Substituted cyclohexylaminopyrimidines

Details Substituted cyclohexylaminopyrimidines Substituted cyclohexylaminopyrimidines

1999-07-29

2001-03-06

Shah, Mukund J. (Department: 1624)

Plant protecting and regulating compositions

Plant growth regulating compositions

Organic active compound containing

C504S239000, C504S240000, C504S242000, C504S243000, C544S293000, C544S319000, C544S326000, C544S329000

Reexamination Certificate

active

06197729

ABSTRACT:

The invention relates to new substituted cyclohexylaminopyrimidines and their use as pesticides, especially insecticides and acaricides.
In our WO 93/19050, we have described pyrimidines inter alia substituted in the 4-position by cycloalkylamino. One substituent described on the cyclohexyl group is haloalkyl. However no compounds are exemplified in this application with such substituents and especially no compounds are disclosed with a fluoroalkyl substituent.
In our WO 9611913 we have disclosed other 4-cyclohexylaminopyrimidines, in which the cyclohexyl can be substituted by various substituted alkyl groups. Only three such compounds are disclosed carrying a fluorinated alkyl group. two of these carry an extra substituent, namely hydroxy and cyclohexyl respectively and the third group is isopropyl substituted by only one fluorine.
We have now found that certain fluoroalkyl-substituted cyclohexylamino compounds have especially valuable properties.
Thus the invention provides the use as pesticides of compounds of formula I
where
R
1
is hydrogen, chlorine, fluorine or methyl,
R
2
and R
3
, which may be the same or different from each other, are hydrogen, halogen, cyano, (C
1
-C
4
)-alkyl, vinyl, ethynyl, (C
1
-C
4
)-alkoxy, (C
1
-C
4
)-alkoxy-(C
1
-C
4
)-alkyl, fluorovinyl or fluoroethyl, or
R
2
and R
3
together with the linking carbon atoms form a benzo ring, and
R
4
is (C
2
-C
4
)-alkyl, (C
2
-C
4
)-alkenyl or (C
3
-C
4
)-alkinyl, each of which is substituted by at least two fluorine atoms and optionally substituted by C
1-4
-alkoxy, cyanomethoxy, (C
3
-C
4
)-alkenyloxy or (C
3
-C
4
)-alkynyloxy,
and acid addition salts.
Most of the compounds of formula I are novel and the invention includes compounds of formula I as defined above with the proviso that R
4
is not 3,3,3-trifluoropropyl or 2,2,2-trifluoro-1-methylethyl when R
2
is ethyl and R
3
is chloro; and R
4
is not 2,2,2-trifluoro-1-methylethyl when R
2
is methyl and R
3
is chloro or bromo.
It generally preferred that
R
1
is hydrogen,
R
2
is (C
1
-C
4
)-alkyl, especially ethyl or methoxymethyl,
R
3
is preferably hydrogen, methoxy, ethynyl or halogen, especially chlorine or fluorine.
R
4
preferably includes a trifluoromethyl group. Particularly preferred groups for R
4
are 3,3,3-trifluoropropyl or 2,2,2-trifluoro-1-methylethyl.
The present invention relates to the compounds of the formula I in the form of the free base or an acid addition salt. Acids which can be used for salt formation are inorganic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or organic adds, such as formic acid, acetic acid, propionic acid, malonic acid, oxalic acid, fumaric acid, adipic acid, stearic acid, oleic acid, methanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid.
In the compounds of the invention, the NH and R
4
are in a cis configuration. The compounds may contain one or more asymmetric carbon atoms or stereoisomeric producing double bonds. Enantiomers or diastereomers can therefore occur. The invention relates both to pure isomers and to mixtures thereof. The mixtures of diastereomers can be separated into the components by customary methods, for example by selective crystallisation from suitable solvents or by chromatography. Racemates can be separated into the enantiomers by customary methods, thus, for example, by salt formation with a chiral, enantiomerically pure acid, separation of the diastereomeric salts and liberation of the pure enantiomers by means of a base.
The compounds of formula I may be prepared in known manner, for example by reacting a compound of formula II
where R
1
, R
2
and R
3
are as defined under formula I and L is a leaving group, for example halogen, alkylthio, alkanesulfonyloxy, arylsulfonyloxy, alkylsulfonyl or arylsulfonyl, with a nucleophile of formula III
where R
4
is as defined above under formula I, and, if desired, converting the compound of the formula I obtained in this manner or in another manner into its acid addition salt.
The leaving group L can be varied within wide limits and can be, for example, halogen, such as fluorine, chlorine, bromine or iodine; alkylthio, such as methyl- or ethylthio; alkylsulfonyloxy, such as methane-, trifluoromethyl- or ethylsulfonyloxy; arylsulfonyloxy, such as benzenesulfonyloxy; or toluenesulfonyloxy, alkylsulfonyl such as methyl- or ethylsulfonyl; or arylsulfonyl such as phenyl- or tolylsulfonyl.
The abovementioned reaction is generally carried out in a temperature range from 20-150° C., advantageously in the presence of a base and, if appropriate, in an inert organic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidin-2-one, dioxane, tetrahydrofuran, 4-methyl-2-pentanone, methanol, ethanol, butanol, ethylene glycol, ethylene glycol dimethyl ether, toluene, chlorobenzene or xylene. It is also possible to employ mixtures of these solvents.
Suitable bases are, for example, alkali metal or alkaline earth metal carbonates, bicarbonates, hydroxides, amides or hydrides, such as sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydroxide, sodium amide or sodium hydride, or organic bases, such as triethylamine or pyridine, or a second equivalent of the nucleophile of formula III.
The compounds of the formula II are in most cases known from the literature or can be prepared by methods similar to those that are known (cf. EP-A-370 391, EP-A-470 600, DE-A-43 31 179, DE-A-44 04 702).
The nucleophiles of the formula III can be prepared by known processes, for example by reducing an oxime or an azide with a suitable reducing agent, for example a complex metal hydride or hydrogen in the presence of a hydrogenation catalyst, reductive amination or Leuckart-Wallach reaction of a ketone or Gabriel reaction of an alkyl halide or alkyl tosylate.
A method suitable for preparing the cyclohexylamines of formula III, is the reductive amination of appropriately substituted cyclohexanones with ammonium salts and sodium cyanoborohydride or with ammonium and hydrogen in the presence of metal catalysts such as nickel, ruthenium, rhodium or palladium, the proportion of the desired cis-amine being particularly high with this method.
A further method is the hydrogenation of anilines or aromatic nitro compounds in the presence of hydrogenation catalysts.
Some suitably substituted cyclohexanone intermediates are known from the literature, or they can be prepared by known synthesis processes. Such processes are, for example:
a) hydrogenation of the phenol ring and oxidation of the resulting cyclohexanol, the fluorine-containing radical R
4
being synthesised by standard processes.
b) derivatisation of a mono-protected cyclohexane-1,4-dione:
At least of R, R
1
or R
4
contains fluorine.
c) derivatisation of a protected cyclohexanone
Further processes:
Some of the reactions described above can in principle also be carried out on heterocycle precursors of the formulae IV (cf. DE-A-4331178).
Further possibilities for synthesising the final products of the formula I are the application of known halogenating reactions on appropriate heterocycle precursors, such as, for example, the conversion of alcohol derivatives into halogen-containing radicals R
4
; for example
Aldehydes and ketones of formula V, where R
6
is hydrogen or C
1-6
-alkyl and n is 1 to 3, can be fluorinated to give compounds of the invention as follows.
The compounds of formula V, which are novel, can be prepared for example by oxidising the appropriate alcohols. In the case of the aldehydes (R
6
=HO, the alcohols can be obtained by reduction of the corresponding ester. These intermediates are also novel. The invention thus includes compounds of formula VI
where R
6′
is hydrogen or C
1-6
-alkyl and n is 1 to 3.
Collections of compounds of the formula (I) which can be synthesised by the schemes above, may also be prepared in a parallel manner, and this may be effected manually or in a semiautomated or fully automated manner. In this case, it is possible, for example, to

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