Note: Descriptions are shown in the official language in which they were submitted.
.o6449
- ` This invention relates to new chemical compounds,
pesticidal com~ositions containing the compounds as active
ingred~:ent and the use of the compounds in controlling pests.
The compounds of the invention have the following
general formula
R4 ~ N~ R3
r X=C NE~lR2
in which X is oxygen or sulphur, R3 is an alkylthio group
containing 1-4 carbon atom~, an alkenylthio group con~aining
2-4 carbon a~oms, a benzyl-thio group optionally substituted
with one or two halogen, nitro, methoxy, trihalomethyl or
methyl substituents, alko,yalkyl containing 2-4 car~on atoms
or alkylthioaL~yl containing 2-4 carbon atoms, R4 is alkyl
~~ ~ ~ 15 containing up to 10 carbon atoms or cycloalkyl contain~ng up to 10 carbon atoms, and Rl and R2 are each alkyl conta~ning 1
~ ~ to 4 carbon atoms, alkenyl containing 2 to 4 carbon atoms,
y~; ~ alkoxyalkyl containing 2 to 4 carbon atom~ or chloroal~yl
containing 1 to 4 carbon atoms, or Rl and R , together with
~ 20 the nitrogen atoms to which the~ are attached, form a
i ; ~ heterocyclic ri~g, optionally containing 1 to 4 methyl
- ~ sùbstituents attached to carbon atoms of the heterocyclic ring, -~
r(~ ; selected from morpholino, l-pyrrolidinyl and l-piperidino;
. J
and acid~addition salts formed with an inorganic or organic acid. -~
The radicals Rl and R2 can be the same or different and
when they are alkyl they contain 1 to 4 carbon atoms.
; Examples o~ alkyl groups include methyl, ethyl, propyl,
j~ isopropyl and n-butyl, the most preferred group being methyl.
When Rl or ~2 is alkenyl it contains 2 to 4 carbon
atoms an~ c~n ~è,~-io~ ë~ampie, allyl or 2-methylallyl~ When
2 - ~-
-- . `
1064490
1 2
R or R is an alkoxyalkyl radical it preferably contains 2 to ~- :
4 carbon atoms and can be, for example 2~methoxyethyl and
2-ethoxyethyl. Values of Rl or R2 when it is a chloroalkyl
` radical contain 1 to 4 carbon atoms and it is suitably
:-
substituted with a single
. ~, .
,~ ' . ..
.`'~,'
,
"~
.. .
. :
.,.'~il:
~,.,' ~ ' '
';' ~ ' '
;'
` ~ 1 ., ' '
~',~ ",
~: ~
~ ' .~
~:;~ 1 , . .
'
, "
S~ '~ ' ' ' ' .
.
'' - 2a - :
~ ~ . . . : , . . .
~064490
chlorine atom; examples include chloromethyl and 2-chloroethyl.
When the group NRlR2 is substituted heterocyclic it
can be substituted by for example 1 to 4 alkyl, especially
methyl, substituents attached to carbon atoms of the
heterocyclic ring. Such alkyl-substituted heterocyclic groups
include for example 2,6-dimethylmorpholino, 4-methyl-1
piperidino, 2-methyl-1-piperidino, 2,6-dimethyl-1-piperidino
and 2-ethyl-1-piperidino. The heterocyclic radical NRlR2 is
preferably chosen from l-pyrrolidinyl, l-piperidino and, most
suitably, morpholino.
Preferred groups of compounds are those in which
(a) both Rl and R2 are methyl, (b) Rl is methyl and R2 is
methyl, ethyl or propyl, and (c) Rl and R2, together with the ~1
nitrogen atom to which they are attached, form a morpholino
group. It is also preferred that X is oxygen.
The radical R3 is optionally substituted alkylthio,
alkenylthio, aralkylthio, alkoxyalkyl or alkylthioalkyl. When
;l it is optionally substituted alkylthio the radical can be
{~ branched or unbranched and examples include methylthio,
~ 20 ethylthio, propylthio, isopropylthio, butylthio, sec.
`i butylthio, pentylthio and hexylthio. The alkylthio group ~;;
contains 1 to 4 carbon atoms and especially preferred radicals ;
are methylthio and ethylthio. The alkylthio group can be
substituted with one or more substituent such as one or more
",
halo atoms, an alkoxy group, an alkoxycarbonyl group, an
;- alkylthio group, an alkenyloxy group or a dialkylamino group.
Examples of these substituents include chloro, bromo,
. .~:~ .
. ,~ ,
: _ 3 _
., ~ .
'' ~ ,:
i,, ,
.: "'~ :
10644~0
fluoro, methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl,
methylthio, ethylthio, vinyloxy, dimethylamino and diethylamino.
Particularly preferred instances of R3 when it is a substituted
alkylthio group are methoxymethylthio, ethoxycarbonylme-
S thylthio, methylthiomethylthio, vinyloxyethylthio anddimethylaminoethylthio.
When R is an optionally substituted alkenylthio
group it can be branched or unbranched and can be, for
example, optionally substituted allylthio, 2-methylallylthio,
- 10 prop-2-enylthio or but-2-enylthio, and contains 2 to 4 carbon
atoms. When the radical is substituted preferred
substituents are one or two halogen atoms such as for example,
bromo, fluoro and especially chloro.
. ,~ .
~1~ When R3 is benzylthio, it may be substituted with
, . ~ .
one or more substituents such as hologen, nitro, alkoxy,
, trihalomethyl or alkyl especially methyl. There are most
i~ suitably one or two substituents on the phenyl ring. Examples
of such groups are benzylthio, 4-chlorobenzylthio, 2,4-
~ dichlorobenzylthio, 2-methyl-4-chlorobenzylthio, 2-methyl-
i~ 20 benzylthio, 2,4-dimethylbenzylthio, 3-nitrobenzylthio, 2-
methoxybenzylthio, 4-methoxybenzylthio and 3-trifluoromethyl-
benzylthio.
When R is optionally substituted alkoxyalkyl or
alklthioalkyl it contains 2 to 4 carbon atoms and preferred
values are methoxymethyl and methylthiomethyl, especially
methoxymethyl.
The radical R4 is alkyl or cycloalkyl and preferably
contains up to 10 carbon atoms. Thus when R4 is alkyl it can
be straight or branched chain and can be for example
~ .. ,; .
.. -, ~ .
- 4 -
~' ''
.. . .
.-... ~
1064490
, ~,
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec. butyl,
tert. butyl, l-methylbutyl, l-ethylprapyl, pentyl, tert.
pentyl, hexyl, 1,1,2-trimethylpropyl, heptyl, l~l~et~ylpn~
2,3,3-trimethylbut-2-yl, octyl, 2-ethylhexyl, nonyl or
decyl. Preferably R4 contains 3 to 5 carbon atoms and
especially pre~erred valuas of R4 when it is an alkyl
group are isopropyl, tert. butyl, sec. butyl, l-ethylpropyl
and tert. pentyl. When R4 is cycloalkyl it can oontain,
for example, up to 8, and more especially from 3 to 7, carbon
atoms in the cyclo ring. m e cycloaL~yl group can optionally -
contain one or more substituents on the ring, for example,
one or more lower alkyl, especially methyl, substituents.
.;
A lower alkyl substituent is preferably in the l-position
attached to the cycloalkyl carbon atom joined to the imidazole
ring and when there is more than one substituent on the
cycloalkyl group they can be the same or differënt. Thus,
~, for example, values of R4 include cyclopropyl, cyclobutyl,
~; l-methylcyclobutyl, cyclopentyl, l-methylcyclopentyl,
cyclohexyl, l-methylcyclohexyl, l-methylcyclohexyl
l~ 20 containing 1,2 or 3 further meth 1 substituents such as
for example 1,3-dimethylcyclohexyl, 1,4-dimethylcyclohexyl,
cycloheptyl or cyclooctyl. Preferably, when R4 is cycloalkyl,
it contains five or six carbon atoms in the cyclo ring and
` is cyclopentyl optionally containing 1 to 3 methyl substituents
- 25 or cyclohexyl optionally containing 1 to 3 methyl substituents.
",
A particular group of compounds o~ formula I is one
in which X is oxygen or sulphur, R3 is alkylthio,
alkenylthio; aral~ylthio or alkoxyalkyl, R4 is alkyl or
cycloalkyl, and Rl and R2 are each alkyl, alkenyl,
~l 30
. _ . . . . .
` 1064490
alkoxyal~yl or haloalkyl, or Rl and R2, together with
the nitroge~ atom to which they are attached, form a
heterocyclic ring optionally containing 1 to 4 alkyl
; substituents attached to carbon atoms of the heterocyclic
ring, selected from morpholino, thiamorpholino,
pyrrolidi~yl and l-piperidino.
` An especi~lly preferred compound of formula I is one
;~ in which X is oxygen, R3 is alkylthio, R4 is alkyl, and
- and R2 are bo~ methyl or Rl and R2, together with the
~; 10 nitrogen atom ~o which they are attached, form an optionally
substitute~ morpholino group. Compounds of formula I in which the
~- 1 2
; group NR ~ is ~orpholino have the added advantage of low
mammalian toxicity.
,~ In utilising their pesticidal properties the compounds
~;1,` 15 of the invention are preferably used as the free base but
may also be e~ployed as an acid addition salt which can be
,1 formed with an inorganic or organic acid, for example
hydrochloric, hydrobrom:c, hydroiodic, hydrofluoric,
sulphuric, nitric, phosphoric, perchloric, sulphamic, formic,
acetic, trichloroacetic, oxalic ,fpf cric, benzenesulphonic,
dodecylbenzenesulphonic, p-toluenesulphonic, stearic,
flavianic, embo~ic or tetraiodophthailic acids. Such salts
are pesticidally active by virtue of the imidazole cation
~ .
content of the s lt. --
2~ We have fo~d that the compounds of the present
~ invention have pesticidal activity and can, for instance,
`!~ be used to combat insects. They are especially~use~ul in
-~ controlli~ig aphids such as, for exaimple, Aphis ~abae,
I
. !
-~ ~ 30
; ''~ ' '`' ` ' " i ' ~ . ' ~ . ' ` .
'`'' ;' ' " `: '' '~ ' ; :
~ ' `
. `'i'....... .. .
:~
~ ~ i064490
~ Me~oura viciae, Mvzus persicae, Phorodon _umNli, Eriosoma
.~ . . . .
s~ laniFerum, Brevicorvne brassicae and Acrythosi~hon Pisum.
Other insect species which can be controlled include for
example the larvae of the diamond back moth (Plutella
maculipennis) the larvae of the codling moth (Cydia
'.,?j ` ~ 5 omonella). caterpillars such as for exiample those of the
~; ; cabbage which butterfly (Pieris brassicae) and plant
hoppers such as for example the green rice leafhopper
(Ne~hotettix cinctice~s). In addition the compounds are
active against sheep blow fly (Lucilia sericata)
and~aoarids for example adults of the two spotted mite
(Tetranvchus urticae). ;~; AccordLngly the inventLon also includes a pesticidal,
preferably an insecticidal, composition which comprises
as an active ingredient a compound of the invention
together with a diluent. The diluent can be a solid or a
liquid, optionally in associatLon with a surface-active agent,
for example. a dispersing agent, emulsifying agent or
wetting -gent. ~ ~~~~
, ~
More than~one compound o$~the invention can be
20 ~ included ln the~compos1t10n. If desired the composition
`can also oontain-one~or more additional pesticides, such as
compounds known to possess fungicidal, acaricidal or insecticidal
; activity.~Exa~ples oi insecticldal compounds include an
organochlorine compound such as for example DDT, benzene
hexachloride or dicofol; an organophosphorus compound such as
f~or exn~ple fenitrothion azinphos-methyl, demeton or
dimethoate; or a~ca~rbamate such as for example carbaryl.
8xamp1es~of fungicidal compounds that can be used, include
binapacryl, beno~yl, captan and maneb.
." .; . . . ., , .. . -, . , . - ., .. .
1064490
The co~position o~ the invention can take any of the
forms known in the art for the formulation o~ pesticidal
compounds ~or ex2mples solutions, aqueous dispersions,
aqueous emulsi~ns, dusting powders, dispersible powders, -
5 fumigants, emulsifiable concentrates and granules. Such
compositions i~clude not only a ¢omposition in a suitable
.. ..
~orm for application but also a concentrated primary
composition ~nich requires dilution with a suitable quantity
or water or o~her diluent before application. Dispersible
powders and e3ulsifiable concentrates are typical examples of
such primary compositions.
As a disp_rsion, the composition comprises a compound
of the inventio~ dispersed in an aqueous medium. It is:i,
often convenien~ to supply the consumer with a primary
',r, ~ ' 15 composition which can be diluted with waterto form a
; dispersion of t~e desired concentration. The primary
composition can be provided in any one of the following
forms. It ca~ ~e a dispersible solution which comprises a
compound of the invention dissolved in a water-miscible
- 20 ; solvent with t~e addition of a ~ispersin~g agent. Alternatively
it can be a dispersible powder which comprises a compound
of the in~en~ion and a dispersing agent. A further alternative
comprises a co~ound of the invention in the form of a
finely ground p~wder in association with a dispersing agent
and intimately mixed with water to give a paste or cream
~ . ~
which can if desired be added to an emulsion of oil in
water to give a dispersion of active ingredient in an aqueous
oil emulsion.
An emulsion comprises a compound of the inventio~
, - 8
' ~ '' ' , ~ ' , ' ` ' ' ' ~ ' ' ' . " '
i;'. ' ' '' . ' ~ '
. '
"~
'
` ` ^ `' 1064490 ~
dissolved in a water-immiscible solvent which is formed
into an emulsion with water in the presence ol an
emulsi~ying agent. An emulsion of the desired concentration
can be formed from a primary composition of the following -
types. A concentrated stock emulsion can be supplied
comprising a compound of the invention in combination with
an emulsifying agent, water and a water-immiscible solvent.
Alternatively an emulsifiable concentrate can be supplied
to the user comprising a solution of a compound of the
- 10 invention in a water-immlscible solvent containing an
emulsifying agent.
A dusting powder comprises a compound o~ the invention
`; intimately mixed and ground with a solid pulverulent
.,
diluent, for example kaolin.
~ . .
A granular solid comprises a compound of the invention
associated with similar diluents to those which can be
employed in dusting powders, the mixture being granulated
by known methods. Alternatively it comprises the active
ingredient absorbed or adsorbed on a pre-for~ed granul~r
diluent for example fuller's earth, attapulgite or lime~tone
grit.
The concentration of the active ingredient in a
composition intended for direct application to the pests is
~ i
generally within the range 0.001 to 10 per ce~t by weight, ~`
especially 0.005 to 5 per cent by weight. In a primary
composition the amount of active ingredient can vary widely
.~ .
and can be, for example, from 5 to 95 per cent by weight of
the compo~ition.
f'..i
0 _ 9_
`' :', ' , _ . "
: ' ' . ::' . ' .: - ,. ',. ' .. ' ':'. '' : .'' ' : . , ' . ' . ... ..
,~ .
~ 644gO
Also included in the invention is a method for `-
i combating pests which comprises applying a compound of
; the present invention to the locus of the pests, i.e. the
pests or their habitat. A particular embodiment of this
method is a method for protecting plants from insects in
~ particular aphids, which comprisesapplying a compound o~
i the present invention to plants or their surroundings.
In controlling pests the active compound can be
applied on its own or preferably as one of the compositions
described above. Direct treatment is oiten the preferred
method by for example spraying, dusting or fumigation of
plants infested with insects. Alternatively the active
compound can be applied to the soil in which plants are
` grown as granules or as a root drench. In such instances
the active compound is absorbed by the roots of the plant
and confers protection from the insects. A preferred
`(~ applicaticn rate of the active ingredient is within the
range 0.005 to 10 lb./acre, more particularly 0.01 to
- 5 lb./acre. m e compounds of the present--invention can be
` 20 used to protect a variety of pla~ts from aphids, for
example, ornamental plants such as roses, and crop plants
such as fruit trees, leguminous crops, potatoes, hops,
. ,~,. .
~ sugar beet, cotton, maize, rice and tobacco.
~ ....... . - .
m e compounds of the present invention can be prepared
... . .
by a process which comprises reacting an imidazole of the
general formula
. . ~
,
~ 30 - 10 -
' ~, '
, ~ .. . . . . . . . . ....
' ' ` ' . ' ,
` ` ` ' ; , ~': . ~'' ',
; " . ' ` ' , ' '
." ~ ~ '
~ r~~\ 1064490
R4 N
R3 II
N
H
in which R3 and R4 are as defined above, with a carbamoyl
; 5 halide or thiocarbamoyl halide of the general formula
Z-CXNRlR2 ~III) in which Rl, R2 and ~ are as defined above
and Z is halogen, for example, chlorine or bromine,
preferably chlorine. The reaction is most suitably effected
ln the presence of an inert organic li~uid as the reaction
medium which is preferably a solvent for the reactants.
Advantageously the reaction is effected in the presence
;~ of a suitable base,for example, a tertiary amine such as
triethylamine, pyridine or alkali métal carbonate, in
order to take up the hydrogen halide produced in the reaction.
Alternatively the imidazole can be reacted with an alkali
metal hydride, such as sodium hydride, to form an N-alkali
metal derivative, before reaction with a halide of formula
III. In preparing the compounds by this route the reactants
are preferably reacted together ~t a temperature of from
0 to 120C. for example from 50 to 95C. The salts of the
invention can readily be prepared by treatment o~ the
product thus prepared with acid by wellknown methods.
The imidazole compounds of formula II in which R3 is
;~; optionally substituted alkylthio, alkenylthio, aralkylthio,
alkoxyalkyl or alkylthioalkyl and R4 is cycloalkyl or alkyl
containing more than one carbon atom are novel compounds.
?
~`.` :'! : .
- 30 - 11 -
,. ~
:, ~ , ~ . . . ' .
" . ,' " ' .' . . ' ' ' ' ',' , . . '~ ' ' ' , . . ' ' .': " .
~ `` 1064490
Compo~nds of formula II in which R3 is optionally ;.
, substituted all~ylthio, alkenylthio or aralkylthio can be
.~: prepared by, for example,-reacting an alkali metal
; thiocyanate wiih an appropriate aminomethyl ketone of the
general formula
`~. R4CoCH2NH2 - '
~ to give a ~hiol of the following formula
:............................. 4
R I _ N
~ IV
;~ 10 ~ N - SH
H
; which in its turn, can be alkylated, alkenylated or aralkyl-
ated according to well known methods to give compound~ of
formula II. Alternatively, compounds of formula II in
t~ 15 which R3 $s optionally substituted alkylthio, alkenylthio or
aralXylthio can be prepared by reacting, in the presènce of
alkali, an a-hialo~etone of the general formula R4CoCH2Z in
, "
which Z is a halogen atom with an S-alkylisothiouronium salt
of the followi~g formula
~ ~3 ~ ~
. H2N-C=NH2 A~ :
. .; ~ ,
in which:R3:is as defined immediately above and A representJ
a suitable anion, for example,sulphate or halide.
Those compounds of formula II in which R3 is optionally
substltuted aIkoxyalkyl or alkylthioalkyl can be made by,
: : for example, condensing an aldehyde of the general formula
:: i ::
R3CHo in which ~ is optionally substituted alkoxyalkyl or
alkylthioalkyl with an acyloxylated ketone of the general
formula R4C ~ ~ in which B is acyloxy, in the presence of
` ammonia.
. - 12 -
: ` - . ~ , : . . .
.. . .. . .
, " : , ,
, . . , . , ,`, ' ' .
` - 1064490
Carbamo~-l nalides or thiocarbamoyl halides of the
~enerai formula III can be prepared by reacting a secondary
amine of the general formula RlR2NH with a carbonyl halide
or thiocarbonyl halide of the general formula CXZ2 in which
Z is halogen, preferably chlorine, in accordance with
known methods.
The compounds of the present invention can also be
prepared by a process which comprises reacting a carbamoyl
halide or thiocarbamoyl halide of the general formula
~ 10
" ~ R4~1_R3
CXZ
in which R3, R4 and X are as defined above, Z being halogen
~l 15 preferably chlorine, with a secondary amine of the
; general formula RlR2NH, Rl and R2 being as defined above. m e
;, compound of formula V can be prepared by reaction of an~hl
~ imidazole of formula II with a carbamoyl or thiocarbamoyl
. . . ,, _ . . .
halide CXZ2 in which Z is halogen.
., ., ~ .
; 20 In a further method of preparing the compounds of the
~ invention a carbonylbisimidazole or thiocarbonylbisimidazole
sl~ of the general formula
.~ X
R ~ ~ 3 ~ ~ VI
, , ,
in which R3, R4 ard X are as defined above, can be reacted
with a secondarg amine of the general formula RlR2NH, Rl and
.,
;~ R' being as defined above. The compound of formula VI can be
prepared by reacting an imidazole of formula II with about
- 13 -
`` ~064490
0.5 molecular proportions of a carbamoyl or thiocarbamoyl
halide CXZ2 ~ n which Z is halogen.
It will be appreciated that the reactions described
above for the preparation of compounds of formula I may
give either or both of two isomeric products, depending
on which nitrogen atom in the imidazole ring is substituted
(the free hydrogen of the imidazole molecule of formula II
can be associa ed with either-of the ring nitrogen atoms).
m e products of t~e present invention may conveniently be
~ 10 designated as l-(N,N-disubstituted-carbamoyl or -thiocarbamoyl)-
-l 2-R~-4(5)-R4-i~idazoles and this designation corresponds to- --
formula I which e~compasses both of the isomeric forms. The
current state of our knowledge indlcates that the solid
products of the reactions described above, after purification
,. 41, 15 by conventiomal techniques such as crystallization, are
obtained in ~a~y instances as substantially pure
~ 4-substituted compounds. Our knowledge also indicates; that the liquid products of t~e reactions described above,
after isolation ~y conventional techniques such as
~ 20 distillatio~ i~ vacuo, are obtai~ed in many instances
-, predominantly i~ the 4-substituted isomeric form. Such
4-substituted isomers may be designated as l-tN,N-
~ disubstituted-carbamoyl or-thiocarbamoyl)-2-R3--4-R4-imidazoles.
; m e iollowing examples illistrate the invention.
.. . . .
Where the physical properties of compounds are tabulated,
a solid is characterised by the melting point and a li~uid
.
~ by its boiling ~oint.
. . I .
. '
14
' " '
~, . .
, .. . .
.. : . - . . . . , , ~
. ! ' ~, ' , , : '.'. . , , ' , ,
'. ' ' ; ,.
:'', , ' ' " . ' :'.' .
'. ,. ' , . ' , . ,.. ' ' ' ~ ` ,: .
':' ' . ' ' , ., ,. ' , ~ , : . ' ,
~'' ' ' '.' "''." .
,
-- ``1064490
This example illustrates the preparation of compounds
according to the invention. -
5.1 ml. DLmethylcarbamoyl chloride in 20 ml. dry -
dioxan was added to a mixture of g.2 g. 2-ethylthio-
4-tert. butylimidazole and 8.4 ml. triethylamine in 30 ml.
dry dioxan. A~ter heating the mi~xture on a steam bath for
24 hours, the triethylamine hydrochloride was removed and
the product, l-dimethylcarbamoyl-2-ethylthio-4(5)-tert.
butylimidazole, distilled. It had a boiling point of
108-111C. at 0.10-0.12 mm. Hg. pressure and on cooling
; crystallised to a solid with a melting point of 45C.
The Z-ethylthio-4-tert. butylimidazole employed in the
above reaction was prepared in the following w~y.
i
104 g. Po~assium phthalimide was suspended in a
solution of 100 g. bromopinacolone in 300 ml. dry toluene.
is reaction mixture was stirred on a steam bath for 18
~'
`,~ hours and the solid precipitate filtered off and washed with
toluene. The washings were added to the filtrate which was
I ~ 20 heated on a steam bath to concentTated. The product, 3,3-
; ~ dimethyl-l-phthal~midobutan-2-one, crystallised out on cooling.
It wa~ washed with light petroleum (b.p. 80-100C) and its
... . . .
,,
meltlng point was 97-101.5C. 82.6 g. 3,3-Dimethyl-l-
phthalimidobutan-2-one was refluxed for 10 hours with a -
mixture o~ 465 ml. concentrated hydrochloric acid, 400 ml.
water and 324 ml. acetic acid. The mixture was
evaporated, 360 ml. water were added and the solution
", ~ ' ' .
. .,~ .
~ 30 - 15 -
-", ~
- -- ` 1064490
chilled in ice. Phthalic acid was filtered off and the
solution again evaporated, the residual solid being dissolved
in warm absolu~e alcohol. Ether was added to the cooled
solution and l-amino-3,3-dimethylbutan-2-one hydrochloride
precipitated as product, m.p. 199-200C.
35.2 g. 1-~mino-3,3-dimethylbutan-2-one hydrochloride
and 30 g. po~assium thiocyanate in 50 ml. water were
heated on the steam bath for two hours. After cooling,
k1 the solid formed was collected washed with water, dried and
recrystallised from industrial methylated spirit to give
4-tert. butyl~inidazole-2-thiol, m.p. 232-234C. A solution/
suspension of this material in industrial methylated spirit
was added to a solution of 4.5 g. sodium hydroxide in 100 ml.
water. 17.6 g. Ethyl iodide was then added and the mixture
was shaken for twenty minutes. The resulting product was
neutralised by passing in carbon dioxide and the methylated
spirit removed by evaporation. The solid was collected,
-I washed with waier, dried, and on recrystallisation from
toluene gave 2-e~hylthio-4-tert. butylimidazole, mp.ll6.5-120C
EXAMPLE 2 f
.' ! .
` This example illustrates a method of preparing l-dimethyl-
carbamoyl-2-methylthio-4(5)-tert. butylimidazole.
~. 1
1.2 g. Sodium hydride in mineral oil (50 per cent disper-
; sion) was added to 3.4 g. 2-methylthio-4-tert. butylimidazole
in dry tetrakydrofuran. When the evolution of hydrogen had
~ ..
!
.. . . .
1 ~30 - 16 -
~ . . .
. ., . ~ .
,, . ' ' . , , : ,, ... ' ' ~ . ' . .
`` 1064490
ceased, 2.7 g. dimethylcarbamoyl chloride was carefully -
- added. Hea~ was evolved and a precipitate formed. After aperiod of ~n hour the solid was removed and the product
distilled. It was l-dimethylcarbamoyl-2-methylthio-4(5~-
tert. butyli~'dazole, b.p. 107C. at 0.07 mm. Hg pressure.
The imidazole reactant used in the above preparation
-~ was prepared in a similar way to that of 2-ethylthio-4-tert.
butylimidazole described in-Example 1.
EXAMPLE 3
This exa~ple illustrates a further method o~ preparing
~ compounds according to the invent~on.
;-1~ To a stirred solution of 11.3 g. 2-methox~methyl-4-tert.
_s : butylimid ole in 30 ml. tetrahydrofuran and 20 ml.
triethylamine was added 8 g. dimethylcarbamoyl chloride.
The result~g mixture was boiled under reflux for three hours
i. .
'~ and then diluted with methylene chloride, washed with water
:i - .
, and the methyle~e chloride solution then dried over
magnesium su~phate. Evaporation of the solvent left a
~, residue which distilled under reduced pressure to give the
;
product, 1-dim~hylcarbamoyl-2-methoxymethyl-4(5)-tert.
butylimidazole, ~.p. 106-108C. at 0.1 mm. Hg pressure.
, ,~ .
`~ m e imidazole reactant used in the above preparation' t~ :
was prepared i~ the following way.
To a solution of 123 g. potassium acetate in 1200 ml.
methanol was added 143 g. bromopinacolone. This reaction
. .
mixture was re~luxed for two hours, then cooled and filtered.
The filtrate was added with stirring to a solution of 320 g.
- 17 -
" ,. ~ .
.,: . . ....
I, ' .'
""',.'' .. "' ,'' . , ' .,.. ' " '. "' "'.; '. ~. '' .. ''." " ' ; ' ', ,' ', .-
-`` 1064490
cupric acetate moni~hydrate in 1600 ml. 25 per cent ammonia
and 1400 ml. water, followed by addition of 100 g. 77 per
cent aqueous solutions of methoxyacetaldehyde. The temperature
of the reaction mixture was maintained at 30-40C. for an
hour and the mixture then heated on a steam bath for a
iurther four hours. After cooling overnight, the insoluble
copper salt was collected, washed with water and suspended in
500 ml. of 4~-acetic acid. A solution oi 133 g. po~assium
ferricy~n7de in 400 ml. water was added and the precipitated
copper complex removed and washed with water. m e combined
supernatant liquors were basified (pH. 9-10) with 5N-sodium
hydroxide a~Zid extracted with ether. m e ethereal extracts
were combined, washed with water and dried over magnesium
sulphate. rne solvent was evaporated and the residue re-
crystallised from petroleum ether (b.p. 60-80C.) to give
,
the product, 2-methoxymethyl-4- '~ert. butylimidazole, m.p.
- 65-66C.
The iollowLng compounds were prepared in an analogous
manner.
1-dimethylcarbamoyl-2-metho~methyl-4(5)-sec.
butylimidazole, b.p. 108-110C./0.01 mm.
1-dimet~ylcarbonyl-2-methoxymethyl-4(5)-(1-methylcyclo-
ii ; pentyl)imidazole, b.p. 132-134C/0.2 mm.
,1~ 1-morpholi~ZZcarbonyl-2-methoxymethyl-4(5)-
(l-me~ylcyclopentyl)imidazole, m.p. 150-152C.
i; l-(N-meihyl-N-ethylcarbamoyl)-2-methoxymethyl-4(5)-
tert.LZutylimidazole, b.p. 112-114C/0.2 mm.
: . `1
~1 l-(N-met`Qyl-N-ethylcarbamoyl)-2-methoxymethyl-
~!
~-1 4(5)-sec.butylimidazole, b.p. 116-118C/0.25 mm.
,;~ ., .
~i ~ 30 - - 18 -
.~., ' ~''
. ~. .
. i ... . . . .. . . " .. ,, .. . - . : .
. i , ., . . : ~ . . . . . . . ~ .. - ., , - . . .. ~ .
, - , : ., , ,, . ~ ... . . . : .,
~ ' 1064490
l-dimethylcar~amoyl-2-methoxymethyl-4(5)-(1-ethylpropyl)-
imidazole, b.p. 118-120C/0.1 mm.
dimethylcarbamoyl-2-methoxymethyl-4(5)-(1-
me~hylcyclohexyl)imidazole b.p. 145-146C/0.1 mm.
i-dimetnylcarbamoyl-2-methoxymethyl-4(5)-tert.pentyl-
imidazole, b.p. llSC/0.2 mm.
l-morpholinocarbonyl-2-methoxymethyl-4(5)-tert.
' O
~ .
~''r - pentylimidazole, b.p. 1~8-140 C/0.1 mm. -
51' 1-morpholinocarbonyl-2-methoxymethyl-4(5)-tert.
butylim;dazole, m.p. 57-58C.
~, The following intermediates were isolated in the course
-i~ of prepari g the above compound~.
.~
2-methoxym~thyl-4-sec.butylimidazole, b.p. 122-124C/0.6 mm.
2-methoxymethyl-4-(1-methylcyclopentyl)imidazole,
b.p. 126-128C/0.~ mm.
2-methoxymethyl-4-(1-ethylpropyl)imidazole, b.p.
126-128C/0.2 mm.
2-methoxymethyl-4-(1-methylcyclohexyl)imidazole b.p.
142-144C/0.5 mm.
r 1
2-methoxymethyl-4-tert. pen~ylimidazole, b.p. 116-118/
0.4 ~.
~ r ~ 25
` ~ '
. -!
' ~J~ ~ :
. j~ .:
- 19 -
~:: '` ' , , ,
. .. , ~ .
'~ d 1064490
~, h
J ~
h
:'
.~ .
: h
- a 0 ........... ,~ ,~
,. ~ ~ O ~ Ei ~
~ ~ O O O O O
;~ a) ~ ) V O O O 1-l ~) V
~ O O O O V O
O ~S ~ ~ D CD O O O O O O C~l
1 llS V V V r-l lO V ~ C~l ~ ~ ~ ~ N C.) ~ V CU
X cq~ ooo.-1oo,1,Iv~vV,1o,1o~1
Oq I!`~r-lI~)~IIOOOOI~Drl~l
~1 1~ ~ 1~ J ~D ~O ~1 ~ ~ O a~) 11~ ~O 1!` 1 ~C) O
H 0 O I I I ~1 1 1 ~ C~l O O O r l ~1 1 ;1' I C~l
q~
s~
~ o ~l ~l ~ ~l ~ ~l ~ ~l o o o p~
~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~l ~l o o o ~
, J ~ Q ~ ~ ~ oP~ ~oi
j ~ ~3 o ~ h
. ~ ~Jh h h h hh h h c> oo O 0 ~ 0
~; o ~ ~ a a) a) a a) ~ a~ 0 ~Q tq I I I I
. 1 . ~i ~ ~ o
l . o ~
:' 0 ~ S
~ o
O O ~ S O O O l
O' ~ S O ~ O rl ~ O
g E03 ~ S h ~ ~ ~ S ~ ~ ~ ~ ~ ~ S
, .'1, .,1 0 ~ ,1 o ,1 ,1 o ~ ~ ~ ~ ~1 ,1 ~ ,1 ,1 ~ ,~ ,
0 ~ ~ o o ~ o~ ~ ~ ~ ~ s 0~ ~ s s ~ ~ ~
H o ~ ,~ h ~; _1 0
.,~ j ~ 0 ~,1 ,,1 ,
~ _I h xl ~ ~ S ~ ~ ~ S S
O 0 0 a) a) a) ~ a~ a) a) Q) a~ ~ ~ a) a~ a~ a) a) a-
! ~ ~ ~. e
~ ~rl
' 0 ~ +
; ? ::
. .,"~, . . .
i,, . ~, , . C V --
,.., ~
1064490
. i .
! :
,1 o ,1 _I
. . - E~ '
~ a~ o o o o ~ ~ '
.: . 0 ~: C> V V V ~
., ~ 0 oo o o ~ ~3 - '
." ~ ~ 0 0 ~ 0
- Oq ~ ~ ~ ,~ ~ æ X
~1 ~,1 o ,~
,` 0 II ~ ~ I I 1 0
o ~ O cr~ o ~ ~
~ ~n~,~ ~ J ,1 ~ _I ~
: P~ ~ -- 'd ~ ~ ~ o
~S --I ~ --I h N
0 0 ~C) ;~'
I o o ~ I 0 ~1 a) c)
I ~ ~ ~I H p~ _1 0 ~ 0~ C~ Oc~ O O
0 O ~ ~1 0 0 ~ V
V ~ ~1 ao o o o
., ~ s~ ~ ~q I o I I o~
s~ ~1 ~ o a~ 1 o o
a) 3~ 0 I r-~
,~,, p, o I ,1 ~1 ~1 ~1 ~ ~1 a~ r` ~
,' ~1 0 - H ~ rl _ _
~t . r~ l H h a~
oP' ~ $ ~ ~
X r I ~ o o o o o o o o ~1 o ~1
3 ,~ O
~ . ~ O ~ O ~ , "
~ : ;~ a) ~ ~ E ~ ~ ~
'"': , 1~ ~1 $ 0~ 1 ~ $ 0 P.
.1 h ~
,j 0
. I 0 0
O C~¦
0 q~ ~ $ ~
~D g J~
'"7 0 0 0 ' O 0 0~I ~1 , -
N 0 S l h h h h h ~ ~ O O O
. I S~ ~ ~ 0 h a) o ~ t O ~>
~ S ~ <~ ~
~1 P a~ ~ O q~
"' 1 Ei a) ~3 ~3 6 ~ ~ ~ l ,~~ ~ o .~S~ .,O~ o ~ o
x ~ a~ a~ ,s:: O ,s~ h ~1 H S --IS S
5 ,~ ~t h ~ ~ P, S ~
,1 ,1 ,1 ,1 ,1 H E E~ ~ ~1 o ~ ~1 o +~t ~ ~ ~ ~I r~l
h h ~ ~P. h ,1 ~ ~ ,1 ~. :~.
~1 ~ ~ ~ S S 5' ~D (> P: N S P. S ~ ~ J ~ S P-
,' 1: PC ~ ~ ~ ~ +' ~ ~ U~ ~ O O ~ O -1 P. .0 S ~t o
Q) 0 ~ Q~ 0 0 I h a> 0 H ~t a) h
E E3 E E Ei H ~ ~ ~ P. El ~ 0 ~: SS
. .~,
!
j , :
:-
t~ 21 -- .
! ,~ .
','i . , '~
' " "' " ' '""` "'' ' ' ' ,' ' ' "`' '~ ''' ' ';' ~ , '' ~ ""'" ' '` ''
, '
10 6 4490
.~ .
...
` ~
~;. $~ o~ o~oV C~
. j ~ . . o . ~ 0 o o . o
a~ V V ~ V ~ ~1 ~ ~I V
o o ,1 o o ~ ,1 ~ o o
, ~. ~ 0 0 I Ll~ ~ I I ~1 0 ~1
. ~ .~1 ~ ~ a~ ~ ~ I ~ 0 I c~ I
. ~ o I I C~ o ~ ~ o
. o v ~ ~ _, ~ o ,, ,1 ,1 o~ o
.,.,, ~q~ ~ ~ ~ o ,
~: 0 ~ ~ ~
i~ oo~ o~oooo
. ! x x x
. Ii o o sO ,,
1, ~ - o~ o~ ~ s ~ ~ ~
,, h h ~ ~ ~ S ~: O ~ f
j ~ ~ ~ DO~ h ~ ~
~;
'~'i.; o l o ~ ~ o o o ~a o ~ ~.
I S ~: --I S
: /
22
`. ', . :
. ,. , . , . . ~ . . ' , . , '.. , - . . ' ., ,.:. ' ~ . . ~ .
' " ' " " . ' - ~ ~, ''.. ' . -. ' ' ;; .;.; ' . . ' . . ' . .. .'. '~ . . . '.,
",, . . ' ' . ', ' ~ , ., , ' ' ' 1, , ' . .. . .. ~ .. ', ' ' , . , - ' . ~ , '
, . ,.. . ;.;~
' ' . ', : ' ' ,' '' . .'~ "'' . ;" " . '. " . ~ ' - '.
064490
Intermediates of the formula IV were prepared in
: a similar way to that described in Example 1. :~
. 4 Physical State
R _and Constant
sec. butyl solid, 109-112C.
. isopropyl solid, 147-150C
;~ 5 l-methylcyclohexyl solid, 205C.
.~ l-ethylpropyl solid, 171C. ~ -
. cyclohexyl solid, 260-261C.
l-methylcyclopentyl solid, 182-183C.
tert. pentyl solid, 174C.
'.. . ~ 10
, . .
,, ' . .
; t
; !
.'1
.: : : ; ` : ''
: ~
.','~i, ~ ,f , .,
~,` j~:, . .
~ 20
, "~, ~
"~
: - 23 _
. , .
, . , . ~ , .
----' 1064490
,~
a~ . . . . . ~3 . .
C~ ~1 H r I O ~ l N ~1 ~1
0 0000 0 ~O`O~OO
32 G) ~ ~ ~ J~ ~3 ~ ~
. . ~ ~ V V V ~) OV LO C~ ~ ~I V V
,j ,_ 0 S:~ O O O O ' O O O O O
~: ~ 0 ;1 c~l ~0 ~ O CD -1 0 a) o ~ ~o
U~ ~ CU O C~l O V ~ V 1~ V ~ ~ ~D ~ N
E~ oq ~1 ~~ ) O ~1 0 V ~I r~ V ~~1 ~1
I I I I ~ V O O I ~;t O I I o
X al o ~I O J ~ 0 0 C~ D J ;1' 0 ~)
X ~ S~ 0 0 ~1 0 ~I J r~
'-" ~1 --I ~1 ~1 ~1 0 0 _I O rl O rl rl _I _I _I rl
' h
0
2 N P~ h
~ h ~ h h 0 S~ ~3 0~, ~7 ~ h e
O ~ 1 o o ~ ~ ~, o u~ oq o~
C)
.",,~ ~ o O
E3 h S ~ :~
O O X O O O O O O ~
rl O ~ rl O ~ 1 0 ~1 0 0
0 o ~ S .~S, ~ ~ -Sl ~ S .~S, .~,S, ,~ S ~ ; S .¢
~, . i rl 0 ' ~ 'I 'I I ~I ~ ~I ~1 ~1 ~1 ~ ~I S S O ~ ~
: ~ ,D 0 ~ h ~ ~ h ~I P.
~: h ~ P S I ,s~ S P :~ S a> ~D P~
. , ~ ~ 0 ~ O ~ ~ ~ S ~ ~ ~ O ~ ~ E~ E3 0
o h 0 ~ o o 0 h :~ (O I 1 0 ~
H 0 ~4 E3 ,CI 13 a) E~ E3 E~ Pl . E~ I 0 ,0
~0
., ~ ~ S ~ S~ S~
.. j q I ~1 h cr:l ~ ~ ~ ~ S O ~ ~ ~ ~ ~1 ~ ~ ~ ~ ~
o o 0 o ~ 0 ai ~ h o oa> a~ ~1 0 a~ ~> o o ~-
S ~
l~:: 0~ l s~ s s~ s~
:~l v ~
; ~
' ':' -- 24 --
'`';
.
` - 1064490-
. .
. '.
. . ~ , . ..
. . ~o
. $~ o ~ ~ ~ ,, ,, o rl ~ ~ ~ ~ ~ ~ ~ ~ ,,
. ~d~ OO O O-OOOOO OOO O OO O
. ,
~Q~ V V o V V V V V V V V V V V V V V
. o~ ooo o ooooo ooo o oo o
. ,I s:: Cl~ o cu ;~ O ~D N O O N c~l O O 1
O ~ C~ ~ V ~ V C~l ~ ~ ~O ~ ~ ~ ~ ~ U~ ;~ U~
O V~1 ~I V ~1 0 r1 0 ~1 ~I r-l ~ ~1~1 ~1 ~ ~1 ~1
. _lI I O I O~ I ~ I I I ~ I ~ I I I I I I
v~d Ir~ J O O C~ 0 ;t O O OO O ~D 0 In ~ o
.'~; .
?' ,1 i~
- ~. o al a> o ~ o _ I ~ ~1 ~1 ~1 ~1 ,1
o --I ~ O ~ O ~'
o o o ~ h h ~ h h o
0 ~1
s~ 3 ~:
~ I ~ I ~ h O a) P~
s s ~ ~' r s ~ ~ O ,o~ ~ ~ ~ ~ s ~,' '~ ~ .S:
~; ~ S ~ i ~ S S p S S ~ o
.~ e e ~ e e e e e e e a~ ee e El ~i e e
0 a) c) 0 ~ ~ a) ~ a) 0 a~ 0 ~ 0 a) a~ 0 a~ ~
e e ~ e e e eie e ~ 6 e e e e ~ 6 e 6
.
. .
`~ 25
~. , .
.' , ' ' ~ '
' '. ' . ' " . ~ " '' ~ ' ''
' . ' ~' ' ' ' ' '' '~' ' ' ' ' :
lOG4490-
. .
..
~ ~ .
a) o
h N
a~
p~
p,, ~ 0
~ U2 ~ 1
~ ~ ~ O C~ O
~1 S a~ o o o o o
. a) ~ o v .
~ V ~ V V
+~ V ' O ~ V V O O O
O O O O O ~ 0 0
C ~ u~ v v c~l ~1 ~I v ~ rn ;~- 1~ v v
~1) ~ 1~ O O ~1 1~ 0 0 O ~ ~-1 ~ O O
a1 ~ 0 ~ V o ~ I ~ ~o o o ~ ~ ao u~ ~ V ~O
I I I O O rl O O I 1~ 0 ~ 1~ ~ Ir~ I O
O O 1~ 0 -J ~ ~I r-l ~ O 0 ~1 ~ ' O ~1 _~ ~ O ~O 1
~ ~ ~ o o o o o ~ o o o o o o ~ - ~ ~ o o o
' ,i H C~l
. .. 0 ~ :'
~1 0 - .,
;... ' ld 'I ,So ,sO r-l
0 0 ~ ~1~ ~ o o p,
0 0 S: ~~ .0 ~, ~ O P ~ ~ h
h 0 ~ :~ ~1. X X ~ rl X ~ ~ ~ +'
'' i 0 ~1 :~. ~ o o ~ ~ o
~ 0 h 0 ~ >, 0o o o o o o ~
h ~ 0 ~ ~:4 ~ ~1 o o ~1 ~1 o ~ q oo ~ _I ~1
0 0 f
O
. .~ N ~
.~ 0 0 ,
,c~ - .:
. ~ ~
~i h
~0 0
~ o ~ ~ ~o
q~ o o o ~l o o o o ~ o o o
~:
a) ~ h 0 ~ ~ ~ ~ ~ ~ ~ ~ h P
0 ~ 0 0 p,
E~ O ~ ~ ~ ,S ~ ~ O +~ 1 0 ~ ~ .C O
~: -1 X h 0 :~ 0 ~ 0 0 h ~ o 0 ~ h
H oq ~ P, ~ Q E; 0 ~ 1 rl 0 ~ p, ~ P.
.
:`
. . .
26 -- -~ ~
: ~ 1064490
't
. _ , .
.
.
$~
: `; $~
.
.. '' ~ o
1' ~v
,,
,.~`,, o C~ . V -. ...
o o o O~ Oi ~ ~ Ov Ov J
,: O ~ ~1 ;~ ~1 ~1 0 ~O I
:~ ~, O O O O O O O O O ~
`;'~' ' :'''
~:~ $ :~ ~ ~ ` :
X
~ ` 0 1 1 ~D 0 0 0 a~ 0 a
.~ '~ 5 -1 ~1 ~ ~ ~ ~ ~ ~ ~a
;: '.7,
~"` `t'' '''
O ~ O ~
",: 0 ~--1 0 0 0 0
~xl o e o~ 0 o~
O O O O ~Q O ~ 7~
S ~ ~ S 0 S ~ ~ ~ S
; t, ~ ~ S~ S E0
,., '! ~ ~ O ~ S ~ O ~ O
e E3 7P~ ~ ~0 ~ I I I I
,,
. ~,
- ` - 27 -
. ..
`
`
"` ~064490
Inte~edia'es of the ~ormula IV were prepared in a
similar way to ~-hat described in Example 1.
:.......... ,
~ Physical State
R and Constant
. ~ .
ethyl solid, 163-165C.
propyl solid, 183-184C. : : -
methylbutyl . solid, 88-90C.
.~ isobutyl solid, 185-186C. ~
, methyl solid, 246C. .
l-ethylpropyl solid, 171C. . :~
` 10 , ,
.,. . ~ .
.; . .:
:
" " ~ . .
~, .
:, . .
-: : 20
~ 25
1:
.,~1 :
! ' 'i
. ' I .
~ . . .
:~ , ' .
- 28 - ~. -
.. ...... . . " . , - .,. .- .. . . .... ., -, .. .. .... .... : .. . - .. .
.: , . , :
, . . . . . . i :,: .: " ~: ..
.
~-` 1064490
EXA~
This exa~ple illustrates the preparation of compounds
according LO ~e invention
1.8 ~. ~odium hydride in mineral oil (50 per cent
dispersion) was added gradually to a solution of 5.4 g.
4-isopropyl-2-methylthioimidazole in 30 ml. dry tetrahydrofuran.
After a pe-iod of 30 minutes 5.05 g. morpholinocarbonyl --
chloride was added. Heat was evolved and the mixture
refluxed ~or an hour. The tetrahydrofuran was filtered
and evaporated to give a residue which on crystallisation from
, ~ ~ petroleum ether ~b.p. 100-120C.) gave the product,
l-morpholinocarbonyl-2-methylthio-4(5)-isopropylimidazole
m.p. 63-65C.
j~ The imidazole reactant used in the above preparation
. ,~ . .
was prepared i~ the following way.
126 g. 3-~Iethylbutan-2-one in 600 ml. methanol was
treated with 74 ml. bromine which wa~ added dropwise at
o
~` ~ a temperature of about 10 C. The solution was quenched on
ice and the bromoketone then separated and washed with water.
The aqueous liauors were extracted with three 50 ml. portions
of petroleu~ ether and the combined bromoketone and petrol
portions added ~o 216 g. potassium phthalimide in 500 ml.
dimethylfo~amide. The mixture waæ then heated with
j .,
~ stirring on a steam bath for two hours then filtered to
.~ .
remove i~soluble matter and poured into three litres of water
with stirrinb~. The solid was collected, dried, and
: I;
recrystallised from industrial methylated spirit, 3-methyl-1-
i phthalimidoouuan-2-one, m.p. 98-99C.
~ ~ 30 - 29 -
.. . . .
. , . , . . ~ .
,
" :' , ' ' . ' : ~. , '
'' ' - ' ..
' ' ,: ' ,
, . : '
1064490
176.3 g. Of the phthalimidoketone was refluxed for 20
~ hours with a mi~ture of one litre of concentrated hydrochloric
- acid, 1020 ml. water and 710 ml. acetic acid. The solution
was evaporated and the residue taken up in 800 ml. water.
After separation o~ phthalic acid, the solution was
-il evaporated to dryness. The solid was air-dried to free it
~~ from excess acid, l-amino-3-methylbutan-2-one hydrochloride, -
~ m.p. 155-158C. -~
- An aqueous solution of 98.8 g. of the aminoketone and
-i
- 10 63.6 g. potassium thiocyanate was heated on a steam-bath
for 2~ hours. The oil which deposited solidified to give
3i 4-isopropyli~dazole-2-thiol, m.p.147-150C.
, .
~ A solution of 6.16 g. potassium hydroxide in 50 ml.
. , .
; industrial met~ylated spirit was added to 14.2 g.
~ 15 4-isopropylim;dazole-2-thiol in 150 ml. industrial methylated
.. ... .. .....
spirit, followed by 15.6 g. methyliodide. The solution was
refluxed for 1~ hours and the solvent then evaporated. After
treating the residue with water the remaining æolid was
collected ~nd recrystallised from ethyl acetate. It was
2-methylthio 4-isopropylimidazole, m.p. 96-98C.
e following compounds of general formula I were
:. ,. - .
~. 3; prepared in an analogouæ manner.
.
~' 25
~, .
- ,
- 3 -
.~, -:.
: ~ :
~ -~
. E E ~ ~ E u~
O O O O 0.0
, o
:~' . 0 ~ u~ oV oV ' oVll oV oV oV
'; ~ 0 ' ~ 0 ~ ) O U~
~ . u~ ~ V V J J V V O a~ V ~ V V ~ V C~l V V ~) V J J
'.. . Oqo o ~ ~1 0 0 ~1 ~1 0 0 0 ~1 0 0 ~1 0 0 0 0 0 0 ~1 ~1
;~ .~ C~J O I ~ > O I O t~J 11~ 1 ~D ~D I ~ ~1 ~I 1-~ ~1 ~ I I
:~ 0 o ~ n O C;~ O 0 C' 1!~ ~ J ~1 ~ I ~ ~ ~
~ ~ . ~ V O O~ O J 1 0 0 1 1 ~1 ;1 J 1-l 1 8 o ' o~ ~ ~ ~
O O o --I o o o _I o o o ~1 o o rl o o o o o o
,_
,,:~,
!'
: '~ . O ~I
;~ S S ~1 ,D ,0 ,C~ ,n ,c~ O O ~
- j h h t~ S~ o o S - El O o o o o o o h ~ o o o 0 0 0
h a~ 0 C~ 0 0 a~ ~) 0 oq i ~q oq oq I I
: !
',l' :
. . , ~
;, ~
. ~, . .
s
~ ..
: t O O r~ O O O O O ~ O o O O O
S ~ ~ ~1 s: ~ ~ ~ ~ ~ l ~ 'I ~ ~
X ~ ~ S~ ~ X ~ ~ X 0~ ~ X ~ X ~
D S ~ S ~ ~ ~ ~ ~ ~ ~ S :~ S ~ ~ ~ ~-
0 ~3 ~ ~ ~0 ~ ~0 ~0 ~ ~ h 6q O 0 ~ 0 ~ ~ 0 ~ h
~; ~1 ._
'i OOOOOOS~OOOOOOOOOOOOOOOO
.. j V 0 0 ~d 0 G~ 0 ~1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
; O O O O O C~ ~ O O ~ O ~ C) O ~ O O ~> O O O O
. ~ S ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
' ~ O O O O O O ~1 O' O O O O O O O O O O O O O O O
S S S S S ~ O S ~ S S S S S S S ~ ~ S S S S S
` :~ O O O O O O ~- O O O O O O O O O O O ~ O C) O O O
~ .
:~ .
.~ .
-- 31 -- _ .
;~ , = _.. . , =, . .. . .. .. . .
.~ .
, : . .. .
~ .
.. . . .
.
:: . :; . . . ~ . ~ ,, ,.,.. `
.- . ~ . .
. . . . . .
. ~ , . . . .
,~ . . .. . .
, ' : ' . .
~` 1064490
.: :
.
.
o o o o
~ ~ ~
V V V V
~ o o o o
CQ ~ ~
;~ V V ~ C~
~ ~ ,1 o o V ,, ,1 o ,
0 o I ~ ~1 o I I I
OV ~ ~ ~ O ~
;~ I I ~ ~ ~ I ~D
~ ~ ~ o
:~ ~ OD ~ u~ ~D
s 0 0 ^ - ^
P~ ~ ^ ^ ~.~ ^
_~ o o o _I ~ o
.
,,
., . ~, .
.: .
.. ,, o
~, ....
P~ o ~ ,1 ,1 ,
o ~ ~ ~ ~ ~ --
. h O
J
., .
~ s ~ ~ ~ ~ ~
.i a~ ~ E3 h h h h O
I a.) I ~D a) ~ ~ a
. 1 - .
" ' O
,., O
,' j S
., ,~, o ,.
` _l _l ,~;,
.i . ~ +S, ,~, ,.
a~ ~1 a>
.':`: I ,~ ~ . , :'. . .
O ~ O O ~ O ~1
. ~ .S S S S: h S
;, O ~ ~ ~
, +, .1~ .~ -~ O ~ S ~ .:
, ~
., X
.,~ V ~1 ~1 _I ~1 ~1 ~1 ~1 ~1
Z ~
D: O O O O O O O O
~ ~ ~ ~ ~ h
- ~ 0 0 ~ a~ 0 0 ~11
'~, O O O O o o O o
'' , ~0 ~0 ~0 0~ ~0 ~0 ~0 0~ .
OOOOOOrlO
" ~ ~ S 5 S S
! ~ h ~ ~ ~ h P,
'"`: ' OOOOOO~O
E3 E~ Ei 13 ~ El
:
.:' - . , .
- 32
.
,. . . `~ .
'i`~l`
..
` ` 1064490
,; `
EXAMPLE 7
: :t
This exæmple describes the preparation of
thiocarbamoylimidazole compounds of the invention.
17.0 g. 2-l~e~hylthio-4-tert. butylimidazole were
dissolved in 200 ml. dry dioxan, after which 13.9 ml.
... .
triethyl~mi~e ?nd 12.3 g. dimethylthiocarbamoyl chloride
were added. The mixture was refluxed for eight hours,
then cooled and the precipitate of triethylamine
hydrochloride filtered off. On distilling off the dioxan
a brown oil rem~ined. Thi3 oil was extracted with two
50 ml. portions o~ petroleum ether (b.p. 60-80C.) and
, . .
on cooling a solid was deposited which was collected and
recryst~lised from petroleum ether (b.p. 80-100C.) with
charcoal to give l-dimethylthiocarbamoyl-2-methylthio-4(5)-
tert.butylimidaz31e, m.p. 94-96C.
~` The followlng compounds were prepared in an analogous
~ ,;j.
,~, manner.
~¦ l-dimethyl~hiocarbamoyl-2-ethylthio-4(5)-(1-methylcyclo-
¦ ~ hexyl)imidazole, b.p. 180-190C/0.2 mm.
1-dimethylthiocarbamoyl-2-methylthio-4(5)-tert. pentyl-
~; imidazole, b.p. 126-130C/O.l mm.
,4j:
~ EXAMPLE 8
;1~ This example describes the preparation of l-(N-methyl-
N-2-ethoxyethyl)carbamoyl-2-methylthio-4(5)-tert.
'~ 25 butylimidazole and related compounds.
A solution o~ 7 g. 2-methylthio-4-tert. butylimidazole
in 45 ml. dry te~rahydrofuran was added to 2.4~ g. sodium
hydride in mineral oil (60 per cent dispersion~ The resulting
, ' ~ .
- 30 - 33 -
; ,
,, .
' ' ' . ' ,
.
~ ~ 1064g90 : `
mixture was cooled to a temperature of between O and 5C. and
then 10 g. 1-(N-methyl-N-2-ethoxyethyl)carb ~oyl
chloride added whilst the reaction mixture was maintained
below 5C. After ~iltering to remove solid precipitate
the filtrate was refluxed on a steam bath for two hours.
On distillation the product, l-(N-methyl-N-2-ethoxyethyl)
carbamoyl-2-methylthio-4(5)-tert.butylimidazole, was
collected, b.p. 130-134C./O.l mm. Hg pressure.
The following compounds were also prepared by a similar
` 1~ method; 1-(N-methyl-N-2-ethoxyethyl)carbamoyl-2-methylthio-
4(5)-isopropylimidazole, b.p. 132-134C.jO.l mm. -
l-(N-methyl-N-2-ethoxyethyl)carbamoyl-2-methylthio-4~5)-
(l-methylcyclohexyl)imidazole, b.p. 165-168C/0.2 mm.
~: EXAMPLE 9
Thls example illustrates an alternative method of
preparing the intermediate 2-methylthio-4-tert. butylimidazole
;l of formula II by a route which comprises reacting an
a-haloketone with an S-alkylisothiouronium salt.
A mixture of 17.9 g. a-bromopinacolonej--16.7 g.
S-methyl-iso-thiouronium sulphate~and 32 g. sodium carbonate
in 100 ml. water and 100 ml. ethanol was stirred under
reflux for a period of 1 hour. m e ethanol w~s distilled
off and after the addition of a further quantity of 100 ml.
. ~ . ' ! ' .,
water, 150 ml. toluene was added. The mixture was stirred
~t~ ~ ~ 25 vigorously for ten minutes and the hot toluene separated
~` and washed with 1OO ml. hot water. 70 ml. of the toluene
and traces of water were distilled off and the remaining
toluene solution stirred at 0C. for 30 minutes when
crystalline 2-methylthio-4-tert. butylimidazole separated.
- 30 The product w~s ~iltered off, washed with cold toluene and
. ~
~ _ 34 _
. .. . .
,. . .
~`~ 1064490
j . ~
- dried, m.p. 149-150C.
EXAMPLE 10 ''
m is example describes the preparation of salts
. ~
of the invention.
A concentrated solution of 1.2. g. l-dimethylcarbamoyl-
2-methylthio-4(5)-tert. butylimidazole in 50 ml. ether
~' was added to a concentrated solution of 1.5 g. flavianic
acid in 4 1. ether. The flavianate crystallised on
standing and was filtered off, m.p. 205-206C with
decomposition. On recrystallisation from industrial
methylated spiri*s a pure sample was obtained, m.p. 206C.
with decomposition.
, In a similar manner the followLng acid addition salts
were prepared
salt meltin~ point C
i~ bromide 18~C. with decomposition
!': picrate 169-171C.
nitrate 152C. with decompo~ition
, .
f
EXAMPLE 11
This example illustrates the preparation of
emulsifiable concentrates according to the invention.
Emulsifiable concentrates suitable for d1lution with
~., ,
water to form an a~ueous emulsion were prepared from the
following ingredients: %W/v
Active compound 25.0
Calcium dodecylbenzenesulphonate 3.0
- Nonylphenoxypolyethoxyethanol* 3.0
~ Xylene 100.0% vol,
',.'',~ ~
0 _ 35 _
.
- ~ , . . ..
. . , .: :
lg6449~ '
*nonylphenol-ethylene oxide condensate containing
' an average of 14 mols. ethylene oxide per mol. nonylphenol.
; Emulsifiable concentrates containing the following
compounds were prepared:
~- 5 1-dimethylcarbamoyl-2-methylthio-4(5)-~ert. butylimidazole
l-dimethylcarbamoyl-2-ethylthio-4(5)-tert. butylimidazole
l-dimethylcarbamoyl-2-methoxymethyl-4(5)-tert.butylimidazole
l-morpholinocarbonyl-2-methylthio-4(5)-tert. butylimidazole
; 10 EXAMPLE 12
This example illustrates the preparation of granules
according to the invention.
Granules containing 5% W/w o~ the compounds referred
to in Example 11 were prepared by impregnating granules
f fuller's earth (mesh size 20/40 British Standard Sieve)
with a solution of the carbamoylimidazole compound in
' methylene chloride and then evaporating the methylenë
,,'''~! chloride from the impregnated granules.
`~ EXAMPLE 13
This example illustrates the preparatio~ of dispersible
powders according to the inventiQn.
Dispersible powders were prepared from the following
ingredients: YoW/w
Active compound 25.0
2~ - Silicic acid 25.0
Calcium lignosulphonate10.0
Sodium dioctylsulphosuccinate 0.5
Kaolin to 100.0
0 - 36 -
. ,. ~ , ,
., , ~,.' ,'~; ~ '. `
: ,~ , .. . ......... . . .
` ; 1064490
,. ,, -- .
Dispersible powders containing the compounds
referred to in Example 11, were prepared.
EXAMPLE 14
This example illustrates the aphicidal properties
of the compounds of the invention.
Briad bean plants 3-5 cm~ high were infested with
` ~ aphids (Me~oura viciae) and then sprayed with an aqueous
dispersion containing 250 parts per million W/v of the
, .
i~ carbamoylimidazole compounds of Examples 1 to 8 and 10.
;, . .
; ~ 10 Each plant was kept under a lamp glass for 24 hours and then
4i~ ~'
examined. It was iound that at least 50 per cent of the
aphids were killed. m e aphid population of control `~
'I :
~ plants that had been treated with an aqueous spray not
.; ~, ~ , .
containing any test compound were not affected.
EXAMPLE 15
This example further illustrates the aphicidal
properties oi compounds of the invention.
Broad bean plants 3-5 cm. high were infested with
balckbean aphids (~b~ fabae) and then sprayed with an
aqueous dispersion containing 10~ parts per million W/v
of each active compound listed below. The plants were
Xept under a lamp glass for 24 houræ and then examined.
In all cases at least 50 per cent of the aphids were
Xilled. The aphid populations of control plants that
had been treated with an aqueous spray not containing any
: ~ } ~
test compound were not affected.
37
,., . :
. i . ~ . .
., ~' : . ' . . . ' ' 1 , ' ' : '
", ' ~ "
. . ~ :
~ .
: ~ . ' , '
1064490
5~ 1-dimethylcarbamoyl-2-methylthio-4(5)-tert. butylimidazole
' l-morpholinocarbonyl-2-methylthio-4(5)-tert. butylimidazole
< l-morpholinocarbonyl-2-methylthio-4(5)-sec. butylimidazole
` l-morpholinocarbonyl-2-methylthio-4(5)-isopropylimidazole
5 1-morpholinocarbonyl-2-methylthio-4(5)-1-ethylpropylimidazole
:~ l-dimethylcarbamoyl-2-methylthio-4(5)-isobutylimidazole
EXAMPLE 16
This example illustrates the systemic activity
of compounds of the invention against the aphid Me~oura
~. ~
' ~r1~ viciae.
The compounds to be tested were applied as soil
. . .
drenches. 25 ml. of an aqueous test solution was watered
; into tne soil in an 8 cm. diameter plant pot containing
~,~...................................................................... .
~'3 a single broad bean plant. A cardb~ard shield was placed
around the plant so that only a part of it protruded.
' m is was infested with aphids. After three days the
aphicidal effect was assessed by counting the numbe~3of live
and dead aphids.
m e following compounds were found to-have an LD5
of less than 100 p.p.m. ~ ~-~
, p l-dimethylcarbamoyl-2-methylthio-4(5)-tert. butylimidazole
; . .
l-dimethylthiocarbamoyl-2-methylthio-4(5)-tert. butylimidazole
l-morpholinocarbonyl-2-methylthio-4(5)-tert. butylimidazole
l-dimethylcarbamoyl-2-allylthio-4(5)-sec butylimidazole
~.-",
25 1-dimethylcarbamoyl-2-ethylthio-4(5)-(1-methylcyclopentyl)
imidazole
dimethylcarbamoyl-2-but-2-enylthio-4(5)-tert. pentylimidazole
- 38 -
-~ .
.
-- 1064~90
~XAMPLE 17
m is example illustrates the activity of 1-
dimethylcarbamoyl-2-methylthio-4(5)-tert. bu~ylimidazole
against larvae of the cabbage white butterfly (Pieris
l~ 5 brassicae).
- Ten larvae were placed in a tube together with a
square of cabbage leaf which had been dipped Ln the test
solution and allowed to dry. After twenty-four hours
untreated cabbage was added as food and after a further
twenty-four hours an assessment was made o~ ihe mortality
of the larvae by counting the numbers of live and dead
insects.
Two replicates were carried out employing a test
solution o~ 200 p.p. m. At this level of corcentration
the active compound gave greater than 50 per cent control
of the larvae
.` .i . '
; , ~
: - . .
- 20
- . ,
,.~, .
. "1 ' .
~ 25
'"' ~
~ ':',1
' ~ 30 _ ~9 _
. , .
