CA2020016A1 - Microbicides - Google Patents

Abstract

Microbicides Abstract Compounds of formula I and their acid addition salts are valuable microbicides and may be used in the form of compositions in plant protection for preventing and controlling an attack by microorganisms.
(I) In the formula:
X is oxygen or sulfur, Het is a 5- or 6-membered heterocycle which has from one to three identical or different hetero atoms selected from nitrogen, oxygen and sulfur and which is unsubstituted or mono-, di- or tri-substituted by identical or different substituents selected from halogen, cyano, nitro, C1-C4alkyl, C3-C6cycloalkyl, C1-C4alkoxy, C1-C3haloalkoxy and trifluoro-methyl, B is -CH2-CH(R2)-CH2- or -CH=C(R2)-CH2- or -CH2-C(R2)=CH-, R1 is halogen, C1-C4alkyl or C1-C4alkoxy, n is from 0 to 2, m is 0 or 1, R2 is hydrogen or C1-C4alkyl, R3 is hydrogen or C1-C3alkyl, R4 is hydrogen, hydroxy, C1-C3alkoxy or unsubstituted C1-C4alkyl or C1-C4alkyl substituted by hydroxy or by C1-C3alkoxy, and Z is oxygen, sulfur or -CH2-.

Description

::` 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 ~ : -. ~

.',:

$~

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.
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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 . . , : .

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 . . , 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 - ~ .;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

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) .: ' .:
with an amine of formula V to give a compound of formula VII

~ .

~;2~

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~

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.

. .
,:

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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~ ~

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 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 ~

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 ~

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 ~

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 ~ ~

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. ~ ~ -. , ,', ' ', ;

::

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 ~< .

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~

CiS-DMM =--N oans-DMM = -N ~o CH3 CH3 ~:
~ ,, .

~CH3 ~ .
~ans-DMp =--N~

~: : : . .- , . ,, :

`, : ~ `, : ~, : .

202001~ ~

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
, 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 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~

No. Q A XPhys.
data ' ~, .
c~
128 CF -_~ cis-DMM OnD :1.5090 ; ~ .

[nitrate: m.p. 148C] - ~ ;
1.29. 2-thienyl Pip. O

1.30. 3-chloro-2-pyridyl _ N~

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~ ~

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~

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

..

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 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 , ~
. ~ :

75~ CH3 ~/ ~ Pip. ~ O ~ ~ "~
N ::

1.76. ~ ~ ~4,6-dimethyl-,2~ cis DMM , o n34 :1.5288, , pyrimidinyl 1.77. 2-thienyl --N~ ~

1.78. ~ 2-pyrimidlnyl cis-DMM O `

` 2~2~01~

No. Q A X Phys.
data 1.79. CF3 ~ DMM S ;

1.80. 5-bromo-2-pyridyl DMP O

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 ~

No. Q A X Phys. :
data 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

N~ o -.. . .
\= N CH3 1 .92. : 3 ni~o 2 pyridyl ~ Pip. o 193.~ ~ DMM S
; ~ . . .

~ 1 .94. ~ ~ 02N ~ Pip.

.` - ~ .. ` . .~

2~

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

. .

$

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 ;

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 ~ -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 .

1.147. . 5-bromo-2-pyridyl_ N/--<~
,,~ ," ,,~
1.148. 4-pyridyl DMP O
f; !, CH3CH2 Cl 1.149. ~ ~ trans-DMM O

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~
... .

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

1.165. N DMM O :~
CH3 ` ;

CH3_1~ ,~ DMM O

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 ~ ' ~

., : : .

Table 2 Q--X _,~ 1 3 4 ~ CH2- CH--CH2- A '~

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 ~ ;

~: .

. ~, - : - -. -. .

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~

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

CI CH2CH3 `~
2 26- ~ 4_ O __¢~ Pip.

2 ~ 2 ~

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
'`:~

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 :

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 ~

; .
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 2.52. 3--O~N ;~

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~

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~

No. -X-Q T A Phys.
data . .

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

. .
"

~ :, ' ,:~

~ ,~

, , .

' ~
~::::

Table 3 Q-~ :`
'.
No. Q . Y A Phys.
data ~ ;

3.1. CF3 ~ -CH2 DMM
N

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~

No. Q Y A Phys.
data .

3.8.3,5-dichloro-2-pyridyl ¦ Morph -CH=C- .

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-3 .15. 5-chloro-2-pyridyl ¦ Pip.
-CH=C-:, : .
CK C
3. 16. ~ ~ ¦ DMM
~ ~ -CH=C- :
: ; ~ N

''~'''"'',.','',`'''`',''','"'"'`,'''.'"'."''""'' ''"""'"~'',`''''''''''' ~' `' 202~

No. Q Y A Phys.
data 3.17. 5-chloro-2-pyridyl ¦ DMM
-CH=C~

3.18.2-oxazolyl ¦ DMM ~ ;
-CH2-CH- ~ ~ ' '; :~' .. : :-N
~ CH3 3.20. N ¦ Pip.

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.

-- 52 - 2 ~ 2 ~

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 .
: . - .,.

-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. - ~

: ~ ~. ''': ' ;~", .

~; ' '. ::~' 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.
- ~
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 ~ , ... ........ . ...

(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 ' 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.
- .:

-

Claims (32)

1. Compounds of formula I
(I) wherein:
X is oxygen or sulfur, Het is a 5- or 6-membered heterocycle which has from one to three identical or different hetero atoms selected from nitrogen, oxygen and sulfur and which is unsubstituted or mono-, di- or tri-substituted by identical or different substituents selected from halogen, cyano, nitro, C1-C4alkyl, C3- C6cycloalkyl, C1-C4alkoxy, C1-C3haloalkoxy and trifluoro-methyl, B is -CH2-CH(R2)-CH2- or -CH=C(R2)-CH2- or -CH2-C(R2)=CH-, R1 is halogen, C1-C4alkyl or C1-C4alkoxy, n is from 0 to 2, m is 0 or 1, R2 is hydrogen or C1-C4alkyl, R3 is hydrogen or C1-C3alkyl, R4 is hydrogen, hydroxy, C1-C3alkoxy or unsubstituted C1-C4alkyl or C1-C4alkyl substituted by hydroxy or by C1-C3alkoxy, and Z is oxygen, sulfur or -CH2;
including the acid addition salts of those compounds.

2. Compounds according to claim 1, wherein the 5- or 6-membered heterocycle Hetcontains at least one N atom, R1 is halogen, methyl or methoxy, n is 0 or 1, m is O and R2 and R3 are each independently of the other hydrogen or methyl.

3. Compounds according to claim 2, wherein X is oxygen and R4 is hydrogen, hydroxy, methyl, methoxy, hydroxymethyl, hydroxyethyl, methoxymethyl or methoxyethyl.

4. Compounds according to claim 3, wherein Het is an unsubstituted or substituted pyridyl radical.

5. Compounds according to claim 4, wherein B is the chain -CH2-CH(CH3)-CH2- or -CH=C(CH3)-CH2- and the pyridyl radical is unsubstituted or substituted by not more than two identical or different substituents selected from halogen, NO2, -OCHF2 and CF3.

6. Compounds according to claim 5, 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.

7. Compounds according to claim 3, wherein Het is an unsubstituted or substituted pyrimidinyl radical.

8. Compounds according to claim 7, wherein B is the chain -CH2-CH(CH3)-CH2- or -CH=C(CH3)-CH2- and the pyrimidinyl radical is unsubstituted or mono- to tri-substituted by identical or different substituents selected from halogen, C1-C4alkyl and cyclopropyl.

9. Compounds according to claim 8, 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.

10. Compounds according to claim 3, wherein Het is an unsubstituted or substituted pyrazinyl radical.

11. Compounds according to claim 10, 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 C1-C4alkyl and/or halogen.

12. Compounds according to claim 11, 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.

13. Compounds according to claim 3, wherein Het is an unsubstituted or substituted 1,3,5-triazinyl radical.

14. Compounds according to claim 13, 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.

15. Compounds according to claim 14, 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.

16. Compounds according to claim 3, wherein Het is an unsubstituted or substituted thiazolyl radical.

17. Compounds according to claim 16, wherein B is the chain -CH2-CH(CH3)-CH2- or-CH=C(CH3)-CH2- and the thiazolyl radical is unsubstituted or mono-substituted by NO2 or by halogen.

18. Compounds according to claim 17, 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.

19. Compounds according to claim 3, wherein Het is an oxazolyl radical, Z is oxygen or -CH2- and R3 and R4 occupy the two positions adjacent to Z and both are hydrogen or both are methyl.

20. Compounds according to claim 3, wherein Het is an unsubstituted or C1-C4alkyl-substituted 1,2,4-triazolyl radical, Z is oxygen or -CH2- and R3 and R4 occupy the two positions adjacent to Z and both are hydrogen or both are methyl.

21. Compounds according to claim 3, wherein Het is an unsubstituted or C1-C4alkyl-substituted 1,2,4-imidazolyl radical, Z is oxygen or -CH2- and R3 and R4 occupy the two positions adjacent to Z and both are hydrogen or both are methyl.

22. Compounds according to claim 3, wherein Het is an oxadiazole radical, Z is oxygen or -CH2- and R3 and R4 occupy the two positions adjacent to Z and both are hydrogen or both are methyl.

23. Compounds according to claim 3, wherein Het is a thiadiazole radical, Z is oxygen or -CH2- and R3 and R4 occupy the two positions adjacent to Z and both are hydrogen or both are methyl.

24. Compounds according to claim 1, 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 C1-C4alkyl.

25. Compounds according to claim 24, wherein X is oxygen, n is 0 or 1, m is 0, R1 is halogen, methyl or methoxy, R2 is hydrogen or methyl and R3 is hydrogen or methyl, and R4 is hydrogen, methyl, hydroxy, methoxy, hydroxymethyl or methoxymethyl.

26. Compounds according to claim 25, 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.

27. A process for the preparation of compounds of formula I according to claim 1, which comprises a) reacting an amine of formula II
(II) at from 0° to 220°C with a heterocycle of formula III
Het- A2 (III) wherein one of the radicals A1 and A2 is a nucleofugal leaving group and the other is the group -XMe, wherein Me is hydrogen or a metal cation, while the substituents R1, R3, R4, B, X and Z and also n are as defined under formula I; or b) condensing a heterocyclic diphenyl ether of formula IV
(IV), wherein C is a nucleofugal leaving group, at from 0° to 120°C with an amine of formula V

(V) wherein the substituents R1, R3, R4, B, X, Het and Z and also n are as defined under formula I; or c) if B is the chain -CH2-C(R2)=CH- or -CH2-CH(R2)-CH2-, reacting an aldehyde offormula VI
(VI) at from -25°C to +300°C with an amine of formula V to give a compound of formula VII
(VII) within the scope of formula I and, if desired, subsequently hydrogenating the double bond, the substituents R1, R2, R3, R4, X, Het, n and Z being as defined under formula I; and, if desired, subsequently oxidising the resulting compounds of formula I wherein m=0 to obtain the corresponding N-oxides (m=1) of formula I.

28. Microbicidal compositions containing as at least one active ingredient a compound of formula I according to claim 1, together with a suitable carrier.

29. A composition according to claim 28 containing as active ingredient a compound according to any one of claims 2 to 26.

30. The use of compounds of formula I according to any one of claims 1 to 26 forcontrolling or preventing an attack by phytopathogenic microorganisms.

31. A method of controlling or preventing an attack on plants by phytopathogenicmicroorganisms, which comprises applying a compound of formula I according to any one of claims 1 to 26 to the plant, to parts of the plant or to the locus thereof.

32. A method according to claim 31, wherein the parts of plants are the seeds.