Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-09-02
2001-04-10
Chang, Ceila (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S256000, C514S318000, C544S333000, C546S193000, C546S207000, C546S208000, C546S209000, C546S210000, C546S211000
Reexamination Certificate
active
06214845
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, alkoxy, haloalkoxy, 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 or haloalkoxy;
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; no more than two of R
3
and R
4
are methyl; each aliphatic moiety contains not more than 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.
Preferred are those compounds in which
in X the heterocycle is selected from 1,2,4-oxadiazolyl, oxazolinyl, pyridazinyl, pyrazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrolyl, 2H-tetrazol-5-yl, 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, and trifluoromethoxypyridyl;
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, pyrid-2-yl, pyrimidin-2-yl, pyrol-3-yl, 2H-tetrazol-5yl, 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—, —O—CH
2
—, or —O—CH(CH3);
R
1
and R
2
are independently selected from p-trifluoromethoxyphenyl, p-trifluoromethylphenyl, 5-trifluoromethylpyrid-2-yl, and 5-trifluoromethoxypyrid-2-yl;
and the corresponding N-oxides and agriculturally acceptable salts.
The N-oxides include the piperidine N-oxides, the pyridine N-oxides, or both.
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 piperidin-4-ylcarboxylate was reacted with either an appropriately substituted alky 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)hydroxymethyl]piperdine (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.
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-diethylaminocarbonylpiperdin-4-ylcarboxylate (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]piperidine (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(4-trifluoromethoxyphenyl)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-ylcarboxylate. 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(substituted phenyl or pyridyl)hydroxymethyl]piperidine (II) described above, can also be reacted, as shown in Schema 2a, with an appropriately substituted acid chloride, for example, 4-(1-methyltetrazol-5-yl)benzoyl chloride, under basic conditions, yielding the corresponding N-(substituted carbonyl)-4-[bis-(substituted phenyl or pyridyl)hydroxymethyl]piperidine (G). Intermediate (G) is reduced with borane-methyl sulfide complex, affording the desired N-(substituted alkyl)-4-[bis(substituted)hydroxymethyl]piperidine (I), for example, N-[4-(1-methyltetrazol-5-yl)phenylmethyl]-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine (Compound 8).
Schema 4 shows the method used when R
1
and R
2
are not the same. Here 4-aminocarbonylpiperidine is reacted with an appropriately substituted alkyl halide, for example, 4-(1,3-dioxolan-2-yl)phenylmethyl chloride, under basic conditions, affording the corresponding N-(substituted alkyl)-4-aminocarbonylpiperidine (H). Treatment of intermediate (H) with phosphorous oxychloride yields the corresponding N-(substituted alkyl)-4-cyanopiperidine (J), which is in turn reacted with the Grignard reagent of an appropriately substituted halide, for example, 2-trifluoromethoxyphenylmagnesium bromide, yielding the corresponding N-(substituted alkyl)-4-(substituted carbonyl)piperidine (K). Intermediate (K) is reacted with a different Grignard reagent of an appropriately substituted halide, for example, 4-trifluoromethoxyphenylmagnesium bromide, yielding the desired N-(substituted alkyl)-4-[di(substituted phenyl)hydroxymethyl]piperidine (I), for example, N-[4-(1,3-dioxolan-2-yl)phenylmethyl]-4-[(4-trifluoromethoxyphenyl)(2-trifluoromethoxyphenyl)hydroxymethyl
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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