6-phenyl-pyrazolopyrimidines

Details 6-phenyl-pyrazolopyrimidines 6-phenyl-pyrazolopyrimidines

2000-12-12

2003-04-22

Ford, John M. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C544S281000

Reexamination Certificate

active

06552026

ABSTRACT:

The present Invention relates to pyrazolopyrimidines of formula I
in which
R
1
is C
1
-C
10
-alkyl, C
2
-C
10
-alkenyl, C
2
-C
10
-alkynyl, C
2
-C
10
-alkadienyl, or C
1
-C
10
-haloalkyl,
 where these 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
1
-C
6
-alkylcarbonyl, C
3
-C
6
-cycloalkyl, C
1
-C
6
-alkoxy, C
1
-C
6
-haloalkoxy, C
1
-C
6
-alkoxycarbonyl, 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
3
-C
6
-alkynyloxy and C
1
-C
4
-alkylenedioxy, which may be halogenated;
 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,
 where the cyclic systems may be partially or fully halogenated or may carry one to three groups R
b
:
R
b
is halogen, cyano, nitro, hydroxyl, mercapto, amino, carboxyl, aminocarbonyl, aminothiocarbonyl, alkyl, haloalkyl, alkenyl, alkenyloxy, alkynyloxy, alkoxy, haloalkoxy, alkylthio, alkylamino, dialkylamino, formyl, alkylcarbonyl, alkylsulfonyl, alkylsulfoxyl, alkoxycarbonyl, alkylcarbonyloxy, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, where the alkyl groups in these radicals contain 1 to 6 carbon atoms and the abovementioned alkenyl or alkynyl groups in these radicals contain 2 to 8 carbon atoms;
Y is oxygen, sulfur, NR
2
or a single bond; wherein
R
2
represents a hydrogen atom or C
1
-C
10
-alkyl, C
2
-C
10
-alkenyl, C
2
-C
10
-alkynyl, C
2
-C
10
-alkadienyl, 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, where R
2
may be substituted by one or more R
a
, 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 or more R
c
radicals;
m is 0 or an integer from 1 to 4;
L each independently is halogen, nitro, C
1
-C
10
-alkyl, C
1
-C
10
-alkoxy, and
X is halogen.
Moreover, the invention relates to processes for preparing these compounds, to compositions comprising them and to their use for controlling phytopathogenic fungi.
U.S. Pat. No. 4,567,263 discloses pyrazolopyrimidines which are substituted in the 7-Position by an unsubstituted amino group. These compounds are said to be active against various phytopathogenic fungi.
International Patent Application WO-A 96/35690 embraces pyrazolo-pyrimidines, to which a substituted phenyl is attached in the 2-position by a phenyl optionally via a linking group.
U.S. Pat. No. 5,817,663 discloses pyrazolopyrimidines, which are substituted by a pentafluorophenyl group in the 6-Position.
However, none of these documents discloses specifically 5-halopyrazolopyrimidines which are substituted in the 6-Position by a phenyl group having up to 4 substituents.
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 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 L, m and X are as defined in formula I; with an alcohol, amine or thiol of formula V
R
1
—Y—M  V
in which R
1
and Y are as defined in formula I, and M represents a hydrogen atom or a free or complexed metal atom, to produce compounds of formula I.
For the preparation of the compounds wherein Y represents O, S or NR
2
, M is preferably a hydrogen atom or a alkali metal.
For the preparation of the compounds wherein Y represents a single bond, M represents a free or complexed metal atom, such as for example Li, Mg or Zn in the presence of a transition metal, in particular Cu.
Compounds of formula IV are novel and can be prepared by reacting 5-amino-pyrazole with 2-phenyl-substituted malonic acid ester of formula II,
wherein L and m 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-A 770 615.
The resulting 5,7-dihydroxy-6-phenyl-pyrazolopyrimidine of formula III
wherein L and m 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.
If phosphorus oxybromide or phosphorus oxychloride is used for the halogenation of III the presence of a mineralic acid, such as polyphosphoric acid, and pyridinium salts, preferably pyridinium halides, such as pyridinium bromide or chloride, is preferred.
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-A 770 615.
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, [e.g. Chemistry Letters, pp. 367-370, 1981].
Compounds of formula IVA are particularly preferred.
Accordingly, the Invention relates to the novel intermediates of formula IV, in particular 5,7-dichloro-6-(2,4,6-trifluorophenyl)pyrazolo[1,5-&agr;]pyrimidine and 5,7-dichloro-6-(2-chloro-6-fluorophenyl)pyrazolo[1,5-&agr;]pyrimidine, and to the corresponding 5,7-dihydroxy-6-phenyl-pyrazolo[1,5-&agr;]pyrimidines of formula III.
The reaction between the 5,7-dihalogen-6-phenyl-pyrazolopyrimidines of formula IV and the compound of formula V, wherein Y is 0, S or NR
2
, is preferably carried out in the presence of an inert 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.
The reaction between the 5,7-dihalogen-6-phenyl-pyrazolopyrimidines of formula IV and the compound of formula V, wherein Y represents a single bond, is conveniently carried out in the presence of a solvent.
Suitable solvents include ethers, such as dioxane, diethyl ether and, especially, tetrahydrofuran, hydrocarbons such as hexane, cyclohexane or mineral oil, and aromatic hydrocarbons, for example toluene, or mixtures of these solvents.
The reaction is suitably carried out at a temperature in the range from −100° C. to +100° C., the preferred reaction temperature being from −80° C. to +40° C.
It is also preferred that the reaction is carried out in the presence of copper ions, preferably equimolar amounts of copper(I) halides, in particular copper(I) iodide.
Furthermore the compounds of formula I, where

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