Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-07-06
2002-03-26
Rotman, Alan L. (Department: 1609)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S333000, C514S341000, C544S298000, C544S333000, C544S334000, C544S335000, C546S255000, C546S276100
Reexamination Certificate
active
06362192
ABSTRACT:
The present invention relates to compounds of the formula I
and salts thereof, in which the substituents and the index n have the following meanings:
Q is —C(═CHCH
3
)—COOCH
3
,
—C(═CHOCH
3
)—COOCH
3
,
—C(═NOCH
3
)—COOCH
3
or
—C(═NOCH
3
)—CONH(CH
3
);
R
1
is hydrogen, halogen, C
1
-C
4
-alkyl, C
1
-C
2
-haloalkyl, C
1
-C
4
-alkoxy or C
1
-C
2
-haloalkoxy;
R
2
is halogen, C
1
-C
4
-alkyl, C
1
-C
2
-haloalkyl, C
1
-C
4
-alkoxy;
n is 0, 1 or 2, where the substituents R
2
may be different if n=2;
R
3
is phenyl, pyridyl or pyrimidyl, where the phenyl, pyridyl or pyrimidyl radical may carry one or, independently of one another, two or three of the following substituents: halogen, cyano, C
1
-C
4
-alkyl, C
1
-C
2
-haloalkyl, C
1
-C
4
-alkoxy, C
1
-C
2
-haloalkoxy or C
1
-C
4
-alkoxycarbonyl.
Patent EP-A 579 071 describes, in a general way, hetaryl acetic acids, in particular those having a 5-ring-hetaryl radical, as crop protection agents. Pyridin-3-ylacetic acid derivatives which are substituted in position 2 and have fungicidal activity are described in WO-A 95/06033 and WO-A 98/12179. WO-A 98/12179 additionally mentions an activity of the compounds claimed against animal pests.
Finally, WO-A 97/24332 discloses phenylacetic acid derivatives having a pyrazolyloxy substituent ortho to the acetic acid group which are active against harmful fungi and animal pests.
However, with respect to the activity spectra and application rates, the prior art compounds of this type are not satisfactory.
It is an object of the present invention to provide improved active compounds against harmful fungi and animal pests.
We have found that this object is achieved by the compounds I defined at the outset and their salts.
Furthermore, we have found compositions for controlling harmful fungi and animal pests which comprise the compounds I or salts thereof, and the use of the compounds I and salts thereof and of the compositions comprising them for this purpose.
The compounds I can be obtained a variety of ways by processes known per se. In principle, it is immaterial during their synthesis whether the pyrazolyloxy radical in position 2 or the grouping “Q” in position 3 at the pyridine ring is constructed first.
The compounds I are obtainable for example via the compounds Z (Synthetic route 1) which for their part are obtainable by reaction of compounds of the formula II with hydroxypyrazoles of the formula III.
where:
L is a leaving group customary for nucleophilic aromatic substitution, such as fluorine, chlorine, bromine or the nitro group and, in particular, chlorine or fluorine;
W is a group which makes possible or facilitates the nucleophilic exchange of the group L and which additionally—as described below—can be converted into the group Q of the compounds I, eg.: —CO—CO—OR′, —CO—CO—NHR′, —CO—OR′ or —CO—CH
3
(R′=C
1
-C
4
-alkyl), in particular —CO—CO—OCH
3
.
1a) This reaction is usually carried out at 0-120° C., preferably at 20-60° C.
Suitable solvents are aromatic hydrocarbons such as toluene, o-, m- and p-xylene, halogenated hydrocarbons such as methylene chloride, chloroform and chlorobenzene, ethers such as diethyl ether, diisopropyl ether, tert-butyl methyl ether, dioxane, anisole and tetrahydrofuran, nitriles such as acetonitrile and propionitrile, and dimethyl sulfoxide, dimethylformamide, dimethylacetamide, 1,3-dimethylimidazolidin-2-one and 1,3-dimethyltetrahydro-2(1H)-pyrimidinone; particular preference is given to dimethyl sulfoxide, dimethylacetamide and dimethylformamide.
It is also possible to use mixtures of the abovementioned solvents.
In general, suitable bases are: basic, inorganic compounds, for example alkali metal and alkaline earth metal hydrides such as lithium hydride, sodium hydride, potassium hydride, calcium hydride, alkali metal and alkaline earth metal carbonates such as potassium carbonate and calcium carbonate, furthermore silver carbonate and alkali metal bicarbonates such as sodium bicarbonate, organometallic compounds and alkali metal and alkaline earth metal alkoxides such as potassium methoxide, potassium tert-butoxide and dimethoxymagnesium. Organic bases, for example tertiary amines such as trimethylamine, triethylamine, diisopropylethylamine and n-methylpiperidine, pyridine, substituted pyridines such as collidine, lutidene and 4-dimethylaminopyridine and bicyclic amines are also suitable. Particular preference is given to sodium hydride, potassium carbonate and potassium tert-butoxide.
The bases are generally employed in equimolar amounts or, if appropriate, as solvent.
For the reaction, it may be advantageous initially to treat the compounds III with base and to react the resulting salt with the compound II.
Furthermore, it may be advantageous for the reaction to add a catalytic amount of a crown ether such as, for example, 18-crown-6 or 15-crown-5 or any other customary phase-transfer catalyst.
Suitable for use as phase-transfer catalysts are ammonium halides and ammonium tetrafluoroborates such as benzyltriethylammonium chloride, benzyltributylammonium bromide, tetrabutylammonium chloride, hexadecyltrimethylammonium bromide or tetrabutylammonium tetrafluoroborate and phosphonium halides such as tetrabutylphosphonium chloride or tetraphenylphosphonium bromide.
The starting materials II required for preparing the compounds I are known from the literature [WO-A 95/06033; J.Heterocycl.Chem. 30 (1993), 717; WO-A 97/17328; WO-A 97/24317], or they can be prepared in accordance with the literature quoted.
For example, the &agr;-keto esters IIa (W=—CO—CO—OCH
3
) can be synthesized as shown in Scheme 1.
1b) The reaction of the pyridylcarboxylic acid A to give acyl chloride B is carried out in a manner known per se [Houben-Weyl, Supplement Volume 5, p. 59 ff., 225 ff. and 664 ff.; J.Heterocycl.Chem, 30 (1993), 771] using customary chlorinating agents at 0° C.-150° C., preferably at 10° C.-100° C., if appropriate in the presence of an inert organic solvent. Suitable chlorinating agents are all reagents which are customarily used for this purpose, in particular SOCl
2
, (COCl)
2
, PCl
3
, AlCl
3
and PCl
5
. The chlorinating agents are generally employed in excess or, if appropriate, as solvent.
1c) The reaction of the acyl chloride B to give cyanide C is carried out in a manner known per se [WO-A 97/29093] at 0° C.-150° C., preferably at 10° C.-100° C., using an inorganic cyanide in an inert organic solvent, if appropriate as a mixture with water in the presence of a customary phase-transfer catalyst (for example trialkylammonium halides such as tributylammonium chloride or bromide).
Suitable inorganic cyanides are cyanides of metals of the first main group or of the sub-groups of the Periodic Table, for example lithium, sodium, potassium, copper and silver, in particular copper and sodium, and organic cyanides such as trimethylsilyl cyanide.
1d) The reaction of the cyanide C to give &agr;-keto ester IIa is carried out in a manner known per se via a Pinner reaction [WO-A 97/29093] at 0° C.-150° C., preferably at 10° C.-100° C., in the presence of an acid, using methanol as solvent.
The &agr;-keto esters IIaa, which carry a chlorine substitutent in positon 2 of the pyridine ring, can be prepared, as shown diagrammatically in Scheme 2, in only one step starting from 2-chloro- 3-iodo- or 2-fluoro-3-iodopyridines D in a Grignard reaction (cf. Tetrahedron, 52 (1996), 13513-20), or by ortho-metallation of 2-chloro- or 2-fluoropyridines of the formula E and subsequent reaction with methyl &agr;-oxo-&agr;-(1H-imidazol)acetate (J. Heterocyclic Chem., 34 (1997), 789).
The starting materials III are likewise disclosed in the literature, or they can be prepared by the processes described therein. 3-
Hydroxypyrazoles:
J. Heterocycl. Chem. 30 (1993), page 49; Chem. Ber. 107 (1974), page 1318; Chem. Pharm. Bull. 19 (1971), page 1369; Tetrahedron Lett. 11 (1970), page 875; Chem. Heterocycl. Comp. 5 (1969), page 527; Chem. Ber. 102 (1969), page 3260; Chem. Ber. 109 (19
Ammermann Eberhard
Bayer Herbert
Cullmann Oliver
Gewehr Markus
Götz Roland
BASF - Aktiengesellschaft
Covington Raymond
Keil & Weinkauf
Rotman Alan L.
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