperature, the reaction mixture was diluted with methyl tert-butyl ether and washed repeatedly with saturated aqueous ammonium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. 2.2g of product are obtained, which contains 71%, according to HPLC analysis, of 2- (1-chloro-cycloprop-1-yl) -1- (2-chlorophenyl) -3- (4, 5-dihydro-1, 2, 4-triazole-5-thione-1-yl) -propan-2-ol. After recrystallization from toluene, the melting point of this material was 136-138 ℃.

Example 2

a) Preparation of the Compounds of the formula

A mixture of 2.78g (10mmol) of 3-chloro-2- (1-chloro-cyclopropan-1-yl) -1- (2-chlorophenyl) -propan-2-ol and 4.9ml (100mmol) of hydrazine hydrate was heated at 80 ℃ for 3 hours with stirring. The reaction mixture was then cooled to 20 ℃, 15ml of methyl tert-butyl ether was added and the aqueous phase was separated off. The organic phase is washed once with 5ml of water and then dried over 1g of sodium sulfate. The reaction mixture was filtered, mixed with 0.3g (10mmol) of paraformaldehyde and 0.76g (20mmol) of ammonium thiocyanate and heated at 55-60 ℃ for 3 hours with stirring. The mixture was cooled to room temperature, mixed with methyl tert-butyl ether and washed 3 times with saturated aqueous ammonium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. 2.4g of product are obtained, which contains 68.3% 2- (1-chloro-cycloprop-1-yl) -1- (2-chlorophenyl) -2-hydroxy-3- (1, 2, 4-triazolidin-5-thione-1-yl) -propane, according to HPLC analysis. After addition of a small amount of dichloromethane, 2- (1-chloro-cycloprop-1-yl) -1- (2-chlorophenyl) -2-hydroxy-3- (1, 2, 4-triazol-ane-5-thione-1-yl) -propane precipitated as a crystalline solid.

Melting point: 152 ℃ and 154 DEG C

b) Preparation of the Compounds of the formula

A mixture of 1.71g (5mmol)2- (1-chloro-cycloprop-1-yl) -1- (2-chlorophenyl) -2-hydroxy-3- (1, 2, 4-triazolidine-5-thione-1-yl) -propane, 12.5ml n-butyl acetate and 0.25g (7.5mmol) sulphur powder was heated at 100 ℃ for 9 hours with stirring, during which the progress of the reaction was monitored by HPLC analysis. The reaction mixture was cooled to room temperature, diluted with methyl tert-butyl ether and washed repeatedly with saturated aqueous ammonium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. 2.5g of product are obtained, which contains 72.2% 2- (1-chloro-cycloprop-1-yl) -1- (2-chlorophenyl) -3- (4, 5-dihydro-1, 2, 4-triazole-5-thione-1-yl) -propan-2-ol, according to HPLC analysis. After recrystallization from toluene, the melting point of this material was 137-138 ℃.

Example 3

A mixture of 27.8g (0.1mol) 3-chloro-2- (1-chloro-cycloprop-1-yl) -1- (2-chlorophenyl) -propan-2-ol and 48.5ml (1mol) hydrazine hydrate was heated under nitrogen with stirring at 100 ℃ for 5 hours. After cooling the two-phase system to room temperature, the hydrazine phase was decanted and the residue was washed once with 20ml of water. 25.9g of product are obtained, which contains 86.8% 2- (1-chloro-cyclopropan-1-yl) -3- (2-chlorophenyl) -2-hydroxy-propyl-1-hydrazine according to HPLC analysis. The calculated yield is 94.5% of theory. The crude material was recrystallized from acetonitrile to give 2- (1-chloro-cycloprop-1-yl) -3- (2-chlorophenyl) -2-hydroxy-propyl-1-hydrazine as a solid, m.p. 86-88 ℃.

¹H NMR Spectrum (400MHz, CDCl)₃，TMS)

δ＝0,8-1,05(m，3H)；1,25(m，1H)；2,7(d，1H)；2,95(d，1H)；3,45(d，1H)；3，6(d，1H)；

2,8-3,5(3H，NH)；4,6(1H，OH)；7,1-7,5(m，4H)ppm

Example 4

A mixture of 2.74g (10mmol) [2- (1-chloro-cycloprop-1-yl) -3- (2-chlorophenyl) -2-hydroxy ] -propyl-1-hydrazine, which has been recrystallized from acetonitrile, 10ml toluene and 0.5ml water is added beforehand at 0 ℃ under nitrogen. Formaldehyde gas (obtained by depolymerisation of 0.36g (12mmol) of paraformaldehyde at about 150 ℃) was passed into the mixture with a nitrogen stream with stirring at 0 ℃. After the addition was complete, stirring was continued for 30 minutes at 20 ℃ and the mixture was then mixed with 0.82g (10mmol) of sodium thiocyanate and 1.2g (10mmol) of sodium hydrogen sulfate. The resulting reaction mixture was stirred at 20 ℃ for 2 hours and then diluted with 100ml of dichloromethane. The solid was filtered off and the organic phase was concentrated under reduced pressure. 3.28g of product are obtained, which contains 98.6% 2- (1-chloro-cycloprop-1-yl) -1- (2-chlorophenyl) -2-hydroxy-3- (1, 2, 4-triazolidin-5-thione-1-yl) -propane, according to HPLC analysis. The calculated yield is 95% of theory.

Melting point: 157 ℃ and 158 ℃.

Example 5

A mixture of 2.74g (10mmol) [2- (1-chloro-cycloprop-1-yl) -3- (2-chlorophenyl) -2-hydroxy ] -propyl-1-hydrazine, which has been recrystallized from acetonitrile, and 10ml toluene is mixed with 0.74ml (10mmol) 40% formalin solution at 0 ℃ under nitrogen. After the addition was complete, the mixture was stirred for a further 30 minutes at 20 ℃ and then admixed with 0.82g (10mmol) of sodium thiocyanate and 1.2g (10mmol) of sodium hydrogen sulfate. The resulting reaction mixture was stirred at 20 ℃ for 2 hours and then diluted with 100ml of dichloromethane. The solid was filtered off and the organic phase was concentrated under reduced pressure. 3.3g of product are obtained, which contains 93.9% 2- (1-chloro-cycloprop-1-yl) -1- (2-chlorophenyl) -2-hydroxy-3- (1, 2, 4-triazolidin-5-thione-1-yl) -propane, according to HPLC analysis. The calculated yield is 90.2% of theory.

Melting point: 154 ℃ and 155 ℃.

Example 6

A mixture of 2.74g (10mmol) of [2- (1-chloro-cycloprop-1-yl) -3- (2-chlorophenyl) -2-hydroxy ] -propyl-1-hydrazine, which has been recrystallized from acetonitrile, and 10ml of toluene is mixed with 1.2g (10mmol) of sodium hydrogensulfate, 0.74ml (10mmol) of a 40% formalin solution and 0.82g (10mmol) of sodium thiocyanate, in this order, under nitrogen at 0 ℃. After the end of the addition, the mixture was stirred at 20 ℃ for 2 hours and then diluted with 100ml of dichloromethane. The solid was filtered off and the organic phase was concentrated under reduced pressure. 3.4g of product are obtained, which contains 83.1% 2- (1-chloro-cycloprop-1-yl) -1- (2-chlorophenyl) -2-hydroxy-3- (1, 2, 4-triazolidin-5-thione-1-yl) -propane, according to HPLC analysis. The calculated yield is 83% of theory.

Melting point: 136 ℃ and 138 ℃.

Comparative examples

Example A

A mixture of 3.12g (10mmol) of 2- (1-chloro-cycloprop-1-yl) -1- (2-chlorophenyl) -3- (1, 2, 4-triazol-1-yl) -propan-2-ol and 45ml of anhydrous tetrahydrofuran was mixed with 8.4ml (21mmol) of n-butyllithium in hexane at-20 ℃ and stirred for 30 min at 0 ℃. The reaction mixture was then cooled to-70 ℃ and mixed with 0.32g (10mmol) of powdered sulfur and stirred at-70 ℃ for 30 minutes. The mixture was warmed to-10 ℃, mixed with ice water and adjusted to pH5 by addition of dilute sulfuric acid. The mixture was extracted repeatedly with ethyl acetate, and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. This gives 3.2g of product which, according to GC analysis, contains 95% 2- (1-chloro-cycloprop-1-yl) -1- (2-chlorophenyl) -3- (4, 5-dihydro-1, 2, 4-triazole-5-thione-1-yl) -propan-3-ol. After recrystallization from toluene, the melting point of this material was 138-139 ℃.

Example B

3.12g (10mmol)2- (1-chloro-cycloprop-1-yl) -1- (2-chlorophenyl) -3- (1, 2, 4-triazolidin-1-yl) -propan-2-ol, 0.96g (30mmol) sulphur powder and 20ml dry N-methylpyrrolidone were heated at 200 ℃ for 44 hours with stirring. The reaction mixture was then concentrated under reduced pressure (0.2 mbar). The resulting crude product (3.1g) was recrystallized from toluene. This gives 0.7g (20% of theory) of 2- (1-chloro-cyclopropan-1-yl) -1- (2-chlorophenyl) -3- (4, 5-dihydro-1, 2, 4-triazole-5-thione-1-yl) -propan-2-ol as a solid, m.p. 138-.

Claims (11)

1. Process for preparing triazolinethione derivatives of formula (I)

Wherein

R¹And R²The same or different, each represents an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted aralkyl group, an optionally substituted arylalkenyl group, an optionally substituted aryloxyalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group,

it is characterized in that

a) In a first step, a hydrazine derivative of the formula (II)

Wherein

R¹And R²Each of which is as defined above, respectively,

with formaldehyde and a thiocyanate of the formula (III)

X-SCN (III)，

Wherein

X represents sodium, potassium or ammonium,

in the presence of a diluent and, if appropriate, in the presence of an acid, and

b) in a second step, the triazolidinethione compound of the formula (IV) formed is reacted

Wherein

R¹And R²Each of which is as defined above, respectively,

alpha) with an oxidizing agent, if appropriate in the presence of a catalyst and in the presence of a diluent,

or

Beta) with formic acid of the formula (V)

HCOOH (V)。

2. The process as claimed in claim 1, wherein the starting material is 2- (1-chloro-cyclopropan-1-yl) -3- (2-chlorophenyl) -2-hydroxy-propyl-1-hydrazine of the formula

3. The process according to claim 1, characterized in that the formaldehyde used for the first step is paraformaldehyde, gaseous formaldehyde or formaldehyde in the form of a formalin solution.

4. The process as claimed in claim 1, wherein the reactant used for carrying out the first reaction stage is ammonium thiocyanate.

5. The process as claimed in claim 1, wherein the reactant used for the first reaction stage is sodium thiocyanate in the presence of an acid.

6. The process as claimed in claim 1, wherein the reactant used for the first reaction stage is sodium thiocyanate in the presence of sodium hydrogen sulfate and water.

7. The process according to claim 1, characterized in that the first reaction stage is carried out at a temperature of-20 ℃ to +100 ℃.

8. The process of claim 1, characterized in that the second reaction step of scheme (α) is carried out at a temperature of 0 ℃ to 120 ℃.

9. The process as claimed in claim 1, wherein the second reaction stage of scheme (. beta.) is carried out at a temperature of from 50 ℃ to 100 ℃.

10. A triazolidinethione compound of formula (IV)

Wherein

R¹And R²The same or different, each represents an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted aralkyl group, an optionally substituted arylalkenyl group, an optionally substituted aryloxyalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group.

11. Process for preparing triazolinethione derivatives of formula (I)

Wherein

R¹And R²The same or different, each being optionally substitutedAn alkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted aralkyl group, an optionally substituted arylalkenyl group, an optionally substituted aryloxyalkyl group, an optionally substituted aryl group or an optionally substituted heteroaryl group,

it is characterized in that

1-chloro-2-hydroxy-ethane derivatives of formula (VI)Wherein R is¹And R²As defined above, with hydrazine hydrate, if appropriate in the presence of a diluent, reacting the hydrazine derivative of the formula (II) formedWherein R is¹And R²As defined above, directly without separation from formaldehyde and the thiocyanate of formula (III)

X-SCN (III), wherein X represents sodium, potassium or ammonium, in the presence of a diluent and, if appropriate, in the presence of an acid, and the triazolidinethione compounds of the formula (IV) which are formedWherein R is¹And R²Each of which is as defined above, respectively,

alpha) with an oxidizing agent, if appropriate in the presence of a catalyst and in the presence of a diluent, or

Beta) with formic acid of the formula (V)

HCOOH (V)。