Note: Descriptions are shown in the official language in which they were submitted.
1'~30S47
- 1 - PP.32247A
HALOGRNATED ESTERS
This application is a division of Serial No. 425,180,
filed April 5, 1983.
This invention relates to a method of combatting insect
and similar invertebrate pests and to novel cyclopropane
derivatives useful as insecticides, to processes for t'neir
preparation, and to compositions comprising them.
Certain naturally occurring esters of cyclopropane
carboxylic acids have long been known to possess
insecticidal properties, but these compounds have been too
easily degraded by ultra violet light to be of much use in
agriculture. Several groups of synthetic compounds based on
cyclopropane carboxylic acids (for example those disclosed
in British patent specifications nos. 1,243,858 and
1,413,491) have been evaluated in an attempt to discover
compounds of sufficient light stability for use as general
agricultural insecticides.
A particularly useful group of such compounds is that
disclosed in 8ritish patent specification no. 2,000,764 an-1
Belgian patent no.~63,151. These compounds combine good
light stability with excellent contact and resi~ual
insecticidal properties, but, in common with the compounds
2~ described in British patent specifications 1,243,853 and
1,~13,491, they possess an unsatisfactory toxicity to fish
which precludes their use as insecticides in certain
situations, e.g. in rice where pisciculture is carried on
in the rice paddies.
The present invention relates to certain novel halo-
substituted phenoxybenzyl esters of 3-(2-halo(or tri-
fluoromethyl)-3,3,3-trifluoropropenyl)-2,2-dimethyl-
cyclopropane carboxylic acids with an extremely high level
of insecticidal and acaricidal activity which are much less
toxic to fish.
Accordingly this invention provides a method of
combatting insect pests at a locus where fish are present or
liXely to be present which comprises applying to the locus a
composition comprising a compound of formula~
~23~i47
-- 2 --
Rl- Ce CH CH - C~l - C - O - C~
12 C
/\
CH3 Ca3
(I)
wherein one of Rl and R2 is halomethyl and the other is
halomethyl or halo, X is hydrogen or cyano and Y is halo, in
an amount which is insecticidally effective but which is
substantially non-toxic to the fish.
Particular loci where the method may be practised
include for example rice paddies, areas of forest w~ere
pesticide run off passes into streams and laXes, and
recreational or amenity areas where fish are kept eg, for
angling.
Preferably one of Rl and R2 is trifluoromethyl and
the other is chloro, X is hydrogen or cyano and Y is fluoro,
chloro or bromo. Especially preferred are the compounds 3-
(4-chlorophenoxy)benzyl and ~-cyano 3-(4-
chlorophenoxy)benzyl 3-(2-chloro-3,3,3-trifluoroprop-1-en-1-
yl)-2,2-dimethylcyclopropane carboxylate.
It will be appreciated by those skilled in the art that
the compounds represented by formula I are capable of
existing in various geometrical and stereoisomeric forms.
Thus there may be cls and trans isomers arising from the
substitution pattern of the cyclopropane ring, and E- and ~-
isomers arising from the substituted vinyl group when
is not identical with R2. In addition two of the three
carbon atoms of the cyclopropane are capable of existing in
either R- or S-configurations since they are asymmetrically
substituted.
Specific compounds suitable for use in the method of
the invention are set out in Table I wherein the meanings
12305~7
-- 3 --
for Rl, R2, X and Y and the isomeric composition of each
compound is given in the form Z or E (geometry of double
bond)- (+), (+) or (-)-cls or trans (stereochemistry of
cyclopropane acid moiety)-(2/S), (S) or (2) (absoluble
S configuration of carbon bearing group X). -
_
~..230547
TABLE I
COMPOUND Rl R2 X Y ISOMERIC
NUMBER COMPOSITION
1 CF3 Cl CN Cl Z-(+)-c lS- ( R/S)
2 CF3 F CN Cl Z-(+)-cls-(R/S)
3 CF3 Br CN Cl Z-(+)-cls/trans-(R/S)
4 CF3 CF3 CN Cl (+)-cls/trans-(R/S)
CF3 Cl H Cl Z-(+)-cis
6 CF3 Cl CN Br Z-(+)-cls-(R/S)
7 CF3 Cl CN F Z-(+)-cls-(R/S)
8 CF3 Cl CN Cl Z-(+)-trans-(R/S)
9 CF3 Cl CN Cl Z-(t)-trans-(R/S)
CF3 Cl CN Cl Z-(+)-cis-(S)
11 CF3 Cl CN Cl Z-(~)-trans-(S)
.
lZ~05~7
_. 5
In a further aspect the invention provides compounds of
formula I wherein Rl, R2 and Y are as defined
hereinabove and X is cyano.
The compounds according to ~ormula I are esters and may
be prepared by conventional esterification processes, of
which the following are examples.
ta) An acid of formula:-
Rl--C = CH CH--CH--C--Q
12 \ /
R C (II)
/\
CH3 CH3
where Q represents the hydroxy group and Rl and R2 haveany of the meanings given hereinabove, may be reacted
directly with an alcohol of formula:-
HO - C'H ~
X 0 ~ Y (III)
where X and Y have any of the meanings given hereinabove,
the reaction preferably taking place in the presence of an
acid catalyst, for example, dry hydrogen chloride.
(b) An acid halide of formula II w~ere Q represents a
halogen atom, preferably a chlorine atom, and Rl and R2
have any of the meanings given hereinabove, may be reacted
(i) with an alcohol of formula III, the reaction preferably
taXing place in the presence or a base, for example,
pyridine, alkali metal hydroxide or carbonate, or alkali
metal alkoxide, or (ii) when X is cyano, with an aldehyde of
formula:
1231)~
-- 6
O = CE~ ~
O~Y
in the presence of an alkali metal cyanide.
(c) An acid of formula II or, preferably, an alkali metal
salt thereof, may be reacted with halide of formula:-
Ql _ CH ~
~ Y (IV)
where Ql represents a halogen atom, preferably the
chlorine atom, X, R3,R4 and R5 have any of the meaningsgiven hereinabove, or with the quaternary ammonium salts
derived from such halides with tertiary amines, for example
pyridine, or trialkyl amines such as triethylamine.
(d) A lower alkyl ester of formula II where Q represents a
lower alkoxy group containing up to six carbon atoms,
preferably the methoxy or ethoxy group, and Rl and R2
have any of the meanings given hereinabove, is heated with
an alcohol of formula III to effect a transesterification
reaction. Preferably the process is performed in the
presence of a suitable catalyst, for example, an alkali
metal alkoxide, such as sodium methoxide, or an alkylated
titanium derivative, such as tetramethyl titanate.
123054~7
-- 7
~ 11 of these conventional processes for the preparation
of esters may be carried out using solvents and diluents for
the various reactants where appropriate, and may be
accelerated or lead to higher yields of product when
performed at elevated temperatures or in the presence of
appropriate catalysts, for example phase-transfer
catalysts.
The preparation of individual isomers may be carried
out in the same mannsr but commencing from the corresponding
individual isomers of compounds of formula II. These may be
obtained by conventional isomer separation techniques from
mixtures of isomers. Thus cis and trans isomers may be
separated by fractional crystallisation of the carboxylic
acids or salts thereof, whilst the various optically active
species may be obtained by fractional crystallisation of
salts of the acids with optically active amines, followed by
regeneration of the optically pure acid.
The optically pure isomeric form of the acid (or its
equivalent acid chloride or ester) may then be reacted with
the appropriate alcohol to produce a compound of formula I
in the form of an individually pure isomer thereof.
The preparation of the compounds of Formula II w~erein
Q is hydroxy, alkoxy or halo, and Rl and R2 are as
defined hereinabove, useful as intermediates in the
preparation of the compounds of Formula I, is fully
described in British Patent Specification 2,000,764 and in
Belgian patent no. 863151.
When the processes for preparing the compounds of
Formula I are performed using intermediates which are
themselves mixtures of isomers the products obtained will
also be mixtures of isomers. Thus, the product would be a
mixture of (+)~cis and (+)-trans isomers ~perhaps with one
form predominating) if the intermediate acid or acid
derivative was used in the form of a mixture of (+)-cls and
(+)-trans isomers. If a single isomer, of the acid,
~230547
-- 8 --
e.g. the (+)-cis isomer with Z-configuration in the 2-
chloro-3,3,3-trifluoropropenyl group, was used, the product
would also be the single isomer of t'nat stereochemical
configuration, or a pair of isomers if there is an
asymmetric carbon atom in the alcohol moiety.
The compounds of formula I may be used to combat and
control infestations of insect pests and also other
invertebrate pests, for example, acarine pests. The insect
and acarine pests which may be combatted and controlled by
the use of the invention compounds include those pests
associated with agriculture (which term includes the growing
of crops for food and fibre products, horticulture and
animal husbandry), forestry, the storage of products of
vegetable origin, such as fruit, ~rain and timber, and also
those pests associated with the transmission of diseases of
man and animals.
In order to apply the compounds to the locus of the
pests they are usually formulated into compositions which
include in addition to the insecticidally active ingredie~t
or ingredients of formula I suitable inert diluent or
carrier materials, and/or surface active agents. The
compositions may also comprise another pesticidal material,
for example another insecticide or acaricide, or a
fungicids, or may also comprise a insecticide synergist,
such as for example dodecyl imidazole, safroxan, or
piperonyl butoxide.
The compositions may be in the form of dusting powders
wherein the active ingredient is mixed with a solid diluent
or carrier, for example kaolin, bentonite, kieselguhr, or
talc, or they may be in the form of granules, wherein the
active ingredient is absorbed in a porous granular material
for example pumice.
Alternatively the compositions may be in the form of
liquid preparations to be used as dips or sprays, which are
generally aqueous dispersions or emulsions of the active
12305~1L7
_ 9 _
ingredient in the presence of one or more known wetting
agents, dispersing agents or emulsifying agents (surface
ac~ive agents).
~etting agents, dis~ersing agents and emulsifying
agents may be of the cationic, anionic or non-ionic t~pe.
Suitable agents of the cationic type include, for example,
quaternary ammonium compounds, for example cetyltrimethyl
ammonium bromide. Suitable agents of the anionic type
include, for example soaps, salts of aliphatic monoesters or
sulphuric acid, for example sodium lauryl sulphate, salts of
sulphonated aromatic compounds, for example sodium
dodecyLbenzenesulphonate, sodium, calcium or ammonium
lignosulphonate, butylnaphthalene sulphonate, and a mixture
of the sodium salts of diisopropyl- and tri-
isopropylnaphthalene sulphonates. Suitable agents of thenon-ionic type include, for example, the condensation
products of e~hylene oxide with fatty alcohols such as oleyl
alcohol or cetyl alcohol, or with alkyl phenols such as
octyl phenol, nonyl phenol and octyl cresol. Other non-
ionic agents are the partial esters derived from long chainfatty acids and hexitol anhydrides, the condensation
products of the said partial esters with ethylene oxide, and
the lecithins.
The compositions may be prepared by dissolving the
active ingredient in a suitable solvent, for e~ample, a
ketonic solvent such as diacetone alcohol, or an aromatic
solvent such as trimethylbenzene and adding the mi~ture so
obtained to water which may contain one or more '~nown
wetting, dispersing or emulsifying agents. Other suitable
organic solvents are dimethyl formamide, ethylene
dichloride, isopropyl alcohol, propylene glycol and other
glycols, diacetone alcohol, toluene, kerosene, white oil,
methylnaphthalene, xylenes and trichloroethylene, ~-methyl-
2-pyrrolidone and tetrahydro furfuryl alcohol (THFA).
12305'~7
-- 10 --
The compositions to be used as sprays may also be in
the form of aerosols wherein the formulation is held in a
container under pressure in the presence of a propellant
such as fluorotrichloromethane or dichlorodifluoro~ethane.
~he compositions which are to be used in the form of
aqueous dispersions or emulsions are generally supp`lied in
the form of a concentrate containing a high proportion of
the active ingredient or ingredients, the said concentrate
to be diluted with water before use. These concentr~tes are
often required to withstand storage for prolonged periods
and after such storage, to be capable of dilution with water
to form aqueous preparations which remain homogenous for a
sufficient time to enable them to be applied by conventional
spray equipment. The concentrates may contain 10-85% by
weight of the active ingredient or ingredients. ~'nen
diluted to form aqueous preparations such preparations may
contain varying amounts of the active ingredient depending
upon the purpose for which they are to be used. ~or
agricultural or horticultural purposes, an aqueous
preparation containing between O.OQ01~ and 0.1% by weight of
the active ingredient is particularly useful.
In use the compositions are applied to the pests, to
the locus of the pests, to the habitat of the pests, or to
growing plants liable to infestation by the pests, by any of
the known means of applying pesticidal compositions, for
example, by dusting or spraying.
The compositions of the invention are very toxic to
wide varieties of insect and other invertebrate pests,
including, for example, the following:-
Aphis fabae (aphids)
Megoura viceae (aphids)
Aedes aegypti (mosquitoes)
Dysdercus fasciatus (capsids)
Musca domestica (houseflies)
Pieris brassicae (white butterfly, larvae)
1230S~7
Plutella maculipennis (diamond bacX month, larvae)
Phaedon cochleariae (mustard beetle)
Telarius cinnabarinus (carmine spider mite)
Aonidiella spp. (scale insects)
Trialeuroides spp. (white flies)
Blattella germanica (cockroaches)
Spodoptera littoralis (cotton leaf worm)
Chortiocetes terminifera (locusts)
Diabrotica spp. (rootworms)
Nilaparvata lugens (plant hoppers)Nephotettix virescens (leaf hoppers)
Chilo suppressalis (stem borers)
Tryporyza _ncurtulos (stem borers)
The compounds of formula I and compositions comprising
them have shown themselves to be particularly useful in
controlling pests of rice, for example Nephotettix spp. and
Nilaparvata spp. They are also very useful in combatting
insect and acarine pests which infest domestic animals, such
as Lucilia sericata, and ixodid tic~s such as Boophilus
spp., Ixodes spp., Amblyomma spp., Rhipicephalus spp., and
- Dermaceutor spp. They are effective in combatting both
susceptible and resistant strains of these pests in their
adult, larval and intermediate stages of growth, and may be
applied to the infested host animal by topical, oral or
parenteral administration.
The following Examples illustrate the various aspects
of the invention.
12305~7
- 12 -
EXAMPLE 1
This Example illustrates the insecticidal properties of
Compound no.l of Table I.
The activity of the compound was determined using a
variety of insect pests. The compound was used in the form
of liquid ~reparations containing 100, 50, 25, 10 or 12
p.p.m. by weight of the compound. The preparations were
made by dissolving the compound in a mixture of solvents
consisting of 4 parts by volume of acetone and 1 part by
volume of diacetone alcohol. The solutions were t'nen
diluted with water containing 0.01% by weiqht of a wetting
agent sold under the trade name "LISSAPOL" NX until the
liquid preparations contained the required concentration of
the compound. "Lissapol" is a Trade ~lark.
The test procedure adopted with regard to each pest was
basically the same and comprised supporting a number of the
pests on a medium which was usually a host plant or a
foodstuff on which the pests feed, and treatin~ either or
both the pests and the medium with the ~reparations. The
mortality of the pests was then assessed at periods usually
varying from one to three days after the treatment. Details
are given in Table IIA.
The results of the tests are given in Table IIB for
each of the products A to ~d at the rate in parts per million
given in the second column as a grading of mortality on a
scale of 0-9 wherein
0 represents less than 10% mortality
1 " from 10 to 19%
2 " " 20 to 29% "
3 " " 30 to 39% "
4 " " 40 to 49~ "
" " 50 to 59~ "
6 " " 60 to 69~ "
1i:3~)5~7
- 13 -
7 " " 70 to 79% "
8 " " 80 to 8~ "
9 " " 90 to 100% "
In Table IIB the pest organism used is designated by a
letter code and the pest species, the support medium or
food, and the type and duration of test is given in Table
IIA. - -
~23C~5~
-- 14 --
O^
H ~,q
E~ :~ ,i ~ ~t ~ ~ .
~ JJ
a . ~ C
~1
o ~ U C~ U
E~ ~ ~ u~
U~
C ~q ~q ,. ~ h
~, C o ~ a) o o
~ U U ~ ~ U U ,~
S~
I,q (q 3 o
o ~ ~ ~ iq s~
E~ O~ s~
~ ~ O ~ ~ ,~
O ~ O ~ ~ ~5
C~ ~3 :~ ~ Q, ~ a~
G ~ ~q C~ ~3 E ~
'- H ~ S ~5 0
~ ~ X .~ P
¢ ~~ _I p
~ 0-~
H U F U U ~ ~4 cq ~q
O~ 3
~ tq I 1~ n5 S!~ E~
_l la ~1 S
e ~ ~ ~ ~ o
C~~5 0 h ~ O
UHU 1~ ~ 3 ~ ~ ~ h~ ~) a)
!~ .,1 I .,1 O X ~ ~1 ~ ~_
D~ ~ ~1 ~ ~ U
u~ ~q ~,
~ a) ~ o x ,9 0
E~ F .,~ ~ ~1 ,Q U E ~,
u~ O ~ a~ ~1:1 ~ lo ~,~ h Q) S
~ ~a ~ ~ c_ ~ c^ q~ ~q~ O
c~ Q) ~. O o _1 O o ~J 0 3
~J Iq O ~ ~ o E~ ~ ~q .,, h ~) C.` ~q
U ~ ~ ~ ~ ~ ~ ~ ,1 S~ O .,
t,q O O O h ::5 ,~ h S Q~ ~a O
~ ,C ~ U n~ --I ~Q, ~ h C
-- u~ ~ _,~ ~ ~a _ .,, u
I ,~
ul a~ `'
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E-l H
E~ H a ~ u ~
a) ~ a ~ ~ .
_
~ .~ tq
C ~ O ~ al
o~ ~ ~ V
U_ : - ~
~2305~7
-- 15 --
TABLE I I 13
__
PEST SPECIES
COMPOUND RATE
NUMBER( ppm ) 11 DSL PX Al? DB
1 100 9 9 9 9 9
1 50 9 9 .9 9 9 .
1 25 g O 1 7 9 0
1 12 9 0 1 2 9 0
100 9 9ll 9 9 5
1 9 0 9 3
~ 100 9 9 7 9 5
6 10 6 9 6 9 3
7 100 O 9 9 9 9
7 10 0 9 9 9 5
8 100 9 9 9 9 5
8 10 9 9 8 9
~3~5~7
- 16
EXAMPLE 2
This Example illustrates the improved safety to fish of
the compounds for use in the method of the invention
compared with known compounds of similar chemical type.
Table III sets out the LC50 values for young trout and
carp in parts per million for the compounds for use in the
method of this invention and parts per billion for the known
(reference) compounds.
TABLE III
COMPOUND NO LC50 LC50
(Table I) Trout Carp
1 20 ppm
10 ppm
6 _ 10 pp~
7 1 ppm
Cyhalothrin* 0.73 ppb 1.34 ppb
Cypermethrin** ca 2 ppb
(+)~-cyano-3-phenoxybenzyl (+)-cis-3-(2-2-chloro-3,3,3-
trifluoroprop-l-en-l-yl)-2,2-dimethylcyclopropane
carboxylate.
** (+)-~-cyano-3-phenoxybenzyl (+)-cis/trans-3-(2,2-
dichlorovinyl)-2,2-dimethylcyclopropane carboxylate.
~2~0547
~ 17 -
EXA~IPLE 3
This Example illustrates the preparation of (t)~~~
cyano-3-(4-chlorophenoxy)benzyl alcohol.
Glacial acetic acid (2.0 ml) was added to a well
stirred mixture of ~-chlorophenoxybenzaldehyde (4.65 g),
sodium cyanide (1.18 g) and water (10 ml), a temperature
being maintained in the range 10 15C during the addition.
After completing the addition the mixture was stirred for a
further one hour at this tem~erature, extracted with
methylene chloride and the extracts dried over anhydrous
magnesium sulphate. The residual oil (5.0 g) remaining
after evaporation of the solvsnt, which was shown by infra-
red spectroscopy to consist principally of the desired
~roduct together with a small amount of unreacted aldehyde,
was used without further purification in the followinq
~xample.
Infra red (liquid film): 3400 (broad), 1585, 1485,
1260 cm~l
(A small peak at 1700 cm 1 was also present indicating
some unreacted aldehyde).
EXAMPLE 4
This Example illustrates the preparation of (+)-~-
cyano-3-(4-chlorophenoxy)benzyl (+)-cis-3-(Z-2-chloro-3,3,3-
trifluoroprop-l-en-l-yl)-2,2-dimethylcyclopropane
carboxylate (compound no.l, Table I).
A mixture of (+)-cis-3-(Z-~-chloro-3,3~3-trifluoro-
prop-1-en-1-yl)-2,2-dimethylcyclopropane carboxylic acid
(1.0 g) was refluxed with excess thionyl chloride to convert
it to its acid chloride. The excess thionyl chloride was
removed by evaporation under reduced pressure and the
residue freed from the final traces by azeotropic
distillation with dry toluene.
12~)54~
- 18 -
The acid chloride was dissolved in dry toluene
(10 ml) and mixed with the (+)~ cyano-3-(4-chlorophenoxy)-
benzyl alcohol (1.16 g) obtained in the previous Example. To
the stirred mixture at the ambient temperature was added a
S solution of dry pyridine (0.5 g) in dry toluene (2.0 ml),
resulting in the formation of a white precipitate. After
stirring for one hour the mixture was diluted with more
toluene and then washed with water, and with saturated
aqueous sodium bicarbonate solution, and dried over
anhydrous magnesium sulphate. After filtering to remove the
solid matter the filtrate was concentrated by removal of the
solvent by evaporation under reduced pressure and colourless
residual oil (2.2 g) was purified by wet column
chromatography (silica gel column, chloroform eluent) to
yield pure (+)~-cyano-3-(4-chlorophenoxy)benzyl (+)-c1s-3-
(Z-2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-
dimethylcyclopropane carboxylate (1.2 9) as a colourless
oil.
N.m.r. (CDC13) ppm : 1.15-1.40 (m,6H); 1.92-2.37 (m,2H);
6.27 (d,l~); 6.67-7.46 (m,9H).
Infra red (liquid film): 3075, 2950, 1740, 1650, 1585,
1485, 1300, 1270, 1250, 1160,
1130, 1075, 1000, 950, 760 cm~
EXAMPLE 5
Other compounds useful in the method of the invention
may '~e prepared by the procedures of ~xamples 3 and 4 from
the appropriate reactants as follows:
(a) (+)-~-cyano-3-(4-chlorophenoxy)benzyl (+)-trans-3-(Z-2-
chloro-3,3,3-trifluoroprop-1-en-yl)-2,2-
dimethylcyclopropane carboxylate (compound no 8, Table
I).
123~5~
- 19 -
E~ n.m.r.(CDC13)ppm: 1.24-1.42(m,6H); 1.82-
2.64(m,2H); 6.?2(d,lH);
6.48(d,1ii); 6.98-7.62(m,3H).
Infra red (liquid film): 3060, 2960, 1740, 1650, lS85,
1485, 1280, 1150cm~l
(b) (+)~ cyano-3-(4-fluorophenoxy)benzyl (+)-cis-3-(Z-2-
chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-
dimet'nylcyclopropane carboxylate (compound no 7, Table
I).
lH n.m.r.(CDC13)ppm: 1.20-1.44(m,6H); 2.00-
2.44(m,2~)' 6.46(~,1H); 6.90-
7.52(m,9H)
Infra red (liquid film): 3070, 2960, 1740, 1650, 1580,
1500, 1200, 1150cm~l
(c) (+)-~-cyano-3-(4-bromophenoxy)benzyl (+)-cis-3-(Z-2-
chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-
dimethylcyclopropane carboxylate (compound no 6, Table
I).
lH n.m.r.(CDC13)ppm: 1.20-1.44(m,6H); 2.00-
2.44(m,2H); 6.48(d,1~);
6.86-7.68(m,9H).
Infra red (liquid film): 3080, 2690, 1740, 1650, 1550,
1460, 1270, 1150cm~l
(d) (+)-3-(4-chlorophenoxy)benzyl (+)-cls-3-(Z-2-chloro-
3,3,3-trifluoroprop-1-2n-yl)-2,2-dimethylcyclopropane
carboxylate (compound no 5, Table I).
H n.m.r.(CDC13)ppm: 1.30(s,6H); 2.00-2.36(m,2H);
5.12(s,2H); 6.90-7.50(m,9H);
Infra red (liquid film): 3070, 2960, 1725, 1650, 1580,
1480, 1140cm~l