Note: Descriptions are shown in the official language in which they were submitted.
::` 2~i2~
PS/5-17644/=
Microbicides ~ i
The present invention relates to aminoaliphatic heterocyclylphenyl ethers of formula I
below and to the acid addition salts thereof. The invention relates a1so to the preparation
of those substances and to microbicidal compositions that contain at least one of those
compounds as active ingredient. The invention relates also to the use of the compounds for ~ ;
controll;ng harmful microorganisms, especially phytopathogenic fungi.
The compounds according to the invention have the formula
(Rl)n R3
ue~X~
()m
wherein~
X is oxygen or sulfur,
Het is a 5- or ~membered heterocycle which has from one to three identical or different
hetero atoms se!ected from nitrogen, oxygen and sulfur and which is unsubstituted or
mono-, di- or;~i-substituted by identical or different substituents selected from halogen,
cyano, nitro, Cl-C4aL~cyl, C3-C6cycloa1kyl, Cl-C4alkoxy, Cl-C3haloalkoxy and trifluoro-
methyl,
B is -iCH2-CH(R2)"CH2- or -C~=C$R2)-~H2- or -CH2-C(R2)=CH-,
Rl is halogen, Cl-C4alkyl or Cl-C4alkoxy,
n;is from O to 2,
m is O or l,
R2 is hydrogen or Cl-C4alkyl, ~ ~ -
R3 is hydrogen or CI-C3alkyl,
R4 is hydrogcn, hydroxy, Cl-C3alkoxy or unsubstituted Cl-C4alkyl or Cl-C4alkyl -
substitutedbyhydroxyorbyCl-C3alkoxy,
and
~ : -
. ~
.',:
$~
- 2 -
Z is oxygen, sulfur or -CH2;
including the acid addition salts of those compounds.
Depending on the number of carbon atoms indicated, the term alkyl by itself or as part of
another substituent, such as aL~coxy or haloalkoxy, etc., is to be understood as meaning, for
example, the following straight-chained or branched groups: methyl, ethyl, propyl, butyl
and their isomers, for example isopropyl, isobutyl, tert.-butyl, etc.. Halogen and halo are
fluorine, chlorine, bromine or iodine. HaloaL~coxy is therefore a mono- to per-halogenated
alkoxy radical, for example OCHC12, OCH2F, OCCl3, OCH2Cl, OCHF2, OCHFCH3,
OCH2CH2Br, OC2CIs, OCH2Br, OCHBrCI, etc.. C3-C6cycloalkyl is cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl.
Examples of suitable 5- or 6-membered heterocycles having one, two or three identical or
different hetero atoms N, O andlor S are pyridine, pyrimidine, pyrazine, pyridazine,
triazine, thiazole, oxazole, thiadiazole, oxadiazole, triazole, imidazole, furan, thiophene
and the corresponding hydrogenated or partially hydrogenated heterocycles, for example
piperidine, morpholine, thiomorpholine, pyran, tetrahydrofuran, etc.. This list is not
limiting. ~ ;
Examples of salt-forming acids are inorganic acids: hydrohalic acid, such as hydrofluoric
acid, hydrochloric acid, hydrobromic acid or hydriodic acid, and also sulfuric acid,
phosphoric acid, phosphorous acid and nitric acid, and organic acids, such as acetic acid,
trifluoroacetic acid, trichloroacetic acid, propionic acid, tartaric acid, glycolic acid,
thiocyan~c acid, lactic acid, succinic acid, CitFiC acid, benzoic acid, cinnamic acid, oxalic ~ - ,;
acid, formic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid,
salicylic acid, p-aminosalicylic acid, 2-phenoxybenzoic acid or 2-acetoxybenzoic acid.
These acids are added to the free compounds of formula I in accordance with methods
known per se.
::
The compounds of formula I are stable at room temperature. They can be used in the
agricultural sector or related fields preventively and curatively for controlling plant-
destruchve microorganisms. The compounds of formula I according to the invention are
distinguished by very good fungicidal action and easy application in a wide range of
concentrations.
The folIowmg groups of substances, including their acid addition salts, are preferred on
,
3 2~20~1~
account of their pronounced microbicidal activity.
Compounds of the sub-group of formula I are preferred, wherein the 5- or 6-membered
heterocycle Het contains at least one N atom, Rl is halogen, methyl or methoxy, n is O or
1, m is O and R2 and R3 are each independently of the other hydrogen or methyl
(sub-group la).
Within sub-group la, preferred compounds are those wherein X is oxygen and R4 ishydrogen, hydroxy, methyl, methoxy, hydroxymethyl, hydroxyethyl, methoxymethyl or
methoxyethyl (sub-group laa).
An important class of compounds comprises those of sub-group laa wherein Het is an
unsubstituted or substituted pyridyl radical (sub-group lb). ~ ~
Of those compounds, preference is given to those wherein B is the chain - ~ -
-CH2-CH(CH3)-CH2- or -CH=C(CH3)-CH2- and the pyridyl radical is unsubstituted orsubstituted by not more than two identical or different substituents selected from halogen,
NO2, -OCHF2 and CF3 (sub-group lbb).
,, .. ~ .
Of the last-mentioned compounds, preference is given to those wherein Z is oxygen or - ~ -
-CH2- and R3 and R4 occupy the two positions adjacent to Z and both are hydrogen or both
are methyl. ;~
Another important class of compounds is that of sub-group laa wherein Het is an
unsubstituted or substdtuted pyrimidinyl radical (sub-group lc). - ~ -
Of those compounds lc, preference is given to those wherein B is the chain ~ -
-CH2-CH(CH3~-CH2- or -CH=C(CH3) CH2~ and the pyrirnidinyl radical is unsubsdtuted
or mono- to tri-substituted by identical or different substituents selected from halogen,
Cl-C4alkyl and cyclopropyl (sub-group lcc).
Of the last-montioned compounds, preference is given to those wherein Z is oxygen or ~ ~ ~
-CH2- and R3 and R4 occupy the two positions adjacent to Z and both are hydrogen or both ; .~ ` -
aremethyl.
.
Another important class of compounds is that of sub-group laa wherein Het is an
. . ,
: .
4 2
unsubstituted or substituted pyrazinyl radical (sub-group ld).
.
Of those compounds ld, preference is given to those wherein B is the chain
-CH2-CH(CH3)-CH2- or -CH=C(CH3)-CH2- and the pyrazinyl radical is unsubstituted or
substituted a maximum of twice by Cl-C4alkyl and/or halogen (sub-group ldd).
Of the last-mentioned compounds, preference is given to those wherein Z is oxygen or
-CH2- and R3 and R4 occupy the two positions adjacent to Z and both are hydrogen or both
are methyl.
Another important class of compounds is that of sub-group laa wherein Het ;s an
unsubstituted or substituted 1,3,5-triazinyl radical (sub-group le).
Of the compounds le, preference is given to those wherein B is the chain
-CH2-CH(CH3)-CH2- or -CH=C(CH3)-CH2- and the 1,3,5-triazinyl radical is
unsubstituted, alkyl-substituted and/or halo-substituted (sub-group lee).
Of the last-mentioned compounds, preference is given to those wherein Z is oxygen or
-CH2- and R3 and R4 occupy the two positions adjacent to Z and both are hydrogen or both
are methyl. ~
Another important class of compounds within sub-group laa comprises those wherein Het ~ -
is an uosubstituted or substituted thiazolyl radical (sub-group lf).
Of the compounds lf, preference is given to those wherein B is the chain
-CH2-CH(CH3)-CH2- or -CH-C(CH3)-CH2- and the thiazolyl radical is unsubstituted or
monosubstituted by NO2 or by halogen (sub-group lff).
Of the last-mentioned compounds, preference is given to those wherein Z is oxygen or
-CH2- ~and R3 and R4 occupy the two positions adjacent to Z and both are hydrogen or both ~ ~ ~
are methyl. ~, -
Another important class of compounds within sub-group laa comprises those wherein Het
is an oxazolyl radical (= sub-group lg), especially those wherein Z is oxygen or -CH2- and
R3 and R4 occupy the two positions adjacent to Z and both are hydrogen or both are
methyl. ~ -
-s-
:
Another important class of compounds within sub-group laa comprises compounds
wherein Het is an unsubstituted or Cl-C4alkyl-substituted 1,2,4-triazolyl radical (= sub-
group lh), especially those wherein Z is oxygen or -CH2- and R3 and R4 occupy the two
positions adjacent to Z and both are hydrogen or both are methyl.
A further important class of compounds within sub-group laa comprises compounds
wherein Het is an unsubstituted or Cl-C4alkyl-substituted 1,2,4-imidazolyl radical (=
sub-group li), especially those wherein Z is oxygen or -CH2- and R3 and R4 occupy the -
two positions adjacent to Z and both are hydrogen or both are methyl.
A further important class of compounds within sub-group laa comprises compounds
wherein Het is an oxadiazole radical (= sub-group lj), especially those wherein Z is
oxygen or -CH2- and R3 and R4 occupy the two positions adjacent to Z and both are
hydrogen or both are methyl.
, ~ .
A further important class of compounds within sub-group laa comprises compounds
wherein Het is a thiadiazole radical (= sub-group lk), especially those wherein Z is
oxygen or -CHr and R3 and R4 occupy the two positions adjacent to Z and both arehydrogen or both are methyl.
A further important sub-group of compounds comprises those compounds of forrnula I
wherein Het is an unsubstituted thienyl radical or a thienyl radical substituted by not more ~ -
than two identical or different substituents selected from halogen and Cl-C4aLkyl
(sub-group lm). -;
-
Of the compounds lm, preference is given to those wherein X is oxygen, n is O or 1, m is
O, Rl is halogen, meithyl or me~hoxy, R2 iS hydrogen or methyl and R3 is hydrogen or
methyl, and R4 is hydrogen, methyl, hydroxy, methoxy, hydroxymethyl or methoxymethyl
(sub-group lmm).
Of the last-mentioned compounds, preference is given to those wherein Z is oxygen or
-CHr and R3 and R4 occupy the two positions adjacent to Z and both are hydrogen or both
are methyl.
.
The novel compounds of formula I can be prepared, if m=O, by
. . ,
- 6-
a) reacting an amine of formula II
(Rl)n IR3
6~ B N~ ~Z (II)
Al R4
with a heterocycle of formula III
Het-A2 (III)
: .
wherein one of the radicals Al ~nd A2 is a nucleofugal leaving group and the other is the
group -XMe, wherein Me is hydrogen or, preferably, a metal cation.
Preferably, Al = XMe. Metal cations Me are, for example, alkali metal cations, for
examp1e lithium, sodium or potassium cations, or alka1ine earth metal cations, for example
magnesium, calcium, strontium or barium cations.
Nucleofugal leaving groups are, for example, reactive esterif1ed hydroxy groups esterified -~
by a hydrohalic acid, for example by hydrofluoric, hydroch10ric, hydrobromic or hydriodic
acid, or by~ a 10wer alkanesulfonic acid, or by an unsubstituted or substituted benzene- or
ha10-su1fonic acid; for example, hydroxy groups esterified by methane-, ethane-, benzene-,
p-toluene- or fluoro-sulfonic acid. ~ -
Some of the compounds of formula II wherein Al is OH or SH are known, or they can be
prepared by procases known ~Q se (e.g. EP-A-262 870).
The~ substituents Rl, R3,iR4, B,! X and Z and also n are as defined under formula I.
:
The reaction is preferably carried out in a relatively polar but inert organic solvent, for
example N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide,
acetonitrile, benzonitrile, etc.. Such solvents may be used in combination with other inert
solvents, such as aliphatic or aromatic bydrocarbons, for example benzene, toluene, ;~
xylene, hexane, petroleum ether, chlorobenzene, nitrobenzene, etc..
~ .
Elevated tornperatures of from O to 220C, preferably from 120 to 170C, are - ~ ~
2~2~6
- 7 -
- ~ .;5~ 1
advantageous. The reaction mixture is advantageously heated under reflux.
The compounds of formula I wherein m=0 may also be prepared by
b) condensing a heterocyclic diphenyl ether of formula IV
l)n ~ ~ ~
Het-X ~ B-C tIV), ~ ~
, ~ . . , .~ !
wherein C is a nucleofugal leaving group, with an amine of formula V
R3
H-N Z (V)~
R4 ~ ~-
The reaction may be carried out without solvents or in the presence of solvents at from 0
to 120C.
As solvents there may be used, if required, ethers (e.g. diethyl ether, tetrahydrofuran, ~ ;
dioxane), alcohols (e.g. ethylene glycol, methanol, ethanol), N,N-dimethylformamide,
N,N-dimethylacetamide, dimethyl sulfoxide, etc., but excess amine of formula V may also
be used. ~~
c) Compounds of formula I wherein m=0 and B is the chain -CH2-C(R2)=CH- or
-CH2-CH(R2)-CH2- can also be obtained ,by reacting an aldehyde of formula VI
~Rl)n
Het-X t ¦¦
~CH2--fH--CHO (VI)
R2
.: ' .:
with an amine of formula V to give a compound of formula VII
~ .
~;2~
- 8 -
Hcl-X~c~Z--C=CII--N Z (Vll)
R2 R4 ~ ~:
within the scope of formula I and, if desired, subsequently hydrogenating the double bond.
The reaction of an aldehyde of formula VI with an amine of formula V is carried out at
temperatures of from -25C to +300C, preferably at from +10 to 200C, advantageously
using an inert solvent. Suitable inert solvents are aliphatic and aromatic hydrocarbons and
also chlorinated hydrocarbons, for example petroleum ether, hexane, toluene, xylene,
benzene, chlorobenzene, methylene chloride, chloroform, dichloroethane,
dibromomethane; and also ethers, such as diethyl ether, methyl tert.-butyl ether, dioxane,
tetrahydrofuran ( I'HF); and also alcohols, such as methanol, ethanol, ethylene glycol, -
glycerolj or esters, such as methyl acetate or ethyl acetate.
The presence of water-removing agents is advantageous. There may be used, for example,
anhydrous Na2SO4, MgSO4, CaCl2, silica gel, Al2O3 or molecular sieve.
Acidic catalysts accelerate the reacdon, for example hydrogen chloride, hydrogenbrornide, sulfuric acid, nitric acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic
ac;d, methanesulfonic acid, etc..
If the unsaturated enamines of formula VII (within the scope of formula I of the present
invention) are to be hydrogenated to form saturated compounds, metal hydrides, for
example~ sodiurn hydride, potassium hydfide or lithium borohydride, may be used as
~; reducing agents for that reaction.
:: :-:
Suitable solvents or mixtures of solvents with one another that may be used are the
above-mentioned alcohols, ethers, esters and aromatic hydrocarbons, as well as acetic acid
or water.
: ~ ' ..
Also suitable as reducing agents are aluminium hydrides, such as lithium aluminium
:
2020Q'~
hydride or aluminium diisobutyl hydride, which are advantageously employed in the
above-mentioned ethers or hydrocarbons or mixtures of those solvents.
The hydrogenation is carried out in the temperature range of from -60 to +200C,
preferably from -20 to +120C.
Formic acid is also suitable as reducing agent, and the reaction is preferably canied out in
the absence of a solvent. The formic acid is added dropwise to the enamine at a
temperature of from 0 to 100C, preferably from 50 to 70C, if necessary with cooling.
Compounds of formula VII may also be hydrogenated catalytically. Suitable catalysts are -
especially noble metal catalysts, for example platinum, palladium - optionally deposited
on carbon - and Raney nickel. Palladium-on-carbon is preferred. ~ ~ ;
Suitable inert solvents are hydrocarbons, such as benzene, toluene or xylene, and alcohols,
such as methanol or ethanol. Toluene is preferred. The reaction temperature chosen is
advantageously in the range of from 0 to +50C, preferably room temperature.
From the compounds of formula I wherein m=0 obtained in accordance with a), b) or c)
above, it is possible, if desired, to obtain the corresponding N-oxides (m=1) of formula I
by oxidation.
As oxidising agents there may be used, inter alia, hydrogen peroxide, perbenzoic acid,
peracetic acid and m-chloroperbenzoic acid.
The reaction is carried out in a temperature range of from -20 to 200C, preferably from 0
to 120C, in an inert solvent. Examples of solvents are chlorinated hydrocarbons (e.g.
chloroform, dichloromethane, d,ichloroeth, ane), alcohols (e.g. methanoL ethanol, ethylene
glycol), ethers (e.g. diethyl ether, THF, dioxane), N,N-dimethylformamide, N,N-
dimethylacetamide, dimethyl sulfoxide, etc.. These solvents may be used alone or in
combination.
The present invention relates to all the above-described processes a), b) and c), including
variants thereof and the optional subsequent oxidation step (to obtain N-oxides).
The compounds of formulae IV and VI are novel, but they can be prepared in accordance
2~2~Q~
- 10-
with the customary methods of preparative organic chemistry, for example analogously to
the processes described in DE-OS 27 52 135.
When R2 is alkyl, the propane derivatives of formula I always have an asymmetric *C
atom in the 2-position and can therefore be in two enantiomeric forms. In general, a
mixture of both enantiomers is formed when these substances are prepared. This mixture
can be separated into the pure optical antipodes in customary manner, for example by the
fractional crystallisation of salts with optically active strong acids. The two enantiomers
may have different biological activities. Whenever cis/trans isomerism occurs as a result
of a double bond in the 2-position, the same considerations apply.
The present invention relates to all the pure enantiomers and diastereoisomers and
mixtures thereof with one another. ~ t
' :
Surprisingly, it has been found that the compounds of formula I have, for practical field
application purposes, a very advantageous microbicidal spectrum against fungi and
bacteria. Compounds of formula I have very advantageous curative, preventive andsystemic properties and can be used for protecting cultivated plants. With the compounds
of formula I it is possible to inhibit or destroy the microorganisms which occur in plants or
in parts of plants (fruit, blossoms, leaves, stems, tubers, roots) in different crops of useful
plants, while at the same time the parts of plants which grow later are also protected from
attack by such microorganisms.
The compounds are effective against the phytopathogenic fungi belonging to the following
classes: Ascomycetes (e.g. Venturia, Podosphaera, Erysiphe, Monilinia, Pyrenophora,
Uncinula); Basidiomycetes (e.g. the genera Hemileia, Rhizoctonia, Puccinia); Fungi
imperfecti (e.g. Botrytis, Helminthosporium, Fusarium, Septoria, Cercospora, Colleto-
trichurn, Rhynchosporium, Pse,ydocercosporella and Alternaria). In addition, thecompounds of formula l have a systemic action. They can also be used as dressing agents
for protecting seeds (fruit, tubers, grains) and plant cuttings against fungus infections as
well as against phytopathogenic fungi which occur in the soil. The compounds according
to the invention are distinguished by the fact that they are particularly well tolerated by
plants.
The invention therefore also relates to microbicidal compositions and to the use of the
compounds of formula I for controlling pathogenic microorganisms, especially plant-
destructive fungi, and for protecting plants from attack by such microorganisms.
Target crops for the areas of indication disclosed herein to be protected within the scope of
the present invention are, for example, the following species of plants: cereals (wheat,
barley, rye, oats, rice, sorghum and related crops), beet (sugar beet and fodder beet),
pomes, drupes and soft fruit (apples, pears, plums, peaches, almonds, cherries, straw-
berries, raspberries and blackberries), leguminous plants (beans, lentils, peas, soybeans),
oil plants (rape, mustard, poppy, olives, sunflowers, coconut, castor oil plants, cocoa
beans, groundnuts), cucumber plants (cucumber, marrows, melons), fibre plants (cotton, ~,
flax, hemp, jute), citrus fruit (oranges, lemons, grapefruit, mandarins), vegetables
(spinach, lettuce, asparagus, cabbages, carrots, onions, tomatoes, potatoes, paprika), - -
lauraceae (avocados, cinnamon, camphor), or plants such as maize, tobacco, nuts, coffee,
sugar cane, tea, vines, hops, bananas and natural rubber plants, as well as ornamentals -
(flowers, shrubs, deciduous trees and conifers). This list does not constitute a limitation.
The compounds of formula 1 are normally applied in the form of compositions and can be
applied to the crop area or plant to be treated, simultaneously or in succession, with further
compounds. These further compounds can be fertilisers or micronutrient donors or other
preparations that influence plant growth. However, they can also be selective herbicides,
insecticides, fungicides, bactericides, nematicides, molluscicides or mixtures of several of
these preparations, if desired together with further carriers, surfactants or other
application-promoting adjuvants customarily employed in the art of formulation.
Suitable carriers and adjuvants can be solid or liquid and correspond to the substances
ordinarily employed in formulation technology, e.g. natural or regenerated mineral sub-
stances, solvents, dispersants, wetting agents, tackifiers, thickeners, binders or fertilisers.
The compounds of,formula I arR used in ynmodifled form or, preferably, together with the
adjuvants conventionally employed in the art of formulation, and are therefore formulated
in known manner e.g. into emulsifiable concentrates, coatable pastes, directly sprayable or
dilutable solutions, dilute emulsions, wettable powders, soluble powders, dusts,granulates, and also encapsulations in e.g. polymer substances. As with the nature of the
compositions, the methods of application are chosen in accordance with the intended
objectives and the prevailing circumstances. In the agricultural sector, advantageous rates ~ -
of application are normally from 50 g to 5 kg of active ingredient (a.i.) per hectare,
preferably from 100 g to 2 kg a.i./ha, most preferably from 150 g to 800 g a.i./ha.
. .
,:
202001~ ~
- 12-
Suitable solvents are: aromatic hydrocarbons, preferably the fractions containing 8 to 12
carbon atoms, e.g. xylene mixtures or substituted naphthalenes, phthalates such as dibutyl ~ ;
phthalate or dioctyl phthalate, aliphatic hydrocarbons such as cyclohexane or paraffins,
alcohols and glycols and their ethers and esters, such as ethanol, ethylene glycol, ethylene
glycol monomethyl or monoethyl ether, ketones such as cyclohexanone, strongly polar
solvents such as N-methyl-2-pyrrolidone, dimethyl sulfoxide or dimethylformamide, as ~ `,
well as vegetable oils or epoxidised vegetable oils, such as epoxidised coconut oil or
soybean oil; or water.
~:
Particularly advantageous application-promoting adjuvants which are able to reduce
substantially the rate of application are also natural (animal or vegetable) or synthetic ~ -
phospholipids of the series of the cephalins and lecithins, such as, for example,
phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol or Iysolecithin. ;
Depending on the nature of the compound of formula I to be formulated, suitable
surface-ac~ive compounds are non-ionic, cationic andlor anionic surfactants having good
emulsifyingj dispersing and wetting properties. The term "surfactants" will also be
understood as comprising mixtures of surfactants.
.
The surfactants customarily emp10yed in the art of formulation are described, inter alia, in
the following publications:
"Mc Cutcheon's Detergents and Emulsifiers Annual"
BC Publishing Corp., Ringwood New Jersey, 1981;
Helmut Stache "Tensid-Taschenbuch" Carl Hanser-Verlag
Munich/Vienna 1981. ,,
M. and J. Ash. "Encyclopedia of Surfactants", Vol. I-III, Chemical Publishing
Co., New York, 1980-1981.
The agrochemical compositions usually contain 0.1 to 99 %, preferably 0.1 to 95 %, of a
compound of formula I, 99.9 to 1 %, preferably 99.8 to 5 %, of a solid or liquid extender,
and 0 to 25 %, preferably 0.1 to 25 %, of a surfactant.
. . ~ '.
.
2~2~Ql~ ~
- 13-
Whereas commercial products will preferably be formulated as concentrates, the end user
will normally employ dilute forrnulations.
The following Examples serve to illustrate the invention in greater detail, but do not
constitute a limitation thereof. Temperatures are given in degrees Celsius. Percentages
and parts are by weight.
Preparation Examples ~ -
Example 1: Preparation of
CH3
CHr fH--CH2- N O
CF3 ~;~ O ~ 3 CH3
.,~, ...
4-r3- ( 3-(5-trifluoromethvl-2-pvridvloxv)phenvl 1 -2-methvlproPvll-
2,6-dimethvlmorpholine
2.7 g of 30 % sodium methanolate are added at room temperature to a solution of 3.6 g of
4-[3-(3-hydroxyphenyl)-2-methylpropyl]-2,6-dimethylmorpholine in 40 ml of absolute
methanol. The mixture is heated under reflux for half an hour, then methanol is removed
in a rotary evaporator and 50 ml of absolute dimethylformamide are added to the crystal-
line sodium salt. 2.0 g of 2-chloro-5-trifluoromethylpyridine and 0.3 g of catalytically
active potassium iodide are added thereto. The mixture is then stirred at 100C for
18 hours and then cooled to room temperature. The reaction mixture is poured onto
l50 ml of water and extracted three times, wi,th 50 ml of ethyl acetate each time. The
combined organic phases are washed twice with 100 ml of water each time, dried over
sodium sulfate, filtered and freed of solvent by evaporation. The brown oily residue is
purified by chromatography over a silica gel column with hexane/ethyl acetate (2:1). The
title compound is obtained in the form of a yellow oil; n23: 1.5012.
, . '
Example 2: Preparation of
:
2 ~2 ~
- 14-
Cl CU3 ;
0 ~ CH3
N
Cl ',
4-~3-~3-(2~5-dichloro-3-pvridvloxy~phenyl)-2-methvlpropyll-2~6-dimethYlmorpholine
0.8 g of solid sodium methanolate are added to a solution of 3.6 g of
4-[3-(3-hydroxyphenyl)-2-methylpropyl]-2,6-dimethylmorpholine in 40 ml of absolute
methanol, and the mixture is heated under reflux for 30 minutes. The methanol is then
removed in a rotary evaporator and 50 ml of absolute dimethylacetamide, 2.5 g of2,5-dichloro-3-fluoropyridine and 0.3 g of potassium iodide are added to the crystalline
sodium salt. This mixture is stirred at 120C for 20 hours and is then cooled to room -
temperature and poured onto 250 ml of water. After extracting three times with 100 ml of
ethyl acetate each time, the organic phases are combined, washed twice with 150 ml of
water each time, dried over sodium sulfate, filtered, and freed of solvent in a rotary evapo- ~;
rator. The dark oily residue is purified by chromatography over a silica gel column using
hexane/ethyl acetate (2:1). Evaporation of the eluant mixture yields a yellow oil;
D3: 1.5508-
Synthesis of intermediates
Example 3: Preparation of
C~ H3
CH= C--CHO
3 -(3-benzvloxv~henvl)-2-methacr:olein
31.8 g~of 3-benzyloxybenzaldehyde are dissolved in 200 ml of methanol, 0.5 g of
powdered~potassium hydroxide are added thereto, and the mixture is heated to 45C.
26.0 g~of proplonaldehydo are added dropwise at that temperature (+ 5C) within a period
of ~one hour, and ~he mixture is stirred at 40-45C for 4 hours. The solvent is then evapo-
' '' :
2 ~
- 15-
rated off in a rotary evaporator and the oily residue is poured onto S00 ml of water and -`
extracted three times with 150 ml of diethyl ether each time. The organic phases are
combined, washed twice with 200 ml of water each time, dried over so~ium sulfate,
filtered and concentrated. The title compound is obtained in the form of a yellow oil;
n20: 1.6217.
.
: , .
, . ,
- ` 2 ~ 2 ~
- 16
Example 4: Preparation of
~CH3 ~ ~
CHz--CH--CH20H ; ~;
CH20~
:. :
~ .
3-(3-benzvloxvphenYI)-2-methYlproPanol
10.0 g of lithium aluminium hydride are heated under reflux in 350 ml of absolute
tetrahydrofuran with nitrogen gassing. 44.2 g of the 3-(3-benzyloxyphenyl)-2-methyl-
acrolein cbtained in Example 3, dissolved in 70 ml of absolute tetrahydrofuran, are added
dropwise under reflux within a period of 2 hours, and the mixture is heated under reflux
for a further 3 hours. It is then cooled to roorn temperature and 250 ml of ice-water are
carefully added dropwise, with cooling. 300 ml of diethyl ether are then added to the `;~
reaction mixture, which is then filtered with suction over Hyflo. The organic phase is
separated from the filtrate and the aqueous phase is extracoed twice with 250 ml of ether
each time. The organic phases are combined, washed three times with 250 ml of water ~-~
each time, dried over sodium sulfate, filtered and freed of solvent by evaporation. The
oily residue is purified by chromatography over a silica gel column with hexane/ethyl
acetate (3:1).
Evaporation of the eluant mixture yields a yellow oil; ;
2: 1.5624. ~
, - ~ , , . ,~
2 0 2 0 0 ~ ~
- 1 7 -
Example 5: Preparation of
CH2--CH--CH20S02~ CH3
~CH~
l-(p-tosvloxv)-2-methvl-3-(3-benzyloxvphenvl)-propane
21.0 g of 3-(3-benzyloxyphenyl)-2-methylpropanol are introduced into 80 ml of pyridine,
and the mixture is cooled to -5C. 17.2 g of p-toluenesulfonyl chloride are added in
portions within a period of one hour at from -5C to 0C, and the mixture is stirred at 0
for 4 hours. The reaction mixture is then poured onto 300 ml of ice-water and extracted
three times with 200 ml of diethyl ether each time. The organic phases are combined,
washed twice with 150 ml of 2N hydrochloric acid each time and three times with 200 ml . -
of water each time, dried over sodium sulfate and filtered. The solvent is then evaporated ;~
off.
The oily residue is chromatographed over a silica gel column with hexane/ethyl acetate
(1:1). The title compound is obtained in the form of a yellow oil; n22: 1.5667.
Example 6: Preparation of
CH3 '
/~
CH2--CH--CHz--NyO
~CH2~ CH3 CH3
4-r3-(3-benzvloxvphenvl)-2-methylpropvll-2~6-dimethvlmorpholine
8.7 g of the 1-(p-tosyloxy)-2-methyl-3-(3-benzyloxyphenyl)-propane obtained in Example
S and 5.6 g of dimethylmorpholine are stirred at 100C for 1 1/2 hours and then the
mixture is cooled to room temperature and 50 ml of water and 50 ml of ethyl acetate are --
added thereto. The organic phase is separated off and the aqueous phase is extracted twice
with 50 rnl of ethyl acetate each time. The organic phases are combined, washed three ~ ~ -
times with 150 m! of water each time, dried over sodium sulfate, filtered and concentrated. ~ ~ -
. , ,', ' ', ;
::
- 18-
The oily residue is purifled by chromatography over a silica gel column with hexane/ethyl
acetate (2:1). Evaporation of the eluant mixture yields a yellow oil; n22: 1.5381.
Example 7: Preparation of
CH3
~< .
CH2--CH--CH2--N O
HO ~ CH3 CH3
~i
4-~3-(3-hydroxvphenyll-2-methvlpropvll-2.6-dimethYlmorDholine
10.0 g of the 4-[3-(3-benzyloxyphenyl)-2-methylpropyl]-2,6-dimethylmorpholine obtained
in Example 6 are hydrogenated at room temperature within a period of 19 hours in 70 ml
of ethyl acetate in the presence of 1.0 g of palladium-on-carbon (5 %). The catalyst is
then separated off by filtration and the solvent is removed in a rotary evaporator. The title
compound is obtained in the form of a viscous yellow oil;
n55 : 1.5109.
The following compounds are prepared in this manner or in accordance with one of the
methodsindicatedabove. Inthefollowing,
A : ~
Morph = --N o
pjp = --N~_) ~: '. : .
CH3 : : - ~
: ~ ::. . :
`: :
. ~
; `~ 2~2 ~
- 19- ~. ,,
.
DMP= --N~ cis-DMP= --N~
CH3 CH3
CH3 CH3
CiS-DMM =--N oans-DMM = -N ~o
CH3 CH3 ~:
~ ,, .
~CH3 ~ .
~ans-DMp =--N~
CH3
~: : : . .- , . ,, :
`, : ~ `, : ~, : .
202001~ ~
- 20 -
Table 1
CH2- CH--CHz--A
Q--X~ CH3
No. Q A X Phys.
data
.1. CF3 ~3 DMM O nD3 :1.5012
Cl
1.2.a CF3~ cis-DMP O n~9 :1.5083
\= N
1.2.b trans-DMP ~ nD9 :1.5088 ` ` ~ :
~. ~ ;,:
1.3. 2,5-dichloro-3- Pip. S ;~
pyridyl ~ ;
4 a~ Pip. o
l.S.~ 2-thienyl Mo~ph O :
1.6. ~ ~ 2-pyridyl DMM O `~
17 ~ CF3 {~ ~ ; thiomorpholine O
mldinyl _ N~
':: :: ~:
2~2Q~6
- 21 - - :
No. Q A X Phys.
data
~ ............. .
1.9. 2-thiazolyl Pip. O
,
CH3
1.10. ~N~ DMM O
: , .
''
c
e~ : , ' ,
1.11. CF3 ~\>-- Morph O ~ ~ ;
N
:''~ '. '`' '
: 1.12. ~L DMM O ~ ;
1.13. 2-pyrazinyl Pip. O
1 14 ~ C~3 ~ cis-DMM o nD5 :1.5066
N :~ .
1.15. CF~ , trans-DMM O
~ ,
1.16. :2,5-dichloro-3- Pip. O
pyridyl ~ -
1.17. 3-fluoro-5-chloro- Mo}ph S
2-pyridyl
: :
-
`"''."'''""''','''"'''''' ".''''`'' '` '' '`'
2~f20016
- 22 -
No. Q A X Phys.
data
1.18. 2-pyridyl Pip. O ~: -
1.19. 2-thienyl DMM O ~ ~
,- . ~: .
1.20. 3,5-dichloro-2- DMM S
pyridyl
~Nr5~ Pip-
1.22. 3-fluoro-5-chloro- DMM o nD5 :1.5352
2-pyridyl
1.23. 5-chloro-2-pyridyl Pip. O ;~
; 1.24. N~ \~ DMM O
Cl
1.25 CF3 {~ Pip. S
N
1.26. ~ ~2-pynmldinyl DMM O
f ~ ~ 1.27~ 5-bromo-2-pyridyl Pip. O
:-~ :~ : .. , ,-
;~ :
202~
- 23 -
No. Q A XPhys.
data
' ~, .
c~
128 CF -_~ cis-DMM OnD :1.5090 ; ~ .
[nitrate: m.p. 148C] - ~ ;
1.29. 2-thienyl Pip. O
CH3
1.30. 3-chloro-2-pyridyl _ N~
CH3
1.31. ~ Pip O
CH3 ;
`
CH3-CH2 Cl
\~/
1.32. N \~_ DMM
1.33. ~ 2-thiazolyl DMM O
1 34 ~ Cl~3{~ DMP O
1.35.~ ~ ; 3-fluoro^5-chloro^ trans-DMM O
2-py dyl
1.36 ~ ~ 3-iluoro-5-chloro^ cis^DMM o n40 :1.5314
2-pyridyl [nitrate: m.p. 128C]
202001~ ~
- 24 -
No. Q A X Phys.
data ~ :~
.
,
1.37. 2-pyrimidinyl Pip. O -~
c
1.38. CF3 ~ thiomorpholine S ~ ~
N 1 : ~ -
'," ,' ":
1.39. 2,5-dichloro-3- DMM O n25 :1.5508
pyridyl
1.40. 2-pyridyl Morph O
1.41. 3,5-dichloro-2- Pip. O
pyridyl
."
,42. ~L Pip. O
.; , ~.
1.43. 5-chloro-2-pyridyl thiomorpholine O
3-chloro-2-pyridyl ~ Morph O
1.4~. ~ 2,5-diGhloro-3- DMP O
pyridyl
1.46. ~ 2-pyrazinyl DMM S
.47.~ CP3~-- _N~
1.48. -~ 2-thienyl cis-DMM O --
2~2~
- 25 -
No. Q A XPhys.
data
1.49. 2-thienyl trans-DMM O
c~
1.50. CF3 ~ DMM O
N
1.51. 5-bromo-2-pyridyl DMM OnD2 :1.5483
F
1.52. cl~ Morph O
N
3CH2 Cl ;
~; 1.53. ~ ~ ~ Pip. O
1.54. ~ 2 pyridyl~ DMM S
; 1.55. ~ 5-chloro-2-pyridyl _ N/~ ~ ~ :
55~ 4-pylimidinyl ~DMM O
~157` ~; CF3 ~ cis-DMP O
1.58. ~ ~ ~ 2-pyrimidinyl Morph O
..
- 26 -
No. Q A X Phys.
data
1.59. 2,5-dichloro-3- Morph O - ~
pyridyl ;
Cl ;
1.60. CF3 ~ --N,3CH3 0 ;
N
F ~ ~ ~
1.61. cl~ DMP O r~5 :1.5320 ~ ~;
N
1.62. 2-thienyl DMM S :~
1.63. 3,5-dichloro-2- DMP O
pyndyl
1.64. 3 -chloro-2-pyridyl DMM O
l.ff5. ~ 5-chloro-2-thienyl Pip. O
1.66. ~ ~ ~2-pyrazinyl DMM O
1.67. 5 chloro~2-pyridyl~ DMP '; O
L6a ~ 3-thienyl ~ ~ Pip. O
1~.69. ~ 3~ Morph O
2 Q 2 0 ~
- 27 - '
No. Q A X Phys.
data
CH3
1.70. cl~ --N~
N ~ :
1.71. 3,5-dichloro-2- Morph O
pyridyl
.
1.72. CF3 ~ Pip. O
N
:,~, :- ` . '': :
1.73. 2,5-dichloro-3- c,is-DMM o nDS :1-5428 '~
: ~: s
pyndyl
1.74. 2,5-dichloro-3- trans-DMM O ' ;~ h
pyridyl , ~
. ~ :
CH3
75~ CH3 ~/ ~ Pip. ~ O ~ ~ "~
N ::
1.76. ~ ~ ~4,6-dimethyl-,2~ cis DMM , o n34 :1.5288, ,
pyrimidinyl
OCH3
1.77. 2-thienyl --N~ ~
1.78. ~ 2-pyrimidlnyl cis-DMM O `
` 2~2~01~
28
No. Q A X Phys.
data
1.79. CF3 ~ DMM S ;
1.80. 5-bromo-2-pyridyl DMP O
F CH20CH3
1.81. Cl_~ --N/~)
\= N \~
1.82. 3,5-dichloro-2- DMM O nD :1.5458
pyridyl
~: CH20H ,-
1.83. ; 2,5-dichloro-3- --N~
pyridyl
1.84. ~ 5-chloro-2-pyridyl DMM S `:
CH OCH
1.85. ~ 5-chloro-2-thienyl _ N/ . . ~- -
1.86. ~ 3-chloro-2-pyridyl DMP O ; : -
- ~ 2 ~ 2 ~
- 29
No. Q A X Phys. :
data
CH3
1.87. ~=N Pip O
CH3CH2 Cl
1.88. ~ DMP O
N
N
1.89.6-methoxy-2-pyr~dyl Pip. O .
F
1.90. Cl~ cis-DMP O
N
CH3
N~ o -
.. . .
\= N CH3
1 .92. : 3 ni~o 2 pyridyl ~ Pip. o
193.~ ~ DMM S
; ~ . . .
~ 1 .94. ~ ~ 02N ~ Pip.
.` - ~ .. ` . .~
2~
-30-
No. Q A X Phys.
data
c~
.95. CF3 ~ \~-- Pip. O ~ ~ -
N
1.96. 5-chloro-2-thienyl DMM O
1.97. S-bromo-2-pyridyl trans-DMM O
1.98. 4-pyrimidinyl Pip. O
1.99. 5-nitro-2-thiazolyl DMM O
: . ,~
1.100. 4-pyndyl . Pip. O
F OH
1.101- a--~/ ~ / \~ O
1.102.~ 5 chl~-2-pyridyl Mo:ph O
1;.103. ~ 2-pyrazinyl DMP~ O
1.104. 3,5-dichloro-2- trans-DMM O
pyrldyl ~
n
1.105.~ 3,5-dichloro-2- cis-DMM O r~ 1.5454 -~
pyridyl [nitrate: Smp. 146C]
1.106. ~ ~5-chloro-2-thienyl DMP O
io7. ~ ~ ~ 3-thienyl DMM O
. .
$
- 31 -
No. Q A X Phys. ; ~
data ~ -
1.108. 3-chloro-2-pyridyl Pip. O
1.109. 5-nitro-2-pyridyl DMM O
Cl
1.110. N~=~ Pip. O
cl
1.111. 3-pyIidyl DMM O ~ ~1
F
1.112. cl~ DMM S ~ ,
,~ .
`= N ` `
CH3CH2 Cl
1.113. ~ cis-DMM O
114. ~ 5-chloro-2-pyridyl DMM O
.lis.; 4-methyl-2-pyridyl 1 i ' Pip~ ' O,
N ~hlOmOrphOline O
~ : . , .
:: ~
- 2B~
- 32~
~,
No. Q A X Phys.
data
~ .
:'
1.117 5-chloro-2-thienyl Morph O ~-.
1.118. 5-bromo-2-pyridyl --N3cH3 o ~; ~
CH3CH2 Cl
1.119. ~ cis-DMP O
N
N
CU3--~ DMM O
N
1.121. 4-py~idy1 DMM O .;~
1.122. 3 5-dohloro 2 ~ O
pynd~
:~ :1.123., 4-mçthy!2-py~idyl ~ ; DMM i, O
.
24. ~: ~ cis-DMM O
1.125. ~ ~ ~L trans-DMM O
: :: :~ ~, : . :
;
2 ~2 ~
,~
.
- 33 ~
No. Q A X Phys.
data
CH3 Cl : :
1.126. N~ Pip. O
\= N
1.127. 5-chloro-2-thienyl cis-DMP O
1.128. S-pyrimidinyl DMM O ;
CH3
1.129. 3,5-dichloro-2- /~ O
--N / .
pyridyl
:: ~ , - -. , .
l.i30 S-pyrimidinyl Pip. O ;~
1.131. 4 -pyrimidinyl DMP O
CH3 ;`,
1.133. 3-chloro-2-pyridyl DMM S
134. ~ 3-nitro-2-pyridyl DMM O
135. ~ 3,5-dichloro-2- cis-DMP O
pyridyl ~;
136. ~ 5-chloro-2-thienyl DMM S ~ -
- 34 - -
No. Q A XPhys.
data
,
1.137. 5-chloro-2-pyridyl cis-DMM On47 :1.5375 ~ -
1.138. 5-chloro-2-pyridyl trans-DMM O
CH3 Cl
1.139. N~ DMM O `; . ;,~
\= N ;~
1.140. F2CH0 ~3
1.141. 6-methoxy-2-pyridyl DMM O
1.142. F2CHO~ DMM O
N
I.IU.~ 3-pyridyl ~ Pip. O
CH20H ~ ~ -
1.144~ 5-chloro-2-pyridyl ~ / ~ O
1.145. 5-chloro-2-thienyl trans-DMM O
i.146.~ ~ 5-chloro-2-thienyl cis-DMM O
:::: .
:: :
2020~16
- 35 - ~ ~
, .
No. Q A X Phys.
data
.
CH3
1.147. . 5-bromo-2-pyridyl_ N/--<~
,,~ ," ,,~
1.148. 4-pyridyl DMP O
f; !,
CH3CH2 Cl
1.149. ~ ~ trans-DMM O
CH20CH3
1.150. 5-chloro-~-pyridyl ~ O ~ s:
1.151. 3-chloro-2-pyndyl ~cls-DMM O
:: i - ~ N
1:.152.: ~ ~ DMM : ~ O
3~ F3c--~0~ DMM
54-~ CH3 J~ Plp. 0 : :
:1.-155.~ `N DMM O
: ~ ~ : : ::
2~20~
... .
- 36- - -
No. Q A X Phys.
data
1.156. CH3 1~ ~ DMM O
N--N
1.157- CH3 1~o~ DMM O
~ : :
CP3 :~
\l--N
1.158. N~N DMM O
CH3 '~
~r N
1.159. ~N~ DMM O
~,, .
H
~ ~ ,
.~, . . .
N--N , ~ ;
.160. F3c ~o~ Pip. O ~ -
1.16i. N~S~ DMM O
CH3 ~ N
1.162.i ~ CH3'~N~ I i ,i ~DMM ~
t.:~163- ~ CU3--~ ~ DMM O - -~
~ - ~ ",
::
, ~ ~
'.''.,'`.;.'~,''','.`,','`.'`""'`' '`'
2020~1~
- 37 ~
No. Q A X Phys.
data : . -
CH30 ~:
~N
1.164. N~NJ~ DMM O
CH3 - ~ :
N--N
CF3
1.165. N DMM O :~
CH3 ` ;
CH3_1~ ,~ DMM O
CH3
1.167. :~ DMM O
OCHFCI
1168.~ ~ ~cl~ cis-DMM O :ng :1.5245
: ~ 1.169. j~ ~ cis-DMM O nD :1.5632 -.
02N,, S `
Q ~ CzH5
~ ~ cis-DMM nD4 :1.5318
H5C2 ~ ' ~
.,
: : .
- 38
Table 2
3 2 CH
Q--X _,~ 1 3
4 ~ CH2- CH--CH2- A '~
S T 6
No. -X-Q T A Phys.
data
. ~ ~
2.1 4--o ~3 CF3 DMM
c~
, ~
2-2- 4-- ~3CF3 Morph
N
:
F
~ :' , :
2-3- 3_o~}cl 4-F DMM
: :: ~ I ~ N
~2.4.~ 2--O~}CI pj ~ ;
N
~2 5 ~ ;; 3--:o~
,:: ~ : .
::
2 ~ 2 ~
- 39 - ~ ~ :
No. -X-Q T A Phys. ~ -
data
. :-
2.6. 3--o~3CF3 4-CI Pip.
N
Cl CH2CH3
2.7. 4--o ~N DMM
Cl ~. :
2.8. 3_o~ - Pip.
2.9. 4 o ~3 DMM
.`~`-. '.
F ~:
2-10- ~ 4 o~3cl 2-Cl Pip.
: N . ~:
2.11. 3 ~} CF3 4-CI DMM
N ~ :
..
~: ~ Cl
3--s ~ ~ DMM ~ ;
~: .
. ~,
- : - -
. -
. .
- 40 -
No. -X-Q T A Phys.
data
2.13.4--O ~ CF3 Pip. ~ `~
N
:. :,; ,: ':
2.14. 3o ~L cl 4-CI DMM
s
c~
2.15. 4--o~3CF3 - DMM
N
,.~
Cl : : '
2-16 3_o~ Pip.
N
2.17. 4--olnLcl - DMM :
s
~: , :
., cl ::
2.1~. ~ 3--~ 4-F Pip.
,
2.19. ~; 4 ~}CI DMM
N
.
:, :: : : ~ ~, -
:::: : .
.
~:: ~ , . , -.-
`` 2~
- 41 -
No. -X-Q T A Phys.
data
F ` ~
2-20-4 _ O ~3 Cl 2-CI DMM ~:
N 1 ~
Cl . :- -:
2.21.4--~ - Pip. ~ -
N ~:
Cl
::.: ~ , '
Cl ~.';
,.
3_ O ~ DMP ~ ~
' ~ :
, ;'
2.23.2----< 3 - DMM
: ~ N
F
~ ~' ,
2.24. ` ~ 3 o~ =~cl 4-C~3 Pip.
CH3 .
2.25. ~ ~ 4--o~ DMM
CH3
CI CH2CH3 `~
2 26- ~ 4_ O __¢~ Pip.
2 ~ 2 ~
- 42 -
No. -X-Q T A Phys.
data
c~
2.27. 3 _ o ~ DMM ~ :
N :
2-28- 4_o~3cl ~ Pip.
2.29. 3 ol~Lcl 4-CI Pip.
cl ~: .
2-30- 3_ 0 ~ ~ trans-DMM
~.
c~
2-31 3_ 0 ~ ~ cis-DMM ; - ~.
\=/ '
~ ..
' cl ~ .
2.32. 3--=~ 4-F DMM
Cl
, ~
c
2-33- 4 _ o ~3 CF3 - Pip. ~ ;
N , : '
,:
:
' '". ~' "
. ' ' ' , ~ ' .
2 0 2 0 0 ~
- 43 ~
No. -X-Q T A Phys.
data
CH3 ~ - -
2.34. 3--O~N DMM
'`:~
CH3
Cl
2.35. 3--O~CI 4-Cl Pip.
N
.
2.36. 4 o~3+ - Pip.
2.37. 2--O ~3 CI _ DMM ~:
N ;
2.38. 3--O~ CI 4-P Pip. ;
N
2.39. ~ 4--S~=jN DMM ~ .s~ -
'40' 4-o~3c~
2.41. ~ ~ ~ 3--0~}CF3 4-OCH3 DMM
,
~,
.,
rl ~ ~ 5
2020~16 :
- 44 -
No. -X-Q T A Phys.
data
;
2.42. 4 o~ - Pip. -~
F
2.43. 4-- ~ cl ~ DMM
N
4 o
2.44. ~ - DMM
S
2.45. 4 0~ Pip. ~: -
N ..
2.46. 3--~/ ~cl 4-CH3 DMM
N
Cl ~CH2CH3
2.47.~ ~ 4_5 ~N DMM
N
~ ~ Cl
2.48- 3--o <// ~ cis-DMM
\= N
2 0 2 ~
- 45 -
; .
No. -X-Q T A Phys.
data
c
~ans DMM
Cl
2.50. 3--s ~CF3 4-CI Pip.
cl
2 51 4--O~/ ~N DMM
N=(
Cl
CH3
2.52. 3--O~N ;~
CH3
2-53 3 O l~ ) DMM
2.54. 4 ~ ~ DMM ~ . -
2.55. 4 OlnLCI - Pip. .
S
46 2 ~ 2 ~
.
No. -X-Q T A Phys.
data
cl
2.56. 3_ o ~ cl 4-Cl DMM
N
~N
3_ 0 ~ - DMM ~ ~ ~
cl :
2.58. 4-- ~ DMM
cl ' ,:: :. " " ' '
N
2.59. 4--O--~!LN02 DMM
.
; 2.60. 3 O ~CF3 4-OCH~ Pip.
N ~ . .,~.
F
2-61-, 4--Sj~}CI ~ ; DMM
N
2.62. ~ 4_ o J~IL N02 - Pip.
2~
- 47 -
No. -X-Q T A Phys.
data
~N
3--S ~
2.63. \==( - DMM
cl :
2.64. 4--o ~3 cl ~ trans-DMM
N
2.65. 4_o ~3cl - cis-DMM
N
Cl `~
2.66. 3--S ~} CF3 4-CI DMM
N
~ .`~, ` :,. . ~
2.67. ~ ~ 2--0~ DMM
2.68. 4--O~N _ DMM
2,69.~ ~ ~ 3--S ~ ~ _ DMM
2~Q~
- 48 -
No. -X-Q T A Phys.
data
. .
CH3
2.70. 4--O ~=~ CH3 DMM
N
2.71. 4--o~l+ - DMM ~ ~ .
.:
- ~ , ;
.
N-- .:. :
2.72. 3--~o~ - Pip.
N--N
2.73.3 O I~N~I DMM
CH3
. .
"
~ :, ' ,:~
~ ,~
, , .
' ~
~::::
- 49 -
Table 3
Y--CH2--A
Q-~ :`
'.
No. Q . Y A Phys.
data ~ ;
3.1. CF3 ~ -CH2 DMM
N
CH3
3.2.3-pyridilzinyl -CH2-CH~
F ;
~ 3.3. cl~ ¦ DMM ; ~ ~
\= N -CH=C.
~4. ~ ~ dichl~3-pyndyl ; cuz-lu- P ~ ;
3.5. ~ c~3 ~= \;~_ -CH=CH- DMM
N
3.6. ~ CH3
3.7. ~2-pyrimidinyl -C~2CH2- DMM
2~2~0~
- 50 -
No. Q Y A Phys.
data
.
CH3
3.8.3,5-dichloro-2-pyridyl ¦ Morph
-CH=C- .
CH3
3.9. 3,5-dichloro-2-pyridyi ¦ DMM .
-CH=C-
F
~ CH3 ; -~:
3.10. cl~// \~ I Pip. '
\ / -CH=C~
` - N
CH3 ;~
3.11. 5-chloro-2-thiazolyl ¦ DMM
-CH=C-
: CH2CH3
~; ~ 3.12. ~ 2,5-dichloro-3-pyridyl -CH2-CH- DMM
:~ CH3 :~
3.13. 2-pyrazinyl ¦ DMM
-CH=C- :
3 1~ L I DMM
S , , , -CH=C-
CH3
3 .15. 5-chloro-2-pyridyl ¦ Pip.
-CH=C-
:, : .
CK C
3. 16. ~ ~ ¦ DMM
~ ~ -CH=C- :
: ; ~ N
''~'''"'',.','',`'''`',''','"'"'`,'''.'"'."''""'' ''"""'"~'',`''''''''''' ~' `'
202~
- 51 -
No. Q Y A Phys.
data
CH3
3.17. 5-chloro-2-pyridyl ¦ DMM
-CH=C~
CH3
3.18.2-oxazolyl ¦ DMM ~ ;
-CH2-CH- ~ ~ '
'; :~' .. : :-
N--N CH3 DMM
O -CH2-CH-
N
~ CH3
3.20. N ¦ Pip.
-CH2-CH-
CH3
N--N CH
3.21.~ JJ~ 1 3 Pip.
O -CH2~H-
Formulation Exam~?les for active ingredients of formula I ~(throu~hout. percenta es are by
F1. Solutions ~ a) b) c) d)
a compound of the,Tables ~ 80 ~o 10 % 5 % ~ 95j %
ethylene glycol monomethyl ether 20 %
polyethylene glycol (mol. wt. 400) - 70 %
N-methyl-2-pyrrolidone - 20%
epoxidised coconut oil - - 1 % 5 %
ligroin (boiling range 160-190C) - - 94 %
Those~solutions are suitable for use in the forrn of micro-drops.
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F2. Granulates a) b)
a compound of the Tables 5 % 10 %
kaolin 94 %
highly dispersed silicic acid 1 %
attapulgite ~ 90 %
The active ingredient is dissolved in methylene chloride, the solution is sprayed onto the
carrier, and the solvent is then evaporated off in vacuo.
F3.Dusts a) b) ;
acompoundof theTables 2% 5 % -
highlydispersedsilicic acid 1% 5 %
talcum 97 %
kaolin - 90 %
Ready-for-use dusts are obtained by intimately mixing the carriers with the active
ingredient.
. ~ ~
F4.Wettablepowders a) b) c)
a compound of the Tables 25 % 50 % 75 %
sodium lignosulfonate 5 % 5 % -
sodium laurylsulfate 3 % - 5 % .
sodium diisobutylnaphthalene-
sulfonate - 6 % 10 %
octylphenol polyethylene glycol
ether (7-8 moles of ethylene oxide) - 2 %
highly dispersed silicic acid 5 % 10 % 10 %
kaolin ~ 62 % 27 %
The active ingredient is thoroughly mixed with the adjuvants and the mixture is
thoroughly ground in a suitable mill, affording wettable powders which can be diluted
with water to give suspensions of the desired concentration.
: . ,
F5. Emulsifiab!e con~entrate -
a compound of the Tables 10 %
octyiphonol polyethylene glycol .
: . - .,.
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ether (4-5 moles of ethylene oxide) 3 %
calcium dodecylbenzenesulfonate 3 %
castor oil polyglycol ether
(35 moles of ethylene oxide) 4 %
cyclohexanone 30%
xylene mixture 50 %
Emulsions of any required concentration can be obtained from this concentrate by dilution
with water.
F6. Coated ~eranulate
a compound of the Tables 3 % ~ -
polyethylene glycol (mol. wt. 200) 3 %
kaolin 94 % ~
~ , ,
The finely ground active ingredient is uniformly applied, in a mixer, to the kaolin
moistened with polyethylene glycol. Non-dusty coated granulates are obtained in this
manner. ~ -
Bio!o~ical Examples~
Example B 1: Action a,eainst Puccinia graminis on wheat ~-
a) Residual protective action
Wheat plants are sprayed 6 days after sowing with a spray mixture (0.02 % activeingredient) prepared from a wettable powder formulation of the test compound. After 24
hours the treated plants are infected with a uredospore suspension of the fungus. The
infected plants are incubated for 48 hours at 95-100 % relative humidity and about 20C
and then stood in a greenhouse, !at about ~2C. IEvaluation of rust pustule development,is, ~,
made 12 days after infection. - ~
: ~ ~. ''': '
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54 2020016
b) Systemic action
Wheat plants are watered S days after sowing with a spray mixture ~0.006 % active
ingredient, based on the volume of the soil) prepared from a wettable powder formulation
of the test compound. After 48 hours the treated plants are infected with a uredospore
suspension of the fungus. The infected plants are then incubated for 48 hours at 95-100 %
relative humidity and about 20C and then stood in a greenhouse at about 22C.
Evaluation of rust pustule development is made 12 days after infection. ~-
Untreated and infected control plants exhibited 100 % Puccinia attack. Compounds of the
Tables exhibited good activity (5-20 % attack) against Puccinia fungi. Compounds nos.
1.1, 1.2a, 1.2b, 1.10, 1.13, 1.14, 1.28, 1.29, 1.31, 1.36, 1.39,1.42, 1.51, 1.61, 1.75, 1.87,
1.91, 1.105, 1.168, 1.170 inter alia inhibited attack to 0-5 %.
Example B2: Action against Cercospora arachidicola on roundnut plants
a) Residual protective action
Groundnut plants 10-15 cm in height are sprayed with a spray mixture (0.02 % active
ingredient) prepared from a wettable powder formulation of the test compound, and
infected 48 hours later with a conidia suspension of the fungus. The infected plants are
incubated for 72 hours at about 21C and high humidity and then stood in a greenhouse
until the typical leaf specks occur. Evaluation of the fungicidal action is made 12 days ~ ;
after infection and is based on the number and size of the specks.
b) Systemic action
Groundm:t plants 10- 15 cm in height are watered with a spray mixture (0.06 % active
ingredient, based on the volume of the soil) prepared from a wettable powder formulation
of the test compound. The treated plants are infected 48 hours later with a conidia
suspension of the fungus and then incubated for 72 hours at about 21C and high humidity.
The plants are then ~stood in a greenhouse and evaluation of fungus attack is made 11 days
later.
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Compared with untreated and infected control plants (number and size of the specks = 100
%), Cercospora attack on groundnut plants treated with compounds of the Tables was ~ -
substantially reduced. Thus compounds nos. 1.1, 1.6, 1.10, 1.12, 1.13, 1.14, 1.22, 1.24,
1.28, 1.29, 1.31, 1.32, 1.33, 1.36, 1.39, 1.40, 1.42, 1.43, 1.51, 1.57, 1.58, 1.61, 1.75, 1.82,
1.87, 1.91, 1.105, 1.113, 1.124,1.126, 1.140, 1.143, 1.151, 1.168, 1.169, 1.170, 2.1, 2.2,
2.17, 2.62, 2.70, 2.71 and 3.2 inhibited the occurrence of specks almost completely
~ , ... ........ . ...
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(0-10 %) in the above tests.
Example B3: Action a~ainst Erysiphae ~raminis on barlev
a) Residual protective action
Barley plants about 8 cm in height are sprayed with a spray mixture (0.02 % active
ingredient) prepared from a wettable powder formulation of the test compound. The
treated plants are dusted with conidia of the fungus after 3-4 hours. The infected barley t
plants are stood in a greenhouse at about 22C. The fungus attack is evaluated after 10
days.
b) Svstemic action
A spray mixture (0.006 % active ingredient, based on the volume of the soil) prepared
from a wettable powder formulation of the test compound is used to water barley plants
about 8 cm in height. Care is taken that the spray mixture does not come into contact with
the parts of the plants above the soil. The treated plants are dusted 48 hours later with
conidia of the fungus. The infected barley plants are then stood in a greenhouse at about
22C and evaluation of fungus attack is made after 10 days.
Compounds of forrnula I exhibited good activity against Erysiphae fungi. Untreated and
infected control plants exhibited 100 % Erysiphae attack. Compounds nos. 1.1, 1.2a,1.2b,
1.6, 1.14, 1.20, 1.24, 1.27, 1.28, 1.29, 1.36, 1.40, 1.43, 1.44, 1.61, 1.168, 1.169, 1.170,2.5, ;
2.13, 2.14, 2.15, 2.20, 2.24, 2.41, 2.42, 3.1, 3.2 and 3.19, among other compounds of the
Tables, inhibited fungus attack on barley to 0 to 5 %.
Example B4: Residual protective action against Venturia inaequalis on apple shoots ~ ~
Apple cuttings with 10-20 cm long fresh shoots are sprayed with a spray mixture (0.06 % ~ ~ ;
a.i.) prepared from a wettable powder formulation of the test compound. The treated
plants are infected 24 hours later with a conidia suspension of the fungus. The plants are
then incubated for 5 days at gO-100 % relative humidity and stood in a greenhouse for a
further 10 days at 20-24C. Scab infestation is evaluated 15 days after infection.
Compounds of the Tables inhibited disease attack markedly. Thus compounds nos. 1.1,
1.2a, 1.2b, 1.24j 1.28, 1.40, 1.43j 1.168, 1.170,2.15,2.20,2.24and3.2inhibitedfungus -~
attacl~ almost completely (0-5 %). Untreated and infected shoots exhibited 100 %Venturia attack.
. : ~
202~016
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Example B5: Action against Botrvtis cinerea on beans
Residual protective action
Bean plants about 10 cm in height are sprayed with a spray mixture (0.02 % active
ingredient) prepared from a wettable powder formulation of the test compound. After 48
hours the treated plants are infected with a conidia suspension of the fungus. The infected
plants are incubated for 3 days at 95-100 % relative humidity and 21C and then evaluated
for fungus attack.
Botrytis attack on untreated and infected bean plants was 100 %. Attack after treatment
with one of the compounds of formula I was < 20 %; on treatment with compounds nos.
1.1, 1.2a, 1.2b, 1.10, 1.14, 1.19, 1.22, 1.24, 1.26, 1.28, 1.32, 1.39, 1.51, 1.66, 1.78, 1.82,
1.93, 1.99, 1.120, 1.124, 1.152, 1.157, 1.158, 1.163, 1.165, 1.168, 1.169, 1.170, 2.1,2.9, `
2.14, 2.25, 2.53, 2.59, 3.3, 3.14 inter alia, no attack occurred (0-S %).
. .
Example B6: Action a~ainst Rhizoctonia solani (soil fun~us on rice plants)
a) Protective local soil aPPIication
12-day-old rice plants are watered with a spray mixture (0.006 % active ingredient)
prepared from a formulation of the test compound, without wetting the parts of the plants
above the soil. In order to infect the treated plants, a suspension of mycelia and sclerotia
of R. solani is applied to the surface of the soil. After 6 days' incubation in a climatic
chamber at 27C (day) and 23C (night) and 100 % relative humidity (humidity charnber),
the fungus attack on the foliar sheath, the leaves and the stem is evaluated.
b) Protective local foliar application
12-day-old rice plants are sprayed with a spray mixture prepared from a formulation of the
test compounds. One day later, the treated plants are infected with a suspension of
mycelia and sclerotia of R. solani. After 6 days' incubation in a climatic chamber at 27C
(day) and 23C (night) and 100~% relative humidity (humidity chamber), the fungus attack
on the foliar sheath, the leaves and the stem is evaluated.
,
- ~ Compounds of the Tables exhibited good activity by inhibiting Rhizoctonia attack. Thus,
forexample, compounds nos. 1.1, 1.2a, 1.2b, 1.14, 1.16, 1.17, 1.22, 1.28, 1.39, 1.82, 1.105,
1.168, 2.1, 2.3, 2.4, 2.14, 2.17,3.1 and 3.3 inhibited fungus attack to 0 to S %. On the
other hand, untreated and infected control plants exhibited 100 % attack.
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