Note: Descriptions are shown in the official language in which they were submitted.
S79
Type Ia
The present invention relates to certain new l-azolyl-
l-fluorophenoxy-butane derivatives,to a process for their
preparation and to their use as fungicides.
It has already been disclosed that l-a~olyl-l-chloro-
phenoxy-butane derivatives, for example 4-chloro-1-(4-
chlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)- or
-(imidazol-l-yl)-butan-2-one and 4-bromo-1-(4-chloro-
phenoxy)-3,3-dimethyl-1-(imidazol-1-yl)-butan-2-ol have
good fungicidal properties (see DT-ûS (German Published
lû Specification) 2,632,602 (Le A 17 274) and DT-OS (German
Published Specification) 2,632,603 (Le A 17 273)).
However, their good action is not always completely
satisfactory, especially when low amounts and
concentrations are used.
The present invention now provides, as new compounds,
the halogenated l-azolyl-l-fluorophenoxy-butane derivatives
of the general formula
F 1 5
~ -O - CH - A - 7 CH2Y (I)
~N~B CH3
N-
in which
2û A represents a keto group or a CH(OH) group,
B represents a nitrogen atom or a CH group and
Y represents halogen,
and their physiologically acceptable salts. They have
powerful fungicidal properties.
Preferably, in formula (I), Y represents chlorine or
bromine.
These compounds of the formula (I) in which A
represents the CH(OH) group have two asymmetric carbon
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atoms; they can therefore exist in the form of the two
geometic isomers (erythro form and threo form), which can
be obtained in various proportions. In both cases, they
exist in the form of optical isomers. All the isomers
are incl~ded within the`formula (I).
The invention also provides a process for the
preparation of a halogenated l-azolyl-l-fluorophenoxy-
butane derivative of the formula (I) in which a bromo-
ether-ketone of the general formula
--O - ~ - CO - C - CH2 Y ( I I ),
~ CH~
.
in which
Y has the meaning stated above,
is reacted with an azole of the general formula
~1
~~ ~ (III) ,
in which
B has the meaning stated above,
in the presence of an acid-binding agent and in the
presence of a diluent, and the ketone derivative thereby
obtained is optionally reduced with a Complex borohydride
in a manner which i9 in itself known, if appropriate
in t~ presence of a diluent.
~urthermore, the halogenated l-azolyl-l-fluoro-
phenoxy-butane derivatives obtainable according to the
invention can be converted into the salts by reaction
with acids.
Surprisingly, the active compounds according to the
invention exhibit a considerably higher fungicidal
activity, in particular against species of powdery
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mildew, than the l-azolyl-1-chlolophenoxy-butane derivatives
known from the state of the art, such as 4-chloro-1-(4-
chlorophenoxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)- or
-(imidazol-l-yl)-butan-2-one and 4-bromo-1-(4-chloro-
phenoxy)-3,3-dimethyl-1-(imidazol-1-yl)-butan-2-ol, which
are very closely related compounds chemically and from the
point of view of their action. The active compounds
according to the invention thus represent an enrichment
of the art
If l-bromo-4-chloro-3,3-dimethyl-1-(4-fluorophenoxy)-
butan-2-one and 1,2,4-triazole are used as starting
materials, the course of the reaction can be represented
by the following equation:
F ~ O-CH-CO-~-CH2Cl + ~ ~ Ib~ase
F ~ O-CH-CO-C-CH2Cl
N CH3
.~ - .
If 4-chloro-3,3-dimethyl-1-(4-fluorophenoxy)-1-
(1,2,4-triazol-1-yl)-butan-2-one and sodium borohydride are
used as starting materials, the course of the reaction can
be represented by the following equation:
F ~ O-C~H-CO-~-CH2Cl ~ -~
`N CH~
N_U
F~O-CH-C~I-C-CH2 Cl
N~N - CH3
N
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The formula (II ! provides a general definition of
the bromoether-ketones to ~e used as starting substances.
In this formula, Y preferably represents chlorine or
bromine.
The bromoether-keton`es of the formula (II) have not
hitherto been disclosed in the literature, but can be
obtained by known processes, for example by reacting
fluorophenol with a bromoketone of the formula
CH3 (IV)
Br - C~2 - C0 - I - CH2 Y
CH~
10 in which
Y has the meaning stated above.
The active hydrogen atom which still remains is then re-
placed by bromine in the customary manner (see also the
preparative examples later in this text).
Examples which may be mentioned of the starting com-
pounds of the formula (II) are: l-bromo-4-chloro-(4-
fluorophenoxy)-3,3-dimethyl-butan-2-one and 1,4-dibromo-
(4-fluorophenoxy)-3,3-dimethyl-butan-2-one~
The azoles (III) are well known compounds in organic
chemistrY-
Possible salts of the compounds of ~he formula (I)are salts with physiologically acceptable acids. These
include, as preferences, the hydrogen halide acids(for
example hydrobromic acid and in particular hydrochloric
acid), phosphoric acid, nitric acid, monofunctional and
bifunctional carboxylic acids and hydroxycarboxylic acids
(for example acetic acid, citric acid, sorbic acid and
lactic acid), and sulphonic acids (for example 1,5-
naphthalenedisulphonic acid).
Preferred diluents for the reaction according to the
invention are inert organic solvents. These include
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as preferences, ketones, such as diethyl ketone, and in
particular acetone and methyl ethyl ketone; nitriles,
such as propionitrile, and in particular acetonitrile;
alcohols, such as ethanol or isopropanol, ethers, such as
tetrahydrofuran or dioxan; aromatic, optionally halogenated
hydrocarbons, such as toluene, 1,3-dichlorobenzene or
benzene; formamides, such as, in particular, dimethyl-
formamide; and halogenated aliphatic hydrocarbons, such as
methylene chloride, carbon tetrachloride or chloroform.
The reaction is carried out in the presence of an
acid-binding agent. Any of the inorganic or organic acid-
binding agents which can customarily be used, such as
alkali metal carbonates, for example sodium carbonate,
potassium carbonate and sodium bicarbonate, or such as
lower tertiary alkylamines, cycloalkylamines or aralkylamines,
for example triethylamine, N,N-dimethylcyclohexylamine,
dicyclohexylmethylamine or N,N-dimethylbenzylamine, and
furthermore pyridine and diazabicyclooctane, can be added.
An appropriate excess of the azole of the formula (III) is
preferably used.
The reaction temperatures can be varied within a
substantial range. In general, the reaction is carried
out at from 0 to 150C, preferably at from 60 to 120C.
In carrying out the process according to the invention,
1 to 2 moles of azole and 1 to 2 moles of acid-binding agent
are preferably employed per mole of the compound of the
formula (II). In order to isolate the compound of the
formula (I), the solyent is distilled off, the residue is
taken up in an organic solvent and the mixture is washed
with water. The organic phase is dried over sodium sul-
phate and freed from solvent in vacuo. The residue is
purified by distillation or recrystallisation.
For the optional reduction of the keto compounds, poss-
ible diluents for the reaction according to the invention are
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polar organic solvents.` These 'lnclude, as preferences,
alcohols, such as methanol', ethanol, butanol or isopropanol,
and ethers, such as diethyl ether or tetrahydrofuran. In
general, the reaction is carried out at from 0 to 30C,
preferably at from 0 to 20C. For this reaction, about
1 mole of a borohydride, such as sodium borohydride or
' lithium borohydride, is employed per mole of the corres-
- ponding keto compound. In order to isolate the compound
of the formula (I), the residue is taken up in, for example,
dilute hydrochloric acid and the mixture is then rendered
alkaline and extracted with an organic solvent, or only
water is added to the mixture and the mixture is extracted
by shaking with an organic solvent. Further working up is
carried out in the customary manner.
The active compounds according to the invention ex-
hibit a powerful microbicidal action and can be employed
in practice for combating undesired micro-organisms. The
active compounds are suitable for use as plant protection
agents.
Fungicidal agents in plant protection are employed
for combating Plasmod'iop'ho'romy'cetes, Oomycetes, Chytridio-
mycetes, Zygomycetes, Ascomycetes, Basidiomycetes and
Deuteromycetes.
The good toleration, by plants, of the active com-
pounds, at the concentrations required for combating plant
diseases, permits treatment of above-ground parts of plants,
of vegetative propagation stock and seeds, and of the soil.
As plant protection agents, the active compounds
according to the invention can be used with particularly
good success for combating Erysiphe speci~s. It should
be emphasised that the active compounds according to the
invention not only develop a protective action, but also have
a systemic action. Thus, it is possible to protect plants
against fungal attack when the active compound is fed to
the above-ground parts of the plant via the soil and the
root or via the seed.
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The active compounds can be converted into the
customary formulations, such as solutions, emulsions,
wettable powders, suspensions, powders, dusting agents,
foams, pastes, soluble powders, granules, aerosols,
suspension-emulsion concentrates, seed-treatment powders,
natural and synthetic materials impregnated with active
compound, very fine capsules in polymeric substances,
coating compositions for use on seed, and formulations
used with burning equipment, such as fumigating cartridges,
fumigating cans and fumigating coils, as well as ~LV
cold mist and warm mist formulations.
These formulations may be produced in known manner,
for example by mixing the active compounds with extenders,
that is to say liquid or liquefied gaseous or solid
diluents or carriers, optionally with the use of surface-
active agents, that is to say emulsifying agents and/or
dispersing agents and/or foam-forming agents. In the
case of the use of water as an extender, organic solvents
can, for example, also be used as auxiliary solvents.
As liquid diluents or carriers, especially solvents,
there are suitable in the main, aromatic hydrocarbons,
such as xylene, toluene or alkyl naphthalenes, chlorinated
aromatic or chlorinated aliphatic hydrocarbons, such
as chlorobenzenes, chloroethylenes or methylene chloride,
aliphatic or alicyclic hydrocarbons, such as cyclohexane
or paraffins, for example mineral oil fractions, alcohols,
such as butanol or glycol as well as their ethers and
esters, ketones, such as acetone, methyl ethyl ketone,
methyl isobutyl ketone or cyclohexanone, or strongly
polar solvents, such as dimethylformamide and dimethyl-
sulphoxide, as well as water.
By liquefied gaseous diluents or carriers are meant
liquids which would be gaseous at normal temperature
and under normal pressure, for example aerosol propellants,
such as halogenated hydrocarbons as well as butane,
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propane, nitrogen and carbon dloxide:
As solid carriers there may be used ground natural
minerals, such as kaolins, clays, talc, chalk, quartz,
attapulgite, montmorillonite or diatomaceous earth, and
-~ 5 ground synthetic minerals, such as highly-dispersed silicic
acid, alumina and silicates. As solid carriers ~or granules
there may be used crushed and fractionated natural rocks
- such as calcite, marble, pumice, sepiolite and dolomite,
as well as synthetic granules of inorganic and organic
meals, and granules of organic material such as sawdust,
coconut shells, maize cobs and tobacco stalks.
As emulsifying and/or foam-forming agents there may
be used non-ionic and anionic emulsifiers, such as polyoxy-
ethylene-fatty acid esters, polyoxyethylene-fatty alcohol
ethers, for example alkylaryl polyglycol ethers, alkyl
sulphonates, alkyl sulphates, aryl sulphonates as well
as albumin hydrolysis products. Dispersing agents include,
for example, lignin sulphite waste liquors and methyl-
cellulose.
Adhesives such as carboxymethylcellulose and natural
and synthetic polymers in the form of powders, granules
or latices, such as gum arabic, polyvinyl alcohol and
polyvinyl acetate, can be used in the formulations.
It is possible to use colorants such as inorganic
pigments, for example iron oxide, titanium oxide and
Prussian Blue, and organic dyestuffs, such as alizarin
dyestuffs, azo dyestuffs or metal phthalocyanine dyestuffs,
and trace nutrients, such as salts of iron, manganese,
boron, copper, cobalt, molybdenum and zinc.
The formulations in general contain from 0.1 to
95 per cent by weight of active compound, preferably from
0.5 to 90 per cent by weight.
The active compounds according to the invention can
be present in the formulations or in the various use forms
as a mixture with other active compounds, such as fungi-
cides, bactericides, insecticides, acaricides, nematicides,
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1.~3Z5~79
herbicides, bird repellants, growth factors, plant
nutrients and agents for improving soil structure.
The active compounds can be used-as such or in the
form of their formulations or the use forms prepared there-
from by further dilution, such as ready-to-use solutions,
emulsions, suspensions, powders, pastes and granules. They
are used in t~e customary manner, for example by watering,
immersion, spraying, atomising, misting, vaporising, inject-
ing, forming a slurry, brushing on, dusting, scattering, dry
dressing, moist dressing, wet dressing, slurry dressing or
encrusting.
Especially in the treatment of parts of plants, the act-
ive compound concentrations in the use forms can be varied
within a substantial range. They are, in general, from 1
to 0.0001% by weight, preferably from 0.5 to 0.001%.
In the treatment of seed, amounts of active compound
of 0.001 to 50 g, especially 0.01 to 10 g, are generally
employed per kilogram of seed.
For the treatment of soil, active compound concen-
trations of 0.00001 to 0.1% by weight, especially of
0.0001 to 0.02%, are generally employed at the place of
action.
The present invention also provides a fungicidal
composition containing as active ingredient a compound
of the present invention in admixture with a solid or
liquefied gaseous diluent or carrier or in admixture
with a liquid diluent or carrier containing a surface-
active agent.
The present invention also provides a method of
combating fungi which comprises applying to the fungi,
or to a habitat thereof, a compound of the present in-
vention alone or in the form of a composition containing
as active lngredient a compound of tne present invention
in admixture with a diluent or carrier.
The present invention further provides crops protected
from damage by fungi by being grown in areas in which immediately
prior to and/or during the time of the growing a compound
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of the present invention was applied alone or in admixture
with a diluent or carrier.
It will be seen that the usual methods of providing
a harvested crop may be improved by the present invention.
The fungicidal activity of the compounds of this
invention is illustrated by the following biotest Examples.
Example A
Shoot treatment test/powdery mildew of cereals
(leaf-destructive mycosis)/protective
To produce a suitable preparation of active compound,
0.25 part by weight of active compound was taken up
in 25 parts by weight of dimethylformamide and 0.06
part by weight of alkylaryl polyglycol ether; 975 parts
by weight of water were then added. The concentrate
was diluted with water to the desired final concentration
of the spray liquor.
To test for protective activity, single-leaved
young barley plants of the Amsel variety were sprayed
with the preparation of active compound until dew-moist.
After drying, the barley plants were dusted with spores
of Erysiphe graminis var. hordei.
-
- After 6 days' dwell time of the plants at a tempera-
ture of 21-22 deg.C and 80-90% atmospheric humidity the
occurrence of mildew pustules on the plants was evaluated.
The degree of infection was expressed as a percentage
of the infection of the untreated control plants. 0%
denoted no infection and 100% denoted the same degree
of infection as in the case of the untreated control.
The active compound was the more active, the lower was
3 the degree of mildew infection.
The active compounds, active compound concentrations
in the spray liquor and degrees of infection can be
seen from the table which follows:
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'' a b'`l''e'''A
Shoot treatment test/powdery mildew of
cereal/protective
Active com- Infection
pound concen- in % of
Active compounds tration in the un-
the spray treated
liquor in % control
by weight
.
~H~
Cl- ~ -0-CIH-CO-C-CHzCl 0,00025 100
CH~
N ~ SO~H
- -- x l/2 ~
S03H
CHI
_
F-~ ~ ~0-C~H-C0-CI-CHzCl 0.00025 37,5
~N~N CH~
x l/2 ~
SO~H
Cl- ~ -0-C -C0-C-CHzCl 0,00025 5 t
~ N ~03H
(known) ~ l/2 ~
SO~H
~H3
F- ~ -0-CH C0-~-CH2Cl 0~00025 10~0
(6) ~ N x l/2 ~
SO~H
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ExampIe B
Powdery mildew of barley ('Erys'i'~'he''g~a'mi'~is var.''h'o'rd'ei)
. _ , ,
(fungal disease of cereal shoots)/systemic
The active compound w'as used as a pulverulent seed
treatment agent. mis was prepared by extending the
particular active compound with a mixture of equal parts
by weight of talc and kieselguhr to give a finely pulverulent
mixture of the desired concentration of active compound.
For the treatment of seed, barley seed was shaken
with the extended active compound in a closed glass
bottle. The seed was sown at the rate of 3 x 12 grains
in flowerpots, 2 cm deep in a mixture of one part by
volume of Fruhstorfer standard soil and one part by volume
of quartz sand. The germination and emergence took
place under favourable conditions in a greenhouse. 7
days after sowing, when the barley plants had developed
their first leaf, they were dusted with fresh spores
of Erysiphe gra~inis var. hordei and grown on at 21-22
deg.C and 80-90% relative atmospheric humidity and 16
hours' exposure to light. The typical mildew pustules
formed on the leaves over the course of 6 days.
The degree of infection was expressed as a percentage
of the infection of the untreated control plants. Thus,
0% denoted no infection and 100% denoted the same degree
of infection as in the case of the untreated control.
The active compound was the more active, the lower was
the degree of mildew infection.
The active compounds and concentrations of active
compound in the seed treatment agent, as well as the
3 amount used of the latter, and the percentage infection
with mildew can be seen from the table which follows:
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.
- 13 -
a~
~ a~ -
o
O U~
o
o ~
H ~ C~ . Lr~ r~l
.
~ .
U~
~rl
0 ~ .
O bO . '
aD
rn ~ u~ O O
~13~ ~ -
m ~1 ~ rl ~
~ .~ 0~ 0~
. t~q 0~ S~O,
3 .IS~
. ~ ~S5
?~
'
S~ .
. ~ P~
V~
~ ~-~
E . g_ ~z
~3 ~ (~
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1~325~79
14
Preparative''e'x'a'mp'les
Example 1
CH~
F - ~ - 0 - CH - C0 - C - CH2Cl
CH~ (1)
S~ H
x 1/2 ~
~ . .. . .. . .. ..
SO~H
57 g (0.177 mol) of 1-bromo-4-chloro-3,3-dimethyl-
1-(4-fluorophenoxy)-butan-2-one were dissolved in 600 ml of
absolute acetonitrile, 24.2 g (0.35 mol) of 1,2,4-triazole
were added and the mixture was heated under reflux for 6
hours. m e solvent was distilled off under a waterpump
vacuum, the residue was taken up in 700 ml of methylene
chloride and the organic phase was extracted twice with 1.5
litresof water and dried over sodium sulphate. The solvent
was distilled off under a waterpump vacuum and the oil which
remained was taken up in 200 ml of acetone. 18 g (0.1 mol)
of 1,5-naphthalenedisulphonic acid, dissolved in 100 ml of
acetone, were added and the precipitate which had formed
was filtered off. 47 g ~55.7% of theory) of 4-chloro-3,3-
dimethyl-l-(4-fluorophenoxy)-1-(1,2,4-triazol-1-yl)-butan-
2-one 1,5-naphthalenedisulphonate of melting point 200C
were obtained.
Preparation 'of the starting material
CH~
F - ~ - 0 - ICH - C0 - C - CH2Cl
Br CH~
100.2 g (0.617 mol) of 1,4-dichloro-3,3-dimethyl-
butan-2-one were added dropwise to a solution of 56 g (0.5
mol) of p-fluorophenol and 85 g of potassium carbonate in
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15 -
700 ml of acetone at the boiling point. The mixture was
- stirred under reflux for 6 hours and filtered off and the
solvent was distilled under the filtrate. 101.5 g (83% of
theory) of 4-chloro-3,3-dimethyl-1-(4-fluorophenoxy)-
butan-2-one were obtained and were dissolved in the crude
state in 600 ml of methylene chloride. 66.3 g (0.415 mol)
of bromine were then added dropwise at room temperature in
a manner such that decoloration occurred. The mixture was
subsequently stirred for 30 minutes, the solvent was dis-
tilled off under a waterpump vacuum and 100 ml of pentanewere added to the residue, whereupon the residue
crystallised. 114 g (85% of theory) of 1-bromo-4-chloro-
3 3 3-dimethyl-1-(4-fluorophenoxy)-butan-2-one of melting
point 74C were obtained.
CH,
ClCH2 - CO - C - CH2Cl
CH3
1,050 g (7.8 mol) of 78% pure 4-chloro-3,3-dimethyl-
butan-2-one were dissolv~d in 6 litres of methylene chloride,
and 450 g of chlorine were passed in at 10 to 11C in the
course of 6 hours. Thereafter, the mixture was subsequently
stirred for 30 minutes, excess hydrogen chloride was driven
off with nitrogen and the reaction mixture was distilled
over a 60 cm packed column. 832 g (63% of theory) of 1,4-
dichloro-3,3-dimethyl-butan-2-one of boiling point 52-54~C/
0.1 mm Hg were obtained in a purity of 75%.
E ample 2
.
OH CH~
F - ~ - O - CH - CH - C - CH2Cl (2)
N ~ CH3
N ~
4.75 g (0.12 mol) of sodium borohydride were added
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in portions to 25 g ~0.053 mol) of 4-chloro-3,3-dimethyl-1-
(4-fluorophenoxy)-1-(1,2,4-triazol-1-yl)-butan-2-one
naphthalenedisulphonate (Example l),-dissolved in 400 ml of
methanol~ and the mixture was subsequently stirred at room
temperature for 15 hours. 15 ml of concentrated hydro-
chloric acid were carefully added dropwise, whilst cooling,
the mixture was stirred at room temperature for 2 hours and
half of the solvent was distilled off under a waterpump
vacuum. The reaction mixture was added to 400 ml of saturated
sodium bicarbonate solution and extracted with 300 ml of
methylene chloride and the organic phase was separated off,
washed twice with 100 ml of water each time, dried over
sodium sulphate and concentrated by distilling off the
solvent. After adding 100 ml of diisopropyl ether, the
residue crystallised. 9.1 g (36.4% of theory) of 4-
chloro-3,3-dimethyl-1-(4-fluorophenoxy)-1-(1,2,4-triazol-1-
yl)-butan-2-ol of melting point 87-goc were obtained.
The following compounds of the general formula
CH.,
F - ~ - O - CH - A ~ d - CH2 Y
~ N b H~ (I)
N
were obtained analogously:
Ex-
amplè A B Y Melting point (C)
.. , ,
3 CO N Br 180 (x ~ NDS)
4 CHOH N Br 100
CO CH Br 241 (x ~ NDS)
6 CO CH Cl 254 (x ~ NDS)
7 CHOH CH Br 116
8 CHOH CH Cl 115
NDS = 1,5-naphthalenedisulphonic acid
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