Note: Descriptions are shown in the official language in which they were submitted.
; _ CA 02203998 1997-04-29
r1
E, ~
~rv.~"~
WO 96/13487 ~ ~ 'S'LArr~ PCT/~P95/04088
Heterocyclyl-amino- and heterocyclyl-oxy-cyclo~lk~nyl
derivatives, their u~e as pest control agents and
fungicides
The invention relates to heterocyclyl-amino- and hetero-
cyclyl-oxy-cyclo~lkenyl derivatives, processes for their
preparation and their use as pest control agents and
fungicides.
It is already known that certain 4--cycloalkoxy-substi-
tuted nitrogen-contA;n;ng heterocycl:ic compounds have an
insecticidal, acaricidal, ixodicidal and fungicidal
action (cf. WO 9300536).
Novel 4-amino- and 4-alkoxy-substituted nitrogen-contain-
ing heterocyclic compounds of the formula I
( R ~ ) v
~E ~U-V-R5 (1)
X
R3~A
R 2~N'J~ R 1
in which
R1 is hydrogen, halogen, (C1-C4)-alkyl, (C1-C4)-halo-
alkyl, (C3-C5)-cycloalkyl or (C3-C5)-halocycloalkyl;
R2 and R3 are identical or different and independently of
one another are each hydrogen, halogen, (C1-C4)-
alkyl, (C1-C4)-haloalkyl, (C3-C8)-cycloalkyl,
(C3-C8)-halocycloalkyl, (C1-C4)-alkoxy, (C1-C4)-halo-
alkoxy, (C1-C4)-alkoxy-(C1-C4)-~lkyl, (C1-C4)-halo-
alkoxy-(C1-C4)-alkyl, (C1~c4)~alk~xY-(cl-c4)-halo-
alkyl, (C1-C4)-haloalkoxy-(C1-C4'~-haloalkyl, (C1-C4)-
alkylamino,(C1-C4)-alkylthio,(C1-C4)-alkylsulfinyl,
(C1-C4)-alkylsulfonyl, (C1-C4)-haloalkylthio,
(Cl-C4)-haloalkylsulfinyl, (Cl-C,,~)-haloalkylsulfonyl,
CA 02203998 1997-04-29
-- 2
-
(C1-C4)-alkylthio-(C1-C4)-alkyl, (C2-C4)-alkenyl,
(C2-C4)-alkynyl, (C1-C4)-alko~,ycarbonyl, cyano,
(C1-C4)-cyanoalkyl or thiocyano r or
R2 and R3, together with the carbon atoms to which they
are bonded, form an unsaturated 5- or 6-membered
i~ocyclic ring which, if it is a 5-membered ring,
can contain an oxygen or sulfur atom instead of CH2,
or, if it is a 6-membered ring, can contain one or
two nitrogen atoms instead of one or two CH unit~,
and is optionally substituted by~1, 2 or 3 identical
or different radicals, these radicals being (C1-C4)-
alkyl, (C1-C4)-haloalkyl, pre!ferably trifluoro-
methyl, halogen, (C1-C4)-alkoxy or (C1-C4)-halo-
alkoxy, or
R2 and R3, together with the carbon atoms to which they
are bonded, form a saturated 5-, 6- or 7-membered
isocyclic ring which can contain oxyye~ and/or
sulfur instead of one or two CH2 groups and is
optionally ~ubstituted by 1, 2 or 3 (C1-C4)-alkyl
groups;
A is CH or N;
X is NH, oxyye~ or S(O)q, where q = 0, 1 or 2;
E is a direct bond or a straight-chain or branched
(C1-C4)-alkanediyl group, prefexably a direct bond;
a and b are identical or different and independently of
one another are the numbers 0, 1, 2 or 3, where a
and b are not 3imultaneously 0;
R4 is halogen, (C1-C4)-alkyl, (C3-C7)-cycloalkyl,
(C1-C4)-haloalkyl, (C1-C4)-alkox~, (C1-C4)-halo~lkoxy
or optionally substituted phenyl;
v is 0, 1 or 2;
U is a direct single bond, oxygen, a group S(O)y~
where y = 0, 1 or 2, or a group NR6, in which R6 is
hydrogen, (C1- C4)- alkyl or (C1-C4)-alkoxy;
V i~ a direct single bond, carborlyl or a grouping of
the formula
-C-T- -C-N-~
or
Q ~'
CA 02203998 1997-04-29
.
in which Q is oxygen, sulfur or (C1--C4)-alkylimino, T is
oxygen, sulfur or a group NR6 and T' is (C1-C4)-alkoxy,
(C1-C4)-alkylthio or NR6 R6 , and in which R6 and R6 are
identical or different and have the meAn;ngs given above
for R6; and
R5 is a radical from the series consisting of alkyl,
alkenyl, alkynyl, optionally substituted aryl,
optionally substituted heterocyclyl, cyano, halogen,
nitro, alkyloY;~;no or a group SiR7R8R9, in which R7
and R8 are (C1-C4)-alkyl and R9 i.8 alkyl, cycloalkyl,
aryl or arylalkyl;
and the alkyl, alkenyl, alkynyl or alkyloY; m; no
radicals mentioned for R5, R7, R8 and R9 have, where
appropriate, at least one of the following features:
i. one or more, preferably up to three, non-adjac-
ent CH2 groups are replaced by C0 and/or hetero atom
units, such as 0, S(O)y~ where y = 0, 1 or 2, NR6
or SiR7 R8 , in which R6 has the me~n;ngs given
above for R6 and in which R7 and R8 have the mean-
ings given above for R7 and R8;
ii. 3 to 12 atoms of these raclicals form an up to
12-membered ring;
iii. the radicals are optionally substituted by one
or more, preferably up to three, in the case of
halogen up to the m~Y;ml~m number of, identical or
different radicals from the series consisting of
halogen, alkyl, cycloalkyl, aryl, aryloxy, arylthio,
heterocyclyl, heterocyclyloxy, heterocyclylthio,
haloalkyl, arylalkyl, cycloalkylalkyl, A 1 ,koYy~
haloalkoxy, alkylthio, cycloalkoxy, Al k~nOylOXy,
halo~lkAnoyloxy, cyclo~lkAnoyloxy, cycloalkyl-
~lk~noyloxy, aroyloxy, arylAlk~noyloxy, alkylsul-
fonyloxy, arylsulfonyloxy, heterocyclylcarbonyloxy,
hydroxyl, cyano and nitro, where the cycloaliphatic,
aromatic or heterocyclic ring systems among those
substituents just mentioned can be unsubstituted or
provided with up to three - in the case of halogen,
preferably fluorine, also up to the mAY;m--m number
~ of - identical or different substituents;
CA 02203998 1997-04-29
-- 4
and salts thereof, preferably acid addition salts,
. have been found.
~ Preferred compounds of the formula ~: are those in which
R4 is halogen, preferably fluorine, chlorine and
bromine, (C1-C4)-alkyl, (C1-C4)-haloalkyl, (C1-C4)-
alkoxy, (C1-C4)-haloAlkoxy or (C1-C4)-alkylthio; and
R5 can be (Cl-C20)-alkYl~ (c2-c2o)-alkenyl~ (C2-C20)_
alkynyl, optionally substituted aryl, optionally
substituted heterocyclyl, cyano, halogen, hydroxyl,
carboxyl, nitro, (C1-C20)-alky:Lox;m;nQ or a group
SiR7R8R9, in which R7 and R8 are (C1-C4)-alkyl and R9
is (C1-C20)-alkyl or optionally substituted aryl;
and the alkyl, alkenyl, alkynyl or alkylo~;m;no
radicals mentioned for R5, R7, R8 and R9 have, where
appropriate, at least one of the following features:
i. one or more, preferably up to three, non-adja-
cent CH2 groups are replaced by CO and/or hetero
atom units, such as O, S(O)y~ ~rhere y = O, 1 or 2,
NR6 or SiR7 R8 , in which R6 has the me~n;ng8
given above for R6 and in which R7 and R8 have the
m~n;ng8 given above for R7 and R8;
ii. 3 to 8 atoms of these rad.icals form an up to
8-membered ring;
iii. the radicals are optionally substituted by one
or more, preferably up to three, in the case of
halogen up to the maximum number of, identical or
different radicals from the series consisting of
halogen, (C1-C12)-alkyl, (C3-C~)-cycloalkyl, aryl,
aryloxy, arylthio, heterocyclyl, heterocyclyloxy,
heterocyclylthio, (Cl-C12)-haloalkyl, aryl-(C1-C4)-
alkyl, (C3-C8)-cycloalkyl-(C1-C4)-alkyl, (Cl-Cl2)-
alkoxy, (C1-C12)-halo~lk~Yy, (C1-C12)-alkylthio,
(C3-C8)-cycloalkoxy, (C1-C12)-~lk~noyloxy, (C1-C12)-
halo~lk~noyloxy, (C3-C8)-cyclo~lkAnoyloxy, (C3-C8)-
cycloalkyl-(C1-C12)-~lk~noyloxy~ aroyloxy, aryl-
(Cl-C4)-alkanoyloxy, (Cl-C12)-alkylsulfonyloxy,
arylsulfonyloxy, heterocyclylcarbonyloxy, hydroxyl,
cyano and nitro, where the cycloaliphatic, aromatic
CA 02203998 l997-04-29
t ~ .
-- 5
.~
or heterocyclic ring systems among the substituents
just mentioned can be unsubstituted or provided with
up to three - in the case of halogen, preferably
fluorine, also up to the maximum number of
identical or different substituents and the other
radicals and variables are as defined above;
and salts thereof, preferably acid addition salts.
Compounds of the formula I which are more preferred are
those in which
R1 is hydrogen or fluorine;
R2 is (C1-C4)-alkyl, cyclopropyl, halocyclopropyl,
halo(C1-C2)-alkyl, methoxymethyl or cyano;
R3 is hydrogen, halogen, methyl, ethyl, methoxy,
ethoxy, cyano or (C1-C4)-alkoxycarbonyl; or
R2 and R3, together with the carbon atoms to which they
are bonded, form an optionally substituted unsatu-
rated 5- or 6-membered ring whi.ch, in the case of
the 5-membered ring, can cont.ain a sulfur atom
instead of a CH2 unit, or
R2 and R3, together with the carbon atoms to which they
are bonded, form a saturated 5- or 6-membered ring
which can contain a sulfur or an oxygen atom instead
of a CH2 unit;
A is CH or N;
X is NH or oxygen;
E is a direct bond;
a i 8 the number 1 and b is the number 2;
R4 is hydrogen, (C1-C4)-alkyl, trifluoromethyl or
(C1-C4)-alkoxy;
and the other radicals and variables are defined as
above;
and salts thereof;
in particular those compounds in which
R1 is hydrogen;
R2 is methyl, ethyl, propyl, isoprc)pyl, 1-fluoroethyl,
trifluoromethyl, cyclopropyl or methoxymethyl;
R3 is halogen, methyl, ethyl, methoxy, ethoxy, cyano or
(Cl-C4)- alkoxycarbonyl, or
CA 02203998 1997-04-29
t
- 6 -
R2 and R3, together with the ring system to which they
are bonded, form the c~uinazolin.e or quinoline sys-
tem, which can be substituted by fluorine in the
carbocyclic part, or
R2 and R3, together with the carbon atoms to which they
are bonded, form a saturated 6-membered ring which
can contain an oxy~el~ or sulfur atom instead of a
CH2 group;
r is 0;
U is a direct bond or oxygen; and
V is a direct bond;
and salts thereof.
Particularly preferred compounds of the formula I are
those in which
R1 is hydrogen;
R2 is ethyl, propyl, isopropyl, l-fluoroethyl, tri-
fluoromethyl or methoxymethyl;
R3 is fluorine, chlorine, bromine or methoxy;
or in the case where A is nitroc3en,
R2 and R3, together with the ring system to which they
are bonded, form the c~inazoline system, which can
be substituted by a fluorine atom, or
R2 and R3, together with the ring system to which they
are bonded, form the 5,6,7,8-tetrahydro~uinazoline
system;
A is CH or N;
X is NH or oxygen;
E is a direct bond;
a is the number 1 and
b is the number 2;
v is 0;
U is a direct bond or oxygen and
V is a direct bond;
and salts thereof.
Compounds of the formula I which are most preferred are
those in which
R1 is hydrogen;
CA 02203998 1997-04-29
., 7
R2 is ethyl or methoxymethyl;
R3 is fluorine, chlorine, bromine or methoxy, or
R2 and R3, where A = N, together with the ring system to
which they are bonded, form the quinazoline or the
5,6,7,8-tetrahydroquinazoline system;
R5 i8 (Cl-C20)-alkYl~ (C2-C20)-alkenyl or (C2-C20)-
alkynyl, where 3 - 6 carbon atoms of these hydro-
carbon radicals can form a ring and/or these hydro-
carbon radicals can optionally be substituted by a
phenyl radical, which can be unsubstituted or pro-
vided with up to three, in the case of fluorine also
up to the m~;ml number of, identical or different
substituents;
A is CH or N;
X is NH or oxygen;
E is a direct bond;
U and V together are a direct bond;
v is 0 and
the other radicals and variables are defined as above;
and salts thereof;
in particular those in which
R2 i8 methoxymethyl and R3 is methoxy, or
R2 is ethyl and R3 is chlorine or bromine,
X is NH;
R5 is (C1-C20)-alkyl or (C2-C20)-a:Lkenyl, where 3 - 6
carbon atoms of this radical can form a ring and/or
this radical can optionally be substituted by a
phenyl radical, which can be unsubstituted or pro-
vided with up to three, in the case of fluorine also
up to the ~-Y;m~m number of, identical or different
substituents; and
the other radicals and variables are defined as above;
and salts thereof.
In the above formula I, "halogen" is to be understood as
a fluorine, chlorine, bromine or iodine atom, preferably
a fluorine, chlorine or bromine atom;
the term "(C1-C4)-alkyl" is to be ~mderstood as an un-
branched or branched hydrocarbon radical having 1 - 4
CA 02203998 1997-04-29
~5 ~
- 8 -
carbon atoms, such as, for example, the methyl, ethyl,
propyl, isopropyl, 1-butyl, 2-butyl, 2-methyl~l~yl or
tert-butyl radical;
the term "(Cl-C20)-alkyl" is to be understood as the
abovementioned alkyl radicals, as well as, for example,
the pentyl, 2-methylbutyl or l,1-dim,ethylpropyl radical
and the hexyl, heptyl, octyl, 1,1,3,3-tetramethylbutyl,
nonyl, l-decyl, 2-decyl, undecyl, doc~ecyl, pentadecyl or
eicosyl radical;
the term "(C1-C4)-haloalkyl" is to be understood as an
alkyl group mentioned under the term "(C1-C4)-alkyl", in
which one or more hydrogen atoms are replaced by the
abovementioned halogen atoms, preferably chlorine or
fluorine, such as, for example, t:he trifluoromethyl
group, the 1-fluoroethyl group, the 2,2,2-trifluoroethyl
group, the chloromethyl or fluoromethyl group, the
difluoromethyl group or the 1,1,2,2-tetrafluoroethyl
group;
the term "(C3-C5)-cycloalkyl" is preferably to be under-
stood as the cyclopropyl, cyclobul;yl or cyclopentylgroup;
the term "(C3-C8)-cycloalkyl" is preferably to be under-
stood as the cyclopropyl, cyclobutyl, cyclopentyl, cyclo-
hexyl, cycloheptyl or cyclooctyl group, and also bicyclic
systems, such as, for example, the norbornyl group;
the term "(C3-C8)-halocycloalkyl" is to be understood as
a group mentioned under the term "(C3-C8)-cycloalkyl" in
which one or more hydrogen atoms are replaced by the
abovementioned halogen atoms, preferably chlorine or
fluorine;
the term "(C1-C4)-alkoxy" is under~tood as an alkoxy
group, the hydrocarbon radical of whi.ch haO the m~n;ngs
given under the term "(C1-C4)-alkyl";
the term "(C1-C4)-haloalkoxy" is to be understood as a
haloalkoxy group, the halo-hydrocarbon radical of which
has the ~A-n;ngs given under the term "(Cl-C4)-halo-
alkyl";
the term "(Cl-C4)-alkoxy-(Cl-C4)-alkyl" is to be under-
stood as, for example, a 1-methox~ethyl group, a 2-
CA 02203998 1997-04-29
methoxyethyl group, a 2-ethoxyethyl group, a methoxy-
methyl or ethoxymethyl group, a 3-methoxypropyl group or
a 4-butoxybutyl group;
the term "(C1-C4)-alkylthio" is to be understood as an
alkylthio group, the hydrocarbon radical of which has the
meAn;ngs given under the term "(C1-C~)-alkyl";
the term "(C1-C4)-alkylthio-(Cl-C4)-alkyl" i8 to be
understood as, for example, methylthi.omethyl, ethylthio-
methyl, propylthiomethyl, 2-methylthioethyl, 2-ethylthio-
ethyl or 3-methylthiopropyl;
the term "(C2-C4)-alkenyl" is to be understood as, for
example, the vinyl, allyl, 2-methy1-2-propenyl or 2-
butenyl group;
the term "(C2-C20)-alkenyl" i8 to be understood as the
abovementioned radicals, as well as, for example, the 2-
pentenyl, 2-decenyl or the 2-eicosen~l group;
the term "(C2-C4)-alkynyl" is to be understood as, for
example, the ethynyl, propargyl, 2-methyl-2-propyne or 2-
butynyl group;
the term "(C2-C20)-alkynyl" is to be understood as the
abovementioned radicals, as well as, for example, the 2-
pentynyl or the 2-decynyl group;
the term "(C1-C4)-alkoxycarbonyl" is to be understood as,
for example, the methoxycarbonyl, ethoxycarbonyl, pro-
poxycarbonyl, butoxycarbonyl or tert-butoxycarbonyl
group;
the term "(C1-C12)-alkoxycarbonyl" is to be understood as
the abovementioned radicals, as well as, for example, the
hexyloxycarbonyl, 2-methylhexyloxycarbonyl, decyloxy-
carbonyl or dodecyloxycarbonyl group;the term "cyano-(C1-C4)-alkyl" is to be understood as a
cyanoalkyl group, the hydrocarbon radical of which has
the me~n;ngs given under the term "(C1-C4)-alkyl";
the term "(C1-C20)-alkylidene" is to be understood as, for
example, the exo-methylene, ethylidene, propylidene, 1-
methyl-propylidene, butylidene, octylidene or dodecyli-
dene group;
the term "(C1-C20)-alkylox;~;no" is to be understood as an
o~;m;no group which is etherified on the oxygen by one of
CA 02203998 1997-04-29
~; I
- 10 -
the alkyl groups mentioned under the term "(C1-C20)-
alkyl n;
the term "aryl" is to be understood as an isocyclic
aromatic radical having preferably 6 to 14, in particular
6 to 12, carbon atoms, such as, ~or exz~mple, phenyl,
naphthyl or biphenylyl, preferably phenyl;
the term "heterocyclyl" is to be unflerstood as a hetero-
aromatic or heteroaliphatic ring sy~tem, "heteroaromatic
ring system" being understood as an aryl radical in which
at least one CH group i8 replaced by N and/or at least
two adjacent CH groups are replaced by S, NH or 0, for
example a radical of thiophene, furan, pyrrole, thiazole,
oxazole, imidazole, isothiazole, :isoxazole, pyrazole,
1,3,4-oxadiazole, 1~3~4-th;zl~;azole~ 1,3,4-triazole,
1,2,4-oxadiazole, 1,2,4-thiadiazole, 1,2,4-triazole,
1,2,3-triazole, 1,2,3,4-tetrazole, benzo~b]thiophene,
benzo~b]furan, indole, benzo~c]thiophene, benzo[c]furan,
isoindole, benzoxazole, benzothiazole, benzimidazole,
benzisoxazole, benzisothiazole, benzopyrazole, benzo-
thiadiazole, benzotriazole, dibenzofuran, dibenzothio-
phene, carbazole, pyridine, pyrazine, pyrimidine, pyrida-
zine, 1,3,5-triazine, 1,2,4-triazine, 1,2,4,5-triazine,
quinoline, isoquinoline, ~l;noYz~line, quinazoline,
cinnoline, l,8-naphthyridine, 1,5--naphthyridine, 1,6-
naphthyridine, 1,7-naphthyridine, phthalazine, pyrido-
pyrimidine, purine, pteridine or 4H-quinolizine;
and the term "heteroaliphatic ring system" being under-
stood as a (C3-C8)-cycloalkyl radical in which at least
one carbon unit, preferably up to three carbon units, are
replaced by 0, S or a group NR1l, and R11 is hydrogen,
(Cl-C4)- alkyl, (C1- C4)- alkoxy or aryl;
the term "substituted aryl" is to be understood as an
aryl radical which can be provided with one or more,
preferably up to three, in the case of fluorine up to the
-Y;m-.m number of, identical or dif.ferent radicals from
the series consisting of halogen, (C'1-C4)-alkyl, (C1-C4)-
haloalkyl, (C1-C4)-alkoxy, (C1-C4)-haloalkoxy, (C1-C4)-
alkoxy-(C1-C4)-alkyl, (C1-C4)-alkylthio, (C1-C4)-alkoxy-
alkyl, phenyl ~ rh ~n oYy, haloph ~n o~y ~ ( Cl - C4 ) -
CA 02203998 1997-04-29
- 11 -
alkylphenoxy, (Cl-C4)-haloA~koYyph~noyy~ (Cl-C4)-halo-
alkylphenoxy, phenylthio, heterocycl.yl, heterocyclylthio
or heterocyclyloxy;
the term "substituted heterocyclyl" is to be understood
as a heteroaromatic or heteroaliphat.ic ring system, which
can be provided with one or more, preferably up to three,
in the case of fluorine also up to the mA~;mnm number of,
identical or different radicals from the substituents
listed above under the term "substit:uted aryl";
"cycloaliphatic, aromatic and het.erocyclic radicals"
optionally provided with substituents are to be under-
stood as radicals such as, for example, aryloxy, aryl-
thio, heterocyclyloxy, heterocyclylthio, aroyl, aroyloxy,
cycloalkyl or cycloA~kAnoyl~ which can be provided with
one or more, preferably up to three, in the case of
fluorine also up to the maximum nu~ber of identical or
different substituents of those listed for "substituted
aryl";
the term "aryl-(Cl-C4)-alkyl" is to be understood as an
alkyl group mentioned under the term "(C1-C4)-alkyl"
which is substituted by an aryl radi.cal;
the term "aryloxy" is to be understood as, for example,
the phPnoYy or 1- or 2-naphthyloxy group;
the term "arylthio" is to be understood as, for example,
the phenylthio or the 1- or 2-napht~lylthio group;
the term "heterocyclyloxy" or "heterocyclylthio" is to be
understood as one of the abovementioned heterocyclic
radicals which are linked via an oxygen or sulfur atom.
The substituents with which the various aliphatic,
aromatic and heterocyclic ring syst:ems can be provided
include, for example, halogen, (Cl-C'4)-alkyl, trimethyl-
silyl, (Cl-C4)-haloalkyl, (Cl-C4)-alkoxy, (C1-C4)-halo-
alkoxy, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C1-C4)-alkylthio,
alkylsulfinyl, alkylsulfonyl, phenyl, ph ~noYy~ halo-
ph~noYy~ (Cl- C4)-alkylphenoxy, (C1- C4)- alkoxyphenoxy,
(cl-c4)-haloalkoxyphenoxy~ (C1-C4)-haloalkylphenoxy,
phenylthio, heterocyclyl, heterocyclylthio or hetero-
cyclyloxy, where one or more hydrogen atoms, in the case
CA 02203998 l997-04-29
- 12 -
of fluorine also up to the ~ m number, in the alkyl
radicals and the radicals derived therefrom can be
replaced by halogen, preferably chlorine or fluorine.
Fur~herrore, the definition that "the alkyl, alkenyl,
alkynyl or alkyloy;m;no radicals men~ioned for R5, R7, R8
and R9 have, where appropriate, at: least one of the
following features:
i. one or more, preferably up to three, non-adjacent
CH2 groups are replaced by C0 and/or hetero atom units,
such as 0, S(O)yl where y = 0, 1 or 2, NR6 or SiR7 R8
in which R6 has the m~n;ngs given above for R6 and in
which R7 and R8 have the me~n;ngs given above for R7 and
R8;
ii. 3 to 12 atoms of these radicals form an up to 12-
m~mhered ring;iii. the radicals are optionally substituted by one or
more, preferably up to three, in the case of halogen up
to the maY;mllm number of, identical or different radicals
from the series consisting of halogen, alkyl, cycloalkyl,
aryl, aryloxy, arylthio, heterocyclyl, heterocyclyloxy,
heterocyclylthio, haloalkyl, arylalkyl, cycloalkylalkyl,
alkoxy, haloalkoxy, alkylthio, cycloalkoxy, ~lk~noyloxy,
halo~lk~noyloxy,cyclo~lk~noyloxy,cyc:loalkylAlk~noyloxy,
aroyloxy, arylalkanoyloxy, alkylsulfonyloxy,
arylsulfonyloxy, heterocyclylcarbony].oxy, hydroxyl, cyano
and nitro, where the cycloaliphatic, aromatic or
heterocyclic ring systems among thole substituents just
mentioned can be unsubstituted or provided with up to
three, in the case of halogen, preferably fluorine, also
up to the ~-Y;m-lm n~mher of, identical or different
substituents
embraces, for example, alkoxyalkyl radicals, such as, for
example, the methoxymethyl, methoxyethyl or ethoxyethyl
group; or alkoxy-alkoxy-alkyl radicals, such as, for
example, the methoxy- or ethoxyethoxyethyl group; or
alkylthioalkyl radicals, such as, for example, the
methyl- or the ethylthioethyl group; or alkylsulfinyl-
alkyl radicals, such as, for exam~)le, the methyl- or
CA 02203998 1997-04-29
- 13 -
ethylsulfinylethyl group; or alkylsulfonyl-alkyl rad-
icals, such as, for example, the methyl- or ethylsul-
fonylethyl group; or alkyl-dialkylsilyl-alkyl radicals,
such as, for example, the trimethylsilylmethyl or the
ethyldimethylsilylethyl group; or alkyl-cycloalkyl
radicals, such as, for example, the ~-methyl-cyclohexyl,
3-ethyl-cyclopentyl or the 4-tert-butyl-cyclohexyl group;
or cycloalkyl-alkyl radicals, such a~s, for example, the
cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl,
cyclohexylbutyl or 1-cyclohexyl-1-methylethyl group or
aryl-alkyl radicals, such as, for example, the benzyl,
the 2-phenylethyl, the 1-phenylethyl or the 1-methyl-1-
phenylethyl group, the 3-phenylprop~l or the 4-phenyl-
butyl group, the 2-methyl-2-phenyl-ethyl group or the 1-
methyl or 2-methylnaphthyl group; or heterocyclylalkyl
radicals, such as, for example, the thienylmethyl,
pyridylmethyl, furfuryl, tetrahydrofurfuryl, tetrahydro-
pyranylmethyl or the 1,3-dioxolan-2-ylethyl group; or
aryloxyalkyl radicals, such as, for example, the phenoYy-
methyl or naphthoxymethyl group; or cycloalkyl radicalswhich are monocyclic, as listed above under the term
"(C3-C8)-cycloalkyl", bicyclic, such a8, for example, the
norbornyl radical or the bicyclo[2.2.2]octane radical, or
fused, such as the decahydronaphthyl radical; or else
haloalkyl derivatives of the correspo~;ng groups, such
as, for example, haloalkyl, haloalkoxyalkyl, alkoxy-
haloalkyl, haloalkyl-cycloalkyl or halocycloalkyl
radicals.
The explanation given above appl:ies accordingly to
homologues and radicals derived therefrom.
The explanation given above appl:ies accordingly to
radicals where no concrete number of carbon atoms is
stated, and to homologues or radical~ derived therefrom.
The present invention relates to the compounds of the
formula I in the form of the free b~se or an acid addi-
tion salt. Acids which can be used for salt formation are
CA 02203998 l997-04-29
- 14 -
~,
inorganic acids, such as hydrochloric acid, hydrobromic
acid, nitric acid, sulfuric acid or phosphoric acid, or
organic acids, such as formic acid, acetic acid,
propionic acid, oxalic acid, fumaric acid, adipic acid,
stearic acid, oleic acid, methanesulfonic acid, benzene-
sulfonic acid or toluenesulfonic acid.
The compounds of the formula I sometimes have one or more
chirality elements. Racemates or diastereomers can
therefore occur. The invention relates both to the pure
isomers and to mixtures thereof. The mixtures of dia-
stereomers can be separated into the components by
customary methods, for example by selective crystalliza-
tion from suitable solvents or by chromatography. Race-
mates can be separated into the enantiomers by customary
methods, thus, for example, by salt formation with an
optically active acid, separation of the diastereomeric
salts and liberation of the pure enantiomers by meAn~ of
a base.
The invention furthermore relates to a process for the
preparation of compounds of the formula I, which com-
prises reacting a compound of the formula II
R3
R XN~1~R 1
in which A, R1, R2 and R3 have the meAn;ngs given under
formula I and L is a leaving group, such as, for example,
halogen, alkylthio, ~lk~ne~ulfonyloxy or arylsulfonyloxy,
alkylsulfonyl or arylsulfonyl, with a nucleophile of the
formula III
CA 02203998 l997-04-29
- 15 -
( R ~ )
HX-E~U-V-Rs ( I I I )
in which X, E, a, b, v, U, V, R4 and ~5 ha~e the m~An;n~S
given under formula I, and, if R3 is hydrogen, if appro-
priate halogenating, preferably chlorinating or brominat-
ing, the compounds of the formula ~: thus obtained, or
obtA; ne~ in another manner, in po~iti.on 5 of the hetero-
cyclic radical, or further derivatizing R5 in the side
chain.
The substitution reaction described abo~e i~ known in
principle. The lea~ing group L can be varied within wide
limits and can be, for example, a halogen atom, such as
fluorine, chlorine, bromine or iodine, or alkylthio, such
as methyl- or ethylthio; or alkanesulfonyloxy, such as
methane-, trifluoromethane- or ethanesulfonyloxy, or
arylsulfonyloxy, such aa benzenesulfonyloxy or toluene-
sulfonyloxy, or alkylsulfonyl, such as methyl- or ethyl-
sulfonyl, or arylsulfonyl, such as phenyl- or toluene-
sulfonyl.
The abovementioned reaction is carried out in a tempera-
ture range of 20 - 150~C, expediently in the presence of
a base and if appropriate in an inert organic solvent,
such as N,N-dimethylformamide, N,N-dimethylacetamide,
dimethylsulfoxide, N-methylpyrrolidin-2-one, dioxane,
tetrahydro f uran, 4-methyl-2-pentanone, methanol, ethanol,
butanol, ethylene glycol, ethylene glycol dimethyl ether,
toluene, chlorobenzene or xylene. Mixtures of the 801-
~ents mentioned can also be used. Suitable bases are, for
example, alkali metal or alkaline earth metal carbonates,
bicarbonates, amides or hydrides, such as sodium carbon-
ate, sodium bicarbonate, potassium carbonate, sodium
amide or sodium hydride, or organolithium compounds, such
as n-butyllithium.
CA 02203998 1997-04-29
- 16 -
Suitable bases in the case where X is oxygen are, for
example, alkali metal or alkaline earth metal carbonates,
bicarbonates, amides or hydrides, such as sodium carbon-
ate, sodium bicarbonate, potassium carbonate, sodium
amide or sodium hydride, and in the case where X is NH,
these are, for example, alkali metal or alkaline earth
metal carbonates, bicarbonates, hyclroxides, 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. A second equivalent of an amine of the
formula III can also be employed as an auxiliary base.
The starting compounds of the formula II are either known
or they can be prepared by processe~ analogous to known
processes; cf., for example:
Quinolines: Org. Synth., Coll. Vol. 3,
272 (1955)
1,5-Naphthyridines: J. Amer. Chem. Soc. 68, 1317
(1946) and British Patent
1147760
1,6-Naphthyridines: J. Chem. Soc. 1960, 1790
1,7-Naphthyridines: J. Org. Chem. 19, 2008 (1954)
1,8-Naphthyridines: Synthesis 1974, 809
Pyridopyrimidines: EP-A-414 386
Pteridines: J. Chem. Soc. 1951, 474
Starting substances which are used in the case where A is
a nitrogen atom are acetoacetic e~ter derivatives, which
are converted into the halopyrimidines via the corres-
pon~; ng hydroxypyrimidines:
CA 02203998 1997-04-29
- 17 -
HO HO
( H2N ) C~ XN~J~ SH N2 ~ J
/ (Ba~)
/
R2CH2
POC13
C~O
C H R 3
NH
COOR R I //
--Y\NH2
( a a ~
HO
X~N P 3 ~ I I ( L ~ C I )
The starting compounds of the formula II can furthermore
be obtained by processes analogous to known processes
from malonic ester derivati~es:
Ho
N N2 ~ ~N ~~C I ~ ( 112 . L ~ C I )
ItOOC ( ~) Ho Nll
The compounds of the formula II in lqhich R3 is halogen
can be obt~; neA by halogenation by ~lown processes.
~.
The nucleophiles of the formula III required as starting
substances can be prepared by known. processes, in the
case where X is oxygen, for exampler by reduction of a
carbonyl group with a suitable reducing agent, for
example a complex metal hydride, or in the case of an
CA 02203998 1997-04-29
- 18 -
aldehyde or ketone also with hydrogen and a hydrogenation
catalyst. To prepare the cis-cycloh~YAnols, the precur-
sors for the particularly preferred cis-cyclohexyloxy
derivatives, catalytic hydrogenation of suitably substi-
tuted phenols or reduction of suitably substitutedcycloh~YAnone derivatives with comI~lex hydrides which
carry very bulky sub~tituents, such as, for example,
L-Selectride , is particularly suitable.
In the case where ~lacuna] is NH, the nucleophiles of the
formula III recluired as starting substances can be
prepared by known processes, for example by reduction of
an oxime or of a nitrile 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 an aldehyde or ketone or
Gabriel reaction of an alkyl halide or tosylate. To
prepare the cyclohexylamines, the precursors for the
particularly preferred cyclohexylamino derivatives,
reductive Am;nAtion of suitably substituted
cycloh~YAnones with ammonium ~alts and sodium
cyanoborohydride or with ~m~on;a and hydrogen in the
presence of metal catalysts, such as nickel, ruthenium,
rhodium or palladium, is particularly suitable, the
content of desired cis-amine by this method being
particularly high. Another method :is hydrogenation of
amines in the pre~ence of hydrogenation catalysts.
To prepare the precursors for the particularly preferred
cyclohexanyl derivatives, the following reactions are
suitable in particular:
~0 1.) Alkyl, alkenyl or aryl derivatives (a = 1, b = 2,
U and V = direct bond)
CA 02203998 1997-04-29
" t
19 -
OH
X ~ X R S
R ~9 X
X ~RS
B o ~ B
2.) Alkyl, alkenyl or aryl derivatives (a = 1, 2 or 3,
b = 1, 2 or 3, U and V = direct bond)
R ) ~ B ) r
~R~)
O ~
CA 02203998 1997-04-29
- 20 -
~,~ UO
RS ~ (R4
NH40~ H2N- ~
RS
3.) Cyclohex-3-enyl-amino and -alkoxy derivati~es
(R4) (R4)~
~ ~ Bu 1- ~t9 ~ U-V-R5
/ 2. RS-V-U-X
H3C H3C
(R4)
o ~ U _ V _ R S
EtOH, NH3
H3C
(R4)~ j R4)~
O ~ U-V-R5 ~ HO ~ U-V-R5
NaCNBH3
NH40Ac~
(R4)~
H2N--{~ U-V-R5
Preparation of 1-methoxy-1,4-cyclohexadienes or cyclohex-
3-enones: J. Chem. Soc. Perkin Trans 1, 7 (1983); J. Org.
Chem. 29, 2351 (1964); J. Org. Chem. 41, 531 (1976).
CA 02203998 1997-04-29
- 21 -
While having a good plant tolerance and favorable toxi-
city towards warm-blooded animals, the acti~re compounds
are suitable for controlling ~n;m~l pests, in particular
insects, arachnids, helminths and molluscs, very particu-
5 larly preferably for control of in~ects and arachnids,which occur in agriculture, in animal breeding, in
forestry, in the protection of stored products and
materials and in the hygiene sectc)r. They are acti~re
against normally sensitive and resistant species and all
10 or individual stages of development. The abovementioned
pests include:
From the order of the Acarina, for example, Acarus siro,
Argas spp., Ornithodoros spp., Dermanyssus gallinae,
Eriophyes ribis, Phyllocoptruta olei~rora, Boophilus 8pp.,
15 Rhipicephalus spp., Amblyomma spp., Hyalomma spp., Ixodes
spp., Psoroptes spp., Chorioptes spp., Sarcoptes spp.,
Tarsonemus spp., Bryobia praetiosaL, Panonychus spp.,
Tetranychus spp., Eotetranychus spp., Oligonychus spp.
and Eutetranychus spp..
20 From the order of the Isopoda, for example, Oniscus
asselus, Armadium ~rulgar and Porcellio scaber.
From the order of the Diplopoda, fox example, Blaniulus
guttulatus.
From the order of the Chilopoda, for example, Geophilus
25 carpophagus and Scutigera spp..
From the order of the Symphyla, for example, Scutigerella
immaculata.
From the order of the Thysanura, for example, Lepisma
saccharina.
30 From the order of the Collembola, for example, Onychiurus
armatus.
From the order of the Orthoptera, for example, Blatta
orientalis, Periplaneta americana, l~Jeucophaea madeirae,
Blatella g~ n;ca, Acheta domesticus, Gryllotalpa spp.,
35 Locusta migratoria migratorioides, Melanoplus
differentialis and Schistocerca gregaria.
From the order of the Isoptera, for example,
Reticulitermes spp..
From the order of the Anoplura, fox example, Phylloera
CA 02203998 1997-04-29
~ .
- 22 -
vastatrix, Pemphigus spp., Pediculus hum~anus corporis,
Haematopinus spp. and T;nogn:~thu8 spp..
From the order of the Mallophaga, for example,
Trichodectes pp. and Damalinea spp..
From the order of the Thysanopt:era, for example,
Hercinothrips femoralis and Thrips tabaci.
From the order of the Heteroptera, for example,
Eurygaster spp., Dysdercus intermedius, Piesma quadrata,
Cimex lectularius, Rhodnius prolixus and Triatoma spp..
From the order of the Homoptera, for example, Aleurodes
brassicae, Bemisia tabaci, Trialeurodes vaporariorum,
Aphis gossypii, Brevicoryne brassicae, Cryptomyzus ribis,
Doralis fabae, Doralis pomi, Eriosoma lanigerum,
Hyalopterus ar~n~;n;s, Macrosiphum avenae, Myzus spp.,
Phorodon humuli, Rhopalosiphum padi, Empoasca spp.,
Euscelus bilobatus, Nephotettix cincticeps, Lecanium
corni, Saissetia oleae, Laodelphax striatellus,
Nilaparvata lugens, Aonidiella aurantii, Aspidiotus
hederae, Pseudococcus spp. and Psylla spp..
From the order of the Lepidoptera, for example,
Pectinophora gossypiella, Bupalus piniarius, Cheimatobia
brumata, Lithocolletis blancardella, Eyponomeuta padella,
Plutella maculipennis, Malacosoma neustria, Euproctis
chrysorrhoea, Lymantria spp., Buccu].atrix thurberiella,
Phyllocnistis citrella, Agrotis spp., Euxoa spp., Feltia
spp., Earias insulana, Heliothis spp., Laphygma exigua,
Mamestra brassicae, Panolis flammecl, Prodenia litura,
Spodoptera spp., Trichoplusia ni, Carpocapsa pomonella,
Pieris spp., Chilo spp., Pyrausta nubilalis, Ephestia
kuehniella, Galleria mellonella, Cacoecia podana, Capua
reticulana, Choristoneura fumiferana, Clysia ambiguella,
Homona ma~n~n;~- and Tortrix viridana.
From the order of the Coleoptera, for example, Anobium
punctatum, Rhizopertha ~nm;n;ca, Bruchidius obtectus,
Acanthoscelides obtectus, Hylotrupes bajulus, Agelastica
alni, Leptinotarsa decemlineata, Phaedon cochleariae,
Diabrotica spp., Psylloides chrysocephala, Epilachan
varivestis, Atomaria spp., Oryzaephilus sur;n~m~n~is,
Anthonl~m~l~ spp., Sitophilus spp., Otiorrhynchus sulcatus,
CA 02203998 1997-04-29
~, ~
- 23 -
Cosmopolites sordidus, Ceuthorrynchus assimilis, Hypera
postica, Dermestes spp., Trogoder~a, Anthrenus spp.,
Attagenus spp., Lyctus spp., Meligethes aeneus, Ptinus
spp., Niptus hololeucus, Gibbium p~ylloides, Tribolium
spp., Tenebrio molitor, Atriotes spp., Co~o~rus spp.,
Melolontha melolontha, Amrh;m-llon solstitialis and
Costelytra zealandica.
From the order of the Hymenoptera, ior example, Diprion
spp., Hoplocampa spp., Lasius spp., r~onnmorium pharaonis
and Cespa spp..
From the order of the Diptera, for example, Aedes spp.,
Anopheles spp., Culex spp., Drosophila melanogaster,
MU8Ca 8pp., Fannia spp., Calliphora erythrocephala,
Lucilia spp., Chrysomyia spp., Cuterebra spp.,
Gastrophilus spp., Hypobosca 8pp., Stomoxys spp., Oestrus
spp., Hypoderma spp., Tabanus spp., Tannia spp., Bibio
hortulanus, Oscinella frit, Phorbia spp., Peyo~l~ia
hyoscyami, Ceratitis capitata, Dacus oleae and Tipula
paludosa.
From the order of the SiphonAptera, for example,
Xenopsylla cheopsis and Ceratophyllus spp..
From the order of the Arachnida, for example, Scorpio
maurus and Latrodectus mactans.
From the class of helm;nths, for example, Haemo~ch~
Trichostrongulus, Ostertagia, Cooperia, Chabertia,
Strongyloides, Oesophagostomum, Hyostrongulus,
Ancylostoma, Ascaris and Heterakis, as well as Fasciola
and phytotoxic nematodes, for example those from the
genera Meloidogyne, Heterodera, Ditylenchus,
Aphelenchoides, Radopholus, Globodera, Pratyl~nch
Longidorus and Xiphinema.
From the class of Gastropoda, for example, Deroceras
spp., Arion spp., Lymnaea spp., Galba spp., Succinea
spp., Bi~rh~laria spp., Bulinus spp. and Oncomelania
spp..
From the class of Bivalva, for example, Dreissena spp..
The phytoparasitic nematodes which can be controlled
according to the invention include, for example, the
CA 02203998 1997-04-29
- - 24 -
root-parasitic 80il nematodes, such as, for example,
those of the genera Meloidogyne (root gall nematodes,
such as Meloidogyne incognita, Me].oidogyne hapla and
Meloidogyne javanica), Heterodera and Globodera (cyst-
forming nematodes, such as Globodera rostochiensis,
Globodera pallida and Heterodera trifolii), and of the
genera Radopholus, such as Radopholus similis,
Pratylenchll~, such as Pratylenchl~ neglectus,
Pratyl~nchll~ penetrans and Praty].~nch-l~ curvitatus;
Tylenchlllus such as Tyl~nchlllus semipenetrans,
Tylenchorhynchus, such as Tylenchorhynchus dubius and
Tylenchorhynchus claytoni, Roty:Lenchll~ such as
Rotylen~hll~ robustus, Haliocoty:L~nchllR such as
Haliocotyl~nchll~ multicinctus, Be:Lonoaimus such as
Belonoaimus longicaudatus, Longidoru3 such as Longidorus
elongatus, Trichodorus such as Trichodorus primitivus and
Xiphinema such as Xiphinema index.
The nematode genera Ditylenchll~ (stem parasites, such as
Dityl~nchll~ dipsaci and Dityl~nchll~ destructor),
Aphelenchoides (leaf nematodes, such as Aphelenchoides
ritzemabosi) and Anguina (flower nematodes, such as
Anguina tritici) can furthermore be controlled with the
compounds according to the invention.
The invention also relates to compositions, in particular
insecticidal and acaricidal composit:;ons, which comprise
the compounds of the formula I, in addition to suitable
formulating auxiliaries.
The compositions according to the invention in general
comprise the active compounds of the formula I to the
extent of 1 to 95% by weight.
They can be formulated in various ways, as determined by
the biological and/or chemico-physical parameters.
Appropriate formulation possibilities are therefore:
wettable powders (WP), emulsifiable concentrates (EC),
aqueous solutions (SL), emulsions, ~prayable solutions,
CA 02203998 1997-04-29
- 25 -
oil- or water-based dispersions (SC), suspoemulsions
(SE), dusting powders (DP), seed-dressing compositions,
granules in the form of micro, spray, ab~orption and
adsorption granules, water-dispersib].e granules (WG), ULV
formulations, microcapsules, waxes or baits.
These individual types of formulation are known in
principle and are described, for exa~ple, in:
Winnacker-~uchler, "Chemische Technologie (Chemical
Technology)", Volume 7, C. Hauser Verlag Munich,
4th Edition 1986; van Falkenberg, "Pesticides Formula-
tions", Marcel Dekker N.Y., 2nd Edition 1972 - 73;
K. Martens, "Spray Drying Handbook", 3rd Edition 1979,
G. Goodwin Ltd., T~n~Qn.
The necessary formulating auxiliar.ies, such as inert
materials, surfactants, solvents and further additives,
are likewise known and are described, for example, in:
Watkins, "Handbook of Insecticide Dust Diluents and
Carriers", 2nd Edition, Darland Books, Caldwell N.J.;
H. v. Olphen, "Introduction to Clay Colloid Chemistry",
2nd Edition, J. Wiley & Sons, N.Y.; Marschen, "Solvents
Guide", 2nd Edition, InterscieDce, N.Y. 1950;
McCutcheon's, "Detergents and Emul~ifiers ~nn~ , MC
Publ. Corp., Ridgewood N.J.; Sisley and Wood, "Encyclo-
pedia of Surface Active Agents", Chem. Publ. Co. Inc.,
N.Y. 1964; Schonfeldt, "Grenzflach~r~ktive Athylenoxid-
addukte" (Surface-active Ethylene Oxide Adducts)", Wiss.
Verlagsgesell., Stuttgart 1967; Winnacker-Kuchler,
"Chemische Technologie (Chemical Technology)", Volume 7,
C. Hauser Verlag Munich, 4th Edition 1986.
Combinations with other pesticidally active substances,
fertilizers and/or growth regulators can also be prepared
on the basis of these formulations, for example in the
form of a ready-to-use formulation or as a tank mix.
Wettable powders are preparations which are uniformly
dispersible in water and al~o comprise, in addition to
the active compound and as well as a diluent or inert
CA 02203998 1997-04-29
- 26 -
substance, wetting agents, for examl?le polyoxyethylated
alkylphenols, polyoxyethylated fatty alcohols or alkyl-
or alkylphenol-sulfonates, and dis]?ersing agents, for
example sodium ligninsulfonate or sodium 2~2~-~;n~phthyl-
methane-6,6'-disulfonate. Emulsifiable concentrates are
prepared by dissolving the active co~pound in an organic
solvent, for example butanol, cycloh~Y~none~ dimethyl-
formamide or xylene, or else higher-boiling aromatics or
hydrocarbons, with the addition of one or more emul-
sifiers. Emulsifiers which can be used are, for example:alkylarylsulfonic acid calcium salts, such as Ca dodecyl-
benzene-sulfonate, or nonionic emulsifiers, such as fatty
acid polyglycol esters, alkylaryl polyglycol ethers,
fatty alcohol polyglycol ethers, propylene oxide/ethylene
oxide condensation products, alkyl polyethers, sorbitan
fatty acid esters, polyoxyethylene sorbitan fatty acid
esters or polyoxyethylene sorbitol esters.
Dusting powders are obtained by gr;n~;ng the active
compound with finely divided solid substances, for
example talc or naturally occurring clays, such as
kaolin, bentonite, pyrophillite or diatomaceous earth.
Granules can be prepared either by spraying the active
compound onto adsorbent, grAn~ r inert material or by
applying active compound concentrates to the surface of
carrier substances, such as sand, ka41inites or granular
inert material, by means of a&esive~, for example poly-
vinyl alcohol, sodium polyacrylate or else mineral oils.
Suitable active compounds can also be granulated in the
m~nner customary for the preparation of fertilizer
granules - if desired as a mixture with fertilizers.
In wettable powders, the active compound concentration
is, for example, about 10 to 90% by weight, the r~m~;n~er
to 100% by weight comprising customary formulating
constituents. In emul~ifiable concentrates, the active
compound concentration can be about 5 to 80% by weight.
Dust-like formulations usually co~lprise 5 to 20% by
weight of active compound, and sprayable solutions about
CA 02203998 1997-04-29
'1 ;
- 27 -
2 to 20% by weight. In granules, the active compound
content depends partly on whether the active compound is
present in liquid or solid form, and on which granulating
auxiliaries, fillers and the like are used.
In addition, the active compound formulations mentioned
comprise, if appropriate, the particular customary
tackifying agents, wetting agents, dispersing agent~,
emulsifiers, penetration agents, solvents, fillers or
carrier substances.
For use, the concentrates in the commercially available
form are diluted in the customary marmer, if appropriate,
for example by means of water in the case of wettable
powders, emulsifiable concentrates, dispersions and in
some cases also microgranules. Dust-like and grAnlllAr
formulations and sprayable solutions are usually not
diluted further with additional inert substances before
use .
The application amount re~uired varies with the external
conditions, such as temperature, humidity and the like.
It can vary within wide limits, for example between
0.0005 and 10.0 kg/ha or more of active substance, but is
preferably between 0.001 and 5 kg/ha.
In their commercially available for~nulations and in the
use forms prepared from these formlllations, the active
compounds according to the invention can be present as
mixtures with other active compounds, such as insecti-
cides, attractants, sterilizing agents, acaricides,
nematicides, fungicides, growth-regulating substances or
herbicides.
The pest control agents include, for example, phosphoric
acid esters, carbamates, carboxylic acid esters, formami-
dines, tin compounds, substances prepared by microorgan-
isms and the like. Preferred partners in the mixture are
CA 02203998 1997-04-29
- 28 -
1. from the group of phosphorus compounds
acephate, azamethiphos, azinphos-eth.yl, azinphosmethyl,
bromophos, bromophos-ethyl, chlorfenvinphos, chlormephos,
chlorpyrifos, chlorpyrifos-methyl, demeton, demeton-S-
methyl, demeton-S-methylsulphon, dialifos, diazinon,
dichlorvos, dicrotophos, 0,0-1,2,2,2-tetrachloroethyl-
phosphorothioate (SD 208 304), dimethoate, disulfoton,
EPN, ethion, ethoprophos, etrimfos, f~rh-.~, fenamiphos,
fenitriothion, fensulfothion, fenthion, fonofos, formo-
thion, heptenophos, isozophos, isothioate, isoxathion,malathion, methacrifos, methamidophos, methidathion,
salithion, mevinphos, monocrotophos, naled, omethoate,
oxydemeton-methyl, parathion, parat:hion-methyl, phen-
thoate, phorate, phosalone, phosfolan, phosmet, pho~pham-
idon, p~ny;m, pirimiphos, pirimiphos-ethyl, pirimiphos-
methyl, profenofos, propaphos, proet~mr~os, prothiofos,
pyraclofos, pyridapenthion, quinalphos, sulprofos,
temephos, terbufos, tetrachlorvinphos, thiometon, triazo-
phos, trichlorphon, vamidothion;
2. from the group of carbamates
aldicarb, 2-sec-butylphenylmethyl~arbamate (BPMC),
carbaryl, carbofuran, carbosulfan, cloethocarb, benfura-
carb, ethiofencarb, furathiocarb, isoprocarb, methomyl,
5-methyl-m-cumenylbutyryl(methyl)carbamate, oxamyl,
pirimicarb, propoxur, thiodicarb, thiofanox, ethyl 4,6,9-
triaza-4-benzyl-6, 10-dimethyl-8-oxa-7-oxo-5,11-dithia-9-
dodecenoate (OR 135), 1-methylthio(ethyliden~m;no)-N-
methyl-N-(morpholinothio)carbamate (IJC 51717);
3. from the group of carboxylic acid esters
allethrin, alphametrin, 5-benzyl-3-furylmethyl (E)-(lR)-
cis,2,2-di-methyl3-(2-oxothiolan-3-ylidenemethyl)cyclo-
propanecarboxylate, bioallethrin, bioallethrin ((S)-
cyclopentyl isomer), bioresmethrin, biphenate, (RS)-1-
cyano-1-(6-phenoxy-2-pyridyl)methyl (lRS)-trans-3-(4-
tert-butylphenyl)-2,2-dimethylcyclopropanecarboxylate
(NCI 85193), cycloprothrin, cyhalothrin, cythithrin,
cypermethrin, cyphenothrin, deltamethrin, empenthrin,
CA 02203998 1997-04-29
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esfenvalerate, fenfluthrin, fenpropathrin, fenvalerate,
flucythrinate, flumethrin, fluvalinate (D isomer),
permethrin, pheothrin ((R) isomer), d-pralethrin,
pyrethrins (naturally occurring products), resmethrin,
tefluthrin, tetramethrin, tralometh:rin;
4. from the group of amidines
amitraz, chlordimeform;
5. from the group of tin compound~
cyhexatin, fenbutatin oxide;
6. others
abamectin, Bacillus thuringiensis, bensultap, binapacryl,
bromopropylate, buprofezin, camphec~-lor, cartap, chloro-
benzilate, chlorfluazuron, 2-(4-chlorophenyl)-4,5-di-
phenylthiophene (UBI-T 930), chlorfentezine, 2-naphthyl-
methyl cyclopropanecarboxylate (Ro 12-0470), cyromazin,
ethyl N-(3,5-dichloro-4-(1,1,2,3,3,3-hexafluoro-1-propyl-
oxy)phenyl)carbamoyl)-2-chlorobenzocarboximate, DDT,
dicofol, N-(N-(3,5-di-chloro-4-~1,1,2,2-tetrafluoro-
ethoxy)phenylamino)carbonyl)-2,6-difluorobenzamide
(XRD 473), diflubenzuron, N-(2,3-dihydro-3-methyl-1,3-
thiazol-2-ylidene)-2,4-xylidine, dinobuton, dinocap,
endosulfan,ethofenprox, (4-ethoxyphenyl)(dimethyl)(3-(3-
phenoxyphenyl)propyl)silane, (4-ethoxyphenyl)(3-(4-
fluoro-3-ph~nnYyphenyl)propyl)dimethylsilane, fenoxycarb,
2-fluoro-5-(4-(4-ethoxyphenyl)-4-methyl-1-pentyl)diphenyl
ether (MTI 800), granulosis and nuclear polyhedrosis
~iruses, fenthiocarb, flubenzimi.ne, flucycloxuron,
fluf~nox-l~on, gamma-HCH, hexythiazox, hydramethylnon
(AC 217300), ivermectin, 2-nitromethyl-4,5-dihydro-6H-
thiazine (DS 52618), 2-nitromethy].-3,4-dihydrothiazole
(SD 35651), 2-nitromethylene-1,2-thiazinan-3-cylc~h~
dehyde (WL 108477), propargite, teflubenzuron, tetra-
difon, tetrasul, thiocyclam, trifumuron, imidacloprid.
The active compound content of the use forms prepared
from the commercially a~ailable formulations can be from
CA 02203998 1997-04-29
- 30 -
0.00000001 to 95% by weight of active compound, prefer-
ably between 0.00001 and 1% by weight.
The formulations are used in a customary manner appropri-
ate for the use forms.
The active compounds according to the invention are also
suitable for controlling endo- and ectoparasites in the
veterinary medicines sector and in t:he ~n;m~l h~lch~n~y
sector.
The active compounds according to the invention are used
here in a known manner, such as by oral use in the form
of, for example, tablets, capsules, drinks or granules,
by dermal use in the form of, for example, dipping,
spraying, pouring on (pour-on and spot-on formulations)
and dusting, and by parenteral use in the form of, for
example, an injection.
The novel compounds of the formula I according to the
invention can accordingly also be particularly advantage-
ously employed in livestock husbandry (for example
cattle, sheep, pigs and poultry, SUC]l as chickens, geese
and the like). In a preferred embo~;~~nt of the inven-
tion, the novel compounds are admini~tered orally to the
~n;m~l 8, if appropriate in suitable formulations (cf.
above) and if appropriate with the dr; nk; ng water or
feed. Since they are excreted i~ the feces in an
effective manner, the development of insects in the feces
of the animals can be prevented very easily in this way.
The particular suitable dosages and formulations depend
in particular on the species and the stage of development
of the stock ~n;m~18 and also on the severity of
infestation, and can easily be determined and specified
by the customary methods. In the case of cattle, the
novel compounds can be used, for ex~mple, in dosages of
0.01 to 1 mg/kg of body weight.
The compounds of the formula I according to the invention
CA 02203998 1997-04-29
- 31 -
are also distinguished by an out~t~n~; ng fungicidal
action. Fungal pathogens which have already penetrated
into the plant tissue can successiully be controlled
curatively. This is particularly important and advantage-
ous in the case of those fungal di~eases which can nolonger be controlled effectively with the otherwise
customary fungicides after infection has occurred. The
action spectrum of the compounds claimed includes various
economically important phytopathogenic fungi, such as,
for example, Plasmopara viticola, Erysiphe graminis,
Phytophthora infestaus, Pyricularia oryzae, Pyrenophora
teres, Leptosphaera notorum, Pelliscularia sasatrii and
Puccinia recondita.
In addition, the compounds according to the invention are
also suitable for use in industrial ~ectors, for example
as wood preservatives, as preservatives in paints, in
cooling lubricants for metalworking or as preservatives
in drilling and cutting oils.
The active compounds according to the invention can be
used in their commercially available formulations either
by themselves or in combination with other fungicides
known from the literature.
The following products may be mentioned, for example, as
fungicides which are known from the literature and can be
combined according to the invention with the compounds of
the formula I: aldimorph, andoprim, anilazine, BAS 480F,
BAS 450F, b~n~l~yl, benodanil, benomyl, binapacryl,
bitertanol, bromuconazole, buthiobate, captafol, captan,
carbendazim, carboxin, CGA 173506, cyprofuram, dichlo-
fluanid, dichlomezin, diclobutrazol, diethofencarb,difenconazole (CGA 169374), difluconazole, dimethirimol,
dimethomorph, diniconazole, dinocap, dithianon, dode-
morph, dodine, edifenfos, ethirmol, etridiazole, fenari-
mol, fenfuram, fenpiclonil, fenpropidin, fenpropimorph,
fentin acetate, fentin hydroxide, ferimzone (TF 164),
fluazinam, fluobenzimine, flu~uinconazole, fluorimide,
CA 02203998 1997-04-29
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flusilazole, flutolanil, flutriafol, folpet, fosetyl-
aluminium, fuberidazole, fulsulfamide (MT-F 651), fura-
laxyl, furconazole, furmecylclox, guazatine, hexacon-
azole, ICI A5504, imazalil, imibenconazole, iprobenfos,
iprodione, isoprothiolane, RNF 317, copper compounds,
such as Cu oxychloride, oxine-Cu and Cu oxides, mancozeb,
maneb, mepanipyrim (KIF 3535), metconazol, mepronil,
metalaxyl, methasulfocarb, methfuroxam, MON 24000,
myclobutanil, nabam, nitrothalidopropyl, nuarimol,
ofurace, ox~ yl, oxycarboxin, penconazol, pencycuron,
PP 969, probenazole, propineb, prochloraz, procymidon,
propamocarb, propiconazol, prothiocarb, pyracarbolid,
pyrazophos, pyrifenox, pyroquilon, rabenzazole, RH7592,
sulfur, tebuconazole, TF 167, thiabendazole, thicyofen,
thiophanate-methyl, thiram, tolclofos-methyl, tolyl-
fluanid, triadimefon, triadimenol, tricyclazole,
tridemorph, triflumizol, triforine, validamycin, vinchlo-
zolin, XRD 563, zineb, sodium dodecylsulfonate, sodium
dodecyl sulfate, sodium C13/C15-alcollol ether-sulfonate,
sodium cetostearylphosphate ester, dioctyl sodium sulfo-
succinate, sodium isopropyl-naphthalenesulfonate, sodium
methylenebisnaphthalene-sulfonate, cetyl-trimethyl-
ammonium chloride, salts of long-chain primary, secondary
or tertiary amines, alkyl-propyleneamines, lauryl-
pyrimidinium bromide, ethoxylated quaternized fatty
;ne~, alkyl-dimethyl-benzylammonium chloride and
1-hydroxyethyl-2-alkyl-imidazoline.
The abovementioned combination partners are known active
c~ _o~ ds, most of which are described in Ch. R. Worthing,
S.B. Walker, The Pesticide M~n~ , 7th Edition (1983),
British Crop Protection Council. The active compound
content of the use forms prepared from the commercially
available formulations can vary within wide limits, and
the active compound concentration of the use forms can be
from 0.0001 up to 95% by weight of active compound,
preferably between 0.0001 and 1% by weight. The formula-
tions are used in a customary manner appropriate for the
use forms.
CA 02203998 1997-04-29
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- 33 -
The following examples serve to illu~;trate the invention
without this being limited by these.
A. Formulation examples
a) A dusting powder is ob~A;ne~ by mixing 10 parts by
weight of active compound and 90 parts by weight of
talc, as an inert substance, zmd cn~ninl~ting the
mixture in a h-- ne~ mill.
b) A wettable powder which is rea~ily dispersible in
water is obt~;n~ by mixing 25 parts by weight of
active compound, 65 parts by weight of kaolin-con-
t~;n;ng c~uartz, as an inert substance, 10 parts by
weight of potassium ligninsulfonate and 1 part by
weight of sodium oleoyl methyl tauride, as wetting
and dispersing agents, and gr;n~;ng the mixture in
a pinned disk mill.
c) A dispersion concentrate which is readily dispers-
ible in water is prepared by mixing 40 parts by
weight of active compound with 7 parts by weight of
a sulfosuccinic acid half-ester, 2 parts by weight
of a ligninsulfonic acid sodium ~alt and 51 parts by
weight of water and gr;n~; ng the! mixture to a fine-
ness of less than 5 microns in a gr;n~;ng bead mill.
d) An emulsifiable concentrate can be prepared from
15 parts by weight of active compound, 75 parts by
weight of cyclohexane, as a solvent, and 10 parts by
weight of oxyethylated nonylphenol (10 ethylene
oxide units), as an emulsifier.
e) Granules can be prepared from 2 to 15 parts by
weight of active compound and an inert granule
carrier material, such as attapulgite, pumice gran-
ules and/or c~uartz sand. A suspension of the
wettable powder from Example b) with a solids con-
tent of 30% is expediently used, and this is sprayed
CA 02203998 1997-04-29
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onto the surface of attapulgite granules and the
material is dried and m; ~e~ intimately. The weight
content of the wettable powder here is about 5% and
that of the inert carrier material is about g5% of
the finished granules.
B. Biological examples
Insecticidal and acaricidal action
Example l: Action on the brown p:Lant hopper
Young rice plants (Oryza sativa) were dipped in aqueous
dilutions of a wettable powder concentrate having a
concentration of 250 ppm (based on the active compound),
and after the concentrate had drained off, the plants
were infested with L4 larval stages of the nice brown
plant hopper Nilaparvata lugens.
After being placed in a test cage, these were observed at
28~C and a high atmospheric humidity for 3 days and the
mortality of the test ~n;m~l 8 was det:ermined.
The co ~o~ds according to Examples B and C produced a
100% mortality in the test ~n;m~l 8 at; 250 ppm.
Example 2: Action on diabrotica lmdecimpunctata
Larvae (L3) of the southern corn rootworm (Diabrotica
undecimpunctata) were placed on disks of filter paper
impregnated with in each case 1 ml of an acetone dilution
of a wettable powder in a concentration of 250 ppm, based
on the active compound. After the acetone had evaporated
off, the dishes were closed and kept at 28~C for 3 days
and the mortality of the larvae was then determined.
100% mortality was found with the co~lpounds according to
Examples B and C.
CA 02203998 1997-04-29
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Example 3: Action on the eggs of the American cotton
st~;ner
Disks of filter paper on which eggs (egg age: 2 days) of
the American cotton st~;n~ (Oncopeltus fasciatus) lie
were treated with in each case 1 ml of an aqueous formu-
lation comprising 250 ppm of the particular active
compound. After the deposit had dried on, the disks of
filter paper were kept in Petri dishes at room tempera-
ture and ~-Y;m~m atmospheric humidit:y. After 7 days, the
ovicidal action was determ;ne~. 100% ovicidal action
(mortality of the eggs) was found with Examples B and C.
Example 4: Action on the black bean aphid
Broad bean plants (Vicia faba) heavily infested with
black bean aphids (Aphis fabae, adult population) were
sprayed with an aqueous formulation comprising 250 ppm of
the particular active compound until the formulation
started to drip. After the plants had been grown in a
greenhouse for 3 days, the mortality of the aphids (adult
population) was investigated. 100% mortality was found
with Examples A, B, C and D.
Example 5: Action on the common red spider mite
Bean plants (Phaseolus vulgaris ssp. vulgaris var. nanus)
heavily infested with common red spider mites
(Tetranychus urticae, adult population) were sprayed with
an aqueous formulation comprising 250 ppm of the particu-
lar active compound until the formulation started to
drip. After the plants had been gro~ in a greenhouse for
7 days, the mortality of the spider mites (adult popula-
tion) was investigated. 100% mortality was found with
Examples A, B, C and D.
Example 6: Action on the fruit-tree red spider mite
Apple plants (Malus domestica) heavily infested with
CA 02203998 1997-04-29
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- 36 -
fruit-tree red spider mites (Panonychus ulmi, adult
population) were ~prayed with an aqueous formulation
comprising 250 ppm of the particular active compound
until the formulation started to drip. After the plants
had been grown in a greenhouse for 'i days, the mortality
of the fruit-tree red spider mites (adult population) was
investigated. 100% mortality was found with Examples A,
B, C and D.
Example 7: Citrus mealy-bug
Bean plants (Phaseolus w lgaris ssp. vulgaris var. nanus)
heavily infested with citrus mealy-bugs (Planococcus
citri, larvae of the 2nd development: stage) were sprayed
with an aqueous formulation comprising 250 ppm of the
particular active compound until the~ formulation started
to drip. After the plants had been grown in a greenhouse
for 7 days, the mortality of the citrus mealy-bugs (adult
population) was investigated. 100% mortality was found
with Examples B and C.
Example 8: Action on the housefly
The base and lid of a Petri dish were coated on the
inside with in each case 3 ml of an aqueous dilution of
a wettable powder concentrate comprising 250 ppm of the
particular active compound. After the deposit had dried
on, houseflies (Musca domestica) 24 hours old were placed
in the Petri dishes and these were closed with the
treated lid. After 3 hours at a room temperature of 20~C,
the mortality of the flies was investigated. 100%
destruction was achieved with compo~ds B and C.
Example 9: Ovicidal action (M~n~3llc~ sexta)
Petri dishes were covered with Jaan filter paper on the
inside of the base and 20 1 day old e~ggs of M~n-3llca sexta
were in each case placed on the paper. About 1 ml of a
synthetic insect feed diet was then placed in the center
CA 02203998 l997-04-29
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of the Petri dish and the inside of the base with the
eggs and feed diet were sprayed with an acaueous wettable
powder suspension of the test products correspon~; ng to
600 l/ha. After the Petri dishes had been closed and kept
at room temperature for 5 days, the mortality of the eggs
was determined. Compound B produced an action of 100%.
Example 10:
Larvae (~4) of the cockroach Blaberus craniifer were
injected with active compounds dissolved in methanol.
After application of the compounds according to
Examples B and C (2 x 10-4 g of active ingredient/
animal), 100% mortality was to be found after 48 hours.
Example 11:
Larvae (L4) of the tobacco hawk-moth MAn~c~ sexta were
injected with active compounds dissolved in acetone.
After application of the compound acc:ording to Examples B
and C (2 x 10-4 g of active ingredient/:~n;~Ql), 100%
mortality was to be found after 48 hours.
Use as an antiparasitic
Example 12:
In vitro test on tropical cattle ticks (Boophilus
microplus)
The activity of the compounds according to the invention
against ticks was to be detected in the following test
design:
To prepare a suitable formulation of the active compound,
the active compounds were dissolved i.n a concentration of
10% (w/v) in a mixture comprising dimethylformamide
(85 g), nonylphenol polyglycol ether (3 g) and oxyethyl-
ated castor oil (7 g), and the emulsion concentrates thus
CA 02203998 1997-04-29
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obtained were diluted with water to a test concentration
of 500 ppm.
In each case ten fully satiated females of the tropical
tick Boophilus microplus were immersed in these active
compound dilutions for five minutes. The ticks were then
dried on filter paper and fixed on their back to an
adhesive film for the purpose of laying eggs. The tick~
were stored in a heated cabinet at 28~C and an atmos-
pheric humidity of 90%.
As a control, tick females were dipped only in water. The
inhibition of oviposition two weeks after the treatment
was used to evaluate the activity.
In this test, the compounds according to Example C cause
in each case 100% inhibition of oviposition in an active
compound concentration of 500 ppm.
C. Preparation examples
Example A
4-~4-(1,1,3,3-Tetramethylbutyl)-cyclohex-3-enoxy]-
5,6,7,8-tetrahydroquinazoline
0.46 g (15.3 mmol) of sodium hydride (80% strength
dispersion in mineral oil) was added to a solution of
2.3 g (11.2 mmol) of 4-[(1,1,3,3-tetramethyl)butyl]-
cyclohex-3-enol in 20 ml of tetrahydrofuran and the
mixture was heated under reflux for 3 hours. After
cooling to room temperature, 1.7 g (10.2 mmol) of 4-
chloro-5,6,7,8-tetrahydroquinazoline, dissolved in 5 ml
of tetrahydrofuran, were added and the mixture was heated
under reflux for a further 2 hours. A.fter cooling to room
temperature, isopropanol was added to the reaction solu-
tion and the mixture was subsequerltly stirred for 15
minutes and then extracted with metllylene chloride. The
organic phase was dried and concentrated. For purification,
CA 02203998 1997-04-29
the residue was chromatographed over silica gel with
petroleum ether/ethyl acetate 1 : 1. This gave 2.3 g (66%
of theory) of yellow oil, which gradually solidified.
Preparation examples for4-(4-alkylcyclohex-3-enylamino)-
pyrimidines
Example B
4-t4-(1,1,3,3-Tetramethylbutyl)-cyclohex-3-enylamino]-5-
chloro-6-ethylpyrimidine
1.2 g (13.5 mmol) of R2CO3 were initially introduced into
10 ml of dimethylformamide, 1.6 g (9 mmol) of 4-
[(1,1,3,3-tetramethyl)-butyl]-cyclohex-3-enylamine were
added and the mixture was stirred at 80~C for 4 hours.
For working up, the cooled reaction solution was taken up
in water. The mixture was extracted with ether and the
combined organic phases were washed with water, dried and
concentrated. For purification, the residue was chromato-
graphed over silica gel with petroleum ether/ethyl
acetate 5 : 1. This gave 1.3 g (43.3% of theory) of
colorless oil.
Preparation of 4-[(1,1,3,3-tetrameth~l)-butyl~-cyclohex-
3-enylamine
7 g (33 mmol) of 4-[(1,1,3,3-tetramethyl)-butyl]-cyclo-
hex-3-enone were stirred in 100 g of isopropanol with
2.1 g (33 mmol) of sodium cyanoborohydride and 25.9 g
(0.33 mol) of ammonium acetate in the presence of 7 g of
molecular sieve (3 A) at room tempe ature for 72 hours.
The reaction solution was filtered and the filtrate was
concentrated. The residue was taken up in 15% strength
NaOH and the mixture was extracted with CH2Cl2. The
combined methylene chloride phases were extracted by
stirring twice with dilute hydrochloric acid and the
combined hydrochloric acid phases were rendered basic
with 30% strength sodium hydroxide solution. The mixture
CA 02203998 1997-04-29
r
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was extracted with methylene chloride and the organic
phase was dried and concentrated. 4.6 g (70% of theory)
of yellow oil remained.
Preparation of 4-[(1,1,3,3-tetramethyl)-butyl]-cyclohex-
3-enol
10.0 g (48 mmol) of 4-[(1,1,3,3-tetramethyl)-butyl]-
cyclohex-3-enone were initially introduced into 60 ml of
ethanol, 2.7 g (0.07 mol) of sodium borohydride, dis-
solved in 20 ml of water, were added dropwise and the
mixture was stirred at room temperature for 3 hours. The
reaction solution was concentrated to dryness, the
residue was taken up in water and t:he mixture was ren-
dered weakly acidic with 2N HCl at 0~C. It was extracted
with ether and the combined ether phases were washed with
saturated NaCl solution and dried. Concentration gave
7.1 g (70% of theory) of product as a colorless solid
which was reacted without further purification.
Preparation of 4-~(1,1,3,3-tetrameth~l)-butyl]-cyclohex-
3-enone
40 g (0.17 mol) of 1-methoxy-4-[(1,1,3,3-tetramethyl)-
butyl]-cyclohexa-1,4-diene were initi.ally introduced into
500 ml of methanol, 600 ml of 10% strength H2S04 were
added dropwise at room temperature and the mixture was
subsequently stirred for 2 hours. The reaction solution
was poured onto water and extracted with ether. The
combined ether phases were washed with H20 and saturated
NaCl solution and dried. Concentration gave 37 g (99% of
theory) of colorless liquid, which was reacted without
further purification.
Preparationofl-methoxy-4-~(1,1,3,3-tetramethyl)-butyl]-
cyclohexa-1,4-diene
105 g (0.48 mol) of 4-[(1,1,3,3-tetramethyl)-butyl]-
anisole were initially introduced into a mixture of
CA 02203998 l997-04-29
i. ,
- 41 -
180 ml of tert-butanol and 120 ml of tetrahydrofuran, and
1600 ml of ~mm~;a were con~n~ed in at -78~C. 13.3 g
(1.9 mol) of lithium were added in portions and the
mixture was then refluxed for 1 hour. Methanol and water
were 81Owly added to the reaction solution. After the
ammonia had been evaporated off, the residue was
extracted with ether. The organic phase was washed with
water, dried over MgS04 and concentrated. Thi~ gave
95.8 g (90% of theory) of a colorle~s liquid, which was
reacted without further purification.
Preparation of 4-~(1,1,3,3-tetramethyl)-butyl]-anisole
100 g (0.48 mol) of 4-~(1,1,3,3-tetramethyl)-butyl]-
phenol and 93.8 g (0.68 mol) of R2CO3 were initially
introduced into 260 ml of acetone. 67 g (0.53 mol) of
dimethyl sulfate were added dropwise to the reaction
solution. When the evolution of heat had subsided, the
mixture was heated under reflux for 4 hours, while
stirring. 130 ml of acetone were disl-illed off, 40 ml of
NH40H were added and the mixture was ~3ubsequently stirred
for 10 minutes. Water was then added to the reaction
solution, the mixture was extracted with ether and the
combined organic phases were washed with water, 2N NaOH
and then with saturated NaCl solution and dried over
MgSO4. Concentration gave 105 g (98% of theory) of solid
product, which was reacted without f~lrther purification.
Preparation examples for 4-(1-aryl-1-cyclohexen-4-yl-
amino)-pyrimidine
Example C
5-Chloro-6-ethyl-4-[1-(3-fluoro-4-methoxy-phenyl)-cyclo-
hexen-4-ylamino]-pyrimidine
1.6 g (7 mmol) of 4-amino-1-(3-fluoro-4-methoxy-phenyl)-
cyclohexene, 1.2 g (7 mmol) of 4,5-dichloro-6-ethyl-
pyrimidine and 1.4 g (14 mmol) of triethylamine were
CA 02203998 1997-04-29
r ~
~ 42 ~
heated under reflux in 5 ml of toluene for 10 hours. For
working up, the mixture was diluted with toluene and
extracted by stirring with water. The organic phase was
dried and concentrated. For purificat:ion, the residue was
chromatographed o~er silica gel with pe~roleum ether/
ethyl acetate 7 : 3. This gave 0.6 g (27.6% of theory) of
colorless oil which gradually crystallized. Melting point
86 - 87~C.
Preparation of the educt amine
4-Amino-1-(3-fluoro-4-methoxy-phenyl)-cycloh eYen e
10.1 g (46 mmol) of 1-(3-fluoro-4-methoxy-phenyl)-cyclo-
hexen-4-one, 35.5 g (0.46 mol) of ammonium acetate and
17 g of 3 A molecular sie~e were initially introduced
into 250 ml of isopropanol, and 2.9 g (46 mmol) of sodium
cyanoborohydride were introduced in portions at 0~C,
while stirring. The mixture was stirred at room tempera-
ture for 72 hours, the solvent was ~~tripped off and the
residue was extracted by stirring several times with
methylene chloride/2N sodium hydroxide solution. The
combined methylene chloride phases were extracted by
stirring twice with dilute hydrochloric acid and the
combined hydrochloric acid phases were rendered strongly
basic with 30% strength ~odium hydroxide solution. The
mixture was extracted with methylene chloride and the
organic phase was dried and concentrated. 3.3 g (32.4% of
theory) of product r~m~; neA as a yellow oil which
gradually solidified.
Preparation of 1-(3-fluoro-4-methoxy-phenyl)-cycloh~Yen-
4-one
101.0 g (0.36 mol) of 4-hydroxy-4-(3-fluoro-4-methoxy-
phenyl)-cycloh~Y~no~e ethylene keta:L were stirred in a
mixture of 500 ml of formic acid and 30 ml of water at
room temperature for 24 hours. After the formic acid had
been stripped off, the residue was taken up in methylene
CA 02203998 1997-04-29
- 43 -
chloride and the mixture was washed with sodium bicarbon-
ate solution and water, dried and concentrated. This gave
71 g (89.5% of theory) of colorless solid, which was
reacted without further purification.
Melting point 68 - 70~C.
Preparation of 4-hydroxy-4-(3-fluoro-4-methoxy-phenyl)-
cycloh~no~e ethylene ketal
A Grignard solution was prepared from 100 g (0.49 mol) of
4-bromo-2-fluoroanisole and 13 g (0.53 mol) of magnesium
filings in 350 ml of tetrahydrofuran. A solution of
64.0 g (0.41 mol) of cycloh~y~ne-l~4-dione monoethylene
ketal in 150 ml of tetrahydrofuran was added dropwise to
this at 20 - 30~C. The mixture wa8 stirred at room
temperature for 2 hours and under ref.lux for 2 hours. It
was poured onto ice, solid ammonium chloride was added,
the mixture was diluted with 500 ml of toluene and the
organic phase was separated off, dried and concentrated.
This gave 101 g (88% of theory) of solid product, which
was reacted without further purification.
Melting point 126 - 128~C.
Example D
0.36 g (12 mmol) of sodium hydride (80% strength disper-
sion in mineral oil) was added to a solution of 2.5 g
(11 mmol) of 1-(3-fluoro-4-methoxy-phenyl)-4-hydroxy-
cyclohexene in 30 ml of tetrahydrofuran and the mixturewas heated under reflux for 2 hours until the evolution
of hydrogen had ended. After cooling l-o room temperature,
2.0 g (11 mmol) of 4,5-dichloro-6-ethyl-pyrimidine were
added and the mixture was heated under reflux for a
further 6 hours. After the solvent had been stripped off,
the residue was taken up in water/met:hylene chloride and
the organic phase was dried and concentrated. For purifi-
cation, the residue was chromatographed over silica gel
with petroleum ether/ethyl acetate 4 : 1. This gave 3.0 g
(75.3% of theory) of yellow solid.
CA 02203998 1997-04-29
~ . ,
- 44 -
Melting point 63 - 64~C.
Preparation of the educt 1-(3-fluoro-4-methoxy-phenyl)-4-
hydroxy-cyclohexene
10.0 g (45 mmol) of 1-(3-fluoro-4-methoxy-phenyl)-cyclo-
h~Y~n-4-one were dissolved in 100 ml of methanol, and
0.9 g (23 mmol) of sodium borohydride was added in
portions at 0~C. After the mixture had been stirred at
room temperature for 1 hour, 5 ml of acetone were added,
the solvent was stripped off and the residue was taken up
in 2N sodium hydroxide solution and methylene chloride.
The organic phase was dried and concentrated. 7.4 g
(74.0% of theory) of yellow solid remained, which was
reacted without further purification.
The following were obtained analogou~ly:
Example E
4-(cis-4-tert-Butyl-cyclohex-3-enyloxy)-quinazoline;
melting point 56 - 57~C.
Example F
5-Chloro-6-ethyl-4-(cis-4-tert-butyl-cyclohex-3-enyl-
amino)-pyrimidine; colorless oil.
Example G
5-Bromo-6-ethyl-4-(cis-4-tert-butyl-cyclohex-3-enyl-
amino)-pyrimidine; colorless oil.
Example H
5-Chloro-6-ethyl-4-[4-(3,4-dimethylphenyl)-cyclohex-3-
enylamino]-pyrimidine; colorless oil.
CA 02203998 1997-04-29
- 45 -
Example I
4-[4-(3-Fluoro-4-methoxy)-phenyl-cyclohex-3-enyloxy]-
quinazoline; melting point 82 - 83~C.
