Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-10-07
2001-02-06
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S256000, C514S318000, C514S326000, C544S333000, C546S193000, C546S197000, C546S207000, C546S208000, C546S209000, C546S210000, C546S211000
Reexamination Certificate
active
06184234
ABSTRACT:
The present invention relates to methods for controlling insects. In particular, it relates to control by the application of certain novel N-(substituted arylmethyl)-4-[bis(substituted phenyl or pyridyl)methyl]piperidines to the locus where insect control is needed.
It has now been found that compounds of the following structure and their corresponding N-oxides, as well as their agriculturally acceptable salts, are active as insecticides:
in which U is —(CH
2
)
n
; Q is hydroxy; R is:
in which V, W, Y, and Z are each hydrogen; X is a five- or six-membered heterocycle; optionally substituted with halogen, cyano, alkyl, haloalkyl, alkoxyl, haloalkoxyl, alkoxyalkyl, haloalkoxyalkyl, or aminocarbonyl; and the heterocycle is optionally connected to the phenyl ring through a —O—, —S—, —(CH
2
)
p
—, —C(O)—, or —O(CR
3
R
4
)
q
— linkage; R
1
and R
2
are independently selected from phenyl or pyridyl substituted with haloalkyl, haloalkoxy, pentahalothio, haloalkylthio, haloalkylsulfinyl, or haloalkylsulfonyl; phenyl substituted with —OC(M)
2
O—, where M is halogen, to provide a dihalobenzodioxolyl fused ring; or pyridyl substituted with —OC(M)
2
O— to provide a dihalodioxolenopyridyl fused ring; R
3
and R
4
are independently selected from hydrogen and methyl; n and p are independently 1, 2, or 3; and q is 1 or 2; with the proviso that at least one of R
1
and R
2
is substituted in the para position of the phenyl ring or the 5-position of a 2-pyridyl ring; each alkyl portion of said optional substituent on X wherein the optional substituent is alkyl, haloalkyl, alkoxyl, haloalkoxyl, alkoxyalkyl, or haloalkoxyalkyl contains from 1 to 4 carbon atoms; halogen means bromine, chlorine, or fluorine; each heterocycle contains from 1 to 4 nitrogen atoms, or 1 or 2 oxygen or sulfur atoms, or 1 or 2 nitrogen atoms and an oxygen or sulfur atom; and the corresponding N-oxides and agriculturally acceptable salts thereof.
An embodiment of the present invention is that when q is 2, —O(CR
3
R
4
)
q
is —O(CHCH
3
CHCH
3
)—, —O(C(CH
3
)
2
CH
2
)— or —O(CH
2
C(CH
3
)
2
)—.
Preferred are those compounds in which in X the heterocycle is selected from 1,2,4-oxadiazolyl, oxazolinyl, pyridazinyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,3,5-triazinyl, and 1,2,4-triazolyl, optionally substituted with halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, or haloalkoxyalkyl, and the optional linkage is selected from —O—, —(CH
2
)
p
—, or —O(CHR
3
)
q
—; R
1
and R
2
are independently selected from trifluoromethylphenyl, trifluoromethoxyphenyl, trifluoromethylpyridyl, trifluoromethoxypyridyl, pentafluorothiophenyl, trifluoromethylthiophenyl, trifluoromethylsulfinylphenyl, trifluoromethylsulfonylphenyl, 2,2-dihalo-1,3-benzodioxolyl, pentafluorothiopyridyl, trifluoromethylthiopyridyl, trifluoromethylsulfinylpyridyl, trifluoromethylsulfonylpyridyl, and 2,2-dihalo-1,3-dioxoleno[4,5-b]pyridyl; n is 1, and p and q are independently 1 or 2; with the proviso that halogen means chlorine or fluorine; and the corresponding N-oxides and agriculturally acceptable salts.
Particularly preferred are those compounds in which X is a heterocycle selected from 1,2,4-oxadiazol-5-yl, oxazolin-2-yl, pyrazol-3-yl, pyridin-2-yl, pyrimidin-2-yl, pyrol-3-yl, 2H-tetrazol-5-yl, 1,2,3-thiadiazol-4-yl, 1,2,4-triazol-3-yl, optionally substituted with halogen, cyano, alkyl, haloalkyl, or alkoxyalkyl, and the optional linkage is selected from —O—, —OCH
2
—, or —OCH(CH
3
); R
1
and R
2
are independently selected from p-trifluoromethoxyphenyl, p-trifluoromethylphenyl, 5-trifluoromethylpyrid-2-yl, 5-trifluoromethoxypyrid-2-yl, p-pentafluorothiophenyl and 2,2difluoro1,3-benzodioxol-5-yl; and the corresponding N-oxides and agriculturally acceptable salts. More preferred are those compounds in which X is 2H-tetrazol-5-yl optionally substituted in the 2 position; X is pyridin-2-yl optionally substituted in the 6-position; and X is pyrimidin-2-yl, optionally substituted in the 4-position.
The N-oxides include the piperidine N-oxides, the pyridine N-oxides, or both.
Preferred moieties substituting the five- or six- membered heterocycle representing X is —CH
2
OCH
3
and the haloalkyl —CH
2
)
r
F, where r is 1, 2, or 3, CHF
2
, and CF
3
.
The compounds of the present invention were prepared by methods generally known to those skilled in the art. In the method shown in Schema 1, where R
1
and R
2
are the same, ethyl piperidin4-ylcarboxylate was reacted with either an appropriately substituted alkyl halide, for example, 4-methoxyphenylmethyl bromide, or with an appropriately substituted aldehyde under reductive conditions, for example, 4-phenoxybenzaldehyde, affording the corresponding ethyl N-substituted alkylpiperidin-4-ylcarboxylate (A). Intermediate (A) was then treated with more than two molar equivalents of the Grignard reagent of an appropriately substituted halide, for example, 4-trifluoromethoxyphenyl magnesium bromide, yielding the desired N-(substituted alkyl)4-[bis(substituted)hydroxymethy]piperidine (I), for example, N-(4-methoxyphenylmethyl)-4[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine (Compound 1). Example 1 provides a detailed description of how these reactions are conducted.
Compound (I) of the present invention, as depicted in Schema 1, can be further reacted to obtain additional compounds within the scope of Compound (I). For example, compounds where R
1
and R
2
are phenyl substituted with haloalkylthio can be converted to the corresponding compounds where R
1
and R
2
are phenyl substituted with haloalkylsulfinyl or haloalkylsulfonyl by the mild oxidation of the haloalkylthio moiety with sodium perborate [Synth. Commun.; 1993, 23 (6), 765-769].
Another method, again for cases where R
1
and R
2
are the same, is shown in Schema 2. In this method ethyl piperidin-4-ylcarboxylate is reacted with diethyl carbamoyl chloride, under basic conditions, affording the corresponding intermediate, ethyl N-diethylaminocarbonylpiperidin-4-yl-carboxylate (B). Intermediate (B) is treated with more than two molar equivalents of the Grignard reagent of an appropriately substituted halide, yielding the corresponding N-diethylaminocarbonyl-4-[bis(substituted phenyl or pyridyl)hydroxymethyl]piperdine (C). Intermediate (C) is then treated with lithium aluminum hydride, affording the 4-[bis(substituted phenyl or pyridyl)hydroxymethyl]piperidine (II), for example, 4-[bis(4trifluoromethoxyphenyl)hydroxymethyl]piperidine. As depicted in Schema 2a, intermediate (II) may be reacted with either an appropriately substituted alkyl halide or with an appropriately substituted aldehyde, as previously described, affording the desired N-(substituted alkyl)-4-[bis(substituted phenyl or pyridyl)hydroxymethyl]piperidine (I), for example, N-[4-(2-methyltetrazol-5-yl)phenylmethyl]-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine (Compound 9).
For the preparation of those compounds in which R
1
and R
2
may be pyridyl, the appropriate pyridyl bromide is lithiated at −78° C. with tert-butyllithium, and the resulting product is used as described for the magnesium Grignard reagents.
The preparation of intermediate (II) using the method described above provided relatively low yields of (II). In a preferred method to prepare the intermediate 4-[bis(substituted phenyl)hydroxymethyl]piperidine (II), ethyl piperidin-4-ylcarboxylate was reacted with chlorotrimethylsilane under basic conditions in diethyl ether, affording ethyl N-(trimethylsilyl)piperidin-4-yl-carboxylate. The so-prepared ethyl carboxylate was then reacted with more than two molar equivalents of the Grignard reagent of an appropriately substituted halide, a method previously described, affording intermediate (II) Both steps of this method provided product in good yield. Example 3 provides a detailed description of how this reaction is conducted. Schema 3 shows this method.
The intermediate 4-[bis(substit
Ali Syed F.
Cohen Daniel H.
Cullen Thomas G.
Henrie II Robert N.
Lyga John W.
Chang Ceila
FMC Corporation
FMC Corporation
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