Note: Descriptions are shown in the official language in which they were submitted.
~35Cl 5S~
The present invention provides compounds of the
formula I
CH
R ~ H3 ~ 3
\ CO ~ (I~
CH
wherein R represents hydrogen or methyl, ~a process for the
manufacture of these compoundsg also microbicidal compositions
which contain these compounds as active substance, as well as
a method of using these compounds as microbicides, preferably
i for combating phytopathogenic fungi.
' Bacterial diseases and mycoses in useful plants are
- helped by two factors. On the one hand, in plant hybridizing
, .i
it is a primary objective ~o attain an increase in yield and ~-
, an in~rovemen~ in qualiby, But in this p~ocess the plants
frequently lose some of their naLtural resistance to parasites.
On the other hand, experience has shown that bacteria and
harmful fungi have developed over the years a substantial
resistance to the known pesticides. There is therefore an
urgent need for microbicides that are compatible with the
cultivated plants and destroy their direct parasites.
Cultivated plants within the scope o~ the present
: invention axe, ~or example9 cereals, maize, rice, vegetables,
sugar beet, soya, ground nuts, fruit trees, ornamental plants,
but princ~palLy vines, hops, cucumber plants (cucumbers,
:',~ ~ ..
~ ~ - 2 -
,:,,,; ' '
,~ . .,.; j .. ,. .. , ~ ... .. .. . .
,, -., , . ~ . . . " " , ~,. .. .
, , , . , - .. . .: .. . . . . . .
s~, , ,, . ,
.
~56J ~5~3
marrows, melons), solanaceae, such as potatoes, tobacco and
tomatoes, as well as bananas, cocoa and rubber plants.
rhe present invention is based on the surprising
observation that it is possible to inhibit or destroy with the
compounds of the formula I the fungi which occur on plants or
parts of plants (fruit, blossoms, leaves, stems, tubers, roots)
of these and related cultures or useful plants and also to
protect from such fungi which grow later. The active substances
; are effective against phytophathogenic fungi which belong to
the following classes: ascomycetes (e.g. erysiphacea);
basidiomycetes, above all rust fungi; fungi imperfecti; but
especially against oomycetes which belong to the class of
phycomycetes, e.g~ phytophthora, peronospora9 pseudoperonospora,
pythium or plasmopara. In addition, the compounds of the
formula I have a systemic actionO They can also be used as
seed-dressing agents for protecting seeds ~fruit, tubers,
kernels) and plant cuttings from fungus infections as well as
from phytopathogenic fungi which occur in the soil.
The N-(substituted phenyl)~N-furanoyl-alanine-
2Q methyl esters of the formula I constitute a hither~o unknown
class of new microbicidal active substances which are markedly
superior in their field of use to the conventional commercial
preparations.
Compounds of the formula I are manufactured by a method
- 3 ~
~. .
, ,, . :, . : . :
, : . . : , . :: :
,, . , , . , , , :
~ ~ 5~ ~5 ~
according to the invention, for example by acylation of a
compound of the formula II
N~ COOCl13 (II)
CH3
with furan-(2~carboxylic acid,the acid halide, acid anhydride
or ester thereof, in isolated instances also with a furan-~2)-
~` carboxy amide (transamidation).
By another method according to the invention it is alsopossible to manufacture the c~mpounds of the formula I by
onverting the acyl anilide o~ t~ formula III
.i
~ ~$~ co~ (III)
` CH~
.~'
wit~ bu~l lithium or sodium hydride in~o the corresponding alkali
salt, which is then reacted with t~e ~-halogenopr~pionic acid
methyl ester ko give the desired end product, or else to react
,the anilide of the ~ormula III with the a-halogenopropionic
acid methyl ester in the presence o~ an alkali carbonate, e.g.
K2CO3, as proton acceptor, preferably wi~h the additton of ~-
cata].ytic amounts of an alkali iodide, e.g. potassium iodide.
, ,
, . , . , , . ~ . .. .
, . ...
~: - , , , , . :
,, , ,~
~ ~ 5
In the formulae II and III, R represents hydrogen
or methyl, the term 'lacid halide" denotes preferably acid
chloride or acid bromide and the halogen atom in ~-halogeno-
propionic acid methylester is preferalby chlorine or bromine.
The reactions can be carried out in the presence or absence
of solvents or diluents which are inert to the reactants.
Examples of suitable solvents or diluents are: aliphatic
or aromatic hydrocarbons, e.g. benzene, toluene, ~ylene,
petroleum ether; halogenated hydrocarbons, e.g. chlorobenzene,
methylene chloride, ethylene chloride, chloroform; ethers and
ethereal compounds, e.g. dialkyl ethers, dioxan,tetrahydro-
furan; nitriles, e.g. acetonitrile; N,N-dialk~lated amides,
e.g. dimethyl formamide; anhydrous acetic acid, dimethyl
sulphoxide, ketones, e.g. methyl ethyl ketone, and mixtures
of such solvents.
The reaction temperatures are between 0 and 180C~
preferably between 20C and 120C, It is often advantageous
to use acid acceptors or condensation agents. Su~able
examples are: tertiary amines, e.g. trialkylamines (e.g.
triethylamines), pyridine and pyridine bases, or lnorganic
bases, e.g. the oxides and hydroxides, hydrogen carbonates and
carbonates of alkali metals and alkaline earth metals, as well
as sodium acetate. In the above first manufacturing
method i~ is also possible to use a surplus of the respective
anlline derivative of the formula II as acid acceptor.
' :
- 5 -
. .
,, . , , . , : ,: . . : :: : :
, ; ~, , - , . : ,, , , ~, . .
. , , .: ,: . , . ,,', :,,' . ' : ., ', ~, ' . ,: . ' :, ,
~5~55~
The process of manufacture which procee~ from compounds
o~ the formula II can also be carried out without acid
acceptors; in some instances it is expedient to pass in
nitrogen in order to expel the hydrogen halide that has formed
In other instances it is very advantageous to use dimethyl
formamide as reaction catalyst.
Particulars on the manufacture of the intermediates of
the ormula II can be inferred from the methods which are
generally indicated for the manufacture of aniline-alkane acid
çsters in the following publications:
. . .
J. Org Chem.30, 4101 (1965); Tetrahedron 1967, 487;
Tetrahedron 1967, 493.
The compounds of the formula I contain an asymmetrical
carbon atom in the propionic acid ester chain and can be
resolved into the optical antipodes in the customary -manner.
In this connection, the enantiomeric D-form has the more
pronounced microbicidal action.
.
Within the scope of the invention, those c~mpounds,
their C~mpQs~tlons andtheir use which refer to the D-configu-
ration of the formula I are accordingly preferrred. These
D-forms have in ethanol or acetone a negative angle of rotation.
The pure, optical D-antipodes are manufactured, for
example, by preparing the racemic compound of the formula IV
:
- 6 -
.
:. . .. . : .. . : ~ .
,
, ', , ~ ' .' . ' ' .' ' :~ '
,
. ~ ,: ' , .. .
~5¢~5S~3
R C113
CH-CGOH (IV)
CH3
(R ~ H o r CH3 )
, ' ' .
and then reacting this in known manner with a nitrogen-containing,
optically active base to give the corresponding salt. The
pure D-form is obtained stepwise by frac~ional crystallisa~ion
of the salt and subsequent liberation of the acid of the
formulaIV which is enriched with the optical D-antipode and,
if appropriate, by repetition ~also repetition several times)
of the salt formation, crystallisation and liberation of
the ~-anilinopropionic acid of the formula IV. From this pure
D-form it is then possible to obtain the optical D-configuration
of the ester of the formula II in conventional manner, for
example in the presence of HCl or H2S04~ with methanol. A
.. . ...
~uitable optically active organic base is, for example,
~-phenylethyl amine.
Instead of fractional recrystallization, it is
also possible to obtain the enantiomeric D-form of the formula
. .
IV by replacing the hydroxy group in the naturally occurring
L~) lactic acid by halogen and react~g this product further
with 2,6-dimethy]aniline or 2,3,6-trimethylaniline with
reversal of the configuration~
'' ' ' ' , ' ` - --- ~:
:, - 7 _
,.
', ' ,~ ' '' .' ; .' ' ' ' ' . .' ,':: .' . : ~ ~ '
: ~ 5~ 55 ~
Besides the optical isomerism, when R = CH3, there
occurs in the furanoylation of the compound II (or in the
reaction of the compound III with ~-halogenopropionic acid
methyl ester) an atropisomerism about the phenyl- N~a~is,
as a consequence of the steric hindrance of the two radicals
additionally introduced at the nitrogen atom of the tr;methyl-
aniline. Pr~vided no synthesis is carried out with the aim of
isolating pure isomers, compound 2 (the manufacture of which
` is described hereinafter) occurs in the manufacture as a mixture
.,,
of 4 isomers. However, the better fungicidal action of the
enantiomeric D-form (in comparison to the DgL-form or the
. L-form) is retained. and is not noticeably affected by the
: atropisomerism.
;~ The manufacture of the active substances of the formula I is illustrated by the following Examples 1 and,2,
,
.: . .
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:... : .
.
.
~5q~
Example 1
Manufacture of
C~13
H3 ~ Il-COOC~13
_ N \ ~ ~
CH3 ~ (compound 1)
. ~ .
N~ methoxycarbonylethyl)-N-(furan-(2")-carbonyl)-2,6-di-
methylaniline.
With stirring, -12 6 g of furan-2-carboxylic acid
- chloride are added dropwise to 18.2 g of N-(l-methoxycarbonyl-
ethyl)-2,6-dimethylaniline in 10 ml of anhydrous toluene and
0.2 ml of dimethyl formamide. After the weakly exothermic -
reaction has subsided, the reaction mixture is refluxed for 5
- hours and the hydrogen chloride which has formed is completely
removed by passing in nitrogen. The solvent is removed and the
residue is distilled in vacuo; b.p. 156-168c/o.o6 Torr.
The congealed end product melts between 81 -84 C after recry-
stallisation from toluene/petroleum ether. X-ray powder patterns
show that the product is polymorphous. One of the two modifi-
cations meLts at 85C The enantiomeric D-configuration and
it~ primary products have the following physical data:
.. , :. .
. ', .
.
.
, ... .
.,
: ' ' . . . , - .
' ' ' , ` ' ' . ' , , .:
'. ' , ' ' ~ .
'" ' ', ,'. ' ' . ' , ' ~,"', '. ' , ' ,. . '
' ' '' ' ' ' ' ' ' :~ , . '
5~i 3
CH3
~~~ Cll3 (a) D =+ 10, 7 ~ 0, 3 j C=1, 56 % glv
in e t:hano l
11
(~H3
CH3 (D) -f orlll
~H-*CH~COOCH3 (a)20= -~29 8 -~ 0,5;C=l,52% g/v
in -~e t hano l
`.' CH3
~ ~ -
:, .
: CH3
CH ~CH-COOCH3 (D)-form m.p. 102-103
\~ / (a)D ~ -47,0 ~G,7
\CG_ I~J C=1~73~7/o ~/v in ace.one
C~3
; (compound Ia~
'
~. Example 2
:
Manufacture of
-
CH Cc~13 (compound 2 )
1 3 H - COOC11~
<~ <`&~3
o
. .. .
- lo
: : : .. ....
.
.
~ 5(~55~
N~ metho~ycarbonyl-ethyl3-N-(furan-(2")-carbony~2,3,6-tri-
methylaniline.
a) A suspension of 51.5 g (0.382 mole) of ~,3,6-trimethyl-
aniline, 35.3 g of NaHC03 and 126 ml ~1.15 moles) of 2-bromo-
propionic acid methyl est r is stirred for 6 hours at a bath
temperature of 130 C, then coQled, filtered from NaBr-salt and
distilled. Yield: 67.3 g of ~-(2,3~6-trimethylanilino)-propionic
acid methyl ester ~b.p. 144 -146 C/9 Torr.)
b) A suspension of 33.5 g (0.152 mole) of the ester obtained
according to a) and 18 g (0.17 mole) of sodium carbonate in
200 ml of absolute benzene is treated dropwise with 16.7 ml
~0.17 mole) of furan-2-carboxylic acid chloride at 60 -70 C
and kept thereat for 4 hoursO The reaction mixture is cooled
and filtered and the filtrate concentrated. The end product
crystallises from isopropyl ether (m.p. 98-102C).
The D-form of compound 2 is obtained as a mixture of
~- atropisomers (~cor~ound 2a) by acylating the D-form of the
(2,3,6-trimethylanilino)-p~opionic acid methyl ester with
furan - (2)-carboxylic acid or one of its reactive derivatives.
The percentage amount of each of these isomers obtained depends
: .
on the respective manufacturing conditions.
The compounds of the formula I can be used with other
suitable pesticidal or active substances which promote plant
growth in order to improve their activity spectrum.
The cornpounds of the formula I can be used by themselves
~ 11 _
, , . .. . , . . " ~,: . ~,; :; ,
, . ,, . . : ... . : . ..
, . . .: . . . .. .
;., .: .,
:,, ;: . . ' :' ', ,, , ~ ,
~ 55 ~
or together with suitable carriers and/or other additives.
Suitable carriers and additives can be solid or liquid and corres-.
pond to the customary substances used in formulation technology,
for example natural or regenerated mineral substances3 solvents,
. dispersants, wetting agents, stickersg thickeners, binders or
fertilisers. The amount of acti~e substance in commercially
; useful compositions is between 0.1 and 90 %.
:. The compounds of the formula I can be applied in the
following process forms (the percentages by weight in brackets
denote advantageous amounts of active substance):
s.olid forms: dusts and tracking agents (up to 10 %); granules,
~ coated granul~s, impregnated granules and homogenous
: granules (1 to 80 %);
liquid forms: a~ active substance concentrates which are dis-
persible in water; wettable powders and pastes
(25~90 % in the ~ommercial pack, 0 01 to 15 %
in ready for use solution);
emulsion concentrates and concentrated solutions .-
(10 to 50 %; 0 01 to 15 % in ready for use
solution);
b) solutions (0.1 to 20 %).
: .
- 12 -
'~' " ' ' , ~'
"/~' S ' , ',' .' ' '' '' .. ' ' ~ '',,.', . ' , . ', ' ,
,. . . . .
5~ 5f~
The active substances of the formula I can be formulat-
ed, for example~ as follows:
Dusts: The following substances are used to manufacturfe a) a
- 50 % and b) a 2 % dust:
a) 5 parts of active substance 2
95 parts of talcum;
.:.
b) ~ parts of active substance 1
1 part of highly disperse silicic acid
97 parts of talcum.
- .:
The active substances are mixed with the carriers and
ground and in this form can be processed to dusts for appli-
cation.
, Granules: The following substances are used to manufacture 5 %
~-,
granules: -
. J
~5 parts of active substance 1
!
0.25 parts of epichlorohydrin
0.25 parts of cetyl polyglycol ether
3.50 parts of polyethylene glycol
91 parts of kaolin (particle size 0.3-0.8 mm).
The active substance is mixed with epichlorohydrin and the
, mixture is dissolved in 6 parts of acetone. Then polyethylene
glycol and cetyl polyglycol ether are added. The resultant
solution is sprayed on kaolin and the acetone is evaporated
- 13 _
';,
, ,. , : " i , . ................ , , . i, ,
.. . . ,,, . ,.: , : , , , , ,: ,
~ 5~
in vacuo. Such microgranules are advantageously used for com-
bating soil fungi.
We~table powders: The following constituents are.used to manu-
facture a) a 70 %, b) a 40 %, c) and d) a 25 % and e) a 10 %
wettable powder:
a) 70 parts of N-(l'-methoxycarbonyl-ethyl)-N-tfuran-(2")-
carbonyl~ 2,6-dimethylaniline (active substance
la (D-form) according to the present invention)
parts of sodium dibutyl nap.thylsulphonate
3 parts of naphthalenesulphonic acid/phenolsulphonic
acid/formaldehyde condensate (3:2:1)
parts of kaolin
-. 12 parts of Champagne chalk.
b) 40 parts of active substance 2
parts of the sodium salt of ligninsulphonic acid
1 part of the sodium salt of dibutylnaphthalenesul-
phonic acid
54 par~s of silicic acid.
c) 25 parts of active substance 2a (D-form)
4.5 parts of calcium ligninsulphonate
1.9 parts of a Champagne chalk/hydroxyethyl cellulose
mixture (1:1)
14 :
. : :, . : .
. : : :. ,
105 parts of sodium dibutylnaphthalene sulphonate
19.5 parts of s;licic acid
19.5 parts of Champagne chalk
28.1 parts of kaolin,
.~ .
d) 25 parts of active substance 2
205 parts of isooctylphenoxy-polyoxyethylene-ethanol
1;7 parts of a Champagne chalk/hydroxyethyl cellulose
mixture (1:1)
. ;i
8,3 parts of sodium aluminium silicate
16.3 parts of kieselgu'nr
46 parts of kaolin.
:
I e) 10 parts of active substance la (D-form)
' ~ 3 parts of a mixture of the sodium salts of satur-
-, ated fatty alcohol sulphates
parts of naphthalenesulphonic acid/Eormaldehyde
I condensate
82 parts of kaolin.
The active substances are intimately mixed in suitable mixers
with the additives and ground in appropriate mills and rollexs.
Wettable powders of excellent wettability and suspension power
are obtained. These wettable powders can bP diluted with water
to give suspensions of every desired concentration and can be
used in particulax for application to leaves.
., : -.-
- lS -
Emulsifiable concentrates: The fol~owing substances are used to
to manufacture a 25 % emulsifiable concentrate:
parts of active substance 1
2.5 parts of epoxidised vegetable oil
parts of an alkylarylsulphonate/fatty alcohol
polyglycol ether mixture
parts of dimethyl formamide
S7.5 parts of xylene.
By diluting such concentration with water it is possible to
i manufacture emulsions of every desired concentration which are
~i especially suitable for application to leaves.
., : .
Example 3
; Action against Phytophthora infestans on Solanum lyccpersicum
(tomatoes)
Ia) Residual ~reventive action
Solanum lycopersicum plants of the "Roter Gnom" variety
are infected when 3 weeks old with a zoospore suspension of
Phytophthora infestans after they have been sprayed with a
broth prepared from the active substance processed to a wettable
powder and containing 0.05 % of active substance, and dried.
They are then kept for 6 days in a climatic chamber at 18 to
~.
20C and high humidity, which is produced with an artificial
wet fog. After this time typicàl leaf specks appear. Their
number and size are the criterion for evaluating the tested
subs~ance.
- 16 -
~, .
. .
~ ~ 5~l5
Ib) Curative action
"Roter Gnom"tomato plants are sprayed when 3 weeks old
w~h a zoospore suspension of the fungus and incubated in a
climatic chamber at 18 to 20 C and saturated humidity The
humidifying is interrupted ater 24 hours. After the plan~s
have been dri~ed, they are sprayed with a broth which contains
the active substance formulated as wettable powder in a con-
centratior of 0.05 %0 After the spray coating has dried, the
plants are again kept in the humid chamber for 4 days. Size and
num~er of the typical leaf specks which have occurred during
this time are the criterion for evaluating the effectiveness
of the tested substances.
~ ~ .
II) Preve~tive-systemic action
,The active substance is applied as wettable powda~ in
a concentra~ion of 0.05 % (referred to the volume of the soil)
.
to the surface of the soil of 3 week old "Roter Gnom" tomatoes
in pots. Three days later the underside of the leaves of the
plants are sprayed with a zoospore suspension of Phytophthora :
infestans. The plants are then kept for 5 days in a spray
chamber at 18 to 20C and saturated humidity, after which time
.~ .
typical leaf specks form.The number size of the specks serve
the criterion for evaluating the effectiveness of the tested
8ubstances.
.. , - :.
.
- 17 -
,''~ , . .:-
:.
,, , , . : ~ , . . . ..
' . ' . " ' , ,~ .. ,1,.",.. '.
.
i5~
In these three tes~s, the compounds of the formula X
have a pronounced leaf-fungicidal action, i.eO the fungus in-
fection is below 5 %, When the D-forms of the compunds a-re
applied, i.e. active substances la and 2a, the fungus infection
is below 5 % in all three tests even at rates of application
of 0.02 %.
.i .
Example 4
Action a~ainst ~c~smoporara viticola (Bert. et Curt.
~Berl. et De Toni) on vines
a) Residual preventive action
:i
Vine cuttings of the variety "chasselas" were reared
in a greenhouse. Three plants in the 10 leaf stage were sprayed
with a broth prepared from the active substance and-formulated
as a wettable powder. A~ter the coating layer had dried, the
plants were infected on the underside of the leaves with the
spore suspension of the fungus. The plants were subsequently
kept for 8 days in a humid chamber,after which time symptoms
Q the disease were visible on the control plants. The number
and size of the infected areas on the tested plants served as
criterion ~or evaluating the effectiveness of the tested active
substances~
b) r~Tat
Vine cuttings of the variety "Chasselas" were reared
- 18 -
. . . . .
.
0 S~ 5S ~
in a greenhouse and infected in the 10 leaf stage with a spore
suspension of Plasmopara viticola on the underside of the leaves.
After they had been kept for 24 hours in a humid chamber, the
plants were sprayed with an active s-ubstance broth prepared from
a wettable-powder of the active substance. The plants were
then kept for a further 7 days in a humid chamber, after which
time the symptomsof the disease were visible on the control
plants, The number and size of the infectedareas on the treat-
ed plants served as criterion for evaluating the effectiveness
of the tested substances.
In both th ~e tests of Example 4, the compounds of
the formula I exhibit a pronounced fungicidal action in the
~ollowing concentrations:
`i :
i ~ctive SubstanceConcentration Fungus infection
in a) and b)
1 0,05 % 0 - 5 %
0,0~ % 0 ~ 5 %
- la 0,02 % 0 - 5 `~/0
-I 2 0,05 % 0 - 5 %
; 0,C2 % 0 - 5 %
2a 0,02 % 0 - 5 %
Control _ 100 %
,` ' ~ .
, . .
~.
.
- 19 -
:, .. " .. , . . , , , , , . ~ .. . . .
, .~,,.,,"., ; .; . .. ..
,.: - ,.. ..
~:.;~ - , : ,
Action ag inst Pythium debaryanum in Beta vulgaris (sugar beet~
a) Action after soil application
The fungus is cultivated on sterile oat kernels and
added to a mixture of earth and sand. Flower pots are filled
with the infected soil in which sugar beet seeds are then sown.
Immediately after sowing~ the tests prepara-tions formulated as
; wettable powders are poured in the form of aqueous suspensions
over the soil (00002 % active substance referred to the volume
, 10 of the soil). The pots are then stood for 2-3 weeks in a green-
house at 20-24C. The soil is kept uniformly moist by gently
spraying it with water. The emergence of the sugar beet plants
~ as well as the number of healthy and sick plants are ascert~ined
; in evaluating the tests.
b) Action after seed treatment application
The fungus is cultivated on sterile oat kernels and add-
ed to a mixture of earth and sand. Flower pots are filled with
the infected soil and sugar beet seeds which have been treated with
the test preparations formulated as seed dressing powders are
- 20 sown therein ~0.1 % active substance referred to the weight
of the seeds). The pots are then stood in a greenhouse for 2-3
weeks at 20-24C. The soil is kept uniformly moist by gently
spraying it with water. The emergence of the sugar beet plants
as well as the number of healthy and sick plants are ascertained.
. ~ ' .' .
- 20 -
, . . , . . ~ , .
: ,., ' :
~ 5S ~
Under the conditions of both test a) and test b), 85 %
;~ of the sugar beet plants emerged after treatment with one of
:~ the active substances 1, La, 2 or 2a and had a healthy
appearance. Less than 20 % of the untreated control plants
emerged and their appearance was in par~ ~ickly.
~` '.
., ~'"
. .
~, . .
. , .
- 21 -
" , ~, , . ., :
.. . . .
.. .. . .
