Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-12-12
2003-05-06
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S263000
Reexamination Certificate
active
06559151
ABSTRACT:
The invention relates to 6-(2-trifluoromethyl-phenyl)-triazolopyrimidines of formula I
in which
R
1
and R
2
independently denote hydrogen or
C
1
-C
10
-alkyl, C
2
-C
10
-alkenyl, C
2
-C
10
-alkynyl, C
4
-C
10
-alkadienyl, or C
1
-C
10
-haloalkyl,
C
3
-C
8
-cycloalkyl, C
5
-C
10
-bicycloalkyl, phenyl, naphthyl, or 5- or 6-membered heterocyclyl, containing one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom, or
5- or 6-membered heteroaryl, containing one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom, or
where R
1
and R
2
radicals may be unsubstituted or partially or fully halogenated or may carry one to three groups R
a
,
R
a
is halogen, cyano, nitro, hydroxyl, C
1
-C
6
-alkyl, C
1
-C
6
-haloalkyl, C
3
-C
6
-cycloalkyl, C
1
-C
6
-alkoxy, C
1
-C
6
-haloalkoxy, C
1
-C
6
-alkylthio, C
1
-C
6
-alkylamino, di-C
1
-C
6
-alkylamino, C
2
-C
6
-alkenyl, C
2
-C
6
-alkenyloxy, C
2
-C
6
-alkynyl, C
3
-C
6
-alkynyloxy and C
1
-C
4
-alkylenedioxy, which may be halogenated; or
R
1
and R
2
together with the interjacent nitrogen atom represent a 5- or 6-membered heterocyclic ring, containing one to four nitrogen atoms or one to three nitrogen atoms and one sulfur or oxygen atom, which may be substituted by one to three R
a
radicals;
R
3
is hydrogen, halogen, C
1
-C
10
-alkyl, C
1
-C
10
-alkoaxy and C
1
-C
10
-haloalkyl;
n is 1, 2, or 3; and
X is halogen.
Moreover, the invention relates to processes for their preparation, compositions containing them and to their use for combating phytopathogenic fungi.
U.S. Pat. No. 4,567,263 discloses compounds of the formula
in which R
1
represents alkyl, halogen, alkoxy, cyano, cycloalkyl, aryl, aryloxy, arylthio, aralkyl, arylthio, arylalkyl, arylalkyloxy or arylalkylthio each optionally substituted by halogen or alkoxy; or (R
1
)
n
represents a benzene, indane or tetrahydronaphthalene ring fused with the phenyl ring, aromatic moieties in the above groups being optionally substituted by alkyl, alkoxy, halogen or cyano; n is 1 or 2; R
2
and R
3
are each hydrogen, alkyl or aryl, A represents a nitrogen atom or a CR
4
group, and R
4
is as R
2
but can also be halogen, cyano or alkoxycarbonyl or together with R
3
can form an alkylene chain containing up to two double bonds. The compounds are said to be active against various phytopathogenic fungi.
U.S. Pat. No. 5,593,996 embraces compounds of the general formula
in which R
1
represents an optionally substituted alkyl, alkenyl, alkadienyl, cycloalkyl, bicycloalkyl or heterocyclyl group; R
2
represents a hydrogen atom or an alkyl group; or R
1
and R
2
together with the interjacent nitrogen atom represent an optionally substituted heterocyclic ring; R
3
represents an optionally substituted aryl group; and R
4
represents a hydrogen or halogen atom or a group -NR
5
R
6
where R
5
represents a hydrogen atom or an amino, alkyl, cycloalkyl or bicycloalkyl group and R
6
represents a hydrogen atom or an alkyl group. These compounds are said to be active against fungi.
WO-A 98/46607 discloses funcidal triazolopyrimidines, which are substituted in the 6-position by a 2,4,6-trifluorophenyl group.
It is an object of the present invention to provide compounds having improved fungicidal activity.
We have found that this object is achieved by the compounds defined at the outset. Furthermore, we have found processes for their preparation, compositions comprising them and methods for controlling phytopathogenic fungi using the compounds I.
The compounds of the formula I differ from the compounds known from the abovementioned art in the 6-(2-trifluoromethyl)phenyl group.
The present invention further provides a process for the preparation of compounds of formula I as defined above which comprises treating a compound of formula IV
in which R
3
, n and X are as defined in formula I; with an amine of formula V
in which R
1
and R
2
are as defined in formula I to produce compounds of formula I.
Compounds of formula IV are novel and can be prepared by reacting 5-amino-triazole with 2-(2-trifluoromethyl-phenyl)-substituted malonic acid ester of formula II,
wherein R
3
and n are as defined for formula I, R represents alkyl, preferably C
1
-C
6
-alkyl, in particular methyl or ethyl, under alkaline conditions, preferably using high boiling tertiary amines as for example tri-n-butylamine as disclosed for example by EP-A770 615 to yield compounds of formula III.
The resulting 5,7-dihydroxy-6-phenyl-triazolopyrimidine of formula II;, wherein R
3
and n are as defined for formula I, is subsequently treated with a halogenating agent, preferably with a brominating or chlorinating agent, such as phosphorus oxybromide or phosphorus oxychloride, neat or in the presence of a solvent to give IV.
The reaction is suitably carried out at a temperature in the range from 0° C. to 150° C., the preferred reaction temperature being from 80° C. to 125° C. as disclosed for example by EP-A770 615.
The compounds of formula II are preferably prepared by reaction of the corresponding substituted bromobenzenes with sodium dialkylmalonates in the presence of a copper(I) salt [cf. Chemistry Letters, pp. 367-370, 1981].
The compounds of formula II are preferably prepared by reaction of an alkyl 2-(2-trifluoromethyl-phenyl)-acetate with dialkylcarbonate in the presence of a strong base, preferably sodium ethoxide and sodium hydride (cf. Heterocycles, pp. 1031-1047, 1996).
The reaction between the 5,7-dihalo-6-(2-fluoro-5-trifluorome-thyl-phenyl)-triazolopyrimidines of formula IV and the amine of formula V is preferably carried out in the presence of a solvent,
Suitable solvents include ethers, such as dioxane, diethyl ether and, especially, tetrahydrofuran, halogenated hydrocarbons such as dichloromethane and aromatic hydrocarbons, for example toluene.
The reaction is suitably carried out at a temperature in the range from 0° C. to 70° C., the preferred reaction temperature being from 10° C. to 35° C.
It is also preferred that the reaction is carried out in the presence of a base. Suitable bases include tertiary amines, such as triethylamine, and inorganic bases, such as potassium carbonate or sodium carbonate. Alternatively, an excess of the compound of formula V may serve as a base.
Accordingly, the invention relates to the novel intermediates of formula IV, in particular 5,7-dichloro-6-(5-fluoro-2-trifluorome-thyl-phenyl)-[1,2,4]triazolo[1,5-&agr;]pyrimidine, to the corresponding dialkyl-(3-fluoro-6-trifluoromethylphenyl)-malonates of formula II; and to 5,7-dihydroxy-6-(5-fluoro-2-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-&agr;]pyrimidine.
The substituted phenylacetates which are the starting compounds for compounds of formula II are known and commercially available, and/or they are obtainable by generally known methods.
The reaction mixtures are worked up in a customary manner, for example by mixing with water, phase separation and, if required, chromatographic purification of the crude products. Some of the intermediates and end products are obtained in the form of colorless or slightly brownish, viscous oils, which are purified or freed from volatile components under reduced pressure and at moderately elevated temperatures. If the intermediates and end products are obtained as solids, purification can also be carried out by recrystallization or digestion.
If individual compounds I are not obtainable by the routes described above, they can be prepared by derivatization of other compounds I.
In the symbol definitions given in the formulae above, collective terms were used which generally represent the following substituents:
halogen: fluorine, chlorine, bromine and iodine;
C
1
-C
4
-alkyl and the alkyl moieties of C
1
-C
4
-alkoxy, C
1
-C
4
-alkylthio, C
1
-C
4
-alkylamino, di-C
1
-C
4
-alkylamine or C
1
-C
4
-alkylcarbonyloxy: saturated, straight-chain or branched hydrocarbon radicals having 1 to 4 carbon atoms, specifically methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dime
Ammermann Eberhard
Blasco Jordi Tormo I
Cullman Oliver
Grote Thomas
Gypser Andreas
BASF - Aktiengesellschaft
Keil & Weinkauf
Liu Hong
Raymond Richard L.
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