Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
" ~3~2~ ~
-- 1 --
The inVention relates to the production of 1,2,3~thiadia-
zol-5-yl ureas.
Processes or the production of ureas of the kind mention-
ed have already been discl~sed (DE-OS 22 14 632, DE-OS 26 36
994). These processes use 5-amino-1,2,3-thiadiazole as the
starting material, a substance which is not easily obtainable
nor completely harmless.
There is therefore a need for a process for the technical-
ly simple and safe production of 1,2,3-thiadiazol-5-yl ureas.
This invention provides a process for the preparation
of a 1,2,3-thiadiazol-5-yl urea of the general formula
CH
NH - CO - N
\s/ \R2
in which Rl represents a hydrogen atom, or an alkyl radical
having 1 to 4 carbon atoms, and R2 represents a (Cl-C4)-alkyl,
(C5-C8)-cycloalkyl, methyl-(C5-C8)-cycloalkyl, phenyl, halo-
phenyl, (Cl-C4)-alkylphenyl, (Cl-C4)-akloxyphenyl, nitrophenyl,
trifluoromethylphenyl, pyridyl or pyrimidyl radical, which
comprises reacting a 1,2,3-thiadiazole-5-carboxylic acid azide
of the formula
N - CH
N C - CO - N3 . II
\ /
~S/
with an amine of the general formula
/
H N III
:, :: ~ ; .
3~Z2~
--.~4'--
dl6solved in an inert organic solvent the reaction
product mày then be i~olated in a manner known ~er se.
R1 represents a hydrogen atom or a
(C1-C4)-alkyl radical,~for example methyl, ethyl,
propyl, isopropyl or butyl.
~ hr~a~ R2 represent~ a (C1-C4)-alkyl radical,
for example methyl, ethyl, propyl, isopropyl or butyl,
a (C5-C8)-cycloalkyl radical, for example cyclopentyl or
cyclohexyl, a methyl-(C5 C8)-cycloalkyl radical, for
exa~ple a methylcyclohexyl, the phenyl group, a halo-
phenyl radical, for example 4-chlorophenyl, a (C1-C4)-
alkylphenyl radical, for example 4-methylphenyl, a
(C1-C4)-alkoxyphe~yl radical, for example 4-methoxy-
phenyl, or a nitrophenyl, trifluoromethylphenyl, pyridyl
cr pyrimidyl group.
Advantageou~ly the reaction i~ carried out at a
tempexature of from 20 to 180C, preferably from 50 to
120C, and more especially at the boiling temperature
of.the reaction mixture.
The reaction of the azide of the formula II with
the amine o~ the general formula III i~ preferably
effected in one step.
Preferably, equimolar amounts of the azide of the
formula II and khe ~mine of the general formula III are
u~ed.
- Preferably the 1,2,3-thladiazole-5-carboxylic acid
azide of the formula II used i8 prepared in situ, for
;
~d
example by a method known ~ e, and not isolated from
the reaction mixture obtained, thus a continuous pro-
ce~ made possible.
. ~he 1,2,3-thiadia~ole-5-carkoxylic acid azide of
5. the formula II may be produced, for example, by one of
the ~ollowing methods which are ~nown ~ se
a) by reacting 1,2,3-thiadiazole-5-carboxylic acid o~
the for~ula
N - CH
Il 11 - ~
N C - COOH IV
\S~
with a chloroformic acid alkyl ester of the general
ormula
Cl CO ~ OR3 V
in an inert solvent in the pre~ence of an acid-binding
agent, to form t~e mixed anhydride of the general
1S formula
~--C~
Il ~1 .
~ CO-O-CO-OR3 VI
S
and then reacting this with a solutio~ of an alkali
metal azide of the general formula
M~3 VII
or
~ 5
b) by reactinq a 1,2,3-thiadiazole-5-carboxylic ac~d
halide of the general formula
N - C~
- ~ ~ CO~X VIII
in an inert organic ~olvent with an aqueous 901ution of
an alkali metal azide of t~e general formula
M~3 VII
or
c) b~ reacting 1,2,3-thiadiazole-5-carboxylic acid
hydrazide of the formula
N - CH
~ ~ CO-~H-~2 IX
in an inert solve~t with a solution of an alkali metal
nitrite of the general formula
~ 02 X
or wit~ an alkyl nitrite of the general formula
R3-0-~0 XI
in the presence of an acid, to form ~,2,3-thiadiazole-
5-car~oxyli~ acid azide of the formula
3~
. .i- ~
N ~ -CO~N3 II
\S
In the above formulae,
R3 repre~ent~ a (C1-C~)-alkyl radical,
M repre~ent~ a monovalent metal equivalent, preferably
a sodium, pota~ium or lithium atom, and
X repre~ent~ a halogen atom, preferably a chlorine
atomO
The azide of the formula II obtainable by th~e
method~ doe~ not have to be isolated from ~hs reaction
mixtures obtained and advantageously is not isolated
but is used toge~her with the~e mixture~ directly for
the proce~ of the inven~ion.
The 1,2,3-thiadiazole-5-carboxylic acid or deri-
vative thereof required as starting material can like-
15 wi~e be produced in a manner known ~ e, fox example ~ -
(i) by xeacting an acyl hydrazone of propionaldehyde
of the general formula
,
C~3-CH2-C~ C-~4 XII
wi~h thionyl chloride of the ~onmula
S~C12 XIII
to form 5-methyl-1,2,3-~iadiazole of the formula
3~;~2~
"~ .
c~
H3 XIV
S~
and oxidi~ing this, e.g. with a customary oxidising
agent ~uch as chromium~VI) nxide, potassium permanganate
and nitric acid, to form 1,2,3-thiadiazole~5-car~oxylic
acid of the form~la
~_C~
~ ~ 00~ IV
~S
or
(ii) by reacting an acyl hydrazone of a formylacetic
acid alkyl ester of the general formula
H - C - CH - COOR
il 2 3 XV
~ CO-R4
with thionyl chloride of the form~la
SCC12 . XIII
to form a 1~2,3-thiadiazole-5-carboxylic acid ester of
the general formula
N - CH
~ ~ COOR3 XVI
The~e can then be reacted with hydrazine of the formula
31~24
_ q_
NH2 ~H2 XVII
e.g. as hydrazine hydrate, if desired in a polar organic
solvent, to form 1,2,3-thiadiazole-5-carboxylic acid
hydrazide of the formuia
N - CH
Il 11
N ~ O-~H NH2 IX
S
or hydrolysed, e.g. in known manner wi~h a suitable
inorganic ba~e, e.gO oxide, hydroxide or carbonate of
an alkali metal or alkaline earth metal or, preferably,
an alcoholate, if desired in an organic solvent,.to
form 1,2,3-thiadiazole-5-carboxylic acid of the formula
N - CH
Il 11 '~
C00~ IV
S '.
.
The acid can in turn be reacted, e.g. according to
; known method~ with a customary halogenatiny agent, e~g.
thionyl chloride or pho~phorus pentachloride, to form a
. 15 1,2,3-thiadiazole-5-carboxylic acid halide of the
general formula
--C~
CO-X VIII
\S/
~ 113~12Z~
In the~e formulae, R3 and X have the meanings given
above and ~4 repre3ents an alkoxy radical, preferably
a ~C1-C4)-alkoxy radical~ an amino group or an alkylamino
.group, preferably a (C1-C4~-alkylamino group.
S ~he process according to the invention ~hu~ makes
u~e oE easily obtainable starting qub~tance6 and makeq
it pos3ible to produce the desired products in a ~afe
and technically ~imple manner~
It is o~ great technical advantage that the 1,2,3-
tO thiadiazole-5-carboxylic acid azide of the formula II
does not have to be isolated ~rom the reaction mixture
from which it is produced but can be reacted in a one-
pot process, using ~hese mixtures, directly with an
amine of the general formula III.
It i~ especially s~rprising that this process
results in formation of the desired product and does
not, as was to b~ expected, xe~ult in subQtitution of
the azide radical by the amine to form a 1,2,3-thia-
diazole-5-carboxylic acid amide.
The proces~ of he invention may be carried out,
for example, by adding the crude solution of ~he azide,
in admixture wi~ an equimolar amount of the amine,
dropwise to an inert solvent at the reflux temperature
of the latter or, alternatively,-by adding the azide
solution to the amine diluted with solvent, at the
reflux te~perature of the mixture. The intensity of
reflux can be used to monitor the spontaneous course of
~3~2Z~
the reaction. The azide can, however, be heated in the
presence of an inert solvent also in admixture with the
amine.
The temperature~ are e~pediently 20 to 180C,
preferably 50 to 120 C. Mo~t advantageou~ly, however,
the reaction i~ carried out at the boiling temperature
of the reaction mixture.
Suitable ~olvent3 that are inert t~ward~ the
reactants in the various steps are, for example, ali-
`10 phatic and aromatic hydrocarbons, e.g. cyclohexane,heptane, ligro~n, benzene, toluene and xylene ethexs,
e.g. dioxan, tetrahydrofuran and diisopropyl ethert
esters, e.g. ethyl àcetate and ethyl malonate, ketones,
e.g. acetone, methyl isobutyl ketone, isophorone and
cyclohexanone halogenated hydrocarbons, e~g. chloro-
benzene, methylene chloride, ch~oroform and carbo~
tetrachloride- and carboxylic acid nitriles, e.qO
acetonitrile.
After the reaction has been completed, the reac- 'i
tion mixture may be worked up in a manner known ~er se,
for example by distilling off the solvent used a nor-
mal or reduced pressure, by precipitating with water or,
in a large number of case~, by simply filtering off
the de~ired reaction product~ In thi~ manner, it is
possible to obtain 1,2,3-thiadiazol-5-yl ureas in an
exceptionally pure form and in virtually quantitative
yields, and u~ually no subsequent purification
,
1.
Z2
1~
?3 `
., ". .
opera~ion~ are needed for their further u~e. In general,
problems of ~eparat~on, SllCh as occur, for example, in
the reaction of 5-amino-1 ,2,3-thiadiazole with i90 -
cyanates in which symmetric urea~ occur as by-products "
do not arise here.
The following Examples illustrate the invention~
ExamPle 1
Productio~ of 1-~henyl-3-(1,2,3-thiadiazol-5-yl) urea
from 1,2,3-thiadiaæole~5-carboxylic acid chloride
In a 250 ml three-necked round-bottomed flask
equipped with ~tirrer and thermometer, 40 ml of toluene
were added to a solution of 9.t g (0.14 mole) of ~odium
azide in 40 ml of water. A solution of 14.8 g (0~1
mole) of 1,2,3-thiadiazole-5-carboxylic acid chloride in
80 ml of toluene was added dropwise oYer a period of 15
minutes at 15 to 20C while ~tirring vigorously. Stir-
ring wa~ continued for 1~ hours at 15 to 20C and the
toluene phase wa~ then separated off and dried over mag-
nesium sulphate. 9.14 ml (O.t mole) of aniline were
added at room temperature to the dried solution, which
contained 1,2,3-thiadiazole-5 carboxylic acid azide.
Meanwhile, 80 ml of toluene were pre-heated to
110C in a 250 ml ~hree-necked round-bottomed fla~k
equipped wi~h stirrer, thermometer and reflux condenser.
25 ~he car}~oxylic acia azide/aniline solution was added
dropwi~e to thi~ over a period of 10 minutes in ~uc~ a
manner that the internal temperature was maintained at
.. . ..
,
~L131Z2~
100 to 110C. Pale yellow-coloured crystal~ 3eparated
out immediately with stron~ evolution of gas. The mix-
ture was then ~tirred for a further 5 minutes under
xeflux, cooled to 5C and the cry~tals filtered off andr
dried in vacuo at 40C to constant weight
M.p.: 217C (with decompo~ition)
TLC: eluant = ethyl acetate, R~ value: 0.25
Example 2
Production of 1-~henyl-3-(1,2,3-~hiadiazol-5-vl)-urea
~0 from 1,2,3-thiadiazole-5-carboxvlic acid hYdrazide
In a 500 ml three-necked round-bottomed flask
equipped wi~h stirrer and t~ermometer, 14~4 g (0.1 mole)
o~ 1,2,3-thiadiazole-5-carboxylic acid hydrazide were
dis~olved in 100 ml of water and 12 ml of concentrated
hydrochlori~ acid. ~00 ml of toluene were then added
to this solution. A solution of 7.25 g (0.105 mole) of
~odium nitrite in 20 ml of water was then added drop_
wise to this mixture over a p~riod o* 30 minutes at 0
to 5C. Stirring was continued for 15 minute~ at 0 to
5C, and the toluenP phase was separated off and dried
over magnesium sulphate. 9.14 ml (0~1 mole) of aniline
were then added at room temperaturP to the dried ~olu-
tion whi~h contained 1,2,3-thiadiazole-5-car~oxylic
acid azide.
50 ml ~f toluene were meanwhile pre-heated to 110 &
in a 500 ml ~hree-necked round-bottomed flask equipped
with ~tirrer, thermometer and reflux condenser. The
3~22~
drled carboxyliz acid azide/aniline 901ution wa~ added
dropwise thereto over a period of ~0 minutes in such a
manner that the internal temperature was maintained at
100 to 110C. Yellowi~h crystals separated out
immediately with ~trong evolution of gas. The mixture
wa~ stirred for a further 5 minutes under reflux,
cooled to 5C and the crystal~ filtered off with 8UC-
tion and dried in vacuo at 40C to conRtant weight.
Yield: 16.2 g = 73.6 % of the theoretical yield
M.p.: 217C ~with decomposition3
TLC: eluant = ethyl acetate, Rf value: 0.25
Production of the starting materials:
ExamPle 3
1,2,3-thiadiazole-~-carboxy_ic a _d hydrazide
In a 100 ml three-necked round-bottomed flask
equipped with ~tirrer and ~hermometer, 11.O g ~Oo22
mole~ of hydrazine hydrate were added to 31.6 g (0.2
mole) of 1,2,3-thiadiazole-5-carboxylic acid ethyl
- ester dissolved in 50 ml of ethanol, over a period of
5 minutes at room temperature. ~s the temperature rose
slowly to 50C yellow crystals ~eparated out. Stirring
was continued for one hour at room temperature, and the
cry~tals were then filtered off with 3uction and dried
in vacuo at 40C to consta~t weight.
Yield: 27.4 g = 95 ~ of the thevretical yield
13 ~3~2~
~31 _ ~_
M.p.: 145 - 1~8C
TLC: eluant = ethyl acetate7 Rf value: 0.195
Example 4
1,2,3~thiadia~ole-5-carboxylic acid chloride
In a 250 ml three-necked round-bottomed flask
e~uipped wit~ ~tirxer, cooling apparatus, thermometer
and an outlet into the fume cupboard, 30.0 g (0.23 mole)
of 1,2,3-thiadiazole-5-carboxylic acid in 125 ml of
thionyl chloride were heated under reflux for 2 hours.
The clear bro~.nish ~olution was concentrated by evapora-
tion at 40C and 15 torr and the residue subjected to
fractional distillation.
Yield: 25.0 g = 73.4 % of the theoretical yiel~
b.p.1t: 73 - 76C
Example 5
1,2~3-thiadiazole-5-carboxyli~ acid eth~__ester
In a 500 ml three-necked round-bottomed flask
equipped with ~tirrer, thermometer, reflux ~ondenser,
drying tube and ga~ o~tlet to the fume cup~oard, 50.1 ml
(0.69 mole) of thionyl chloride were cooled to -15C
and 36.2 g ~0.21 mole) of formylacetic acid ethyl ester
semicarbazone were added thereto over a period of 30
minute~ under slightly reduced pressure and at an
intennal temperature of -15 to -10C. The brown solu-
tion was ~tirred for a further hour at -10C and then
diluted wnth 130 ml o~ chloroform. 130 ml of a
13~LZZ~
~aturated ~olution of pota~sium bicarbonate were care-
fully added to the excess thionyl chloride, the temr
perature ~e~ng maintained between -10 and 20C. The
. c~lorofonm phase was separated off, washed with S0 ml
of a ~aturated solution o~ pota~sium bicar~onate, dried
over magnesium sulphate and concentxated by evaporation
at 40C in a water-jet vacuum. The residue waq 9ub-
jected to fractional distillation.
Yield: 28.6 g = 86 % of the theoretical yield
10 b.p.11: 95 - 100C
TLC: eluant = ethyl acetate, Rf value: 0.600
Example 6
1,2,3-thiadiazole-5-carboxylic acid
In a 4 litre three-necked round-bottomed flas~
equipped with ~tirrer, thermometer and reflux conden~er,
152 g (1.1 mole) of potassium carbonate in 1 litre of
water were wanmed to 90C and 50 g (O.5 mole) of 5-
- methyl-1,2,3-thiadiazole were added there~o. A solution
of 158 g (1.0 mole) of potassium permanganate in 1.5
litres of water waq ~hen added dropwi~e over a period
of one hour at 95 to 100C. The reaction solution was
then heated under reflux for a further 30 minute~ until
it had been completely decolorised, and the precipitated
manganese dioxide was filtered off with suction and
washed with 1 litre of hot water. The filtrate was then
concentrated to approximately 1 litre at 50C in vacu~
and acidified with 80 ml of concentrated sulphuric
acid at 20C. This was then carefully extracted 5
timeR using 300 ml of ethyl acetate each time. The
ethyl acetate extracts were dried over magnesium sul-
phate and evaporated to dryness in a water-jet vacuum
at 40C.
Yield: 21.7 g = 33.3 % of ~he theoretical yield
M.p~: 106C (with decomposition).
