Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-08-06
2004-04-13
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C564S310000, C564S314000
Reexamination Certificate
active
06720428
ABSTRACT:
The present invention relates to a novel process for preparing 2-(1,2,4-triazol-1-yl)-ethanols having microbicidal, in particular fungicidal, properties.
It is already known that numerous 2-(1,2,4-triazol-1-yl)-ethanols can be prepared by reacting appropriately substituted oxiranes with 1,2,4-triazole in the presence of a base and a diluent. However, this process has the disadvantage that, in addition to the desired 1,2,4-triazol-1-yl compounds (=“asymmetric triazole”), varying proportions of interfering 1,3,4-triazol-1-yl derivatives (=“symmetric triazole”) are also obtained (cf. Tetrahedron Lett. 30 (1989) 4013-4016). Naturally, this reduces the yield of the 1,2,4-triazol-1-yl derivative. Moreover, removal of the interfering 1,3,4-triazol-1-yl compound renders work-up more difficult, so that the yield of 1,2,4-triazol-1-yl derivative is frequently reduced even further.
It is also already known that 1,2,4-triazoles which are substituted in the 1-position can be obtained by reacting substituted hydrazines with [2-aza-3-(dimethylamino)-2-propene-1-ylidene]-dimethylimmonium chloride (“Gold's reagent”) (cf. Angew. Chem. 72 (1960) 956-959). However, the yields are not satisfactory. A further disadvantage is the fact that 2 mol of dimethylamine are produced per mole of triazolyl derivative.
It is furthermore already known that 1,2,4-triazoles which are substituted in the 1-position can be obtained by reacting hydrazine derivatives with formamidine acetate (cf. “N—C—N Chemicals; Formamidine; Building block for heterocycles and intermediates”, company publication from SKW Trostberg AG, 1989). Thus, 2-(1-chloro-cyclopropyl)-1-(2-chloro-phenyl)-3-(1,2,4-triazol-1-yl)-propane-2-ol can be synthesized by reacting 2-(1-chloro-cyclopropyl)-2-(2-chlorobenzyl)-oxirane with hydrazine hydrate, followed by reaction of the resulting 2-(1-chloro-cycloprop-1-yl)-3-(2-chlorophenyl)-2-hydroxy-propyl-hydrazine with formamidine acetate (cf. DE-A 40 30 039). However, it is disadvantageous that the yield of the desired target product is relatively low.
It has now been found that 2-(1,2,4-triazol-1-yl)-ethanols of the formula
in which
A
1
and A
2
independently of one another represent a direct bond, represent optionally halogen-substituted alkanediyl, represent optionally halogen-substituted alkenediyl, represented optionally halogen-substituted alkinediyl or represent alkanediyl in which a methylene group is replaced by oxygen,
R
1
and R
2
independently of one another represent hydrogen, represent optionally substituted cycloalkyl or represent optionally substituted aryl and
R
3
and R
4
independently of one another represent hydrogen or represent optionally substituted alkyl or
R
3
and R
4
together with the carbon atom to which they are attached represent optionally substituted cycloalkyl, or
R
1
, A
1
and R
3
together with the carbon atoms to which they are attached represent cycloalkyl,
A
2
represents a direct bond, represents optionally halogen-substituted alkanediyl, represents optionally halogen-substituted alkenediyl, represents optionally halogen-substituted alkinediyl or represents alkanediyl in which one methylene group has been replaced by oxygen,
R
2
represents hydrogen, represents optionally substituted cycloalkyl or represents optionally substituted aryl and
R
4
represents hydrogen or represents optionally substituted alkyl, or
R
3
and R
4
represent hydrogen and the groups
R
1
—A
1
— and R
2
—A
2
— together with the carbon atom to which they are attached represent a radical of the formula
can be prepared by reacting hydrazine derivatives of the formula
in which
A
1
, A
2
, R
1
, R
2
, R
3
and R
4
are as defined above
with N-dihalogenomethyl-formamidinium halide of the formula
in which
X represents chlorine or bromine,
if appropriate in the presence of a diluent.
It is extremely surprising that 2-(1,2,4-triazol-1-yl)-ethanols of the formula (I) can be prepared by the process according to the invention in a smooth reaction, since the prior art indicated that there would be interfering side-reactions and decomposition of N-dihalogenomethyl-formamidinium halide of the formula (III). Thus, it follows from Ber. dtsch. Chem. Ges. 16 (1883) 308-311 that N-dichloromethyl-formamidinium chloride is decomposed by water or alcohols. Furthermore, Chem. Ber. 35, (1902) 2496-2511 describes that one equivalent of N-dichloromethylformamidinium chloride reacts easily and completely with two equivalents of a primary amine of the formula R—NH
2
with elimination of three equivalents of hydrogen chloride to give one equivalent of formamidine and one equivalent of disubstituted formamidine of the formula R—N═CH—NH—R. The reaction of o-phenylenediamine with N-dichloromethyl-formamidinium chloride gives benzimidazole (cf. Chem. Ber. 35 (1902), 2496-2511). Phenylhydrazine reacts with N-dichloromethylformamidinium chloride like primary amine; however, the formamidine derivative formed is oxidized further by atmospheric oxygen or a third equivalent of phenylhydrazine to give diphenylformazane of the formula Ph—N═N—CH═N—NH—Ph (cf. Chem. Ber. 35 (1902), 2496-2511). The formation of 1-phenyl-1,2,4-triazole from phenylhydrazine and N-dichloromethyl-formamidinium chloride has not been reported. Taking into account these known reactions, it was without any doubt contrary to expectations that the reaction according to the invention would give the desired type of products in high yield.
The process according to the invention has a number of advantages. Thus, as already mentioned, it makes possible the synthesis of 2-(1,2,4-triazol-1-yl)-ethanols of the formula (I) in high yield, free from the corresponding “symmetric” triazole derivatives. Moreover, it is favourable that the required starting materials and reaction components can be prepared in a simple manner and are available even in relatively large amounts. Finally, it is a further advantage that the yields are higher than those for comparable reactions of hydrazines with formamidine acetate or “Gold's reagent”. Compared to the use of “Gold's reagent”, it is furthermore favourable that the reactions according to the invention with N-dihalogenomethyl-formamidinium halide produce only hydrogen halide and ammonia.
Using [1-(2-chlorophenyl)-2-(1-chloro-cyclopropyl)-2-hydroxy]-propylhydrazine hydrochloride and N-dichloromethyl-formamidinium chloride as starting materials, the course of the process according to the invention can be illustrated by the formula scheme below.
The formula (II) provides 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 hydrazine derivatives of the formula (II) in which
A
1
represents a direct bond, represents optionally halogen-substituted, straight-chain or branched alkanediyl having 1 to 4 carbon atoms, represents optionally halogen-substituted, straight-chain or branched alkenediyl having 2 to 4 carbon atoms, represents optionally halogen-substituted straight-chain or branched alkinediyl having 2 to 4 carbon atoms or represents straight-chain or branched alkanediyl in which one methylene group has been replaced by oxygen, having 2 to 4 chain members,
A
2
represents a direct bond, represents optionally halogen-substituted straight-chain or branched alkanediyl having 1 to 6 carbon atoms, represents optionally halogen-substituted straight-chain or branched alkenediyl having 2 to 6 carbon atoms or represents optionally halogen-substituted straight-chain or branched alkinediyl having 2 to 6 carbon atoms,
R
1
represents cycloalkyl having 3 to 7 carbon atoms which is optionally mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine and/or alkyl having 1 to 4 carbon atoms or represents aryl having 6 to 10 carbon atoms which may be mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, bromine, alkyl having 1 to 4 carbon atoms, cyano,
Bayer Aktiengesellschaft
Harmuth Raymond J.
Henderson Richard E. L.
McKane Joseph K.
Shameem Golam M M
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